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Apostolopoulou M, Lambadiari V, Roden M, Dimitriadis GD. Insulin Resistance in Type 1 Diabetes: Pathophysiological, Clinical, and Therapeutic Relevance. Endocr Rev 2025; 46:317-348. [PMID: 39998445 PMCID: PMC12063105 DOI: 10.1210/endrev/bnae032] [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: 06/23/2024] [Indexed: 02/26/2025]
Abstract
People with type 1 diabetes (T1D) are usually considered to exclusively exhibit β-cell failure, but they frequently also feature insulin resistance. This review discusses the mechanisms, clinical features, and therapeutic relevance of insulin resistance by focusing mainly on human studies using gold-standard techniques (euglycemic-hyperinsulinemic clamp). In T1D, tissue-specific insulin resistance can develop early and sustain throughout disease progression. The underlying pathophysiology is complex, involving both metabolic- and autoimmune-related factors operating synergistically. Insulin treatment may play an important pathogenic role in predisposing individuals with T1D to insulin resistance. However, the established lifestyle-related risk factors and peripheral insulin administration inducing glucolipotoxicity, hyperinsulinemia, hyperglucagonemia, inflammation, mitochondrial abnormalities, and oxidative stress cannot always fully explain insulin resistance in T1D, suggesting a phenotype distinct from type 2 diabetes. The mutual interaction between insulin resistance and impaired endothelial function further contributes to diabetes-related complications. Insulin resistance should therefore be considered a treatment target in T1D. Aside from lifestyle modifications, continuous subcutaneous insulin infusion can ameliorate insulin resistance and hyperinsulinemia, thereby improving glucose toxicity compared with multiple injection insulin treatment. Among other concepts, metformin, pioglitazone, incretin-based drugs such as GLP-1 receptor agonists, sodium-glucose cotransporter inhibitors, and pramlintide can improve insulin resistance, either directly or indirectly. However, considering the current issues of high cost, side effects, limited efficacy, and their off-label status, these agents in people with T1D are not widely used in routine clinical care at present.
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Affiliation(s)
- Maria Apostolopoulou
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibnitz Center for Diabetes Research at Heinrich-Heine University, 40225 Düsseldorf, Germany
- German Center of Diabetes Research (DZD), Partner Düsseldorf, 85764 München-Neuherberg, Germany
| | - Vaia Lambadiari
- 2nd Department of Internal Medicine, Research Institute and Diabetes Center, National and Kapodistrian University of Athens Medical School, 12462 Athens, Greece
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibnitz Center for Diabetes Research at Heinrich-Heine University, 40225 Düsseldorf, Germany
- German Center of Diabetes Research (DZD), Partner Düsseldorf, 85764 München-Neuherberg, Germany
| | - George D Dimitriadis
- 2nd Department of Internal Medicine, Research Institute and Diabetes Center, National and Kapodistrian University of Athens Medical School, 12462 Athens, Greece
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Ji XL, Yin M, Deng C, Fan L, Xie YT, Huang FS, Chen Y, Li X. Hemoglobin glycation index among adults with type 1 diabetes: Association with double diabetes features. World J Diabetes 2025; 16:100917. [PMID: 40236850 PMCID: PMC11947909 DOI: 10.4239/wjd.v16.i4.100917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 12/24/2024] [Accepted: 01/16/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND The hemoglobin glycation index (HGI) represents the discrepancy between the glucose management indicator (GMI) based on mean blood glucose levels and laboratory values of glycated hemoglobin (HbA1c). The HGI is a promising indicator for identifying individuals with excessive glycosylation, facilitating personalized evaluation and prediction of diabetic complications. However, the factors influencing the HGI in patients with type 1 diabetes (T1D) remain unclear. Autoimmune destruction of pancreatic β cells is central in T1D pathogenesis, yet insulin resistance can also be a feature of patients with T1D and their coexistence is called "double diabetes" (DD). However, knowledge regarding the relationship between DD features and the HGI in T1D is limited. AIM To assess the association between the HGI and DD features in adults with T1D. METHODS A total of 83 patients with T1D were recruited for this cross-sectional study. Laboratory HbA1c and GMI from continuous glucose monitoring data were collected to calculate the HGI. DD features included a family history of type 2 diabetes, overweight/obesity/central adiposity, hypertension, atherogenic dyslipidemia, an abnormal percentage of body fat (PBF) and/or visceral fat area (VFA) and decreased estimated insulin sensitivity. Skin autofluorescence of advanced glycation end products (SAF-AGEs), diabetic complications, and DD features were assessed, and their association with the HGI was analyzed. RESULTS A discrepancy was observed between HbA1c and GMI among patients with T1D and DD. A higher HGI was associated with an increased number of SAF-AGEs and a higher prevalence of diabetic microangiopathy (P = 0.030), particularly retinopathy (P = 0.031). Patients with three or more DD features exhibited an eight-fold increased risk of having a high HGI, compared with those without DD features (adjusted odds ratio = 8.12; 95% confidence interval: 1.52-43.47). Specifically, an elevated PBF and/or VFA and decreased estimated insulin sensitivity were associated with high HGI. Regression analysis identified estimated insulin sensitivity and VFA as factors independently associated with HGI. CONCLUSION In patients with T1D, DD features are associated with a higher HGI, which represents a trend toward excessive glycosylation and is associated with a higher prevalence of chronic diabetic complications.
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Affiliation(s)
- Xiao-Lin Ji
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
- Department of Endocrinology, The First Affiliated Hospital, Southwest Hospital, Army Medical University, Chongqing 400038, China
| | - Min Yin
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
- Department of Nutrition, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Chao Deng
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Li Fan
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Yu-Ting Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Fan-Su Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
- Department of Nutrition, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Yan Chen
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
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Madhu SV, Raizada N. Double Trouble. Indian J Endocrinol Metab 2023; 27:189-191. [PMID: 37583408 PMCID: PMC10424108 DOI: 10.4103/2230-8210.379597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/17/2023] Open
Affiliation(s)
- S V Madhu
- Department of Endocrinology, Center for Diabetes Endocrinology and Metabolism, University College of Medical Sciences and Guru Teg Bahadur Hospital, New Delhi, India
| | - Nishant Raizada
- Department of Endocrinology, Center for Diabetes Endocrinology and Metabolism, University College of Medical Sciences and Guru Teg Bahadur Hospital, New Delhi, India
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Bloomgarden Z, Schatz D. Small steps forward: Adjunctive therapy for T1D. J Diabetes 2022; 14:642-645. [PMID: 36205524 PMCID: PMC9574725 DOI: 10.1111/1753-0407.13326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/21/2022] [Indexed: 11/30/2022] Open
Affiliation(s)
- Zachary Bloomgarden
- Department of Medicine, Division of Endocrinology, Diabetes and Bone DiseaseIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Desmond Schatz
- Diabetes Institute, University of Florida College of MedicineGainesvilleFloridaUSA
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Guo K, Zhang L, Ye J, Niu X, Jiang H, Gan S, Zhou J, Yang L, Zhou Z. Metabolic syndrome associated with higher glycemic variability in type 1 diabetes: A multicenter cross-sectional study in china. Front Endocrinol (Lausanne) 2022; 13:972785. [PMID: 36204109 PMCID: PMC9530192 DOI: 10.3389/fendo.2022.972785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 09/05/2022] [Indexed: 11/30/2022] Open
Abstract
AIMS The comorbidity of metabolic syndrome (MetS) and type 1 diabetes mellitus (T1DM) is an obstacle to glucose control in patients with T1DM. We compared glycemic profiles using continuous glucose monitoring (CGM) systems in patients with T1DM with or without MetS. METHODS This was a multicenter cross-sectional study of patients with T1DM (N = 207) with or without MetS. CGM data were collected from study enrollment until discharge during a 1-week study session. We analyzed baseline HbA1c, average glucose, estimated HbA1c, time in range (TIR), time above range (TAR), time below range (TBR), coefficient of variation (CV), postprandial glucose excursions (PPGE) and other glycemic variability (GV) metrics. Logistic regression was developed to investigate the association between MetS and CGM metrics. RESULTS The results showed higher average baseline HbA1c levels, and a higher percentage of patients with baseline HbA1c levels ≥7.5%, in the T1DM with MetS group. Furthermore, MetS was associated with GV, which indicated a higher CV in patients with T1DM with MetS. However, our results showed that TAR, TIR, TBR and other GV metrics were comparable between the two groups. The T1DM with MetS group also had a higher proportion of patients with high CV (≥ 36%) than the group without MetS. In multivariable logistic regression analysis, the presence of MetS was a risk factor for high CV (≥ 36%) in our study participants. CONCLUSIONS T1DM patients with MetS in our study had better β-cell function. However, MetS was associated with worse glycemic control characterized by higher GV and HbA1c levels. Efforts should be expanded to improve treatment of MetS in patients with T1DM to achieve better glycemic control.
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Affiliation(s)
- Keyu Guo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Liyin Zhang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jianan Ye
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiaohong Niu
- Department of Endocrinology, Heji Hospital Affiliated to Changzhi Medical College, Changzhi, China
| | - Hongwei Jiang
- Department of Endocrinology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Shenglian Gan
- Department of Endocrinology, The First People’s Hospital of Changde City, Changde, Hunan, China
| | - Jian Zhou
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Lin Yang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
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Aberer F, Pieber TR, Eckstein ML, Sourij H, Moser O. Glucose-Lowering Therapy beyond Insulin in Type 1 Diabetes: A Narrative Review on Existing Evidence from Randomized Controlled Trials and Clinical Perspective. Pharmaceutics 2022; 14:1180. [PMID: 35745754 PMCID: PMC9229408 DOI: 10.3390/pharmaceutics14061180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/18/2022] [Accepted: 05/30/2022] [Indexed: 12/10/2022] Open
Abstract
Background: In Type 1 diabetes (T1D), according to the most recent guidelines, the everyday glucose-lowering treatment is still restricted to the use of subcutaneous insulin, while multiple therapeutic options exist for Type 2 diabetes (T2D). Methods: For this narrative review we unsystematically screened PubMed and Embase to identify clinical trials which investigated glucose-lowering agents as an adjunct to insulin treatment in people with T1D. Published studies up to March 2022 were included. We discuss the safety and efficacy in modifying cardiovascular risk factors for each drug, the current status of research, and provide a clinical perspective. Results: For several adjunct agents, in T1D, the scientific evidence demonstrates improvements in HbA1c, reductions in the risk of hypoglycemia, and achievements of lower insulin requirements, as well as positive effects on cardiovascular risk factors, such as blood lipids, blood pressure, and weight. As the prevalence of obesity, the major driver for double diabetes, is rising, weight and cardiovascular risk factor management is becoming increasingly important in people with T1D. Conclusions: Adjunct glucose-lowering agents, intended to be used in T2D, bear the potential to beneficially impact on cardiovascular risk factors when investigated in the T1D population and are suggested to be more extensively considered as potentially disease-modifying drugs in the future and should be investigated for hard cardiovascular endpoints.
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Affiliation(s)
- Felix Aberer
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria; (F.A.); (T.R.P.); (O.M.)
- Division of Exercise Physiology and Metabolism, Institute of Sport Science, University of Bayreuth, 95447 Bayreuth, Germany;
| | - Thomas R. Pieber
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria; (F.A.); (T.R.P.); (O.M.)
| | - Max L. Eckstein
- Division of Exercise Physiology and Metabolism, Institute of Sport Science, University of Bayreuth, 95447 Bayreuth, Germany;
| | - Harald Sourij
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria; (F.A.); (T.R.P.); (O.M.)
| | - Othmar Moser
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria; (F.A.); (T.R.P.); (O.M.)
- Division of Exercise Physiology and Metabolism, Institute of Sport Science, University of Bayreuth, 95447 Bayreuth, Germany;
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Abstract
The growing proportion of type 1 diabetes mellitus (T1DM) patients with clinical features of insulin resistance (IR) has led to the description of a distinctive T1DM subgroup, still unrecognised by current guidelines, called double diabetes, assumingly associated with poorer metabolic phenotype and increased risk of micro- and macrovascular complications. The main goal of identifying double diabetes, estimated to be present in up to half of T1DM patients, is timely implementation of appropriate therapeutic interventions to reduce the increased risk of chronic complications and other adverse metabolic traits associated with this condition. Proposed diagnostic criteria are largely divided into three different groups: family history of type 2 diabetes mellitus (T2DM), obesity/metabolic syndrome, and IR. Estimated glucose disposal rate may prove the most reliable marker of double diabetes. In addition to general measures (diet, physical activity, antihypertensive, and lipid-lowering medications, etc.) and development of new insulin preparations with more hepatic action, double diabetes patients may derive more benefit from agents developed for T2DM. Indeed, such potentially promising agents include glucagon-like peptide-1 receptor agonists, sodium-glucose contrasporter-2 inhibitors, and their combination. We are now awaiting long-term trials assessing metabolic and vascular benefits of these medications in double diabetes.
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Affiliation(s)
- Djordje S Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Center of Vojvodina, Novi Sad, SERBIA
- Medical Faculty, University of Novi Sad, Novi Sad, SERBIA
| | - Nikolaos Papanas
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, GREECE
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Chang RC, Thangavelu CS, Joloya EM, Kuo A, Li Z, Blumberg B. Cannabidiol Promotes Adipogenesis of Human and Mouse Mesenchymal Stem Cells via PPARγ by Inducing Lipogenesis but Not Lipolysis. Biochem Pharmacol 2022; 197:114910. [DOI: 10.1016/j.bcp.2022.114910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 01/04/2022] [Accepted: 01/04/2022] [Indexed: 11/02/2022]
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Lin C, Cai X, Yang W, Lv F, Nie L, Ji L. Age, sex, disease severity, and disease duration difference in placebo response: implications from a meta-analysis of diabetes mellitus. BMC Med 2020; 18:322. [PMID: 33190640 PMCID: PMC7667845 DOI: 10.1186/s12916-020-01787-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 09/17/2020] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND The placebo response in patients with diabetes mellitus is very common. A systematic evaluation needs to be updated with the current evidence about the placebo response in diabetes mellitus and the associated factors in clinical trials of anti-diabetic medicine. METHODS Literature research was conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies published between the date of inception and June 2019. Randomized placebo-controlled trials conducted in type 1and type 2 diabetes mellitus (T1DM/T2DM) were included. Random-effects model and meta-regression analysis were accordingly used. This meta-analysis was registered in PROSPERO as CRD42014009373. RESULTS Significantly weight elevation (effect size (ES) = 0.33 kg, 95% CI, 0.03 to 0.61 kg) was observed in patients with placebo treatments in T1DM subgroup while significantly HbA1c reduction (ES = - 0.12%, 95% CI, - 0.16 to - 0.07%) and weight reduction (ES = - 0.40 kg, 95% CI, - 0.50 to - 0.29 kg) were observed in patients with placebo treatments in T2DM subgroup. Greater HbA1c reduction was observed in patients with injectable placebo treatments (ES = - 0.22%, 95% CI, - 0.32 to - 0.11%) versus oral types (ES = - 0.09%, 95% CI, - 0.14 to - 0.04%) in T2DM (P = 0.03). Older age (β = - 0.01, 95% CI, - 0.02 to - 0.01, P < 0.01) and longer diabetes duration (β = - 0.02, 95% CI, - 0.03 to - 0.21 × 10-2, P = 0.03) was significantly associated with more HbA1c reduction by placebo in T1DM. However, younger age (β = 0.02, 95% CI, 0.01 to 0.03, P = 0.01), lower male percentage (β = 0.01, 95% CI, 0.22 × 10-2, 0.01, P < 0.01), higher baseline BMI (β = - 0.02, 95% CI, - 0.04 to - 0.26 × 10-2, P = 0.02), and higher baseline HbA1c (β = - 0.09, 95% CI, - 0.16 to - 0.01, P = 0.02) were significantly associated with more HbA1c reduction by placebo in T2DM. Shorter diabetes duration (β = 0.06, 95% CI, 0.06 to 0.10, P < 0.01) was significantly associated with more weight reduction by placebo in T2DM. However, the associations between baseline BMI, baseline HbA1c, and placebo response were insignificant after the adjusted analyses. CONCLUSION The placebo response in diabetes mellitus was systematically outlined. Age, sex, disease severity (indirectly reflected by baseline BMI and baseline HbA1c), and disease duration were associated with placebo response in diabetes mellitus. The association between baseline BMI, baseline HbA1c, and placebo response may be the result of regression to the mean.
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Affiliation(s)
- Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Lin Nie
- Department of Endocrinology and Metabolism, Beijing Airport Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
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Karras SN, Koufakis T, Zebekakis P, Kotsa K. Pharmacologic adjunctive to insulin therapies in type 1 diabetes: The journey has just begun. World J Diabetes 2019; 10:234-240. [PMID: 31040899 PMCID: PMC6475707 DOI: 10.4239/wjd.v10.i4.234] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 03/13/2019] [Accepted: 03/28/2019] [Indexed: 02/05/2023] Open
Abstract
Treatment of type 1 diabetes (T1D) is currently based exclusively on insulin replacement therapy. However, there is a need for better glycemic control, lower hypoglycemia rates, more effective weight management, and further reduction of cardiovascular risk in people with T1D. In this context, agents from the pharmaceutical quiver of type 2 diabetes are being tested in clinical trials, as adjunctive to insulin therapies for T1D patients. Despite the limited amount of relevant evidence and the inter-class variability, it can be said that these agents have a role in optimizing metabolic control, assisting weight management and reducing glycemic variability in people with T1D. Specific safety issues, including the increased risk of hypoglycemia and diabetic ketoacidosis, as well as the effects of these treatments on major cardiovascular outcomes should be further assessed by future studies, before these therapeutic choices become widely available for T1D management.
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Affiliation(s)
- Spyridon N Karras
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 55535, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 55535, Greece
| | - Pantelis Zebekakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 55535, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 55535, Greece
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Gutierres VO, Assis RP, Arcaro CA, Oliveira JO, Lima TFO, Beretta ALRZ, Costa PI, Baviera AM, Brunetti IL. Curcumin improves the effect of a reduced insulin dose on glycemic control and oxidative stress in streptozotocin-diabetic rats. Phytother Res 2019; 33:976-988. [PMID: 30656757 DOI: 10.1002/ptr.6291] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 12/20/2018] [Accepted: 12/24/2018] [Indexed: 12/14/2022]
Abstract
Insulin with natural antioxidants is emerging as a combination treatment for diabetes mellitus that attempts to exert effective glycemic control without adverse effects. The present study aimed to investigate the additive effects on metabolic disturbances, oxidative damage, and antioxidant defenses in streptozotocin-diabetic rats treated with curcumin and a reduced insulin dose. The best results were obtained in the treatment of diabetic rats with 4-U/day insulin; however, the glycemia levels in these rats were lower than those in normal rats, indicating a risk of hypoglycemia. Isolated treatments using curcumin or insulin in a reduced dose (1 U/day) decreased glycemia, dyslipidemia, and biomarkers of liver and kidney damage and increased the activity of hepatic antioxidants (superoxide dismutase and glutathione peroxidase), however, only to a lesser extent than 4-U/day insulin, without improvements in catalase activity or plasma lipid peroxidation. Decreases in glycemia, dyslipidemia, and tissue damage markers were more evident in the curcumin + 1-U/day insulin treatment than those seen in isolated treatments. The activity of hepatic antioxidants, including catalase, was further increased, and biomarkers of oxidative damage were decreased. Curcumin with a reduced insulin dose appears to be a promising strategy for combating the complications associated with diabetes and oxidative stress.
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Affiliation(s)
- Vânia Ortega Gutierres
- São Paulo State University (Unesp), School of Pharmaceutical Sciences, Department of Clinical Analysis, Araraquara, São Paulo, Brazil.,Graduate Program in Biomedical Sciences Hermínio Ometto University Center, UNIARARAS, 7 Av. Dr. Maximiliano Baruto, 500, CEP 13607-339, Araras, SP
| | - Renata Pires Assis
- São Paulo State University (Unesp), School of Pharmaceutical Sciences, Department of Clinical Analysis, Araraquara, São Paulo, Brazil
| | - Carlos Alberto Arcaro
- São Paulo State University (Unesp), School of Pharmaceutical Sciences, Department of Clinical Analysis, Araraquara, São Paulo, Brazil
| | - Juliana Oriel Oliveira
- São Paulo State University (Unesp), School of Pharmaceutical Sciences, Department of Clinical Analysis, Araraquara, São Paulo, Brazil
| | - Tayra Ferreira Oliveira Lima
- São Paulo State University (Unesp), School of Pharmaceutical Sciences, Department of Clinical Analysis, Araraquara, São Paulo, Brazil
| | - Ana Laura Remédio Zeni Beretta
- Graduate Program in Biomedical Sciences Hermínio Ometto University Center, UNIARARAS, 7 Av. Dr. Maximiliano Baruto, 500, CEP 13607-339, Araras, SP
| | - Paulo Inácio Costa
- São Paulo State University (Unesp), School of Pharmaceutical Sciences, Department of Clinical Analysis, Araraquara, São Paulo, Brazil
| | - Amanda Martins Baviera
- São Paulo State University (Unesp), School of Pharmaceutical Sciences, Department of Clinical Analysis, Araraquara, São Paulo, Brazil
| | - Iguatemy Lourenço Brunetti
- São Paulo State University (Unesp), School of Pharmaceutical Sciences, Department of Clinical Analysis, Araraquara, São Paulo, Brazil
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Isaacs D, Yager S, Parker M, Wolfe L, Luxenburg J, Lekic S. Adjunct Antihyperglycemic Agents in Overweight and Obese Adults With Type 1 Diabetes. Ann Pharmacother 2018; 53:371-384. [PMID: 30499305 DOI: 10.1177/1060028018816728] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE People with type 1 diabetes often have suboptimal glycemic control. The gold standard of treatment is basal-bolus insulin or subcutaneous insulin infusion via insulin pump. Although insulin therapy improves glycemic control, weight gain and hypoglycemia often limit achievement of hemoglobin A1C (A1C) goals. The number of people with type 1 diabetes who are overweight or obese is increasing, and there are many similarities between what was historically called type 1 and type 2 diabetes. Therefore, there is rationale for using antihyperglycemic agents that target other pathophysiological abnormalities to facilitate weight loss and improve glycemic control. DATA SOURCES We performed a MEDLINE search from 1975 through October 2018 to identify articles that studied noninsulin agents in adults with type 1 diabetes and body mass index (BMI) ≥25 kg/m2. STUDY SELECTION AND DATA EXTRACTION Identified articles were included if the study duration was ≥4 weeks, included ≥20 patients, and set mean baseline BMI ⩾25kg/m2. DATA SYNTHESIS This review summarizes 32 clinical trials. Amylin mimetics, sodium-glucose-like transporter-2 inhibitors, and glucagon-like-peptide-1 receptor agonists demonstrate the greatest improvements in body weight and A1C. The most common adverse effects are hypoglycemia and ketosis. Relevance to Patient Care and Clinical Practice: Patients with type 1 diabetes may have interest in starting noninsulin agents. Clinicians need to be knowledgeable in the efficacy and adverse effect profile of these agents, specifically in people with type 1 diabetes. CONCLUSIONS Adding noninsulin antihyperglycemic agents may benefit select overweight or obese adults with type 1 diabetes. These agents are off-label, and if used, close monitoring is essential.
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Affiliation(s)
- Diana Isaacs
- 1 Cleveland Clinic Diabetes Center, Cleveland, OH, USA
| | - Stephanie Yager
- 2 The Ohio State University Wexner Medical Center, Columbus, OH, USA
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Frandsen CS, Dejgaard TF, Madsbad S, Holst JJ. Non-insulin pharmacological therapies for treating type 1 diabetes. Expert Opin Pharmacother 2018; 19:947-960. [PMID: 29991320 DOI: 10.1080/14656566.2018.1483339] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Despite intensified insulin treatment, many persons with type 1 diabetes (T1D) do not achieve glycemic and metabolic targets. Consequently, non-insulin chemical therapies that improve glycemic control and metabolic parameters without increasing the risk of adverse events (including hypoglycemia) are of interest as adjunct therapies to insulin. AREAS COVERED In this review, the authors discuss the efficacy and safety of non-insulin therapies, including pramlintide, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 inhibitors (DPP-4), sodium-glucose cotransporter (SGLT1 and SGLT2) inhibitors, metformin, sulfonylureas, and thiazolidinediones as add-on therapies to insulin in T1D. EXPERT OPINION The current evidence shows that the efficacy of non-insulin therapies as add-on therapies to insulin is minimal or modest with an average HbA1c reduction of 0.2-0.5% (2-6 mmol/mol). Indeed, the current focus is on the development of SGLT inhibitors as adjuncts to insulin in type 1 diabetes. Studies of subgroups with obesity, residual beta-cell function (including newly diagnosed patients) and patients prone to hypoglycemia could be areas of future research.
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Affiliation(s)
| | - Thomas Fremming Dejgaard
- a Department of Endocrinology , Hvidovre Hospital, University of Copenhagen , Hvidovre , Denmark.,b Steno Diabetes Center Copenhagen , Gentofte , Denmark
| | - Sten Madsbad
- a Department of Endocrinology , Hvidovre Hospital, University of Copenhagen , Hvidovre , Denmark
| | - Jens Juul Holst
- c Department of Biomedical Sciences and NNF Center for Basic Metabolic Research , University of Copenhagen , Copenhagen , Denmark
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Abstract
PURPOSE OF REVIEW Insulin therapy alone fails to achieve target glycemic control in the majority of individuals with type 1 diabetes (T1D), motivating the investigation of additive medications. This review focuses on the recent findings on the use of adjunctive pharmacotherapy in T1D. RECENT FINDINGS Metformin and glucagon-like peptide-1 receptor agonists have been associated with weight reduction and decrease in daily insulin requirements without sustainable improvement in glycemic control. Sodium-glucose cotransporter (SGLT)-2 inhibitors, dual SGLT-1/2 inhibitors, and pramlintide have been shown to reduce hemoglobin A1c, induce weight loss, and lower insulin dose. The benefits of dipeptidyl peptidase-4 inhibitors, thiazolidinediones, and alpha glucosidase inhibitors appear to be more limited. Gastrointestinal symptoms and increased hypoglycemia are adverse effects of certain classes. Although not devoid of side effects, additive pharmacotherapies in T1D can improve glycemic control and lower body weight and insulin requirement. Longer studies are needed before consideration for widespread clinical care.
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Affiliation(s)
- Mustafa Tosur
- Section of Diabetes and Endocrinology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, 6701 Fannin St, Suite 10.20, Houston, TX, 77030, USA.
| | - Maria J Redondo
- Section of Diabetes and Endocrinology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, 6701 Fannin St, Suite 10.20, Houston, TX, 77030, USA
| | - Sarah K Lyons
- Section of Diabetes and Endocrinology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, 6701 Fannin St, Suite 10.20, Houston, TX, 77030, USA
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Han JH, Tuan NQ, Park MH, Quan KT, Oh J, Heo KS, Na M, Myung CS. Cucurbitane Triterpenoids from the Fruits of Momordica Charantia
Improve Insulin Sensitivity and Glucose Homeostasis in Streptozotocin-Induced Diabetic Mice. Mol Nutr Food Res 2018; 62:e1700769. [DOI: 10.1002/mnfr.201700769] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 12/31/2017] [Indexed: 12/16/2022]
Affiliation(s)
- Joo-Hui Han
- Department of Pharmacology; Chungnam National University College of Pharmacy; Daejeon Republic of Korea
| | - Nguyen Quoc Tuan
- Department of Pharmacognosy; Chungnam National University College of Pharmacy; Daejeon Republic of Korea
| | - Min-Ho Park
- Chungnam National University College of Pharmacy; Daejeon Republic of Korea
| | - Khong Trong Quan
- Department of Pharmacognosy; Chungnam National University College of Pharmacy; Daejeon Republic of Korea
| | - Joonseok Oh
- Department of Chemistry; Yale University; New Haven CT USA
| | - Kyung-Sun Heo
- Department of Pharmacology; Chungnam National University College of Pharmacy; Daejeon Republic of Korea
| | - MinKyun Na
- Department of Pharmacognosy; Chungnam National University College of Pharmacy; Daejeon Republic of Korea
| | - Chang-Seon Myung
- Department of Pharmacology; Chungnam National University College of Pharmacy; Daejeon Republic of Korea
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Ou HT, Lee TY, Du YF, Li CY. Comparative risks of diabetes-related complications of basal insulins: a longitudinal population-based cohort of type 1 diabetes 1999-2013 in Taiwan. Br J Clin Pharmacol 2017; 84:379-391. [PMID: 29073329 DOI: 10.1111/bcp.13461] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 10/11/2017] [Accepted: 10/15/2017] [Indexed: 12/31/2022] Open
Abstract
AIM We compared the effects of two types of basal insulin: long-acting insulin analogues vs. intermediate/long-acting human insulin, on diabetes-related complications in type 1 diabetes. METHODS A total of 1188 patients with type 1 diabetes who had recently started on long-acting insulin analogues or intermediate/long-acting human insulin were identified in 2004-2008 and followed until death or the end of 2013. Clinical outcomes included acute (i.e. hyperglycaemia, hypoglycaemia) and chronic (i.e. nephropathy, retinopathy, neuropathy, cardiovascular diseases) complications. Diabetes-related complications were measured as a composite outcome which included acute and chronic complications. Cox proportional hazards models were used to assess the time to event hazard ratio. Three propensity score (PS) methods were applied to adjust for baseline imbalances between basal insulin groups, including the PS-matching approach (as the main analysis), standardized mortality ratio weighting (SMRW) and inverse probability of treatment weighting (IPTW). RESULTS Long-acting insulin analogues vs. intermediate/long-acting human insulin had a lower risk for a composite of diabetes-related complications {adjusted hazards ratios [aHRs] [95% confidence interval (CI)] 0.782 [0.639, 0.956], 0.743 [0.598, 0.924] and 0.699 [0.577, 0.846] according to the PS-matching approach, SMRW and IPTW, respectively}. Compared with intermediate/long-acting human insulin, using long-acting insulin analogues had a lower hypoglycaemia risk: aHRs (95% CI) 0.681 (0.498, 0.930), 0.662 (0.466, 0.943) and 0.639 (0.471, 0.867) from the PS-matching approach, SMRW and IPTW, respectively. No statistical differences were found between two types of insulin on individual chronic complications. CONCLUSION A trend of lower diabetes-related complications associated with long-acting insulin analogues vs. intermediate/long-acting human insulin was observed. A reduced hypoglycaemia risk with long-acting insulin analogues was confirmed in this 'real-world' study.
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Affiliation(s)
- Huang-Tz Ou
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Pharmacy, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Tsung-Ying Lee
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ye-Fong Du
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Chung-Yi Li
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Public Health, China Medical University, Taichung, Taiwan
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17
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Ou HT, Lee TY, Li CY, Wu JS, Sun ZJ. Incidence of diabetes-related complications in Chinese patients with type 1 diabetes: a population-based longitudinal cohort study in Taiwan. BMJ Open 2017; 7:e015117. [PMID: 28637729 PMCID: PMC5791549 DOI: 10.1136/bmjopen-2016-015117] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
OBJECTIVE To estimate the incidence densities and cumulative incidence of diabetes-related complications in patients with type 1 diabetes for a maximum of 15-year follow-up. The estimations were further stratified by gender and age at diagnosis (ie, early onset: 0-12 years, late onset:≥13 years). DESIGN A population-based retrospective longitudinal cohort study. SETTING Taiwan's National Health Insurance medical claims. PARTICIPANTS 4007 patients newly diagnosed with type 1 diabetes were identified during 1999-2012. OUTCOME MEASURES Acute complications included diabetic ketoacidosis (DKA) and hypoglycaemia. Chronic complications were cardiovascular diseases (CVD), retinopathy, neuropathy and nephropathy. RESULTS The incidence density of retinopathy was greatest (97.74 per 1000 person-years), followed by those of nephropathy (31.36), neuropathy (23.93) and CVD (4.39). Among acute complications, the incidence density of DKA was greatest (121.11 per 1000 person-years). The cumulative incidences of acute complications after 12 years following diagnosis were estimated to be 52.1%, 36.1% and 4.1% for DKA, outpatient hypoglycaemia and hospitalised hypoglycaemia, respectively. For chronic complications, the cumulative incidence of retinopathy after 12 years following diagnosis was greatest (65.2%), followed by those of nephropathy (30.2%), neuropathy (23.7%) and CVD (4.1%). Females with late-onset diabetes were greatly affected by advanced retinopathy (ie, sight-threatening diabetic retinopathy) and hospitalised hypoglycaemia, whereas those with early-onset diabetes were more vulnerable to DKA. Chronic complications were more commonly seen in late-onset diabetes, whereas early-onset diabetes were most affected by acute complications. CONCLUSIONS Ethnic Chinese patients with type 1 diabetes were greatly affected by DKA and retinopathy. The incidence of diabetes-related complications differed by age at diagnosis and sex.
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Affiliation(s)
- Huang-Tz Ou
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Pharmacy, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Tsung-Ying Lee
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Yi Li
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Public Health, China Medical University, Taichung, Taiwan
| | - Jin-Shang Wu
- School of Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Family Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Zih-Jie Sun
- School of Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Family Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
- Department of Family Medicine, National Cheng Kung University Hospital, Dou-Liou Branch, Dou-Liou, Taiwan
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Skyler JS, Bakris GL, Bonifacio E, Darsow T, Eckel RH, Groop L, Groop PH, Handelsman Y, Insel RA, Mathieu C, McElvaine AT, Palmer JP, Pugliese A, Schatz DA, Sosenko JM, Wilding JPH, Ratner RE. Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis. Diabetes 2017; 66:241-255. [PMID: 27980006 PMCID: PMC5384660 DOI: 10.2337/db16-0806] [Citation(s) in RCA: 411] [Impact Index Per Article: 51.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 11/23/2016] [Indexed: 12/11/2022]
Abstract
The American Diabetes Association, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened a research symposium, "The Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis" on 10-12 October 2015. International experts in genetics, immunology, metabolism, endocrinology, and systems biology discussed genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, as well as complications. The participants debated how to determine appropriate therapeutic approaches based on disease pathophysiology and stage and defined remaining research gaps hindering a personalized medical approach for diabetes to drive the field to address these gaps. The authors recommend a structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate individualized treatment.
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Affiliation(s)
- Jay S Skyler
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | | | | | | | - Robert H Eckel
- University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Leif Groop
- Lund University, Skåne University Hospital, Malmö, Sweden
| | - Per-Henrik Groop
- Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Baker IDI Heart and Diabetes Institute, Melbourne, Australia
| | | | | | | | | | - Jerry P Palmer
- University of Washington and VA Puget Sound Health Care System, Seattle, WA
| | - Alberto Pugliese
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | | | - Jay M Sosenko
- University of Miami Miller School of Medicine, Miami, FL
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Bacha F, Klinepeter Bartz S. Insulin resistance, role of metformin and other non-insulin therapies in pediatric type 1 diabetes. Pediatr Diabetes 2016; 17:545-558. [PMID: 26592507 DOI: 10.1111/pedi.12337] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 09/17/2015] [Accepted: 10/12/2015] [Indexed: 12/28/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) in youth is a challenging chronic medical condition. Its management should address not only the glycemic control but also insulin resistance and cardiovascular disease risk factors which are increasingly recognized to be present in youth with TID. Current knowledge on the mechanisms of insulin resistance in T1DM is reviewed. The use of adjunctive therapies that are beneficial to achieve adequate glycemic control while mitigating the effects of insulin resistance are discussed with a focus on metformin therapy and an overview of other new pharmacologic agents.
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Affiliation(s)
- Fida Bacha
- Children's Nutrition Research Center, Texas Children's Hospital, Baylor College of Medicine Houston, Houston, TX, USA. .,Division of Pediatric Endocrinology and Diabetes, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
| | - Sara Klinepeter Bartz
- Children's Nutrition Research Center, Texas Children's Hospital, Baylor College of Medicine Houston, Houston, TX, USA.,Division of Pediatric Endocrinology and Diabetes, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
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20
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Affiliation(s)
| | - Guang Ning
- Ruijin Hospital, Shanghai Jiaotong University.
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21
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Frandsen CS, Dejgaard TF, Madsbad S. Non-insulin drugs to treat hyperglycaemia in type 1 diabetes mellitus. Lancet Diabetes Endocrinol 2016; 4:766-780. [PMID: 26969516 DOI: 10.1016/s2213-8587(16)00039-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Revised: 12/10/2015] [Accepted: 01/26/2016] [Indexed: 02/06/2023]
Abstract
Insulin treatment of individuals with type 1 diabetes has shortcomings and many patients do not achieve glycaemic and metabolic targets. Consequently, the focus is on novel non-insulin therapeutic approaches that reduce hyperglycaemia and improve metabolic variables without increasing the risk of hypoglycaemia or other adverse events. Several therapies given in conjunction with insulin have been investigated in clinical trials, including pramlintide, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter inhibitors, metformin, sulfonylureas, and thiazolidinediones. These drugs have pleiotropic effects on glucose metabolism and different actions complementary to those of insulin-this Review reports the effects of these drugs on glycaemic control, glucose variability, hypoglycaemia, insulin requirements, and bodyweight. Existing studies are of short duration with few participants; evidence for the efficacy of concomitant treatments is scarce and largely clinically insignificant. A subgroup of patients with type 1 diabetes for whom non-insulin antidiabetic drugs could significantly benefit glycaemic control cannot yet be defined, but we suggest that obese patients prone to hypoglycaemia and patients with residual β-cell function are populations of interest for future trials.
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Affiliation(s)
| | - Thomas Fremming Dejgaard
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Steno Diabetes Center, Gentofte, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
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Abstract
Insulin resistance is a component of several health disorders, most notably impaired glucose tolerance and type 2 diabetes mellitus. Insulin-resistant individuals have an impaired biological response to the usual action of insulin; that is, they have reduced insulin sensitivity. Various methods are used to assess insulin sensitivity both in individuals and in study populations. Validity, reproducibility, cost, and degree of subject burden are important factors for both clinicians and researchers to consider when weighing the merits of a particular method. This article describes several in vivo methods used to assess insulin sensitivity and presents the advantages and disadvantages of each.
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Affiliation(s)
- Kimberly K Trout
- Villanova University College of Nursing, Villanova, Pennsylvania 19085, USA.
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23
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Abstract
Managing severe insulin resistance (IR) in patients with type 1 diabetes (T1DM) can be challenging for both clinicians and patients. As average weight for patients with T1DM has increased in recent decades, IR in this population has become more widespread. Currently, almost 50 % of patients with T1DM are overweight or obese. While intensive insulin therapy is associated with reduction in complications, aggressive treatment can lead to weight gain. With increasing weight, insulin can become less effective to control glycemia, resulting in higher insulin doses and hence more weight gain. Novel strategies to break this vicious cycle are needed. This review will investigate current research on insulin formulations, lifestyle modification, adjunct therapies, and surgery that may help better manage patients with T1DM and IR.
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Munir KM, Davis SN. The treatment of type 1 diabetes mellitus with agents approved for type 2 diabetes mellitus. Expert Opin Pharmacother 2015; 16:2331-41. [DOI: 10.1517/14656566.2015.1084502] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Guclu M, Oz Gul O, Cander S, Unal O, Ozkaya G, Sarandol E, Ersoy C. Effect of Rosiglitazone and Insulin Combination Therapy on Inflammation Parameters and Adipocytokine Levels in Patients with Type 1 DM. J Diabetes Res 2015; 2015:807891. [PMID: 26273677 PMCID: PMC4530282 DOI: 10.1155/2015/807891] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2015] [Revised: 03/10/2015] [Accepted: 03/17/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the efficacy of combined therapy of insulin and rosiglitazone on metabolic and inflammatory parameters, insulin sensitivity, and adipocytokine levels in patients with type 1 diabetes mellitus (type 1 DM). MATERIAL AND METHODS A total of 61 adults with type 1 DM were randomly and prospectively assigned in open-label fashion to take insulin and rosiglitazone 4 mg/day (n = 30) or insulin alone (n = 31) for a period of 18 weeks while undergoing insulin therapy without acute metabolic complications. RESULTS Combination therapy did not significantly improve metabolic and inflammatory parameters, insulin sensitivity, and adiponectin levels. While leptin and resistin levels decreased in both groups (group 1: resistin 6.96 ± 3.06 to 4.99 ± 2.64, P = 0.006; leptin 25.8 ± 17.6 to 20.1 ± 12.55, P = 0.006; group 2: resistin 7.16 ± 2.30 to 5.57 ± 2.48, P = 0.031; leptin 16.72 ± 16.1 to 14.0 ± 13.4, P = 0.007) Hgb and fibrinogen levels decreased only in group 1 (Hgb 13.72 ± 1.98 to 13.16 ± 1.98, P = 0.015, and fibrinogen 4.00 ± 1.08 to 3.46 ± 0.90, P = 0.002). Patients in both groups showed weight gain and the incidence of hypoglycemia was not lower. DISCUSSION The diverse favorable effects of TZDs were not fully experienced in patients with type 1 DM. These results are suggesting that insulin sensitizing and anti-inflammatory characteristics of TZDs were likely to be more pronounced in patients who were not totally devoid of endogenous insulin secretion.
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Affiliation(s)
- Metin Guclu
- Division of Endocrinology, Sevket Yılmaz Research and Education Hospital, 16310 Bursa, Turkey
- Department of Endocrinology and Metabolism, School of Medicine, Uludağ University, 16210 Bursa, Turkey
| | - Ozen Oz Gul
- Department of Endocrinology and Metabolism, School of Medicine, Uludağ University, 16210 Bursa, Turkey
| | - Soner Cander
- Division of Endocrinology, Sevket Yılmaz Research and Education Hospital, 16310 Bursa, Turkey
- Department of Endocrinology and Metabolism, School of Medicine, Uludağ University, 16210 Bursa, Turkey
| | - Oguzkaan Unal
- Department of Endocrinology and Metabolism, School of Medicine, Uludağ University, 16210 Bursa, Turkey
- Acibadem Private Hospital, 16210 Bursa, Turkey
| | - Guven Ozkaya
- Department of Biostatistics, School of Medicine, Uludağ University, 16210 Bursa, Turkey
| | - Emre Sarandol
- Department of Biochemistry, School of Medicine, Uludağ University, 16210 Bursa, Turkey
| | - Canan Ersoy
- Department of Endocrinology and Metabolism, School of Medicine, Uludağ University, 16210 Bursa, Turkey
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Abstract
Historically, clinical management of patients with type 1 diabetes mellitus (T1DM) has been focused on glycaemic control, which is sometimes achieved at the expense of weight gain on intensive insulin regimes. Although HbA(1c) level is an important contributor to increased macrovascular risk, several prospective studies have concluded that factors related to obesity, metabolic syndrome and insulin resistance are more important than HbA(1c) for the prediction of cardiovascular risk, especially for coronary heart disease events. 'Double diabetes mellitus' describes a combination of T1DM with characteristics associated with type 2 diabetes mellitus, including central adiposity and exacerbation of insulin resistance. In lean patients with T1DM, portal insulinopaenia might actually confer cardioprotective effects via changes in hepatic lipid profiles (mainly increased HDL cholesterol levels) and a reduction in hepatic steatosis. In patients with double diabetes mellitus, this situation is reversed and atherothrombotic pathophysiology is potentially accelerated by the combination of chronic hyperglycaemia and abnormal lipid partitioning. The prevalence of double diabetes mellitus is increasing in parallel with the societal trend of increased adiposity. This Review discusses how to identify patients susceptible to double diabetes mellitus and suggests alterations to their clinical management that might reduce their risk of future premature coronary disease.
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Affiliation(s)
- Stephen J Cleland
- Department of Medicine, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK.
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Arrieta-Blanco F, Botella-Carretero JI, Iglesias P, Balsa JA, Zamarrón I, De la Puerta C, Arrieta JJ, Ramos F, Vázquez C, Rovira A. Insulin action in adipose tissue in type 1 diabetes. Int J Gen Med 2011; 4:153-7. [PMID: 21475629 PMCID: PMC3068878 DOI: 10.2147/ijgm.s15809] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Indexed: 01/21/2023] Open
Abstract
Background: Insulin action has been reported to be normal in type 1 diabetic patients. However, some studies have reported an insulin resistance state in these patients. The aim of this study was to investigate insulin resistance in a group of type 1 diabetic patients. We studied the insulin action in adipose tissue and analyzed the effects of duration of disease, body mass index (BMI), and glycosylated hemoglobin on insulin action at the receptor and postreceptor levels in adipocytes. Methods: Nine female type 1 diabetic patients with different durations of disease and eight nondiabetic female patients of comparable age and BMI were studied. 125I-insulin binding and U-[14C]-D-glucose transport was measured in a sample of subcutaneous gluteus adipose tissue obtained by open surgical biopsy from each subject. Results: The duration of disease was negatively correlated with both 125I-insulin binding capacity (r = −0.70, P < 0.05) and basal and maximum insulin-stimulated glucose transport (r = −0.87, P < 0.01, and r = −0.88, P < 0.01, respectively). Maximum specific 125I-insulin binding to the receptors in adipocytes was higher in the group of patients with a shorter duration of disease (P < 0.01). Basal and maximum insulin-stimulated glucose transport was significantly higher in the group with less than 5 years of disease (P < 0.01). No correlation was found between BMI and insulin action. Conclusion: Female type 1 diabetic patients have normal insulin action. There is a high glucose uptake in the early phase of the disease, although a longer duration of disease appears to be a contributing factor to a decrease in insulin action in these patients, and involving both receptor and postreceptor mechanisms.
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Affiliation(s)
- Francisco Arrieta-Blanco
- Unit of Clinical Nutrition and Dietetics, Department of Endocrinology and Nutrition, Hospital Ramóny, Cajal, Madrid, Spain, Irycis, Ciberobn
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German JP, Wisse BE, Thaler JP, Oh-I S, Sarruf DA, Ogimoto K, Kaiyala KJ, Fischer JD, Matsen ME, Taborsky GJ, Schwartz MW, Morton GJ. Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes 2010; 59:1626-34. [PMID: 20424233 PMCID: PMC2889761 DOI: 10.2337/db09-1918] [Citation(s) in RCA: 114] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM. RESEARCH DESIGN AND METHODS Adult male Wistar rats remained nondiabetic or were injected with the beta-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 microg/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured. RESULTS Physiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate-phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM. CONCLUSIONS We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine disorders in uDM. Treatment of diabetes in humans may benefit from correction of leptin deficiency as well as insulin deficiency.
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Affiliation(s)
- Jonathan P. German
- Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington
| | - Brent E. Wisse
- Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington
| | - Joshua P. Thaler
- Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington
| | - Shinsuke Oh-I
- Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington
| | - David A. Sarruf
- Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington
| | - Kayoko Ogimoto
- Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington
| | - Karl J. Kaiyala
- Department of Dental Public Health Sciences, School of Dentistry, University of Washington, Seattle, Washington
| | - Jonathan D. Fischer
- Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington
| | - Miles E. Matsen
- Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington
| | - Gerald J. Taborsky
- VA Puget Sound Health Care System, Department of Veterans Affairs Medical Center, Seattle, Washington
| | - Michael W. Schwartz
- Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington
| | - Gregory J. Morton
- Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington
- Corresponding author: Gregory J. Morton,
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Ghosh S, Collier A, Hair M, Malik I, Elhadd T. Metabolic syndrome in type 1 diabetes. ACTA ACUST UNITED AC 2010. [DOI: 10.1016/j.ijdm.2009.10.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Monte SV, Schentag JJ, Adelman MH, Paladino JA. Glucose supply and insulin demand dynamics of antidiabetic agents. J Diabetes Sci Technol 2010; 4:365-81. [PMID: 20307399 PMCID: PMC2864174 DOI: 10.1177/193229681000400219] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND For microvascular outcomes, there is compelling historical and contemporary evidence for intensive blood glucose reduction in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). There is also strong evidence to support macrovascular benefit with intensive blood glucose reduction in T1DM. Similar evidence remains elusive for T2DM. Because cardiovascular outcome trials utilizing conventional algorithms to attain intensive blood glucose reduction have not demonstrated superiority to less aggressive blood glucose reduction (Action to Control Cardiovascular Risk in Diabetes; Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; and Veterans Affairs Diabetes Trial), it should be considered that the means by which the blood glucose is reduced may be as important as the actual blood glucose. METHODS By identifying quantitative differences between antidiabetic agents on carbohydrate exposure (CE), hepatic glucose uptake (HGU), hepatic gluconeogenesis (GNG), insulin resistance (IR), peripheral glucose uptake (PGU), and peripheral insulin exposure (PIE), we created a pharmacokinetic/pharmacodynamic model to characterize the effect of the agents on the glucose supply and insulin demand dynamic. Glucose supply was defined as the cumulative percentage decrease in CE, increase in HGU, decrease in GNG, and decrease in IR, while insulin demand was defined as the cumulative percentage increase in PIE and PGU. With the glucose supply and insulin demand effects of each antidiabetic agent summated, the glucose supply (numerator) was divided by the insulin demand (denominator) to create a value representative of the glucose supply and insulin demand dynamic (SD ratio). RESULTS Alpha-glucosidase inhibitors (1.25), metformin (2.20), and thiazolidinediones (TZDs; 1.25-1.32) demonstrate a greater effect on glucose supply (SD ratio >1), while secretagogues (0.69-0.81), basal insulins (0.77-0.79), and bolus insulins (0.62-0.67) demonstrate a greater effect on insulin demand (SD ratio <1). CONCLUSION Alpha-glucosidase inhibitors, metformin, and TZDs demonstrate a greater effect on glucose supply, while secretagogues, basal insulin, and bolus insulin demonstrate a greater effect on insulin demand. Because T2DM cardiovascular outcome trials have not demonstrated macrovascular benefit with more aggressive blood glucose reduction when using conventional algorithms that predominantly focus on insulin demand, it would appear logical to consider a model that incorporates both the extent of blood glucose lowering (hemoglobin A1c) and the means by which the blood glucose was reduced (SD ratio) when considering macrovascular outcomes.
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Santos CE, Schrank Y, Kupfer R. Análise crítica dos critérios da OMS, IDF e NCEP para síndrome metabólica em pacientes portadores de diabetes melito tipo 1. ACTA ACUST UNITED AC 2009; 53:1096-102. [DOI: 10.1590/s0004-27302009000900006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2008] [Accepted: 09/04/2009] [Indexed: 12/31/2022]
Abstract
OBJETIVO: Avaliar a frequência de síndrome metabólica (SM) em portadores de diabetes melito tipo 1 (DMT1) maiores de 18 anos, de acordo com os critérios da International Diabetes Federation (IDF), do National Cholesterol Education Program (NCEP) e da Organização Mundial da Saúde (OMS), que foram analisados comparativamente. Secundariamente, verificou-se a associação da síndrome com complicações microvasculares, idade, tempo de duração do diabetes e controle glicêmico. MÉTODOS: Trata-se de estudo transversal com 101 pacientes. RESULTADOS: Foram classificados como tendo SM pelas definições da OMS, IDF e NCEP, respectivamente, 32%, 32% e 26% dos pacientes. Observou-se marcado aumento de SM em pacientes com microalbuminúria (MAU) quando comparado a pacientes sem MAU - aumento este mais significativo com o critério da OMS. CONCLUSÕES: A SM é um achado frequente em portadores de DMT1 e, entre os critérios utilizados para defini-la, o sugerido pela OMS parece ser o mais adequado neste grupo de pacientes.
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From pumps to prevention: recent advances in the treatment of type 1 diabetes. Drug Discov Today 2009; 14:973-81. [DOI: 10.1016/j.drudis.2009.06.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2009] [Revised: 06/07/2009] [Accepted: 06/25/2009] [Indexed: 02/06/2023]
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Sarafidis PA, Nilsson PM. The effects of thiazolidinediones on blood pressure levels – A systematic review. Blood Press 2009; 15:135-50. [PMID: 16864155 DOI: 10.1080/08037050600853720] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Insulin resistance has been proposed to be the underlying disorder of the so-called metabolic or insulin resistance syndrome, which represents the clustering in the same individual of several cardiovascular risk factors, such as type 2 diabetes mellitus, hypertension, abdominal obesity, elevated triglycerides and low high-density lipoprotein-cholesterol. As far as the connection of insulin resistance and compensatory hyperinsulinaemia with hypertension is concerned, a number of mechanisms possibly linking these disturbances have been described, such as activation of sympathetic nervous system, enhancement of renal sodium reabsorption, or impairment of endothelium-dependent vasodilatation. Thiazolidinediones (TZDs) constitute a class of oral antihyperglycaemic agents that act by decreasing insulin resistance, and apart from their action on glycaemic control, they have been also reported to exert beneficial effects on other parameters of the metabolic syndrome. In particular, during recent years a considerable number of animal and human studies have shown that the use of TZDs was associated with usually small but significant reductions of blood pressure (BP) levels. Since a possible beneficial action of these compounds on BP could be of particular value for patients with the metabolic syndrome, this review aimed to summarize and evaluate the literature data in the field, derived either from studies that just examined BP levels among other parameters or from studies that were specifically designed to determine the effect of a TZD on BP.
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Affiliation(s)
- Pantelis A Sarafidis
- 1st Department of Medicine, AHEPA University Hospital, Aristotle University, Thessaloniki, Greece.
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Gabbay MDAL. [Adjunctive therapies to glycaemic control of type 1 diabetes mellitus]. ACTA ACUST UNITED AC 2009; 52:279-87. [PMID: 18438538 DOI: 10.1590/s0004-27302008000200015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2007] [Accepted: 12/10/2007] [Indexed: 11/22/2022]
Abstract
Since Diabetes Control and Complications Trial (DCCT), intensive therapy has been directed at achieving glucose and glycosylated hemoglobin (HbA1c) values as close to normal as possible regarding safety issues. However, hyperglycemia (especially postprandial hyperglycemia) and hypoglicemia continue to be problematic in the management of type 1 diabetes. The objective of associating other drugs to insulin therapy is to achieve better metabolic control lowering postprandial blood glucose levels. Adjunctive therapies can be divided in four categories based on their mechanism of action: enhancement of insulin action (e.g. the biguanides and thiazolidinediones), alteration of gastrointestinal nutrient delivery (e.g. acarbose and amylin) and other targets of action (e.g. pirenzepine, insulin-like growth factor I and glucagon-like peptide-1). Many of these agents have been found to be effective in short-term studies with decreases in HbA1c of 0.5-1%, lowering postprandial blood glucose levels and decreasing daily insulin doses.
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Affiliation(s)
- Mônica de A Lima Gabbay
- Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo, SP, Brasil.
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Abstract
Type 1 diabetes is recognised to include an element of insulin resistance. Insulin resistance is an independent risk factor for the development of macro- and microvascular complications of Type 1 diabetes and may also contribute to the development of the disease. This understanding comes at a time when the incidence of Type 1 diabetes appears to be rising and the public health burden from its vascular complications is high. A variety of safe and efficacious manoeuvres are available to redress insulin resistance in Type 2 diabetes. So far however, clinical trials addressing insulin resistance in Type 1 diabetes have been small with only short periods of follow-up. Regardless, these trials have yielded promising results. This review examines the evidence for insulin resistance in the pathophysiology of Type 1 diabetes and its complications, the problems associated with its measurement, and summarizes the trials aimed at reducing insulin resistance in Type 1 diabetes. This includes a meta-analysis of controlled trials of adjuvant metformin in Type 1 diabetes.
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Affiliation(s)
- T T L Pang
- Division of Medical Sciences, Medical School, University of Birmingham, Birmingham, UK
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Stone ML, Walker JL, Chisholm D, Craig ME, Donaghue KC, Crock P, Anderson D, Verge CF. The addition of rosiglitazone to insulin in adolescents with type 1 diabetes and poor glycaemic control: a randomized-controlled trial. Pediatr Diabetes 2008; 9:326-34. [PMID: 18466213 DOI: 10.1111/j.1399-5448.2008.00383.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE To evaluate the effect of rosiglitazone, an insulin sensitizer, on glycaemic control and insulin resistance in adolescents with type 1 diabetes mellitus (T1DM) RESEARCH DESIGN AND METHODS: Randomized, double-blind, placebo-controlled crossover trial of rosiglitazone (4 mg twice daily) vs. placebo (24 wk each, with a 4 wk washout period). Entry criteria were diabetes duration >1 yr, age 10-18 yr, puberty (>or=Tanner breast stage 2 or testicular volume >4 mL), insulin dose >or=1.1 units/kg/day, and haemoglobin A1c (HbA1c) >8%. Responses to rosiglitazone were compared with placebo using paired t-tests. RESULTS Of 36 adolescents recruited (17 males), 28 completed the trial. At baseline, age was 13.6 +/- 1.8 yr, HbA1c 8.9 +/- 0.96%, body mass index standard deviation scores (BMI-SDS) 0.94 +/- 0.74 and insulin dose 1.5 +/- 0.3 units/kg/day. Compared with placebo, rosiglitazone resulted in decreased insulin dose (5.8% decrease vs. 9.4% increase, p = 0.02), increased serum adiponectin (84.8% increase vs. 26.0% decrease, p < 0.01), increased cholesterol (+0.5 mmol/L vs. no change, p = 0.02), but no significant change in HbA1c (-0.3 vs. -0.1, p = 0.57) or BMI-SDS (0.08 vs. 0.04, p = 0.31). Insulin sensitivity was highly variable in the seven subjects who consented to euglycaemic hyperinsulinaemic clamps. There were no major adverse effects attributable to rosiglitazone. CONCLUSION The addition of rosiglitazone to insulin did not improve HbA1c in this group of normal weight adolescents with T1DM.
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Affiliation(s)
- Monique L Stone
- Department of Endocrinology, Sydney Children's Hospital, Randwick, New South Wales, Australia.
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José Chillarón J, Goday A, Pedro-Botet J. Síndrome metabólico, diabetes mellitus tipo 1 y resistencia a la insulina. Med Clin (Barc) 2008; 130:466-70. [DOI: 10.1157/13118111] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Jones KL. Role of obesity in complicating and confusing the diagnosis and treatment of diabetes in children. Pediatrics 2008; 121:361-8. [PMID: 18245428 DOI: 10.1542/peds.2007-1234] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The alarming increase in the prevalence of obesity in children in the United States and globally raises major concerns about its future adverse impact on public health. One outcome of this disturbing trend that is already evident is the rapidly increasing incidence of type 2 diabetes at all ages. This disease, once thought to be nonexistent in children, is increasing coincident with obesity. This article addresses the role that obesity plays in type 2 diabetes and also explores its effects on other types of diabetes that occur in childhood. The new challenges for physicians who formulate a differential diagnosis of diabetes in children are discussed. Also examined are modifications of traditional diabetes treatment that can be helpful in combating the insulin resistance associated with obesity and that use medications that are not traditionally used in this age group. Cases are presented to illustrate certain points. An underlying thesis suggests that specific classification may not be as important to the clinician as the understanding of pathophysiologic factors that contribute to hyperglycemia in individual patients. Recommendations are offered to the practitioner for diagnosing and treating the obese child or adolescent with diabetes.
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Affiliation(s)
- Kenneth Lee Jones
- Division of Diabetes and Endocrinology, Department of Pediatrics, Rady Children's Hospital, University of California at San Diego, La Jolla, California, USA.
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Bhat R, Bhansali A, Bhadada S, Sialy R. Effect of pioglitazone therapy in lean type 1 diabetes mellitus. Diabetes Res Clin Pract 2007; 78:349-54. [PMID: 17543413 DOI: 10.1016/j.diabres.2007.04.012] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2007] [Accepted: 04/25/2007] [Indexed: 12/31/2022]
Abstract
OBJECTIVE The beneficial effects of metformin in peripubertal adolescents and rosiglitazone in overweight type 1 diabetic subjects, though modest have been demonstrated. This study was designed to analyze the effect of pioglitazone as an adjunctive therapy in post-pubertal lean T1DM. PATIENTS AND METHODS Sixty type 1 diabetic subjects with duration of illness of a year or more with body mass index between 18 and 24.9 kg/m(2) were randomly assigned to receive either 30 mg pioglitazone or placebo once daily for 6 months. The study was double-blinded placebo controlled with 30 subjects in each group, matched for age, sex, anthropometric and metabolic parameters. At the end of the study period, plasma glucose levels, HbA(1c), lipids and insulin requirement were compared between the two groups. RESULTS A significant improvement in post-prandial plasma glucose (PPPG) levels (9.1+/-1.7 and 8.4+/-1.3 mmol/L, p=0.002) and HbA(1c) (7.08+/-0.48 and 6.86+/-0.45%, p=0.001) were observed in the pioglitazone treated group, but not in the placebo treated group (8.3+/-1.8 and 7.8+/-1.8 mmol/L, p=0.06 and HbA(1c) 7.3+/-0.37 and 7.24+/-0.33%, p=0.74, respectively). However, the mean decrease in PPPG and HbA(1c) levels between groups corrected for baseline values at the end of study was significant only for the later (HbA(1c) -0.22+/-0.29 and -0.06+/-0.49, p=0.03), while for the former, it got attenuated (PPPG -0.69+/-1.1 and -0.48+/-1.36, p=0.68). There was no alteration in body weight, body mass index, insulin requirement, blood pressure and lipid profile in both the groups at the end of the study. CONCLUSION Pioglitazone is modestly effective adjunct to insulin therapy in lean type 1 diabetic subjects. It improves post-prandial glucose levels and HbA(1c) without alterations in body weight and insulin requirement.
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Affiliation(s)
- R Bhat
- Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
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Zhang YQ, Tang XQ, Sun L, Dong L, Qin Y, Liu HQ, Xia H, Cao JG. Rosiglitazone enhances fluorouracil-induced apoptosis of HT-29 cells by activating peroxisome proliferator-activated receptor γ. World J Gastroenterol 2007; 13:1534-40. [PMID: 17461445 PMCID: PMC4146895 DOI: 10.3748/wjg.v13.i10.1534] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine whether and how rosiglitazone enhances apoptosis induced by fluorouracil in human colon cancer (HT-29) cells.
METHODS: Human colon cancer HT-29 cells were cultured in vitro and treated with fluorouracil and/or rosiglitazone. Proliferation and growth of HT-29 cells were evaluated by MTT assay and trypan blue exclusion methods, respectively. The apoptosis of HT-29 cells was determined by acridine orange/ethidium bromide staining and flow cytometry using PI fluorescence staining. The expressions of peroxisome proliferator-activated receptor γ (PPARγ), Bcl-2 and Bax in HT-29 cells were analyzed by Western blot.
RESULTS: Although rosiglitazone at the concentration below 30 μmol/L for 72 h exerted almost no inhibitory effect on proliferation and growth of HT-29 cells, it could significantly enhance fluorouracil-induced HT-29 cell proliferation and growth inhibition. Furthermore, 10 μmol/L rosilitazone did not induce apoptosis of HT-29 cells but dramatically enhanced fluorouracil-induced apoptosis of HT-29 cells. However, rosiglitazone did not improve apoptosis induced by fluorouracil in HT-29 cells pretreated with GW9662, a PPARγ antagonist. Meanwhile, the expression of Bax and PPARγ was up-regulated, while the expression of Bcl-2 was down regulated in HT-29 cells treated with rosiglitazone in a time-dependent manner. However, the effect of rosiglitazone on Bcl-2 and Bax was blocked or diminished in the presence of GW9662.
CONCLUSION: Rosiglitazone enhances fluorouracil-induced apoptosis of HT-29 cells by activating PPARγ.
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Affiliation(s)
- Yan-Qin Zhang
- Cancer Research Institute of Nanhua University, Hengyang 421001, Hunan Province, China
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Zdravkovic V, Hamilton JK, Daneman D, Cummings EA. Pioglitazone as adjunctive therapy in adolescents with type 1 diabetes. J Pediatr 2006; 149:845-849. [PMID: 17137905 DOI: 10.1016/j.jpeds.2006.08.049] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2006] [Revised: 06/01/2006] [Accepted: 08/21/2006] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To determine whether the addition of the thiazoladinedione, pioglitazone, to standard therapy improves metabolic control in adolescents with type 1 diabetes (T1D) and clinical evidence of insulin resistance. STUDY DESIGN Randomized, placebo-controlled 6-month 2-site trial of pioglitazone therapy in 35 adolescents with T1D, high insulin requirements (>0.9 U/kg/d), and suboptimal metabolic control (A1c 7.5%-11%), with the primary outcome of change in A1c. Secondary outcomes include change in insulin dose, body mass index (BMI), lipids, and waist and hip circumference. RESULTS Metabolic control (A1c) was improved at 6 months in all subjects (P = .02). There was no significant difference between the pioglitazone and placebo treatment groups at 6 months in either change in A1c (-0.4% +/- 0.9% and -0.5% +/- 1.2%, respectively) or insulin dose. BMI SDS increased by 0.3 +/- 0.3 (kg/m(2)) in the pioglitazone group and remained unchanged in the placebo group (P = .01). There was no significant difference in change in any lipid parameters between the pioglitazone and placebo groups at 6 months. CONCLUSIONS Adjunctive pioglitazone therapy was not effective in improving glycemic control in adolescents with T1D. Pioglitazone was associated with increased BMI.
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Affiliation(s)
- Vera Zdravkovic
- Division of Endocrinology, Hospital for Sick Children, Toronto, Ontario, Canada
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Joosen AMCP, Bakker AHF, Gering MJA, Westerterp KR. The effect of the PPARgamma ligand rosiglitazone on energy balance regulation. Diabetes Metab Res Rev 2006; 22:204-10. [PMID: 16110522 DOI: 10.1002/dmrr.592] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND AIM Fat mass generation requires an energy surplus and the activity of the peroxisome proliferator-activated receptor gamma (PPARgamma). We investigated if the PPARgamma ligand rosiglitazone influences substrate usage, energy expenditure (EE) and energy intake (EI) and, thereby, how PPARgamma activity contributes to susceptibility to obesity. METHODS Twenty healthy males (20-29 years) were randomly assigned to receive a placebo (n = 10) or rosiglitazone (8 mg/d) (n = 10) for seven consecutive days, while staying in a respiration chamber. Food intake was ad libitum. Body composition was determined by underwater weighing (day 1) and deuterium dilution (day 1 and 8). RESULTS Mean (+/-SE) EI was 15.9 +/- 0.9 MJ/d in the placebo group and 18.9 +/- 1.2 MJ/d in the rosiglitazone group. Mean EE was 11.3 +/- 0.3 MJ/d and 12.5 +/- 0.5 MJ/d for the placebo and rosiglitazone groups respectively. This resulted in a cumulative positive energy balance (EB) of 32.3 +/- 5.1 MJ for placebo and 44.7 +/- 6.9 MJ for rosiglitazone. There were no significant differences in EI, EE, and EB between treatments. Both groups did not adjust their fat oxidation to the increased fat intake, but fat oxidation decreased faster in the rosiglitazone group (significantly lower on days 6 and 7). During treatment with rosiglitazone, significantly more fat storage was seen in overweight subjects while this was not the case in the placebo group. CONCLUSIONS Our results suggest a shift in substrate usage during PPARgamma stimulation leading to a preference for fat storage, especially in subjects with a higher BMI.
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Abstract
A resistência à insulina (RI) pode desempenhar um papel, na história natural do diabetes melito do tipo 1 (DM1), maior do que o habitualmente reconhecido. Nas últimas décadas, este papel se tornou mais evidente com o aumento da obesidade e da diminuição da atividade física nos jovens. Esta revisão tem como objetivo apresentar e discutir a RI nas diferentes fases do DM1, bem como a prevalência da Síndrome Metabólica (SM) nessa condição. O aumento na RI, concomitante a uma diminuição da massa de células beta, pode alterar o equilíbrio entre a sensibilidade à insulina e a secreção de insulina, e precipitar a hiperglicemia nos indivíduos com pré-DM1. A RI poderia refletir uma forma mais agressiva de doença autoimune, mediada por fatores imuno-inflamatórios, comuns a ambos os processos, que também mediassem a destruição das células beta (TNF-alfa e IL-6). Estes conceitos fazem parte da "Hipótese Aceleradora". A história familiar de DM2 e a hiperglicemia crônica (glicotoxicidade), durante a fase clínica do DM1, estão associadas a uma diminuição da captação periférica de glicose. A nefropatia diabética (ND), através da inflamação subclínica e do aumento no estresse oxidativo, contribui para a RI e o desenvolvimento da SM. A prevalência da SM no DM1 varia entre 12 a 40%, sendo mais freqüente nos pacientes com ND e controle glicêmico insatisfatório. Estes achados possuem implicações na terapêutica e no prognóstico cardiovascular dos pacientes com DM1.
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Affiliation(s)
- Sergio Atala Dib
- Centro de Diabetes, Departamento de Medicina, EPM, UNIFESP, São Paulo, SP.
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