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He Q, Cheng Z, Li Y, Xing X, Li L, Li X, Zhang J, Xu L, Song W, Li F, Zhang Z, Guo L. A biweekly DPP-4 inhibitor cofrogliptin monotherapy in Chinese patients with impaired glucose tolerance: A phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Diabetes Obes Metab 2025; 27:965-975. [PMID: 39632416 DOI: 10.1111/dom.16096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 11/07/2024] [Accepted: 11/17/2024] [Indexed: 12/07/2024]
Abstract
AIMS To assess the efficacy and safety of cofrogliptin for impaired glucose tolerance (IGT). METHODS In this multicenter, double-blind, placebo-controlled phase 2 trial, IGT patients were randomized 1:1:1 to receive cofrogliptin 10 mg, cofrogliptin 25 mg or placebo once biweekly. The primary endpoint was the change from baseline in glucose total AUC0-3 h during meal tolerance test (MTT) at week 12. RESULTS Among 261 subjects screened, 99 were enrolled. At week 12, significant mean reductions from baseline in glucose total AUC0-3 h during MTT were observed in cofrogliptin groups (10 mg: -1.75 mmol h/L, p = 0.01; 25 mg: -1.54 mmol h/L, p = 0.02) versus placebo (0.36 mmol h/L). Significant benefits were also seen with cofrogliptin for secondary endpoints of the change from baseline in Cmax of glucose during MTT 0-3 h at week 12, and the change from baseline in glucose total AUC0-3 h and Cmax of glucose during OGTT 0-3 h at week 10 versus placebo. Additionally, more cofrogliptin-treated patients achieved normoglycaemia versus placebo at week 10. The incidence of AEs was generally comparable in all groups, and all of AEs were mild or moderate. No serious AEs or severe hypoglycaemia were reported. CONCLUSION A 12-week treatment with cofrogliptin provided significant glucose-lowering, and was safe, well tolerated.
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Affiliation(s)
- Qinghua He
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhifeng Cheng
- Department of Endocrinology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yufeng Li
- Department of Endocrinology, Beijing Pinggu Hospital, Beijing, China
| | - Xiaoyan Xing
- Department of Endocrinology, Hebei Yanda Hospital, Beijing, China
| | - Liping Li
- Department of Endocrinology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
| | - Xinsheng Li
- Department of Endocrinology, Cangzhou Central Hospital, Cangzhou, China
| | - Junqing Zhang
- Department of Endocrinology, Peking university first hospital, Beijing, China
| | - Lingling Xu
- Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China
| | - Weihong Song
- Department of Endocrinology, Chenzhou First People's Hospital, Chenzhou, China
| | - Fangqiong Li
- Department of Clinical Medicine, Haisco Pharmaceutical Group Co. Ltd, Chengdu, China
| | - Zhanhui Zhang
- Department of Clinical Medicine, Haisco Pharmaceutical Group Co. Ltd, Chengdu, China
| | - Lixin Guo
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
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Shimoda M, Katakura Y, Mashiko A, Iwamoto M, Nakanishi S, Anno T, Kawasaki F, Obata A, Fushimi Y, Sanada J, Kohara K, Isobe H, Iwamoto Y, Hirukawa H, Tatsumi F, Kimura Y, Kimura T, Mune T, Kaku K, Kaneto H. Comparison of protective effects of teneligliptin and luseogliflozin on pancreatic β-cell function: randomized, parallel-group, multicenter, open-label study (SECRETE-I study). Front Endocrinol (Lausanne) 2024; 15:1412553. [PMID: 39497800 PMCID: PMC11532122 DOI: 10.3389/fendo.2024.1412553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 09/05/2024] [Indexed: 11/07/2024] Open
Abstract
Aims The aim of this study is to directly compare the effects of SGLT2 inhibitors and DPP-4 inhibitors on β-cell function in patients with type 2 diabetes. Materials and methods We conducted a 26-week, randomized, open-label, parallel-group study, including a 1-2 week drug washout period, in patients with type 2 diabetes with HbA1c ≥7.0% and <9.0% and BMI ≥20 kg/m2 despite treatment with a drug naïve or other than DPP-4 inhibitors or SGLT2 inhibitors. A total of 103 subjects were randomly assigned to receive once daily oral luseogliflozin (L) or teneligliptin (T). The primary endpoint was the effect of L vs. T on the change in logarithmus naturalis (Ln) disposition index (DI) (DI 0-120min; combining measures of insulin secretion and sensitivity) from baseline to week 25-26 (post intervention), which was calculated by conducting an oral glucose tolerance test. Results Ln DI 0-120min were improved in both groups: -0.46 ± 0.68 to -0.20 ± 0.59 (p=0.03) in L group and -0.26 ± 0.60 to -0.05 ± 0.62 (p=0.01) in T group. The change in Ln serum proinsulin/C-peptide ratio, a marker of β-cell dysfunction, was reduced in L group (1.63 ± 0.63 to 1.56 ± 0.68, p=0.16), but rather increased in T group (1.70 ± 0.75 to 1.90 ± 0.51, p=0.01), with significant difference between the two groups (-0.27; p=0.004). Conclusions Improvement of disposition index in subjects with obese type 2 diabetes was comparable between luseogliflozin and teneligliptin. On the other hand, it is likely that alleviation of β-cell dysfunction is more effective with luseogliflozin compared to tenegliptin. Clinical trial registration https://rctportal.niph.go.jp/en, identifier jRCTs061190008.
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Affiliation(s)
- Masashi Shimoda
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | - Yukino Katakura
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | - Akiko Mashiko
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | | | - Shuhei Nakanishi
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | - Takatoshi Anno
- Department of General Internal Medicine 1, Kawasaki Medical School, Okayama, Japan
| | - Fumiko Kawasaki
- Department of General Internal Medicine 1, Kawasaki Medical School, Okayama, Japan
| | - Atsushi Obata
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | - Yoshiro Fushimi
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | - Junpei Sanada
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | - Kenji Kohara
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | - Hayato Isobe
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | - Yuichiro Iwamoto
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | - Hidenori Hirukawa
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | - Fuminori Tatsumi
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | - Yukiko Kimura
- Department of General Internal Medicine 1, Kawasaki Medical School, Okayama, Japan
| | - Tomohiko Kimura
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | - Tomoatsu Mune
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | - Kohei Kaku
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
- Department of General Internal Medicine 1, Kawasaki Medical School, Okayama, Japan
| | - Hideaki Kaneto
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
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Nagayama D, Kawana H, Watanabe Y, Horikawa O, Ohira M, Saiki A. Effects of Vildagliptin, a Dipeptidyl Peptidase-4 Inhibitor, on the Parameters of Glucose Metabolism and the Cardio-Ankle Vascular Index in Individuals with Type 2 Diabetes. J Clin Med 2024; 13:481. [PMID: 38256615 PMCID: PMC10816438 DOI: 10.3390/jcm13020481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 01/02/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
DPP-4 inhibitors are frequently used as first-line agents for the treatment of type 2 diabetes in Japan. This study aimed to examine the effects of vildagliptin on glucose metabolism and arterial stiffness. Twenty treatment-naïve patients with type 2 diabetes (8 males and 12 females) received vildagliptin 50 mg twice daily for 6 months. Self-monitored blood glucose measurements and a 75 g OGTT were performed. Arterial stiffness was assessed using the CAVI. After the vildagliptin treatment, a significant decrease in the median HbA1c (from 8.3 to 6.4%) and fasting HOMA-β (from 26.1 to 34.5%), and a marginally significant decrease in the CAVI (from 8.9 to 8.4, p = 0.087) were observed. The glycemic variability parameters also improved, whereas the insulin sensitivity and oxidative stress remained unchanged. Participants with a lower glycemic variability on the 75 g OGTT after vildagliptin treatment showed a significant decrease in their CAVI. The baseline BMI was significantly higher for the participants with a decreased CAVI than in those with no change in their CAVI (24.5 vs. 20.8 kg/m2). After vildagliptin treatment, a decrease in the CAVI was observed, especially in the individuals with improved glycemic variability on the 75 g OGTT. Vildagliptin may be suitable for vascular protection in individuals with high glycemic variability and/or an elevated BMI.
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Affiliation(s)
- Daiji Nagayama
- Department of Internal Medicine, Nagayama Clinic, Oyama 323-0032, Tochigi, Japan
- Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, Sakura 285-0841, Chiba, Japan; (Y.W.); (O.H.); (A.S.)
| | - Hidetoshi Kawana
- Department of Diabetes and Metabolism, Chiba Kaihin Municipal Hospital, Chiba 261-0012, Chiba, Japan;
| | - Yasuhiro Watanabe
- Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, Sakura 285-0841, Chiba, Japan; (Y.W.); (O.H.); (A.S.)
| | - Osamu Horikawa
- Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, Sakura 285-0841, Chiba, Japan; (Y.W.); (O.H.); (A.S.)
| | - Masahiro Ohira
- Division of Diabetes, Metabolism and Endocrinology, Toho University Ohashi Medical Center, Meguro 153-8515, Tokyo, Japan;
| | - Atsuhito Saiki
- Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, Sakura 285-0841, Chiba, Japan; (Y.W.); (O.H.); (A.S.)
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Di Giuseppe G, Ciccarelli G, Soldovieri L, Capece U, Cefalo CMA, Moffa S, Nista EC, Brunetti M, Cinti F, Gasbarrini A, Pontecorvi A, Giaccari A, Mezza T. First-phase insulin secretion: can its evaluation direct therapeutic approaches? Trends Endocrinol Metab 2023; 34:216-230. [PMID: 36858875 DOI: 10.1016/j.tem.2023.02.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/26/2023] [Accepted: 02/01/2023] [Indexed: 03/03/2023]
Abstract
Our work is aimed at unraveling the role of the first-phase insulin secretion in the natural history of type 2 diabetes mellitus (T2DM) and its interrelationship with insulin resistance and with β cell function and mass. Starting from pathophysiology, we investigate the impact of impaired secretion on glucose homeostasis and explore postmeal hyperglycemia as the main clinical feature, underlining its relevance in the management of the disease. We also review dietary and pharmacological approaches aimed at improving early secretory defects and restoring residual β cell function. Furthermore, we discuss possible approaches to detect early secretory defects in clinical practice. By providing a journey through human and animal data, we attempt a unification of the recent evidence in an effort to offer a new outlook on β cell secretion.
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Affiliation(s)
- Gianfranco Di Giuseppe
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Gea Ciccarelli
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Laura Soldovieri
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Umberto Capece
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Chiara M A Cefalo
- Department of Clinical and Molecular Medicine, University of Rome - Sapienza, Rome, Italy
| | - Simona Moffa
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Enrico C Nista
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy; Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Michela Brunetti
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesca Cinti
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Antonio Gasbarrini
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy; Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Alfredo Pontecorvi
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Andrea Giaccari
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Teresa Mezza
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy; Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
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Kaviani B, Samani MA, Haghshenas H, Dehkordi MG. Development of pyrrolidine and isoindoline derivatives as new DPP8 inhibitors using a combination of 3D-QSAR technique, pharmacophore modeling, docking studies, and molecular dynamics simulations. MOLECULAR SIMULATION 2022. [DOI: 10.1080/08927022.2022.2125511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Affiliation(s)
- Bita Kaviani
- Division of Genetics, Department of Biology, Faculty of Sciences, Islamic Azad University, Shahrekord, Iran
| | - Mojtaba Asad Samani
- Division of Genetics, Department of Biology, Faculty of Sciences, Islamic Azad University, Shahrekord, Iran
| | - Hamed Haghshenas
- Division of Biochemistry, Department of Biology, Faculty of Sciences, Shahrekord University, Shahrekord, Iran
| | - Marzieh Ghani Dehkordi
- Division of Genetics, Department of Biology, Faculty of Sciences, Islamic Azad University, Shahrekord, Iran
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Martinez Cantarin MP. Diabetes in Kidney Transplantation. Adv Chronic Kidney Dis 2021; 28:596-605. [PMID: 35367028 DOI: 10.1053/j.ackd.2021.10.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 11/11/2022]
Abstract
Diabetes mellitus (DM) is one of the most common complications after kidney transplantation and is associated with unfavorable outcomes including death. DM can be present before transplant but post-transplant DM (PTDM) refers to diabetes that is diagnosed after solid organ transplantation. Despite its high prevalence, optimal treatment to prevent complications of PTDM is unknown. Medical therapy of pre-existent DM or PTDM after transplant is challenging because of frequent interactions between antidiabetic and immunosuppressive agents. There is also frequent need for medication dose adjustments due to residual kidney disease and a higher risk of medication side effects in patients treated with immunosuppressive agents. Sodium-glucose cotransporter 2 inhibitors have demonstrated a favorable cardio-renal profile in patients with DM without a transplant and hence hold great promise in this patient population although there is concern about the higher risk of urinary tract infections. The significant gaps in our understanding of the pathophysiology, diagnosis, and management of DM after kidney transplantation need to be urgently addressed.
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Wang Y, Liu H, Zheng M, Yang Y, Ren H, Kong Y, Wang S, Wang J, Jiang Y, Yang J, Shan C. Berberine Slows the Progression of Prediabetes to Diabetes in Zucker Diabetic Fatty Rats by Enhancing Intestinal Secretion of Glucagon-Like Peptide-2 and Improving the Gut Microbiota. Front Endocrinol (Lausanne) 2021; 12:609134. [PMID: 34025574 PMCID: PMC8138858 DOI: 10.3389/fendo.2021.609134] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 04/06/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Berberine is a plant alkaloid that has multiple beneficial effects against intestine inflammation. In our previous study, we have found that berberine also possesses an antidiabetic effect. However, whether berberine is useful in the prevention of type 2 diabetes mellitus (T2DM) through its effect on intestine endocrine function and gut microbiota is unclear. AIM To investigate the effects of berberine in the prevention of T2DM, as well as its effects on intestine GLP-2 secretion and gut microbiota in ZDF rats. METHODS Twenty Zucker Diabetic Fatty (ZDF) rats were fed a high-energy diet until they exhibited impaired glucose tolerance (IGT). The rats were then divided into two groups to receive berberine (100 mg/kg/d; berberine group) or vehicle (IGT group) by gavage for 3 weeks. Five Zucker Lean (ZL) rats were used as controls. Fasting blood glucose (FBG) was measured, an oral glucose tolerance test was performed, and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated. Intestinal expression of TLR-4, NF-κB, TNF-α, mucin, zona occludens-1 (ZO-1) and occludin were assessed (immunohistochemistry). Plasma levels and glutamine-induced intestinal secretion of glucagon-like peptide-1 (GLP-1) and GLP-2 were measured (enzyme-linked immunosorbent assay). The plasma lipopolysaccharide (LPS) level was measured. Fecal DNA extraction, pyrosequencing, and bioinformatics analysis were performed. RESULTS After 3 weeks of intervention, diabetes developed in all rats in the IGT group, but only 30% of rats in the berberine group. Treatment with berberine was associated with reductions in food intake, FBG level, insulin resistance, and plasma LPS level, as well as increases in fasting plasma GLP-2 level and glutamine-induced intestinal GLP-2 secretion. Berberine could increase the goblet cell number and villi length, and also reverse the suppressed expressions of mucin, occludin, ZO-1 and the upregulated expressions of TLR-4, NF-κB and TNF-α induced in IGT rats (P<0.05). Berberine also improved the structure of the gut microbiota and restored species diversity. CONCLUSION Berberine may slow the progression of prediabetes to T2DM in ZDF rats by improving GLP-2 secretion, intestinal permeability, and the structure of the gut microbiota.
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Affiliation(s)
- Ying Wang
- National Health Council (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Haiyi Liu
- Department of Pediatrics, Cangzhou People’s Hospital, Cangzhou, China
| | - Miaoyan Zheng
- National Health Council (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Yanhui Yang
- National Health Council (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Huizhu Ren
- National Health Council (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Yan Kong
- National Health Council (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Shanshan Wang
- National Health Council (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Jingyu Wang
- National Health Council (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Yingying Jiang
- National Health Council (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Juhong Yang
- National Health Council (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- *Correspondence: Juhong Yang, ; Chunyan Shan,
| | - Chunyan Shan
- National Health Council (NHC) Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- *Correspondence: Juhong Yang, ; Chunyan Shan,
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Strategic Preparations of DPP-IV Inhibitory Peptides from Val-Pro-Xaa and Ile-Pro-Xaa Peptide Mixtures. Int J Pept Res Ther 2020. [DOI: 10.1007/s10989-020-10122-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Marrano N, Biondi G, Cignarelli A, Perrini S, Laviola L, Giorgino F, Natalicchio A. Functional loss of pancreatic islets in type 2 diabetes: How can we halt it? Metabolism 2020; 110:154304. [PMID: 32599081 DOI: 10.1016/j.metabol.2020.154304] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/14/2020] [Accepted: 06/25/2020] [Indexed: 02/08/2023]
Abstract
The loss of beta-cell functional mass is a necessary and early condition in the development of type 2 diabetes (T2D). In T2D patients, beta-cell function is already reduced by about 50% at diagnosis and further declines thereafter. Beta-cell mass is also reduced in subjects with T2D, and islets from diabetic donors are smaller compared to non-diabetic donors. Thus, beta-cell regeneration and/or preservation of the functional islet integrity should be highly considered for T2D treatment and possibly cure. To date, the available anti-diabetes drugs have been developed as "symptomatic" medications since they act to primarily reduce elevated blood glucose levels. However, a truly efficient anti-diabetes medication, capable to prevent the onset and progression of T2D, should stop beta-cell loss and/or promote the restoration of fully functional beta-cell mass, independently of reducing hyperglycemia and ameliorating glucotoxicity on the pancreatic islets. This review provides a view of the experimental and clinical evidence on the ability of available anti-diabetes drugs to exert protective effects on beta-cells, with a specific focus on human pancreatic islets and clinical trials. Potential explanations for the lack of concordance between evidence of beta-cell protection in vitro and of persistent amelioration of beta-cell function in vivo are also discussed.
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Affiliation(s)
- Nicola Marrano
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
| | - Giuseppina Biondi
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Angelo Cignarelli
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Sebastio Perrini
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
| | - Luigi Laviola
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
| | - Francesco Giorgino
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
| | - Annalisa Natalicchio
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
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Utzschneider KM, Johnson TN, Breymeyer KL, Bettcher L, Raftery D, Newton KM, Neuhouser ML. Small changes in glucose variability induced by low and high glycemic index diets are not associated with changes in β-cell function in adults with pre-diabetes. J Diabetes Complications 2020; 34:107586. [PMID: 32546421 PMCID: PMC7583355 DOI: 10.1016/j.jdiacomp.2020.107586] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 03/31/2020] [Accepted: 03/31/2020] [Indexed: 01/11/2023]
Abstract
Oscillating glucose levels can increase oxidative stress and may contribute to β-cell dysfunction. We tested the hypothesis that increased glycemic variability contributes to β-cell dysfunction by experimentally altering glucose variability with controlled diets varying in glycemic index (GI). Fifty-two adults with prediabetes received a 2-week moderate GI (GI = 55-58) control diet followed by randomization to a four-week low GI (LGI: GI < 35) or high GI (HGI HI > 70) diet. Those on the HGI diet were randomized to placebo or the antioxidant N-acetylcysteine (NAC). Participants underwent blinded CGMS, fasting oxidative stress markers and an intravenous glucose tolerance test to estimate β-cell function (disposition index: DI). On the control diet, DI was inversely correlated with SD glucose (r = -0.314, p = 0.03), but neither DI nor glucose variability were associated with oxidative stress markers. The LGI diet decreased SD glucose (Control 0.96 ± 0.08 vs. LGI 0.79 ± 0.06, p = 0.02) while the HGI diet increased it (Control 0.88 ± 0.06 vs. HGI 1.06 ± 0.07, p = 0.03). Neither DI nor oxidative stress markers changed after the LGI or HGI diets. NAC had no effect on DI, glucose variability or oxidative stress markers. We conclude small changes in glucose variability induced by dietary GI in adults with pre-diabetes are unlikely to contribute to β-cell dysfunction.
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Affiliation(s)
- Kristina M Utzschneider
- Research and Development, Department of Medicine, 1660 S Columbian Way (151), VA Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Metabolism, Endocrinology and Nutrition, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195-6426, USA.
| | - Tonya N Johnson
- Research and Development, Department of Medicine, 1660 S Columbian Way (151), VA Puget Sound Health Care System, Seattle, WA 98108, USA; Seattle Institute for BIomedical and Clinical Research, Seattle, WA, USA
| | - Kara L Breymeyer
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109, USA
| | - Lisa Bettcher
- Department of Anesthesiology and Pain Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195-6426, USA.
| | - Daniel Raftery
- Department of Anesthesiology and Pain Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195-6426, USA.
| | - Katherine M Newton
- Kaiser Permanente Health Research Institute, 1730 Minor Ave, Seattle, WA 98101, USA.
| | - Marian L Neuhouser
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109, USA.
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11
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Sun Y, Yan D, Hao Z, Cui L, Li G. Effects of Dapagliflozin and Sitagliptin on Insulin Resistant and Body Fat Distribution in Newly Diagnosed Type 2 Diabetic Patients. Med Sci Monit 2020; 26:e921891. [PMID: 32240122 PMCID: PMC7152738 DOI: 10.12659/msm.921891] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background The current study aimed to compare the effects of dapagliflozin and sitagliptin on insulin resistant and body fat distribution in newly diagnosed type 2 diabetic patients. Material/Methods This study was an open-label, parallel controlled study. Patients were included if they were newly diagnosed with type 2 diabetes (<6 months) and had been receiving dapagliflozin or sitagliptin for 12 weeks in combination with a stable dose of metformin in the last month. At baseline and 12 weeks, insulin resistant (homeostatic model assessment of insulin resistance [HOMA-IR]), body fat distribution (waist/hip ratio), fasting blood glucose (FBG), glycated hemoglobin A1c (HbA1c), lipid profiles, and C-reactive protein (CRP) level were compared. Results There were 59 patients receiving dapagliflozin and 67 patients receiving sitagliptin. There was no significant between-group difference in baseline characteristics. After 12 weeks of treatment, compared to the sitagliptin group, the FBG (6.4±0.5 versus 6.7±0.7 mmol/L), HbA1c (7.0±0.4 versus 7.2±0.5%), HOMA-IR (1.6±0.5 versus 1.8±0.6), triglyceride (1.6±0.4 versus 1.8±0.3 mmol/L), and CRP (3.1±0.7 versus 3.3±0.5 mg/L) were slightly lower in the dapagliflozin group. Within each group, compared to baseline, FBG (dapagliflozin [6.4±0.5 versus 7.8±0.7 mmol/L]; sitagliptin [6.7±0.7 versus 7.7±0.6 mmol/L]), HbA1c (dapagliflozin [7.0±0.4 versus 8.0±0.5%]; sitagliptin [7.2±0.5 versus 8.1%±0.6%]), HOMA-IR (dapagliflozin [1.6±0.5 versus 2.4±0.4]; sitagliptin [1.8±0.6 versus 2.5±0.4]), triglyceride (dapagliflozin [1.6±0.4 versus 2.2±0.5 mmol/L]; sitagliptin [1.8±0.3 versus 2.1±0.5 mmol/L]), and CRP (dapagliflozin [3.1±0.7 versus 6.2±1.1 mg/L]; sitagliptin [3.3±0.5 versus 6.1±1.0 mg/L]) were significantly decreased. Conclusions Dapagliflozin and sitagliptin had comparable effects on improving insulin resistant and blood glucose control, and these benefits may be associated with improvement of systemic inflammation.
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Affiliation(s)
- Yue Sun
- Department of Endocrinology, The Third People Hospital of Huizhou, The Affiliated Hospital of Guangzhou Medical University, Huizhou, Guangdong, China (mainland)
| | - Dong Yan
- Department of Urology, Citic Huizhou Hospital, Huizhou, Guangdong, China (mainland)
| | - Zirui Hao
- Department of Endocrinology, The Third People Hospital of Huizhou, The Affiliated Hospital of Guangzhou Medical University, Huizhou, Guangdong, China (mainland)
| | - Lijuan Cui
- Department of Endocrinology, The Third People Hospital of Huizhou, The Affiliated Hospital of Guangzhou Medical University, Huizhou, Guangdong, China (mainland)
| | - Guiping Li
- Department of Endocrinology, The Third People Hospital of Huizhou, The Affiliated Hospital of Guangzhou Medical University, Huizhou, Guangdong, China (mainland)
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12
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Daniele G, Tura A, Dardano A, Bertolotto A, Bianchi C, Giusti L, Kurumthodathu JJ, Del Prato S. Effects of treatment with metformin and/or sitagliptin on beta-cell function and insulin resistance in prediabetic women with previous gestational diabetes. Diabetes Obes Metab 2020; 22:648-657. [PMID: 31802616 DOI: 10.1111/dom.13940] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 11/28/2019] [Accepted: 12/03/2019] [Indexed: 12/21/2022]
Abstract
AIM To investigate the effect of sitagliptin (SITA) and metformin (MET) monotherapy as well as in combination (MET+SITA) on beta-cell function and insulin sensitivity in women with recent gestational diabetes (GDM) and impaired glucose regulation (IGR: impaired fasting glucose and/or impaired glucose tolerance). MATERIAL AND METHODS Forty women were randomly assigned to receive SITA (100 mg qd), MET (850 mg bid) or MET+SITA (50 + 850 mg bid) for 16 weeks. A 75 g oral glucose tolerance test (OGTT) and +125 mg/dL hyperglycaemic clamp followed by 5 g i.v. L-arginine were performed at baseline and end of study. The primary outcome of the study was the mean change in arginine-stimulated insulin secretion rate during the hyperglycaemic clamp test from baseline to 16-week therapy. RESULTS At week 16, body mass index declined in all groups (-1.2 ± 0.2 kg/m2 ; P < 0.05). MET+SITA gave a greater increase of first phase(2-10 min) insulin secretion and arginine-stimulated response (720.3 ± 299.0 to 995.5 ± 370.3 pmol/L and 3.2 ± 0.6 to 4.8 ± 1.0 pmoL/min, respectively, both P < 0.05) compared with MET and SITA. Similarly, MET+SITA was more effective in increasing OGTT-based glucose sensitivity (55.7 ± 11.3 to 108 ± 56.2 pmol x min-1 m-2 x mM-1 ; P = 0.04) and insulin-stimulated glucose disposal (M/I: 2.2 ± 0.5 to 4.6 ± 1.3 mg/kg/min÷μIU/min/ml; P = 0.04; Matsuda index [SI]: 3.1 ± 0.4 to 5.7 ± 1.1; P = 0.03) compared with either MET or SITA. Disposition index (ISSI-2) increased with MET+SITA and SITA (both P < 0.05), while no significant change was observed in MET. Among MET+SITA women, 33% reverted to normal glucose tolerance (NGT) compared with 14% with MET and 7% with SITA (P < 0.05). CONCLUSION This study shows that MET+SITA is superior to SITA and MET monotherapy regarding beta-cell function and insulin sensitivity improvement in IGR women with previous GDM, and may offer a potential pharmacologic intervention to reduce the risk of type 2 diabetes in this high-risk population.
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Affiliation(s)
- Giuseppe Daniele
- Section of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Andrea Tura
- Metabolic Unit, CNR Institute of Neuroscience, Padova, Italy
| | - Angela Dardano
- Section of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Alessandra Bertolotto
- Section of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Cristina Bianchi
- Section of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Laura Giusti
- Section of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Jancy Joseph Kurumthodathu
- Section of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Ishida Y, Murayama H, Shinfuku Y, Taniguchi T, Sasajima T, Oyama N. Cardiovascular safety and effectiveness of vildagliptin in patients with type 2 diabetes mellitus: a 3-year, large-scale post-marketing surveillance in Japan. Expert Opin Drug Saf 2020; 19:625-631. [DOI: 10.1080/14740338.2020.1740679] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
| | | | - Yohei Shinfuku
- Regulatory Office Japan, Novartis Pharma K.K., Tokyo, Japan
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14
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Hayashi T, Murayama H, Shinfuku Y, Taniguchi T, Tsumiyama I, Oyama N. Safety and efficacy of vildagliptin: 52-week post-marketing surveillance of Japanese patients with type 2 diabetes in combination with other oral antidiabetics and insulin. Expert Opin Pharmacother 2019; 21:121-130. [PMID: 31689132 DOI: 10.1080/14656566.2019.1685500] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background: Vildagliptin is a dipeptidyl peptidase-4 inhibitor that reduces glycemia in patients with type 2 diabetes mellitus (T2DM). When approved in 2013, data on vildagliptin combined with >750 mg/day metformin in Japanese patients were limited. There is a need to confirm the safety and efficacy of vildagliptin in combination with oral antidiabetic drugs (OADs).Research design and methods: This 52-week post-marketing surveillance (PMS) observational study in Japanese T2DM patients evaluated the safety and efficacy of vildagliptin in combination with OADs including high-dose metformin or insulin but excluding combination with sulfonylureas alone.Results: During this survey of 3006 Japanese T2DM patients, 13.61% of patients experienced adverse events (AEs) and 2.20% reported a serious AE (SAE). The frequency of AEs/SAEs was similar when in combination with biguanides (12.93%/1.46%), metformin ≥1000 mg/day (12.92%/1.22%), metformin <1000 mg/day (12.62%/1.54%), thiazolidine derivatives (16.71%/2.86%), α-glucosidase inhibitors (13.18%/1.90%), rapid-acting insulin secretagogues (glinides) (20.41%/5.71%), or insulin (15.87%/2.47%). The mean ± SD changes from baseline at endpoint in glycated hemoglobin and fasting blood glucose were -0.76 ± 1.27% and -23.3 ± 57.3 mg/dL, respectively, and these changes were consistent, regardless of concomitant OAD.Conclusions: Long-term vildagliptin combination therapy is safe and effective in Japanese T2DM patients in real-world settings.
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Affiliation(s)
| | | | - Yohei Shinfuku
- Regulatory Office Japan, Novartis Pharma K.K., Tokyo, Japan
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15
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Fiorentino TV, Pedace E, Succurro E, Andreozzi F, Perticone M, Sciacqua A, Perticone F, Sesti G. Individuals With Prediabetes Display Different Age-Related Pathophysiological Characteristics. J Clin Endocrinol Metab 2019; 104:2911-2924. [PMID: 30848793 DOI: 10.1210/jc.2018-02610] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 03/04/2019] [Indexed: 01/10/2023]
Abstract
CONTEXT Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are highly pathophysiologic heterogeneous prediabetes conditions that can occur in all age groups, from youth to elderly people. OBJECTIVE We evaluated whether distinct age-related phenotypes exist among individuals with IFG or IGT. RESEARCH DESIGN 479 young (aged 18 to 35 years), 699 adult (45 to 55 years) and 240 older (≥65 years) subjects underwent an oral glucose tolerance test (OGTT). From the OGTT results, the participants were grouped as follows: young age and normal glucose tolerance (NGT), adult age and NGT, older age and NGT, IFG young subjects, IFG adult subjects, IFG older subjects, IGT young (Y-IGT) subjects, IGT adult (A-IGT) subjects, and IGT older (O-IGT) subjects. MAIN OUTCOME MEASURES Insulin sensitivity and secretion, insulin clearance, and β-cell function. RESULTS Peripheral insulin sensitivity assessed using the Matsuda index, basal and glucose-stimulated insulin secretion, and β-cell function estimated using the disposition index were decreased in IFG adult subjects and IFG older subjects compared with IFG young subjects. A-IGT and Y-IGT subjects exhibited a progressively greater degree of hepatic insulin resistance assessed using the liver insulin resistance index, and reduced insulin clearance compared with O-IGT subjects. In contrast, the Matsuda index did not differ among Y-IGT, A-IGT, and O-IGT subjects. Basal and glucose-stimulated insulin secretion and β-cell function were lower in A-IGT and O-IGT subjects compared with Y-IGT individuals. CONCLUSIONS Subjects with IFG or IGT exhibited different age-related pathophysiologic characteristics. A more precise phenotyping of subjects with IGT or IFG could help to better design individualized preventive approaches to counteract diabetes progression.
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Affiliation(s)
| | - Elisabetta Pedace
- Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro, Italy
| | - Elena Succurro
- Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro, Italy
| | - Francesco Andreozzi
- Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro, Italy
| | - Maria Perticone
- Department of Experimental and Clinical Medicine, University Magna Græcia of Catanzaro, Catanzaro, Italy
| | - Angela Sciacqua
- Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro, Italy
| | - Francesco Perticone
- Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro, Italy
| | - Giorgio Sesti
- Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro, Italy
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16
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Mahat RK, Singh N, Arora M, Rathore V. Health risks and interventions in prediabetes: A review. Diabetes Metab Syndr 2019; 13:2803-2811. [PMID: 31405710 DOI: 10.1016/j.dsx.2019.07.041] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 07/23/2019] [Indexed: 01/03/2023]
Abstract
Prediabetes is a condition which appears prior to the development of diabetes in which blood glucose is abnormally high but do not reach the diagnostic threshold of type 2 diabetes mellitus. It is characterized by a cluster of metabolic abnormalities viz. dysglycemia, dyslipidemia, hypertension, physical inactivity, obesity, insulin resistance, procoagulant state, endothelial dysfunction, oxidative stress and inflammation, placing prediabetic subjects to an increased risk for diabetes and its complications. Recent studies demonstrate that complications of diabetes i.e. microvascular and macrovascular complications may manifest in some prediabetic subjects. This article reviews prediabetes-related risk factors and health issues. In addition, this article also highlights the interventions to prevent the development of diabetes in prediabetic subjects.
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Affiliation(s)
- Roshan Kumar Mahat
- Department of Biochemistry, Gajra Raja Medical College, Jiwaji University, Gwalior, Madhya Pradesh, 474009, India; Department of Biochemistry, Muzaffarnagar Medical College, Muzaffarnagar, Uttar Pradesh, 251203, India.
| | | | - Manisha Arora
- Department of Biochemistry, Muzaffarnagar Medical College, Muzaffarnagar, Uttar Pradesh, 251203, India
| | - Vedika Rathore
- Department of Biochemistry, Shyam Shah Medical College, Rewa, Madhya Pradesh, 486001, India
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17
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Sesti G, Avogaro A, Belcastro S, Bonora BM, Croci M, Daniele G, Dauriz M, Dotta F, Formichi C, Frontoni S, Invitti C, Orsi E, Picconi F, Resi V, Bonora E, Purrello F. Ten years of experience with DPP-4 inhibitors for the treatment of type 2 diabetes mellitus. Acta Diabetol 2019; 56:605-617. [PMID: 30603867 DOI: 10.1007/s00592-018-1271-3] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 12/10/2018] [Indexed: 12/13/2022]
Abstract
Achieving and maintaining recommended glycemic targets without causing adverse e ffects, including hypoglycemia, is challenging, especially in older patients with type 2 diabetes mellitus (T2DM). The introduction of dipeptidyl peptidase-4 (DPP-4) inhibitors, more than 10 years ago, has provided an alternative to conventional medications for the intensification of glucose-lowering treatment after failure of metformin monotherapy, and therefore, marked an important advance in the management of T2DM. By prolonging the activity of incretin hormones, DPP-4 inhibitors induce insulin release and decrease glucagon secretion in a glucose-dependent manner. This results in a more physiologic glycemic control as compared to that ensured by insulin secretagogues (sulfonylureas and glinides). Overall, DPP-4 inhibitors have a favorable safety profile and can be used without dose adjustments in older adults and in patients with mild renal impairment; they have a neutral effect on body weight and do not cause hypoglycemia by themselves. Safety issues, reported mainly in post-marketing surveillance programs and including cardiovascular outcomes and the risk of acute pancreatitis, are being extensively investigated. The aim of this review is to discuss the impact of DPP-4 inhibitors on the treatment of T2DM, after 10 years of experience, with an emphasis on diabetes care in Italy. We will first describe T2DM treatment in Italy and then provide an overview of the main findings from randomized controlled trials, real-world studies and post-marketing surveillance programs with DPP-4 inhibitors.
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Affiliation(s)
- Giorgio Sesti
- Department of Clinical and Surgical Science, University of Magna Graecia of Catanzaro, Catanzaro, Italy.
| | - Angelo Avogaro
- Department of Medicine, University of Padova, Padova, Italy
| | - Sara Belcastro
- Department of Medical Sciences, University of Turin, Turin, Italy
| | | | - Marina Croci
- Department of Medical Sciences and Rehabilitation, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Giuseppe Daniele
- Department of Clinical and Experimental Medicine A.O.U. Pisana, Pisa, Italy
| | - Marco Dauriz
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona and Hospital Trust of Verona, Verona, Italy
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Caterina Formichi
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Simona Frontoni
- Unit of Endocrinology, Diabetes and Metabolism, Department of Systems Medicine, S. Giovanni Calibita Fatebenefratelli Hospital, University of Rome Tor Vergata, Rome, Italy
| | - Cecilia Invitti
- Department of Medical Sciences and Rehabilitation, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Emanuela Orsi
- Diabetes Unit, Fondazione IRCCS'Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - Fabiana Picconi
- Unit of Endocrinology, Diabetes and Metabolism, Department of Systems Medicine, S. Giovanni Calibita Fatebenefratelli Hospital, University of Rome Tor Vergata, Rome, Italy
| | - Veronica Resi
- Diabetes Unit, Fondazione IRCCS'Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Enzo Bonora
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona and Hospital Trust of Verona, Verona, Italy
| | - Francesco Purrello
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
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18
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Foley JE. Insights Into GLP-1 and GIP Actions Emerging From Vildagliptin Mechanism Studies in Man. Front Endocrinol (Lausanne) 2019; 10:780. [PMID: 31781045 PMCID: PMC6856791 DOI: 10.3389/fendo.2019.00780] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 10/25/2019] [Indexed: 01/16/2023] Open
Abstract
Vildagliptin blocks glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) inactivation of the meal induced increases in GLP-1 and GIP so that elevated GLP-1 and GIP levels are maintained over 24 h. The primary insulin secretion effect of vildagliptin is to improve the impaired sensitivity of the β-cells to glucose in subjects with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) and in patients with type 2 diabetes mellitus (T2DM); this effect was seen acutely and maintained over at least 2 years in patients with T2DM. Vildagliptin was also associated with improved β-cell function that is likely secondary to the improved metabolic state. Although there was no evidence of restoration of β-cell mass, the preponderance of the vildagliptin data does indicate that for at least 2 years β-cell function was maintained in vildagliptin treated patients but not in the untreated patients. Vildagliptin suppressed an inappropriate glucagon response to an oral glucose challenge in patients with T2DM, to a mixed meal challenge in patients with T2DM and type 1 diabetes mellitus, and to a mixed meal challenge in subjects with IGT and IFG. The improved glucagon response was maintained for at least 2 years in patients with T2DM and there was no change in the glucagon response in normoglycemic individuals. Vildagliptin lowered glucose levels into the normal range without increasing hypoglycemia. These hypoglycemic benefits appear to be secondary in large part to the improved sensitivity of both the β and α-cell to glucose. In the case of the α-cell, if glucose levels are high, GLP-1 attenuates the glucagon levels and if glucose levels are low, GIP increases glucagon levels. Vildagliptin reduces fatty acid flux from the adipocyte leading to reduced liver fat which in turn leads to increased glucose utilization. The reduced glycosuria and reduced lipo-toxicity associated with vildagliptin therapy does not lead to weight gain presumably due to increased fat mobilization and oxidation during meals and to reduced fat extraction from the gut.
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19
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Nahon KJ, Doornink F, Straat ME, Botani K, Martinez-Tellez B, Abreu-Vieira G, van Klinken JB, Voortman GJ, Friesema ECH, Ruiz JR, van Velden FHP, de Geus-Oei LF, Smit F, Pereira Arias-Bouda LM, Berbée JFP, Jazet IM, Boon MR, Rensen PCN. Effect of sitagliptin on energy metabolism and brown adipose tissue in overweight individuals with prediabetes: a randomised placebo-controlled trial. Diabetologia 2018; 61:2386-2397. [PMID: 30145664 PMCID: PMC6182651 DOI: 10.1007/s00125-018-4716-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 07/09/2018] [Indexed: 01/12/2023]
Abstract
AIMS/HYPOTHESIS The aim of this study was to evaluate the effect of sitagliptin on glucose tolerance, plasma lipids, energy expenditure and metabolism of brown adipose tissue (BAT), white adipose tissue (WAT) and skeletal muscle in overweight individuals with prediabetes (impaired glucose tolerance and/or impaired fasting glucose). METHODS We performed a randomised, double-blinded, placebo-controlled trial in 30 overweight, Europid men (age 45.9 ± 6.2 years; BMI 28.8 ± 2.3 kg/m2) with prediabetes in the Leiden University Medical Center and the Alrijne Hospital between March 2015 and September 2016. Participants were initially randomly allocated to receive sitagliptin (100 mg/day) (n = 15) or placebo (n = 15) for 12 weeks, using a randomisation list that was set up by an unblinded pharmacist. All people involved in the study as well as participants were blinded to group assignment. Two participants withdrew from the study prior to completion (both in the sitagliptin group) and were subsequently replaced with two new participants that were allocated to the same treatment. Before and after treatment, fasting venous blood samples and skeletal muscle biopsies were obtained, OGTT was performed and body composition, resting energy expenditure and [18F] fluorodeoxyglucose ([18F]FDG) uptake by metabolic tissues were assessed. The primary study endpoint was the effect of sitagliptin on BAT volume and activity. RESULTS One participant from the sitagliptin group was excluded from analysis, due to a distribution error, leaving 29 participants for further analysis. Sitagliptin, but not placebo, lowered glucose excursion (-40%; p < 0.003) during OGTT, accompanied by an improved insulinogenic index (+38%; p < 0.003) and oral disposition index (+44%; p < 0.003). In addition, sitagliptin lowered serum concentrations of triacylglycerol (-29%) and very large (-46%), large (-35%) and medium-sized (-24%) VLDL particles (all p < 0.05). Body weight, body composition and energy expenditure did not change. In skeletal muscle, sitagliptin increased mRNA expression of PGC1β (also known as PPARGC1B) (+117%; p < 0.05), a main controller of mitochondrial oxidative energy metabolism. Although the primary endpoint of change in BAT volume and activity was not met, sitagliptin increased [18F] FDG uptake in subcutaneous WAT (sWAT; +53%; p < 0.05). Reported side effects were mild and transient and not necessarily related to the treatment. CONCLUSIONS/INTERPRETATION Twelve weeks of sitagliptin in overweight, Europid men with prediabetes improves glucose tolerance and lipid metabolism, as related to increased [18F] FDG uptake by sWAT, rather than BAT, and upregulation of the mitochondrial gene PGC1β in skeletal muscle. Studies on the effect of sitagliptin on preventing or delaying the progression of prediabetes into type 2 diabetes are warranted. TRIAL REGISTRATION ClinicalTrials.gov NCT02294084. FUNDING This study was funded by Merck Sharp & Dohme Corp, Dutch Heart Foundation, Dutch Diabetes Research Foundation, Ministry of Economic Affairs and the University of Granada.
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Affiliation(s)
- Kimberly J Nahon
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, post zone C7Q, P. O. Box 9600, 2300 RC, Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Fleur Doornink
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, post zone C7Q, P. O. Box 9600, 2300 RC, Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Maaike E Straat
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, post zone C7Q, P. O. Box 9600, 2300 RC, Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Kani Botani
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, post zone C7Q, P. O. Box 9600, 2300 RC, Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Borja Martinez-Tellez
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, post zone C7Q, P. O. Box 9600, 2300 RC, Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
- PROFITH 'Promoting Fitness and Health through Physical Activity' research group, Department of Physical Education and Sport, Faculty of Sport Sciences, University of Granada, Granada, Spain
| | - Gustavo Abreu-Vieira
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, post zone C7Q, P. O. Box 9600, 2300 RC, Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Jan B van Klinken
- Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | - Gardi J Voortman
- Division of Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Edith C H Friesema
- Division of Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Jonatan R Ruiz
- PROFITH 'Promoting Fitness and Health through Physical Activity' research group, Department of Physical Education and Sport, Faculty of Sport Sciences, University of Granada, Granada, Spain
| | - Floris H P van Velden
- Division of Nuclear Medicine, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Lioe-Fee de Geus-Oei
- Division of Nuclear Medicine, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Frits Smit
- Division of Nuclear Medicine, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
- Department of Nuclear Medicine, Alrijne Hospital, Leiderdorp, the Netherlands
| | - Lenka M Pereira Arias-Bouda
- Division of Nuclear Medicine, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
- Department of Nuclear Medicine, Alrijne Hospital, Leiderdorp, the Netherlands
| | - Jimmy F P Berbée
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, post zone C7Q, P. O. Box 9600, 2300 RC, Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Ingrid M Jazet
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, post zone C7Q, P. O. Box 9600, 2300 RC, Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Mariëtte R Boon
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, post zone C7Q, P. O. Box 9600, 2300 RC, Leiden, the Netherlands.
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
| | - Patrick C N Rensen
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, post zone C7Q, P. O. Box 9600, 2300 RC, Leiden, the Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
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20
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Karimi S, Ai J, Khorsandi L, Bijan Nejad D, Saki G. Vildagliptin Enhances Differentiation of Insulin Producing Cells from Adipose-Derived Mesenchymal Stem Cells. CELL JOURNAL 2018; 20:477-482. [PMID: 30123993 PMCID: PMC6099143 DOI: 10.22074/cellj.2019.5542] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 12/20/2017] [Indexed: 12/11/2022]
Abstract
Objective Type 1 diabetes is caused by destruction of beta cells of pancreas. Vildagliptin (VG), a dipeptidyl peptidase IV
(DPP IV) inhibitor, is an anti-diabetic drug, which increases beta cell mass. In the present study, the effects of VG on generation
of insulin-producing cells (IPCs) from adipose-derived mesenchymal stem cells (ASCs) is investigated.
Materials and Methods In this experimental study, ASCs were isolated and after characterization were exposed to
differentiation media with or without VG. The presence of IPCs was confirmed by morphological analysis and gene expression
(Pdx-1, Glut-2 and Insulin). Newport Green staining was used to determine insulin-positive cells. Insulin secretion under
different concentrations of glucose was measured using radioimmunoassay method.
Results In the presence of VG the morphology of differentiated cells was similar to the pancreatic islet cells. Expression
of Pdx-1, Glut-2 and Insulin genes in VG-treated cells was significantly higher than the cells exposed to induction media
only. Insulin release from VG-treated ASCs showed a nearly 3.6 fold (P<0.05) increase when exposed to a high-
glucose medium in comparison to untreated ASCs. The percentage of insulin-positive cells in the VG-treated cells was
approximately 2.9-fold higher than the untreated ASCs.
Conclusion The present study has demonstrated that VG elevates differentiation of ASCs into IPCs. Improvement of this
protocol may be used in cell therapy in diabetic patients.
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Affiliation(s)
- Samaneh Karimi
- Cell and Molecular Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Jafar Ai
- Tissue Engineering and Applied Cell Sciences, Department-School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Layasadat Khorsandi
- Cell and Molecular Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Electronic Address:
| | - Darioush Bijan Nejad
- Cell and Molecular Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ghasem Saki
- Cell and Molecular Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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21
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Wang X, Zheng P, Huang G, Yang L, Zhou Z. Dipeptidyl peptidase-4(DPP-4) inhibitors: promising new agents for autoimmune diabetes. Clin Exp Med 2018; 18:473-480. [PMID: 30022375 DOI: 10.1007/s10238-018-0519-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 07/08/2018] [Indexed: 12/16/2022]
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors constitute a novel class of anti-diabetic agents confirmed to improve glycemic control and preserve β-cell function in type 2 diabetes. Three major large-scale studies, EXAMINE, SAVOR-TIMI 53, and TECOS, have confirmed the cardiovascular safety profile of DPP-4 inhibitors. Based on these results, DPP-4 inhibitors have gained widespread use in type 2 diabetes treatment. It is currently unknown, however, whether DPP-4 inhibitors have similar therapeutic efficacy against autoimmune diabetes. Several in vitro and in vivo studies have addressed this issue, but the results remain controversial. In this review, we summarize experimental findings and preliminary clinical trial results, and identify potentially effective immune modulation targets of DPP-4 inhibitors for autoimmune diabetes.
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Affiliation(s)
- Xia Wang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China.,Department of Metabolism and Endocrinology, Hunan Provincial People's Hospital, Changsha, Hunan, China
| | - Peilin Zheng
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Gan Huang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Lin Yang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China.
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22
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González-Heredia T, Hernández-Corona DM, González-Ortiz M, Martínez-Abundis E. Effect of Linagliptin Versus Metformin on Glycemic Variability in Patients with Impaired Glucose Tolerance. Diabetes Technol Ther 2017; 19:471-475. [PMID: 28581818 DOI: 10.1089/dia.2017.0020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Impaired glucose tolerance (IGT) and glycemic variability may be associated with increased risk of micro- and macrovascular complications. The aim of this study was to assess the effect of linagliptin versus metformin on glycemic variability in patients with IGT. MATERIAL AND METHODS A randomized, double-blind clinical trial with parallel groups was carried out in 16 adult patients with IGT, overweight or obesity. All patients signed an informed consent. The therapies were randomly assigned: (a) metformin 500 mg bid (n = 8) or (b) linagliptin 5 mg a.m. and placebo p.m. (n = 8), both for 90 days. At the beginning of the trial and 3 months later, fasting glucose, glycated hemoglobin A1c, oral glucose tolerance test (OGTT), and glycemic variability [area under the curve (AUC) of glucose, mean amplitude of glycemic excursion (MAGE), standard deviation (SD) of glucose, coefficient of variation (CV) of glucose, and mean blood glucose (MBG)] were measured. Mann-Whitney U, Wilcoxon, and Fisher exact tests were used for statistical analyses. RESULTS Both groups were similar in basal characteristics. After linagliptin administration, a significant decrease in glucose levels at 120 min of OGTT (9.0 ± 0.9 vs. 6.9 ± 2.2 mmol/L, P = 0.012) was observed. Glycemic variability showed a similar behavior and there were no significant differences in the AUC, MAGE, SD of glucose, CV of glucose, and MBG between groups. CONCLUSION Linagliptin administration resulted in better glycemic control according to the decrease of glucose levels by the OGTT at 120 min in patients with IGT. Meanwhile, glycemic variability was not modified in any of the study groups.
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Affiliation(s)
- Tonatiuh González-Heredia
- Department of Physiology, Institute of Experimental and Clinical Therapeutics, Health Sciences University Center, University of Guadalajara , Guadalajara, Mexico
| | - Diana M Hernández-Corona
- Department of Physiology, Institute of Experimental and Clinical Therapeutics, Health Sciences University Center, University of Guadalajara , Guadalajara, Mexico
| | - Manuel González-Ortiz
- Department of Physiology, Institute of Experimental and Clinical Therapeutics, Health Sciences University Center, University of Guadalajara , Guadalajara, Mexico
| | - Esperanza Martínez-Abundis
- Department of Physiology, Institute of Experimental and Clinical Therapeutics, Health Sciences University Center, University of Guadalajara , Guadalajara, Mexico
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Ando H, Gotoh K, Fujiwara K, Anai M, Chiba S, Masaki T, Kakuma T, Shibata H. Glucagon-like peptide-1 reduces pancreatic β-cell mass through hypothalamic neural pathways in high-fat diet-induced obese rats. Sci Rep 2017; 7:5578. [PMID: 28717164 PMCID: PMC5514038 DOI: 10.1038/s41598-017-05371-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 05/30/2017] [Indexed: 12/25/2022] Open
Abstract
We examined whether glucagon-like peptide-1 (GLP-1) affects β-cell mass and proliferation through neural pathways, from hepatic afferent nerves to pancreatic efferent nerves via the central nervous system, in high-fat diet (HFD)-induced obese rats. The effects of chronic administration of GLP-1 (7–36) and liraglutide, a GLP-1 receptor agonist, on pancreatic morphological alterations, c-fos expression and brain-derived neurotrophic factor (BDNF) content in the hypothalamus, and glucose metabolism were investigated in HFD-induced obese rats that underwent hepatic afferent vagotomy (VgX) and/or pancreatic efferent sympathectomy (SpX). Chronic GLP-1 (7–36) administration to HFD-induced obese rats elevated c-fos expression and BDNF content in the hypothalamus, followed by a reduction in pancreatic β-cell hyperplasia and insulin content, thus resulting in improved glucose tolerance. These responses were abolished by VgX and SpX. Moreover, administration of liraglutide similarly activated the hypothalamic neural pathways, thus resulting in a more profound amelioration of glucose tolerance than native GLP-1 (7–36). These data suggest that GLP-1 normalizes the obesity-induced compensatory increase in β-cell mass and glucose intolerance through a neuronal relay system consisting of hepatic afferent nerves, the hypothalamus, and pancreatic efferent nerves.
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Affiliation(s)
- Hisae Ando
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu city, Oita, 879-5593, Japan
| | - Koro Gotoh
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu city, Oita, 879-5593, Japan.
| | - Kansuke Fujiwara
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu city, Oita, 879-5593, Japan
| | - Manabu Anai
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu city, Oita, 879-5593, Japan
| | - Seiichi Chiba
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu city, Oita, 879-5593, Japan
| | - Takayuki Masaki
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu city, Oita, 879-5593, Japan
| | - Tetsuya Kakuma
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu city, Oita, 879-5593, Japan
| | - Hirotaka Shibata
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu city, Oita, 879-5593, Japan
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24
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Anholm C, Kumarathurai P, Pedersen LR, Nielsen OW, Kristiansen OP, Fenger M, Madsbad S, Sajadieh A, Haugaard SB. Liraglutide effects on beta-cell, insulin sensitivity and glucose effectiveness in patients with stable coronary artery disease and newly diagnosed type 2 diabetes. Diabetes Obes Metab 2017; 19:850-857. [PMID: 28124822 DOI: 10.1111/dom.12891] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 01/21/2017] [Accepted: 01/21/2017] [Indexed: 12/31/2022]
Abstract
AIMS The aims of the study were to investigate the effects of the GLP-1 receptor agonist liraglutide as add-on to metformin on insulin sensitivity (Si) and glucose effectiveness (Sg) in addition to its positive effects on beta-cell function in overweight/obese patients with coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). METHODS The design of the study was a randomized, double-blind, placebo-controlled, cross-over trial in patients with stable CAD and newly diagnosed well-controlled T2DM. Patients were treated with liraglutide/metformin vs placebo/metformin for a 12 + 12-week period with ≥2-week wash-out. First phase insulin secretion (AIRg), Si and Sg were estimated by the Bergman Minimal Model, enabling calculation of beta-cell function; Disposition Index (DI) = AIRg × Si. A total of 30 patients from among 41 randomized were available for paired analysis. RESULTS Baseline characteristics were: HbA1c 47 mmol/mol (SD 6), BMI 31.6 kg/m2 (SD 4.8), fasting plasma-glucose 6.9 mmol/L (IQR 6.1; 7.4) and HOMA-IR 4.9 (IQR 3.0; 7.5). Liraglutide treatment improved AIRg by 3-fold, 497 mU × L-1 × min (IQR 342; 626, P < .0001) and DI by 1-fold, 766 (SD 824, P < .0001). Despite a significant weight loss of -2.7 kg (-6.7; -0.6) during liraglutide treatment, we found no improvement in HOMA-IR, Si or Sg. Weight loss during liraglutide therapy did not result in a carry-over effect. CONCLUSION Liraglutide as add-on to metformin induces a clinically significant improvement in beta-cell function in overweight/obese, high cardiovascular risk patients with newly diagnosed well-controlled T2DM and CAD. The effect of liraglutide on DI is mediated entirely by improved AIRg whereas the effects on Si and Sg are neutral.
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Affiliation(s)
- Christian Anholm
- Department of Internal Medicine, Copenhagen University Hospital, Amager, Denmark
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Preman Kumarathurai
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Lene R Pedersen
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Olav W Nielsen
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Ole P Kristiansen
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Mogens Fenger
- Department of Clinical Biochemistry, Copenhagen University Hospital, Hvidovre, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital, Hvidovre, Denmark
| | - Ahmad Sajadieh
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Steen B Haugaard
- Department of Internal Medicine, Copenhagen University Hospital, Amager, Denmark
- Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark
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25
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Hemmingsen B, Sonne DP, Metzendorf M, Richter B. Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk for the development of type 2 diabetes mellitus. Cochrane Database Syst Rev 2017; 5:CD012204. [PMID: 28489279 PMCID: PMC6481586 DOI: 10.1002/14651858.cd012204.pub2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether dipeptidyl-peptidase (DPP)-4 inhibitors or glucagon-like peptide (GLP)-1 analogues are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown. OBJECTIVES To assess the effects of DPP-4 inhibitors and GLP-1 analogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials; MEDLINE; PubMed; Embase; ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform; and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was January 2017. SELECTION CRITERIA We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing DPP-4 inhibitors and GLP-1 analogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these. DATA COLLECTION AND ANALYSIS Two review authors read all abstracts and full-text articles and records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses, we planned to use a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall quality of the evidence using the GRADE instrument. MAIN RESULTS We included seven completed RCTs; about 98 participants were randomised to a DPP-4 inhibitor as monotherapy and 1620 participants were randomised to a GLP-1 analogue as monotherapy. Two trials investigated a DPP-4 inhibitor and five trials investigated a GLP-1 analogue. A total of 924 participants with data on allocation to control groups were randomised to a comparator group; 889 participants were randomised to placebo and 33 participants to metformin monotherapy. One RCT of liraglutide contributed 85% of all participants. The duration of the intervention varied from 12 weeks to 160 weeks. We judged none of the included trials at low risk of bias for all 'Risk of bias' domains and did not perform meta-analyses because there were not enough trials.One trial comparing the DPP-4 inhibitor vildagliptin with placebo reported no deaths (very low-quality evidence). The incidence of T2DM by means of WHO diagnostic criteria in this trial was 3/90 participants randomised to vildagliptin versus 1/89 participants randomised to placebo (very low-quality evidence). Also, 1/90 participants on vildagliptin versus 2/89 participants on placebo experienced a serious adverse event (very low-quality evidence). One out of 90 participants experienced congestive heart failure in the vildagliptin group versus none in the placebo group (very low-quality evidence). There were no data on non-fatal myocardial infarction, stroke, health-related quality of life or socioeconomic effects reported.All-cause and cardiovascular mortality following treatment with GLP-1 analogues were rarely reported; one trial of exenatide reported that no participant died. Another trial of liraglutide 3.0 mg showed that 2/1501 in the liraglutide group versus 2/747 in the placebo group died after 160 weeks of treatment (very low-quality evidence).The incidence of T2DM following treatment with liraglutide 3.0 mg compared to placebo after 160 weeks was 26/1472 (1.8%) participants randomised to liraglutide versus 46/738 (6.2%) participants randomised to placebo (very low-quality evidence). The trial established the risk for (diagnosis of) T2DM as HbA1c 5.7% to 6.4% (6.5% or greater), fasting plasma glucose 5.6 mmol/L or greater to 6.9 mmol/L or less (7.0 mmol/L or greater) or two-hour post-load plasma glucose 7.8 mmol/L or greater to 11.0 mmol/L (11.1 mmol/L). Altogether, 70/1472 (66%) participants regressed from intermediate hyperglycaemia to normoglycaemia compared with 268/738 (36%) participants in the placebo group. The incidence of T2DM after the 12-week off-treatment extension period (i.e. after 172 weeks) showed that five additional participants were diagnosed T2DM in the liraglutide group, compared with one participant in the placebo group. After 12-week treatment cessation, 740/1472 (50%) participants in the liraglutide group compared with 263/738 (36%) participants in the placebo group had normoglycaemia.One trial used exenatide and 2/17 participants randomised to exenatide versus 1/16 participants randomised to placebo developed T2DM (very low-quality evidence). This trial did not provide a definition of T2DM. One trial reported serious adverse events in 230/1524 (15.1%) participants in the liraglutide 3.0 mg arm versus 96/755 (12.7%) participants in the placebo arm (very low quality evidence). There were no serious adverse events in the trial using exenatide. Non-fatal myocardial infarction was reported in 1/1524 participants in the liraglutide arm and in 0/55 participants in the placebo arm at 172 weeks (very low-quality evidence). One trial reported congestive heart failure in 1/1524 participants in the liraglutide arm and in 1/755 participants in the placebo arm (very low-quality evidence). Participants receiving liraglutide compared with placebo had a small mean improvement in the physical component of the 36-item Short Form scale showing a difference of 0.87 points (95% CI 0.17 to 1.58; P = 0.02; 1 trial; 1791 participants; very low-quality evidence). No trial evaluating GLP-1-analogues reported data on stroke, microvascular complications or socioeconomic effects. AUTHORS' CONCLUSIONS There is no firm evidence that DPP-4 inhibitors or GLP-1 analogues compared mainly with placebo substantially influence the risk of T2DM and especially its associated complications in people at increased risk for the development of T2DM. Most trials did not investigate patient-important outcomes.
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Affiliation(s)
- Bianca Hemmingsen
- Herlev University HospitalDepartment of Internal MedicineHerlev Ringvej 75HerlevDenmarkDK‐2730
| | - David P Sonne
- Gentofte Hospital, University of CopenhagenCenter for Diabetes Research, Department of MedicineKildegaardsvej 28HellerupDenmarkDK‐2900
| | - Maria‐Inti Metzendorf
- Institute of General Practice, Medical Faculty of the Heinrich‐Heine‐University DüsseldorfCochrane Metabolic and Endocrine Disorders GroupMoorenstr. 5DüsseldorfGermany40225
| | - Bernd Richter
- Institute of General Practice, Medical Faculty of the Heinrich‐Heine‐University DüsseldorfCochrane Metabolic and Endocrine Disorders GroupMoorenstr. 5DüsseldorfGermany40225
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Zhang CJ, Bidlingmaier M, Altaye M, Page LC, D'Alessio D, Tschöp MH, Tong J. Acute administration of acyl, but not desacyl ghrelin, decreases blood pressure in healthy humans. Eur J Endocrinol 2017; 176:123-132. [PMID: 27913606 PMCID: PMC5325691 DOI: 10.1530/eje-16-0789] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 11/02/2016] [Accepted: 11/08/2016] [Indexed: 01/13/2023]
Abstract
OBJECTIVE To compare the effects of acyl ghrelin (AG) and desacyl ghrelin (DAG) on blood pressure (BP), heart rate (HR) and other autonomic parameters in healthy humans and to elucidate the hormonal mechanisms through which AG could exert its cardiovascular effects. DESIGN Seventeen healthy participants underwent frequent monitoring of systolic (sBP) and diastolic blood pressure (dBP), HR, respiratory rate (RR) and body surface temperature (Temp) during continuous infusion of AG, DAG, combined AG + DAG or saline control before and during an IV glucose tolerance test on 4 separate days. Plasma catecholamines, renin and aldosterone levels were also measured. Differences in outcome measures between treatment groups were assessed using mixed-model analysis. RESULTS Compared to the saline control, AG and combined AG + DAG infusions decreased sBP, dBP, mean arterial blood pressure (MAP), HR and Temp. In contrast, DAG infusion did not alter BP, RR or Temp, but did decrease HR. The AG and AG + DAG infusions also raised plasma aldosterone levels compared to saline (P < 0.001) without affecting renin or catecholamine levels. CONCLUSIONS The decrease in BP, HR, RR and Temp with AG infusion suggests mediation through the autonomic nervous system. The lack of response to DAG suggests that these autonomic effects require activation of the ghrelin receptor.
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Affiliation(s)
- Cecilia J Zhang
- Division of EndocrinologyMetabolism and Nutrition, Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Martin Bidlingmaier
- Medizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität, Munich, Germany
| | - Mekibib Altaye
- BiostatisticsClinical Translational Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Laura C Page
- Division of Pediatric Endocrinology and DiabetesDepartment of Pediatrics, Duke University, Durham, North Carolina, USA
| | - David D'Alessio
- Division of EndocrinologyDiabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
- Division of EndocrinologyMetabolism and Nutrition, Department of Medicine, Duke University, Durham, North Carolina, USA
- Cincinnati Veterans Affairs Medical CenterCincinnati, Ohio, USA
| | - Matthias H Tschöp
- Division of EndocrinologyDiabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
- Institute for Obesity and DiabetesHelmholtz Diabetes Center Munich and Division of Metabolic Diseases, Technical University, Munich, Germany
| | - Jenny Tong
- Division of EndocrinologyDiabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
- Division of EndocrinologyMetabolism and Nutrition, Department of Medicine, Duke University, Durham, North Carolina, USA
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Mulvihill EE, Varin EM, Gladanac B, Campbell JE, Ussher JR, Baggio LL, Yusta B, Ayala J, Burmeister MA, Matthews D, Bang KWA, Ayala JE, Drucker DJ. Cellular Sites and Mechanisms Linking Reduction of Dipeptidyl Peptidase-4 Activity to Control of Incretin Hormone Action and Glucose Homeostasis. Cell Metab 2017; 25:152-165. [PMID: 27839908 DOI: 10.1016/j.cmet.2016.10.007] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 09/06/2016] [Accepted: 10/12/2016] [Indexed: 12/24/2022]
Abstract
Pharmacological inhibition of the dipeptidyl peptidase-4 (DPP4) enzyme potentiates incretin action and is widely used to treat type 2 diabetes. Nevertheless, the precise cells and tissues critical for incretin degradation and glucose homeostasis remain unknown. Here, we use mouse genetics and pharmacologic DPP4 inhibition to identify DPP4+ cell types essential for incretin action. Although enterocyte DPP4 accounted for substantial intestinal DPP4 activity, ablation of enterocyte DPP4 in Dpp4Gut-/- mice did not produce alterations in plasma DPP4 activity, incretin hormone levels, and glucose tolerance. In contrast, endothelial cell (EC)-derived DPP4 contributed substantially to levels of soluble plasma DPP4 activity, incretin degradation, and glucose control. Surprisingly, DPP4+ cells of bone marrow origin mediated the selective degradation of fasting GIP, but not GLP-1. Collectively, these findings identify distinct roles for DPP4 in the EC versus the bone marrow compartment for selective incretin degradation and DPP4i-mediated glucoregulation.
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Affiliation(s)
- Erin E Mulvihill
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Elodie M Varin
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Bojana Gladanac
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Jonathan E Campbell
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - John R Ussher
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Laurie L Baggio
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Bernardo Yusta
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Jennifer Ayala
- Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Center for Metabolic Origins of Disease, Orlando, FL 32827, USA
| | - Melissa A Burmeister
- Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Center for Metabolic Origins of Disease, Orlando, FL 32827, USA
| | - Dianne Matthews
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - K W Annie Bang
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Division of Reproductive Sciences, University of Toronto, Toronto, ON M5S 2J7, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 2J7, Canada
| | - Julio E Ayala
- Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Center for Metabolic Origins of Disease, Orlando, FL 32827, USA
| | - Daniel J Drucker
- Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 2J7, Canada.
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Duvnjak L, Blaslov K, Vučić Lovrenčić M, Knežević Ćuća J. Persons with latent autoimmune diabetes in adults express higher dipeptidyl peptidase-4 activity compared to persons with type 2 and type 1 diabetes. Diabetes Res Clin Pract 2016; 121:119-126. [PMID: 27693949 DOI: 10.1016/j.diabres.2016.09.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 09/04/2016] [Accepted: 09/13/2016] [Indexed: 12/12/2022]
Abstract
AIMS We aimed to determine serum dipeptidyl peptidase-4 (DPP-4) activity in a group of persons with latent autoimmune diabetes in adults (LADA) and to compare it with persons with type 1, type 2 diabetes and healthy controls. METHODS DPP-4 activity measurement was performed in 67 persons (21 with type 1, 26 type 2 and 19 with LADA) and 13 healthy age and gender matched controls. RESULTS Persons with LADA showed highest DPP-4 activity among the study groups (32.71±3.55 vs 25.37±2.84 vs 18.57±2.54 vs 18.57±2.61U/L p<0.001). Mean glutamic acid autoantibody in persons with LADA was 164.32±86.28IU/mL. It correlated with DPP-4 activity (r=0.484, p=0.013). Furthermore, DPP-4 activity correlated with waist circumference (r=0.279, p=0.034) and glycated haemoglobin A1c (r=0.483, p<0.001), as well as with LDL cholesterol (r=0.854, p<0.001) and total daily insulin dose (r=0.397, p=0.001). In the multinomial regression analysis DPP-4 activity remained associated with both LADA (prevalence ratio 1.058 (1.012-1.287), p=0.001) and type 1 diabetes (prevalence ratio 1.506 (1.335-1.765), p<0.001) while it did not show an association with type 2 diabetes (prevalence ratio 0.942 (0.713-1.988), p=0.564). CONCLUSIONS Persons with LADA express higher DPP-4 activity compared to persons with both type 1 and type 2 diabetes. The possible pathophysiological role of DPP-4 in the LADA pathogenesis needs to be further evaluated.
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Affiliation(s)
- L Duvnjak
- Vuk Vrhovac Clinic for Diabetes, Endocrinology and Metabolic Diseases, University Hospital Merkur, Zagreb, Croatia; School of Medicine Zagreb, Croatia
| | - K Blaslov
- Vuk Vrhovac Clinic for Diabetes, Endocrinology and Metabolic Diseases, University Hospital Merkur, Zagreb, Croatia.
| | - M Vučić Lovrenčić
- Vuk Vrhovac Clinic for Diabetes, Endocrinology and Metabolic Diseases, University Hospital Merkur, Zagreb, Croatia
| | - J Knežević Ćuća
- Vuk Vrhovac Clinic for Diabetes, Endocrinology and Metabolic Diseases, University Hospital Merkur, Zagreb, Croatia
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Weber MB, Ranjani H, Staimez LR, Anjana RM, Ali MK, Narayan KMV, Mohan V. The Stepwise Approach to Diabetes Prevention: Results From the D-CLIP Randomized Controlled Trial. Diabetes Care 2016; 39:1760-7. [PMID: 27504014 PMCID: PMC5033082 DOI: 10.2337/dc16-1241] [Citation(s) in RCA: 130] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 07/20/2016] [Indexed: 02/03/2023]
Abstract
OBJECTIVE This study tests the effectiveness of expert guidelines for diabetes prevention: lifestyle intervention with addition of metformin, when required, among people with prediabetes. RESEARCH DESIGN AND METHODS The Diabetes Community Lifestyle Improvement Program (D-CLIP) is a randomized, controlled, translation trial of 578 overweight/obese Asian Indian adults with isolated impaired glucose tolerance (iIGT), isolated impaired fasting glucose (iIFG), or IFG+IGT in Chennai, India. Eligible individuals were identified through community-based recruitment and randomized to standard lifestyle advice (control) or a 6-month, culturally tailored, U.S. Diabetes Prevention Program-based lifestyle curriculum plus stepwise addition of metformin (500 mg, twice daily) for participants at highest risk of conversion to diabetes at ≥4 months of follow-up. The primary outcome, diabetes incidence, was assessed biannually and compared across study arms using an intention-to-treat analysis. RESULTS During 3 years of follow-up, 34.9% of control and 25.7% of intervention participants developed diabetes (P = 0.014); the relative risk reduction (RRR) was 32% (95% CI 7-50), and the number needed to treat to prevent one case of diabetes was 9.8. The RRR varied by prediabetes type (IFG+IGT, 36%; iIGT, 31%; iIFG, 12%; P = 0.77) and was stronger in participants 50 years or older, male, or obese. Most participants (72.0%) required metformin in addition to lifestyle, although there was variability by prediabetes type (iIFG, 76.5%; IFG+IGT, 83.0%; iIGT, 51.3%). CONCLUSIONS Stepwise diabetes prevention in people with prediabetes can effectively reduce diabetes incidence by a third in community settings; however, people with iIFG may require different interventions.
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Affiliation(s)
- Mary Beth Weber
- Emory Global Diabetes Research Center, Hubert Department of Global Health, Emory University, Atlanta, GA
| | | | - Lisa R Staimez
- Emory Global Diabetes Research Center, Hubert Department of Global Health, Emory University, Atlanta, GA
| | | | - Mohammed K Ali
- Emory Global Diabetes Research Center, Hubert Department of Global Health, Emory University, Atlanta, GA
| | - K M Venkat Narayan
- Emory Global Diabetes Research Center, Hubert Department of Global Health, Emory University, Atlanta, GA
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Extrapancreatic contribution to glucose regulation by dipeptidyl peptidase 4 inhibition. Cardiovasc Endocrinol 2016. [DOI: 10.1097/xce.0000000000000088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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Refaat R, Sakr A, Salama M, El Sarha A. Combination of Vildagliptin and Pioglitazone in Experimental Type 2 Diabetes in Male Rats. Drug Dev Res 2016; 77:300-9. [PMID: 27520857 DOI: 10.1002/ddr.21324] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 07/23/2016] [Indexed: 12/25/2022]
Abstract
Preclinical Research The majority of studies on vildagliptin and pioglitazone have focused on their combination in glycemic control. The aim of the present study was to investigate their effects in combination on (i) hyperglycemia-induced oxidative stress and inflammation and (ii) on organs involved in the pathophysiology of diabetes, pancreas, kidney and liver. Type 2 diabetes was induced using low-dose streptozotocin in male Wistar rats. Diabetic rats were treated for 4 weeks, with vildagliptin (10 mg/kg/day), pioglitazone (10 mg/kg/day) and their combination. Diabetic rats showed elevated fasting serum glucose, fasting serum insulin, serum transaminases together with a deleterious lipid profile and elevated serum creatinine and urea concentrations. Serum levels of the inflammatory markers tumor necrosis factor-α (TNF-α) and nitrite/nitrate were also elevated compared to normal rats. Oxidative stress was manifested by lowered hepatic reduced glutathione (GSH) and increased malondialdehyde (MDA) levels. Pancreatic sections from diabetic rats showed degenerated islets with poorly maintained architecture that was prevented by drug treatment. Pioglitazone was generally more effective than vildagliptin in the studied parameters except for the lipid profile where the effect of both drugs was comparable and for the liver enzymes and renal parameters where vildagliptin was more effective. The combination of vildagliptin and pioglitazone produced superior effects than either drug alone. Drug Dev Res 77 : 251-257, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Rowaida Refaat
- Department of Pharmacology, Medical Research Institute, University of Alexandria, Alexandria, Egypt
| | - Ahmed Sakr
- Department of Pharmacology, Medical Research Institute, University of Alexandria, Alexandria, Egypt
| | - Mona Salama
- Department of Pharmacology, Medical Research Institute, University of Alexandria, Alexandria, Egypt
| | - Ashgan El Sarha
- Department of Pathology, Medical Research Institute, University of Alexandria, Alexandria, Egypt
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Ito R, Fukui T, Hayashi T, Osamura A, Ohara M, Hara N, Higuchi A, Yamamoto T, Hirano T. Teneligliptin, a Dipeptidyl Peptidase-4 Inhibitor, Improves Early-Phase Insulin Secretion in Drug-Naïve Patients with Type 2 Diabetes. Drugs R D 2016. [PMID: 26224337 PMCID: PMC4561050 DOI: 10.1007/s40268-015-0096-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Introduction It remains unknown whether dipeptidyl peptidase-4 (DPP-4) inhibitors improve early-phase insulin secretion in Japanese patients with type 2 diabetes (T2D), a disease characterized by impaired insulin secretion. We investigated the changes in insulin secretion before and after treatment with the DPP-4 inhibitor teneligliptin in patients with T2D with a low insulinogenic index (IGI) determined by the oral glucose tolerance test (OGTT). Methods An open-label, prospective clinical study was conducted. Thirteen drug-naïve patients (mean age 55.5 ± 3.9 years) with T2D underwent OGTT before and after teneligliptin 20 mg/day monotherapy. Plasma levels of glucose (PG), insulin, and C-peptide were measured at 0, 30, 60, 90, and 120 min after glucose loading in the OGTT. Homeostasis model assessment (HOMA)-β, IGI, and the total or incremental area under the curve (AUC) for PG and insulin were measured. AUC120min for the secretory units of islets in transplantation (SUIT) index was also measured. Results HbA1c significantly decreased from 8.3 ± 0.4 % at baseline to 6.3 ± 0.2 % after 12 weeks of teneligliptin treatment (p < 0.05). Incremental AUC120min PG also significantly decreased, and β-cell function assessed by IGI30min, AUC120min insulin, and the AUC120min SUIT index significantly increased (0.16 ± 0.05 vs. 0.28 ± 0.06, 2692 ± 333 µU·2h/mL vs. 3537 ± 361 µU·2h/mL, and 4261 ± 442 vs. 8290 ± 1147, respectively; all p < 0.05). HOMA-β was unchanged. The reduction in incremental AUC120min PG was significantly associated with the augmentation of IGI30min and the AUC120min SUIT index. No severe adverse events were observed. Conclusions Twelve weeks of teneligliptin treatment improved IGI30min, AUC120min, and the SUIT index in drug-naïve Japanese patients with T2D.
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Affiliation(s)
- Rika Ito
- Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan,
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Ahrén B, Foley JE. Improved glucose regulation in type 2 diabetic patients with DPP-4 inhibitors: focus on alpha and beta cell function and lipid metabolism. Diabetologia 2016; 59:907-17. [PMID: 26894277 DOI: 10.1007/s00125-016-3899-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 01/22/2016] [Indexed: 12/19/2022]
Abstract
Inhibition of dipeptidyl peptidase-4 (DPP-4) is an established glucose-lowering strategy for the management of type 2 diabetes mellitus. DPP-4 inhibitors reduce both fasting and postprandial plasma glucose levels, resulting in reduced HbA1c with low risk for hypoglycaemia and weight gain. They act primarily by preventing inactivation of the incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, thereby prolonging the enhanced endogenous levels of these hormones after meal ingestion. This in turn causes islet and extrapancreatic effects, including increased glucose sensing in islet alpha and beta cells. These effects result in increased insulin secretion and decreased glucagon secretion being more effective in hyperglycaemic states and reduced insulin secretion and increased glucagon secretion being more effective during hypoglycaemia. Other secondary pharmacological actions of DPP-4 inhibitors include mobilisation and burning of fat during meals, decrease in fat extraction from the gut, reduction of fasting lipolysis and liver fat and increase in LDL particle size. These actions contribute to the clinical effects of DPP-4 inhibition, and the reduced demand for insulin could also lead to a durability benefit. This review summarises the current knowledge of the secondary pharmacological actions of DPP-4 inhibitors that lead to improved glucose regulation in patients with type 2 diabetes, focusing on alpha and beta cell function and lipid metabolism.
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Affiliation(s)
- Bo Ahrén
- Faculty of Medicine, Department of Clinical Sciences Lund, Lund University, B11 BMC, Sölvegatan 19, 22184, Lund, Sweden.
| | - James E Foley
- World Wide Medical Affairs, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
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Tsuboi K, Mizukami H, Inaba W, Baba M, Yagihashi S. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses development of neuropathy in diabetic rodents: effects on peripheral sensory nerve function, structure and molecular changes. J Neurochem 2016; 136:859-870. [PMID: 26603140 DOI: 10.1111/jnc.13439] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 11/03/2015] [Accepted: 11/04/2015] [Indexed: 01/01/2023]
Abstract
Incretin-related therapy was found to be beneficial for experimental diabetic neuropathy, but its mechanism is obscure. The purpose of this study is to explore the mechanism through which dipeptidyl peptidase IV inhibitor, vildagliptin (VG), influences neuropathy in diabetic rodents. To this end, non-obese type 2 diabetic Goto-Kakizaki rats (GK) and streptozotocin (STZ)-induced diabetic mice were treated with VG orally. Neuropathy was evaluated by nerve conduction velocity (NCV) in both GK and STZ-diabetic mice, whereas calcitonin-gene-related peptide expressions, neuronal cell size of dorsal root ganglion (DRG) and intraepidermal nerve fiber density were examined in GK. DRG from GK and STZ-diabetic mice served for the analyses of GLP-1 and insulin signaling. As results, VG treatment improved glucose intolerance and increased serum insulin and GLP-1 in GK accompanied by the amelioration of delayed NCV and neuronal atrophy, reduced calcitonin-gene-related peptide expressions and intraepidermal nerve fiber density. Diet restriction alone did not significantly influence these measures. Impaired GLP-1 signals such as cAMP response element binding protein, protein kinase B/Akt (PKB/Akt) and S6RP in DRG of GK were restored in VG-treated group, but the effect was equivocal in diet-treated GK. Concurrently, decreased phosphorylation of insulin receptor substrate 2 in GK was corrected by VG treatment. Consistent with the effect on GK, VG treatment improved NCV in diabetic mice without influence on hyperglycemia. DRG of VG-treated diabetic mice were characterized by correction of GLP-1 signals and insulin receptor substrate 2 phosphorylation without effects on insulin receptor β expression. The results suggest close association of neuropathy development with impaired signaling of insulin and GLP-1 in diabetic rodents. Diabetic neurons are resistant to insulin and such insulin resistance may contribute to development of neuropathy. DPP-IV inhibitor, vildagliptin, corrected insulin resistance and improved neuropathy irrespective of blood glucose via augmented action of GLP-1.
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Affiliation(s)
- Kentaro Tsuboi
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Hiroki Mizukami
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Wataru Inaba
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Masayuki Baba
- Department of Neurology, Aomori Prefectural Hospital, Aomori, Japan
| | - Soroku Yagihashi
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
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Huang CN, Wang CJ, Yang YS, Lin CL, Peng CH. Hibiscus sabdariffa polyphenols prevent palmitate-induced renal epithelial mesenchymal transition by alleviating dipeptidyl peptidase-4-mediated insulin resistance. Food Funct 2016; 7:475-82. [DOI: 10.1039/c5fo00464k] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Diabetic nephropathy has a significant socioeconomic impact, but its mechanism is unclear and needs to be examined.
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Affiliation(s)
- Chien-Ning Huang
- Department of Internal Medicine
- Chung-Shan Medical University Hospital
- Taichung 402
- Taiwan
- Institute of Medicine
| | - Chau-Jong Wang
- Institute of Biochemistry and Biotechnology
- Chung-Shan Medical University
- Taichung 402
- Taiwan
| | - Yi-Sun Yang
- Department of Internal Medicine
- Chung-Shan Medical University Hospital
- Taichung 402
- Taiwan
| | - Chih-Li Lin
- Institute of Medicine
- Chung-Shan Medical University
- Taichung 402
- Taiwan
| | - Chiung-Huei Peng
- Division of Basic Medical Science
- Hungkuang University
- Taichung City 43302
- Taiwan
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Irwin N, Flatt PR. New perspectives on exploitation of incretin peptides for the treatment of diabetes and related disorders. World J Diabetes 2015; 6:1285-1295. [PMID: 26557956 PMCID: PMC4635139 DOI: 10.4239/wjd.v6.i15.1285] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 09/25/2015] [Accepted: 10/27/2015] [Indexed: 02/05/2023] Open
Abstract
The applicability of stable gut hormones for the treatment of obesity-related diabetes is now undisputable. This is based predominantly on prominent and sustained glucose-lowering actions, plus evidence that these peptides can augment insulin secretion and pancreatic islet function over time. This review highlights the therapeutic potential of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), oxyntomodulin (OXM) and cholecystokinin (CCK) for obesity-related diabetes. Stable GLP-1 mimetics have already been successfully adopted into the diabetic clinic, whereas GIP, CCK and OXM molecules offer promise as potential new classes of antidiabetic drugs. Moreover, recent studies have shown improved therapeutic effects following simultaneous modulation of multiple receptor signalling pathways by combination therapy or use of dual/triple agonist peptides. However, timing and composition of injections may be important to permit interludes of beta-cell rest. The review also addresses the possible perils of incretin based drugs for treatment of prediabetes. Finally, the unanticipated utility of stable gut peptides as effective treatments for complications of diabetes, bone disorders, cognitive impairment and cardiovascular dysfunction is considered.
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Kaku K, Kadowaki T, Terauchi Y, Okamoto T, Sato A, Okuyama K, Arjona Ferreira JC, Goldstein BJ. Sitagliptin improves glycaemic excursion after a meal or after an oral glucose load in Japanese subjects with impaired glucose tolerance. Diabetes Obes Metab 2015; 17:1033-41. [PMID: 26094974 PMCID: PMC5034821 DOI: 10.1111/dom.12507] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2015] [Revised: 05/31/2015] [Accepted: 06/06/2015] [Indexed: 12/14/2022]
Abstract
AIMS To evaluate the efficacy and tolerability of sitagliptin in subjects with impaired glucose tolerance (IGT). METHODS In a double-blind, parallel-group study, 242 Japanese subjects with IGT, determined by a 75-g oral glucose tolerance test (OGTT) at week -1, were randomized (1 : 1 : 1) to placebo (n = 83), sitagliptin 25 mg (n = 82) or 50 mg (n = 77) once daily for 8 weeks. Glycaemic variables were assessed using another OGTT at week 7 and meal tolerance tests (MTTs) at weeks 0 and 8. Primary and secondary endpoints were percent change from baseline in glucose total area under the curve 0-2 h (AUC(0 -2 h)) during the MTT and OGTT, respectively. RESULTS Least squares mean percent change from baseline in glucose AUC(0 -2 h) during the MTT were -2.4, -9.5 and -11.5%, and during the OGTT were -3.7, -21.4 and -20.1% with placebo, sitagliptin 25 mg once daily, and 50 mg once daily, respectively (p < 0.001 for either sitagliptin dose vs placebo in both tests). Sitagliptin treatment enhanced early insulin response during the OGTT and decreased total insulin response, assessed as the total AUC(0 -2 h) during the MTT. Sitagliptin treatment also suppressed glucagon response during the MTT. The incidence of adverse events, including hypoglycaemia, was low and generally similar in all treatment groups. CONCLUSIONS Treatment with sitagliptin significantly reduced glucose excursions during both an MTT and an OGTT; this effect was associated with an increase in early insulin secretion after oral glucose loading as well as a blunted glucagon response during an MTT. Sitagliptin was generally well tolerated in subjects with IGT.
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Affiliation(s)
- K Kaku
- Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
| | - T Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Y Terauchi
- Department of Endocrinology and Metabolism, Yokohama City University, Yokohama, Japan
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Meier JJ, Nauck MA. Incretin-based therapies: where will we be 50 years from now? Diabetologia 2015; 58:1745-50. [PMID: 25994073 DOI: 10.1007/s00125-015-3608-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 03/17/2015] [Indexed: 10/23/2022]
Abstract
The development of incretin-based therapies (glucagon-like peptide 1 [GLP-1] receptor agonists and dipeptidyl peptidase-4 [DPP-4] inhibitors) has changed the landscape of type 2 diabetes management over the past decade. Current developments include longer-acting GLP-1 receptor agonists, fixed-ratio combinations of GLP-1 analogues and basal insulin, as well as implantable osmotic minipumps for long-term delivery of GLP-1 receptor agonists. In longer terms, oral or inhaled GLP-1 analogues may become a reality. In addition, oral enhancers of GLP-1 secretion (e.g. via G-protein-coupled receptors, nuclear farnesoid-receptor X and the G-protein-coupled bile acid-activated receptor [TGR5]) are currently being explored in experimental studies. Combination of GLP-1 with other gut hormones (e.g. peptide YY, glucagon, gastrin, glucose-dependent insulinotropic polypeptide [GIP], secretin, cholecystokinin, vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptide) may enhance the glucose- and weight-lowering effect of GLP-1 alone, and dual or triple hormone receptor agonists may even exploit the properties of different peptides with just one molecule. There is also an increasing interest in employing incretin-based therapies in other areas, such as type 1 diabetes, impaired glucose metabolism, obesity, polycystic ovary syndrome, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), psoriasis or even neurodegeneration. Thus, incretin-based therapies may continue to broaden the therapeutic spectrum for type 2 diabetes and for various other indications in the coming years. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015).
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Affiliation(s)
- Juris J Meier
- Division of Diabetes and GI Endocrinology, University Hospital St Josef-Hospital, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany,
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Increased plasma dipeptidyl peptidase-4 activities are associated with high prevalence of subclinical atherosclerosis in Chinese patients with newly diagnosed type 2 diabetes: a cross-sectional study. Atherosclerosis 2015; 242:580-8. [PMID: 26318108 DOI: 10.1016/j.atherosclerosis.2015.07.042] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Revised: 06/04/2015] [Accepted: 07/24/2015] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Hyperglycemia, insulin resistance, dislipidemia, oxidative stress and inflammation are well-documented risk factors for subclinical atherosclerosis. Dipeptidyl peptidase-4(DPP4) is a newly identified adipokine related to these risk factors. Hence, we aimed to investigate the association between plasma DPP4 activities and subclinical atherosclerosis in type 2 diabetes. METHODS A total of 985 newly diagnosed type 2 diabetic subjects were studied. Plasma DPP4 activity, mannose 6-phosphate receptor (M6P-R), oxidative stress parameters, inflammatory markers and common carotid artery Intima-Media Thickness (c-IMT) were measured in all participants. RESULTS Participants in the highest quartile of DPP4 activity had higher HbA1c, homeostatic model assessment of insulin resistance(HOMA-IR), triglyceride, low-density lipoprotein cholesterol(LDL-C), oxidized LDL, nitrotyrosine, 8-iso-PGF2a, interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), M6P-R, c-IMT compared with participants in the lowest quartile (all P < 0.001). DPP4 activities were associated positively with HbA1c, HOMA-IR, triglyceride, LDL-C, oxidized LDL, nitrotyrosine, 8-iso-PGF2a, IL-6, hs-CRP, M6P-R and c-IMT (all P < 0.05). The ORs for insulin resistance, dislipidemia, oxidative stress and inflammation were higher with increasing DPP4 quartiles (P < 0.001 for trend). In the highest DPP4 quartile, subclinical atherosclerosis risk was significantly higher (OR 4.97; 95% CI 3.03-8.17) than in the lowest quartile. This association remained strong (2.17; 1.21-3.89) after further controlling for HbA1c, HOMA-IR, triglyceride, oxidized LDL, nitrotyrosine, and IL-6. CONCLUSIONS This study shows that increased DPP4 activities are positively and independently associated with subclinical atherosclerosis in type 2 diabetes. Our findings suggest of potential role of DPP4 in the pathogenesis of subclinical atherosclerosis and in the prevention and management of this disease.
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Papaetis GS. Incretin-based therapies in prediabetes: Current evidence and future perspectives. World J Diabetes 2014; 5:817-834. [PMID: 25512784 PMCID: PMC4265868 DOI: 10.4239/wjd.v5.i6.817] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Revised: 09/10/2014] [Accepted: 11/10/2014] [Indexed: 02/05/2023] Open
Abstract
The prevalence of type 2 diabetes (T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance (NGT) and the clinical entity of T2D. Relentless β-cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2D. The huge burden resulting from the complications of T2D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, on β-cell function in patients with T2D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater β-cell mass and function are preserved and the possibility of β-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on β-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2D.
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Ahmadieh H, Azar ST. The role of incretin-based therapies in prediabetes: a review. Prim Care Diabetes 2014; 8:286-294. [PMID: 24666932 DOI: 10.1016/j.pcd.2014.02.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/20/2014] [Accepted: 02/24/2014] [Indexed: 12/25/2022]
Abstract
Prediabetes, a high-risk state for future development of diabetes, is prevalent globally. Abnormalities in the incretin axis are important in the progression of B-cell failure in type 2 diabetes. Incretin based therapy was found to improve B cell mass and glycaemic control in addition to having multiple beneficial effects on the systolic and diastolic blood pressure, weight loss in addition to their other beneficial effects on the liver and cardiovascular system. In prediabetes, several well-designed preventive trials have shown that lifestyle and pharmacologic interventions such as metformin, thiazolidinediones (TZD), acarbose and, nateglinide and orlistat, are effective in reducing diabetes development. In recent small studies, incretin based therapy (DPP IV inhibitors and GLP-1 agonists) have also been extended to patients with prediabetes since it was shown to better preserve B-cell function and mass in animal studies and in clinical trials and it was also shown to help maintain good long term metabolic control. Because of the limited studies and clinical experience, their side effects and costs currently guidelines do not recommend incretin-based therapies as an option for treatment in patients with prediabetes. With future clinical trials and studies they may be recommended for patients with impaired fasting glucose or impaired glucose tolerance.
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Affiliation(s)
- Hala Ahmadieh
- Department of Internal Medicine, Division of Endocrinology and Metabolism, American University of Beirut-Medical Center, 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, United States.
| | - Sami T Azar
- Department of Internal Medicine, Division of Endocrinology and Metabolism, American University of Beirut-Medical Center, 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, United States.
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Heise T, Larbig M, Patel S, Seck T, Hehnke U, Woerle HJ, Dugi K. The dipeptidyl peptidase-4 inhibitor linagliptin lowers postprandial glucose and improves measures of β-cell function in type 2 diabetes. Diabetes Obes Metab 2014; 16:1036-9. [PMID: 24821586 DOI: 10.1111/dom.12312] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 04/03/2014] [Accepted: 05/02/2014] [Indexed: 12/16/2022]
Abstract
Progressive deterioration of pancreatic β-cell function in patients with type 2 diabetes mellitus (T2DM) contributes to worsening of hyperglycaemia. To investigate the effects of the dipeptidyl peptidase-4 inhibitor linagliptin on β-cell function parameters, a pooled analysis of six randomized, 24-week, placebo-controlled, phase 3 trials of 5 mg of linagliptin daily was performed in 2701 patients with T2DM (linagliptin, n = 1905; placebo, n = 796). At week 24, observed improvements in HbA1c, fasting plasma glucose, and 2-h postprandial glucose were significantly greater for linagliptin than placebo (all p < 0.0001). Homeostasis model assessment (HOMA)-%β, as a surrogate marker of fasting β-cell function, was significantly improved with linagliptin, and did not change with placebo (placebo-adjusted mean ± s.e. change for linagliptin: 16.5 ± 4.6 (mU/l)/(mmol/l); p = 0.0003). Further study is required to determine if the significant improvement in HOMA-%β with linagliptin will translate into long-term improvements in β-cell function.
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Affiliation(s)
- T Heise
- Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany
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Anholm C, Kumarathurai P, Klit MS, Kristiansen OP, Nielsen OW, Ladelund S, Madsbad S, Sajadieh A, Haugaard SB. Adding liraglutide to the backbone therapy of biguanide in patients with coronary artery disease and newly diagnosed type-2 diabetes (the AddHope2 study): a randomised controlled study protocol. BMJ Open 2014; 4:e005942. [PMID: 25031198 PMCID: PMC4401817 DOI: 10.1136/bmjopen-2014-005942] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
INTRODUCTION Newly diagnosed type 2 diabetes mellitus (T2DM) in patients with coronary artery disease (CAD) more than doubles the risk of death compared with otherwise matched glucose tolerant patients. The biguanide metformin is the drug of choice in treatment of T2DM and has shown to ameliorate cardiovascular morbidity in patients with T2DM and myocardial infarction (MI). The incretin hormone, glucagon-like peptide-1 (GLP-1) improves β-cell function, insulin sensitivity and causes weight loss and has been suggested to have beneficial effects on cardiac function. The GLP-1 receptor agonist (GLP-1RA), liraglutide, is currently used for treatment of T2DM but its potential effect on cardiac function has not been investigated in detail. We hypothesised that liraglutide added to metformin backbone therapy in patients with CAD and newly diagnosed T2DM will improve β-cell function and left ventricular systolic function during dobutamine stress. METHODS AND ANALYSES 40 patients with CAD and newly diagnosed T2DM will receive the intervention liraglutide+metformin and placebo+metformin in this investigator-initiated, double blind, randomised, placebo-controlled, cross-over 12 plus 12 weeks intervention study with a 2-week washout period. The primary cardiovascular end point is changes in left ventricular ejection fraction during stress echocardiography. The primary endocrine end point is β-cell function evaluated during a frequently sampled intravenous glucose tolerance test. Secondary end points include heart rate variability, diurnal blood pressure, glucagon suppression and inflammatory response (urine, blood and adipose tissue). ETHICS AND DISSEMINATION This study is approved by the Danish Medicines Agency, the Danish Dataprotection Agency and the Regional Committee on Biomedical Research Ethics of the Capital Region of Denmark. The trial will be carried out under the guidance from the GCP unit at Copenhagen University Hospital of Bispebjerg and in accordance with the ICH-GCP guidelines and the Helsinki Declaration. TRIAL REGISTRATIONS NUMBER Clinicaltrials.gov ID: NCT01595789, EudraCT: 2011-005405-78.
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Affiliation(s)
- Christian Anholm
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark
- Department of Internal Medicine, Copenhagen University Hospital, Amager, Denmark
| | - Preman Kumarathurai
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Malene S Klit
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Ole P Kristiansen
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Olav W Nielsen
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Steen Ladelund
- Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital, Hvidovre, Denmark
| | - Ahmad Sajadieh
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Steen B Haugaard
- Department of Internal Medicine, Copenhagen University Hospital, Amager, Denmark
- Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark
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Yang L, Yuan J, Zhou Z. Emerging roles of dipeptidyl peptidase 4 inhibitors: anti-inflammatory and immunomodulatory effect and its application in diabetes mellitus. Can J Diabetes 2014; 38:473-9. [PMID: 25034244 DOI: 10.1016/j.jcjd.2014.01.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Revised: 01/05/2014] [Accepted: 01/19/2014] [Indexed: 12/30/2022]
Abstract
Dipeptidyl peptidase 4 (DPP4) inhibitors have been widely used in the treatment of type 2 diabetes mellitus. It is well known that DPP4 inhibitors exert their antidiabetes effects mainly by inhibiting the enzymatic degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. The anti-inflammatory effect of DPP4 inhibitors was proved by preclinical and clinical studies of type 2 diabetes and coronary artery disease. Preclinical data using DPP4 inhibitors-based therapies in studies of nonobese diabetic mice demonstrated additional effects, including immunomodulation, preserving beta-cell mass, promoting beta-cell regeneration and reversing newly diagnosed diabetes. Thus, these data show that DPP4 inhibitors may be effective for type 1 diabetes mellitus. However, their potential clinical benefits for type 1 diabetes remain to be evaluated. This paper will provide an overview of the progress of the anti-inflammatory and immunomodulatory effects of DPP4 inhibitors in treating both type 1 and type 2 diabetes.
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Affiliation(s)
- Lin Yang
- Diabetes Centre, Institute of Metabolism and Endocrinology, The Second Xiangya Hospital and Key Laboratory of Diabetes Immunology, Ministry of Education, Central South University, Changsha, China
| | - Jiao Yuan
- Diabetes Centre, Institute of Metabolism and Endocrinology, The Second Xiangya Hospital and Key Laboratory of Diabetes Immunology, Ministry of Education, Central South University, Changsha, China
| | - Zhiguang Zhou
- Diabetes Centre, Institute of Metabolism and Endocrinology, The Second Xiangya Hospital and Key Laboratory of Diabetes Immunology, Ministry of Education, Central South University, Changsha, China.
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Tong J, Davis HW, Summer S, Benoit SC, Haque A, Bidlingmaier M, Tschöp MH, D'Alessio D. Acute administration of unacylated ghrelin has no effect on Basal or stimulated insulin secretion in healthy humans. Diabetes 2014; 63:2309-19. [PMID: 24550190 PMCID: PMC4066344 DOI: 10.2337/db13-1598] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Unacylated ghrelin (UAG) is the predominant ghrelin isoform in the circulation. Despite its inability to activate the classical ghrelin receptor, preclinical studies suggest that UAG may promote β-cell function. We hypothesized that UAG would oppose the effects of acylated ghrelin (AG) on insulin secretion and glucose tolerance. AG (1 µg/kg/h), UAG (4 µg/kg/h), combined AG+UAG, or saline were infused to 17 healthy subjects (9 men and 8 women) on four occasions in randomized order. Ghrelin was infused for 30 min to achieve steady-state levels and continued through a 3-h intravenous glucose tolerance test. The acute insulin response to glucose (AIRg), insulin sensitivity index (SI), disposition index (DI), and intravenous glucose tolerance (kg) were compared for each subject during the four infusions. AG infusion raised fasting glucose levels but had no effect on fasting plasma insulin. Compared with the saline control, AG and AG+UAG both decreased AIRg, but UAG alone had no effect. SI did not differ among the treatments. AG, but not UAG, reduced DI and kg and increased plasma growth hormone. UAG did not alter growth hormone, cortisol, glucagon, or free fatty acid levels. UAG selectively decreased glucose and fructose consumption compared with the other treatments. In contrast to previous reports, acute administration of UAG does not have independent effects on glucose tolerance or β-cell function and neither augments nor antagonizes the effects of AG.
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Affiliation(s)
- Jenny Tong
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, OH
| | - Harold W Davis
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, OH
| | - Suzanne Summer
- Clinical Translational Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Stephen C Benoit
- Department of Psychiatry, University of Cincinnati, Cincinnati, OH
| | - Ahrar Haque
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, OH
| | - Martin Bidlingmaier
- Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität, Munich, Germany
| | - Matthias H Tschöp
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, OHInstitute for Obesity and Diabetes, Helmholtz Center Munich and Division of Metabolic Diseases, Department of Medicine, Technical University, Munich, Germany
| | - David D'Alessio
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, OHCincinnati Veterans Affairs Medical Center, Cincinnati, OH
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Zhao Y, Yang L, Xiang Y, Liu L, Huang G, Long Z, Li X, Leslie RD, Wang X, Zhou Z. Dipeptidyl peptidase 4 inhibitor sitagliptin maintains β-cell function in patients with recent-onset latent autoimmune diabetes in adults: one year prospective study. J Clin Endocrinol Metab 2014; 99:E876-80. [PMID: 24432999 DOI: 10.1210/jc.2013-3633] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
CONTEXT Dipeptidyl peptidase 4 (DPP-4) inhibitors have been widely used in type 2 diabetes. An important unanswered question concerns the effect of DPP-4 inhibition on β-cell function in patients with autoimmune diabetes. OBJECTIVE The objective of the study was to investigate the effects of the DPP-4 inhibitor on β-cell function in patients with recent-onset latent autoimmune diabetes in adults (LADA). DESIGN AND SETTING This study was an open-label, randomized-controlled study conducted in the Department of Endocrinology at the Second Xiangya Hospital. PATIENTS AND INTERVENTION Thirty recently diagnosed LADA patients were randomized 1:1 to receive insulin therapy with 100 mg/d sitagliptin (group A, n = 15) or without sitagliptin (group B, n = 15) for 12 months. MAIN OUTCOME MEASURES Fasting and 2-hour postprandial blood samples were obtained at baseline and after 3, 6, 9, and 12 months of treatment to determine blood glucose, glycosylated hemoglobin, and C-peptide levels. RESULTS There were no differences in the clinical baseline data between the two groups. During the 12 months of follow-up, there were no significant differences in glucose and glycosylated hemoglobin levels between the two groups. At 12 months, fasting C-peptide (FCP), 2-hour postprandial C-peptide (CP), and ΔCP (ΔCP = 2 h CP-FCP) levels were not different in group A (P > .05) compared with baseline, whereas in group B the levels of FCP, 2-hour CP and ΔCP were significantly decreased compared with baseline (P < .05). Levels of 2-hour CP were higher in group A than group B at 12 months (P < .05). CONCLUSIONS LADA patients treated with sitagliptin and insulin maintained β-cell function by comparison with insulin alone.
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Affiliation(s)
- Yunjuan Zhao
- Diabetes Center (Y.Z., L.Y., Y.X., L.L., G.H., Z.L., X.L., Z.Z.), Institute of Metabolism and Endocrinology, The Second Xiangya Hospital and Key Laboratory of Diabetes Immunology, Ministry of Education, Central South University, Changsha, Hunan 410011, People's Republic of China; Department of Diabetes and Metabolic Medicine (R.D.L.), Blizard Institute, London E1 2AT, United Kingdom; and Division of Endocrinology, Metabolism, and Nutrition (X.W.), Rutgers University-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903
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Johnson JL, O'Neal KS, Pack CC, Kim MK. Management of a prediabetes case with the DPP-4 inhibitor sitagliptin. Ann Pharmacother 2014; 48:811-5. [PMID: 24676549 DOI: 10.1177/1060028014528681] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE It is important to prevent or slow the progression of prediabetes to type 2 diabetes and, therefore, reduce the risk of long-term complications. New therapeutic options will allow more patients to be effectively managed. Although theorized to be effective for prediabetes, dipeptidyl peptidase-4 (DPP-4) inhibitors have not been studied in this population. The purpose of this article is to report the results of a case in which a patient with prediabetes was treated with the DPP-4 inhibitor, sitagliptin. CASE SUMMARY A 56-year-old woman was diagnosed with prediabetes at a hemoglobin A1C (A1C) of 6.2%. After 6 months of consistent lifestyle modifications, her A1C was 6.3%, and she wanted to start a medication to prevent disease progression. Because of anticipated risk or intolerability with standard prediabetes treatments, she was started on sitagliptin 100 mg daily; 6 weeks later, she noted improvements in glucometer readings. After 18 months on sitagliptin, her A1C had improved to 5.8% without further lifestyle improvements, and by 32 months, her A1C had improved to 5.6%. Her A1C was maintained within or below the prediabetes range of 5.7% to 6.4% over 3 years of treatment with sitagliptin. DISCUSSION Although human studies with DPP-4 inhibitors are lacking, the available studies have shown improvements in β-cell function and postprandial and fasting glucose levels. Furthermore, animal studies have shown a delay in progression of prediabetes. No case reports have been found regarding DPP-4 inhibitor use in prediabetes. CONCLUSION Sitagliptin may have a role in treating prediabetes and should be further studied.
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van Genugten RE, van Raalte DH, Muskiet MH, Heymans MW, Pouwels PJW, Ouwens DM, Mari A, Diamant M. Does dipeptidyl peptidase-4 inhibition prevent the diabetogenic effects of glucocorticoids in men with the metabolic syndrome? A randomized controlled trial. Eur J Endocrinol 2014; 170:429-39. [PMID: 24297090 DOI: 10.1530/eje-13-0610] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Anti-inflammatory glucocorticoid (GC) therapy often induces hyperglycemia due to insulin resistance and islet-cell dysfunction. Incretin-based therapies may preserve glucose tolerance and pancreatic islet-cell function. In this study, we hypothesized that concomitant administration of the dipeptidyl peptidase-4 inhibitor sitagliptin and prednisolone in men at high risk to develop type 2 diabetes could protect against the GC-induced diabetogenic effects. DESIGN AND METHODS Men with the metabolic syndrome but without diabetes received prednisolone 30 mg once daily plus sitagliptin 100 mg once daily (n=14), prednisolone (n=12) or sitagliptin alone (n=14) or placebo (n=12) for 14 days in a double-blind 2 × 2 randomized-controlled study. Glucose, insulin, C-peptide, and glucagon were measured in the fasted state and following a standardized mixed-meal test. β-cell function parameters were assessed both from a hyperglycemic-arginine clamp procedure and from the meal test. Insulin sensitivity (M-value) was measured by euglycemic clamp. RESULTS Prednisolone increased postprandial area under the curve (AUC)-glucose by 17% (P<0.001 vs placebo) and postprandial AUC-glucagon by 50% (P<0.001). Prednisolone reduced 1st and 2nd phase glucose-stimulated- and combined hyperglycemia-arginine-stimulated C-peptide secretion (all P ≤ 0.001). When sitagliptin was added, both clamp-measured β-cell function (P=NS for 1st and 2nd phase vs placebo) and postprandial hyperglucagonemia (P=NS vs placebo) remained unaffected. However, administration of sitagliptin could not prevent prednisolone-induced increment in postprandial glucose concentrations (P<0.001 vs placebo). M-value was not altered by any treatment. CONCLUSION Fourteen-day treatment with high-dose prednisolone impaired postprandial glucose metabolism in subjects with the metabolic syndrome. Concomitant treatment with sitagliptin improved various aspects of pancreatic islet-cell function, but did not prevent deterioration of glucose tolerance by GC treatment.
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Moore MC, Werner U, Smith MS, Farmer TD, Cherrington AD. Effect of the glucagon-like peptide-1 receptor agonist lixisenatide on postprandial hepatic glucose metabolism in the conscious dog. Am J Physiol Endocrinol Metab 2013; 305:E1473-82. [PMID: 24148347 PMCID: PMC3882379 DOI: 10.1152/ajpendo.00354.2013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The impact of the GLP-1 receptor agonist lixisenatide on postprandial glucose disposition was examined in conscious dogs to identify mechanisms for its improvement of meal tolerance in humans and examine the tissue disposition of meal-derived carbohydrate. Catheterization for measurement of hepatic balance occurred ≈16 days before study. After being fasted overnight, dogs received a subcutaneous injection of 1.5 μg/kg lixisenatide or vehicle (saline, control; n = 6/group). Thirty minutes later, they received an oral meal feeding (93.4 kJ; 19% protein, 71% glucose polymers, and 10% lipid). Acetaminophen was included in the meal in four control and five lixisenatide dogs for assessment of gastric emptying. Observations continued for 510 min; absorption was incomplete in lixisenatide at that point. The plasma acetaminophen area under the curve (AUC) in lixisenatide was 65% of that in control (P < 0.05). Absorption of the meal began within 15 min in control but was delayed until ≈30-45 min in lixisenatide. Lixisenatide reduced (P < 0.05) the postprandial arterial glucose AUC ≈54% and insulin AUC ≈44%. Net hepatic glucose uptake did not differ significantly between groups. Nonhepatic glucose uptake tended to be reduced by lixisenatide (6,151 ± 4,321 and 10,541 ± 1,854 μmol·kg(-1)·510 min(-1) in lixisenatide and control, respectively; P = 0.09), but adjusted (for glucose and insulin concentrations) values did not differ (18.9 ± 3.8 and 19.6 ± 7.9 l·kg(-1)·pmol(-1)·l(-1), lixisenatide and control, respectively; P = 0.94). Thus, lixisenatide delays gastric emptying, allowing more efficient disposal of the carbohydrate in the feeding without increasing liver glucose disposal. Lixisenatide could prove to be a valuable adjunct in treatment of postprandial hyperglycemia in impaired glucose tolerance or type 2 diabetes.
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Affiliation(s)
- Mary Courtney Moore
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, and
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Zeng Z, Yang JK, Tong N, Yan S, Zhang X, Gong Y, Woerle HJ. Efficacy and safety of linagliptin added to metformin and sulphonylurea in Chinese patients with type 2 diabetes: a sub-analysis of data from a randomised clinical trial. Curr Med Res Opin 2013; 29:921-929. [PMID: 23672632 DOI: 10.1185/03007995.2013.805123] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVES To evaluate the efficacy and safety of linagliptin in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin and sulphonylurea. RESEARCH DESIGN AND METHODS Data for a pre-defined Chinese subgroup who participated in a Phase III randomised, placebo-controlled, 24 week trial (NCT00602472) were analysed. The primary endpoint was change in HbA1c from baseline to 24 weeks. Apart from safety endpoints, secondary endpoints included changes in FPG and measures of insulin secretion and resistance. RESULTS A total of 192 Chinese patients with T2DM participated in the pre-defined analysis; 144 and 48 patients received linagliptin or placebo, respectively, added to metformin and sulphonylurea. Baseline characteristics (mean [±SD]) for linagliptin and placebo were similar: HbA1c: 8.1% (±0.85) and 8.1% (±0.84); body mass index: 25.9 (±3.2) and 25.6 (±3.4) kg/m², respectively. Placebo-corrected mean (±SE) change in HbA1c from baseline at 24 weeks was -0.68% (0.14) with linagliptin-based treatment (95% CI: -0.96 to -0.39; P<0.0001). Placebo-corrected mean (±SE) change in FPG from baseline at 24 weeks with linagliptin was -18.8 (6.5) mg/dL (-1.0 [0.4] mmol/L; 95% CI: -31.7 to -5.9; P=0.0044). Overall adverse event (AE) rates with linagliptin and placebo including background medication were similar (38.9% and 43.8%, respectively). Drug-related AEs were reported by 12.5% and 2.1% of linagliptin and placebo patients, respectively. Differences were due to hypoglycaemia (10.4% and 0.0%, respectively). No severe hypoglycaemia was reported in either group of this sub-population. CONCLUSION Linagliptin in combination with metformin and sulphonylurea has a favourable safety profile and is an efficacious and well tolerated treatment option for Chinese patients with inadequately controlled T2DM. Reduction of sulphonylurea dose should be considered to minimise risk of hypoglycaemia. Although the findings of this pre-specified sub-analysis may be limited by the number of patients in the subgroup, the results were generally consistent with those for the overall population. CLINICALTRIALS IDENTIFIER: NCT00602472.
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Affiliation(s)
- Zhengpei Zeng
- Peking Union Medical College Hospital, Beijing, China
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