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Patoulias D, Dimosiari A, Fragakis N. Tirzepatide for the treatment of heart failure in Type 2 diabetes mellitus: (SUR)PASS, or not? Future Cardiol 2023; 19:301-312. [PMID: 37552101 DOI: 10.2217/fca-2022-0112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/09/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a rising pandemic, while cardiovascular disease, including heart failure, represents a frequent concomitance, increasing overall morbidity and mortality and, of course, healthcare cost. Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, constituting a novel treatment option in T2DM. This agent exerts additional effects in addition to improvement in glycemic control, which can be of benefit for individuals with T2DM, especially those at risk for or with established cardiovascular disease or heart failure. Current evidence is limited, although suggestive of the cardiovascular safety of tirzepatide. This article provides an overview of available evidence regarding the use of tirzepatide in T2DM, with emphasis on clinical efficacy.
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Affiliation(s)
- Dimitrios Patoulias
- Second Department of Internal Medicine, European Interbalkan Medical Center, Thessaloniki, Asklipiou 10, 57001, Greece
- Second Department of Cardiology, Aristotle University of Thessaloniki, General Hospital 'Hippokration', Konstantinoupoleos 49, 54642, Thessaloniki, Greece
| | - Athina Dimosiari
- Second Department of Internal Medicine, European Interbalkan Medical Center, Thessaloniki, Asklipiou 10, 57001, Greece
| | - Nikolaos Fragakis
- Second Department of Cardiology, Aristotle University of Thessaloniki, General Hospital 'Hippokration', Konstantinoupoleos 49, 54642, Thessaloniki, Greece
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2
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Christensen MB, Gasbjerg LS, Heimbürger SM, Stensen S, Vilsbøll T, Knop FK. GIP's involvement in the pathophysiology of type 2 diabetes. Peptides 2020; 125:170178. [PMID: 31682875 DOI: 10.1016/j.peptides.2019.170178] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/17/2019] [Accepted: 10/17/2019] [Indexed: 02/06/2023]
Abstract
During the past four decades derangements in glucose-dependent insulinotropic polypeptide (GIP) biology has been viewed upon as contributing factors to various parts of the pathophysiology type 2 diabetes. This overview outlines and discusses the impaired insulin responses to GIP as well as the effect of GIP on glucagon secretion and the potential involvement of GIP in the obesity and bone disease associated with type 2 diabetes. As outlined in this review, it is unlikely that the impaired insulinotropic effect of GIP occurs as a primary event in the development of type 2 diabetes, but rather develops once the diabetic state is present and beta cells are unable to maintain normoglycemia. In various models, GIP has effects on glucagon secretion, bone and lipid homeostasis, but whether these effects contribute substantially to the pathophysiology of type 2 diabetes is at present controversial. The review also discusses the substantial uncertainty surrounding the translation of preclinical data relating to the GIP system and outline future research directions.
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Affiliation(s)
- Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sebastian M Heimbürger
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Signe Stensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte Hospital, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte Hospital, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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3
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Deacon CF. Metabolism of GIP and the contribution of GIP to the glucose-lowering properties of DPP-4 inhibitors. Peptides 2020; 125:170196. [PMID: 31706956 DOI: 10.1016/j.peptides.2019.170196] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 01/26/2023]
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with insulinotropic and glucagonotropic actions, and is believed to be the more physiologically important incretin hormone in healthy humans. Together with the other incretin hormone, glucagon-like peptide-1 (GLP-1), it plays an important role in regulating glucose homeostasis. Both GLP-1 and GIP are substrates of the enzyme dipeptidyl peptidase-4 (DPP-4), and DPP-4 inhibitors, which potentiate their effects on glycaemic control, are now used to treat type 2 diabetes (T2D). This review describes how post-translational processing of the GIP precursor molecule and post-release degradation of the secretory products give rise to multiple isoforms of GIP, some, but not all of which are biologically active, and discusses how this impacts upon their measurement by immunological- and bioassay-based methods. DPP-4 inhibitors reduce degradation of GIP, and although the insulinotropic effects of GIP are impaired in patients with T2D, they can be at least partially restored if glycaemic control is improved. Therefore, given that studies with incretin receptor antagonists indicate that not all of the glucose-lowering effects of DPP-4 inhibition can be accounted for by GLP-1 alone, evidence supports the notion that GIP may play a role in mediating the anti-hyperglycaemic effects of DPP-4 inhibition, while its glucagonotropic actions at lower glucose levels may contribute to the low risk of hypoglycaemia associated with DPP-4 inhibitors.
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Affiliation(s)
- Carolyn F Deacon
- Department of Biomedical Sciences, University of Copenhagen, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
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Hegelund Myrbäck T, Prothon S, Edman K, Leander J, Hashemi M, Dearman M, Edenro G, Svanberg P, Andersson EM, Almquist J, Ämmälä C, Hendrickx R, Taib Z, Johansson KA, Berggren AR, Keen CM, Eriksson UG, Fuhr R, Carlsson BCL. Effects of a selective glucocorticoid receptor modulator (AZD9567) versus prednisolone in healthy volunteers: two phase 1, single-blind, randomised controlled trials. THE LANCET. RHEUMATOLOGY 2020; 2:e31-e41. [PMID: 38258274 DOI: 10.1016/s2665-9913(19)30103-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 10/25/2019] [Accepted: 10/28/2019] [Indexed: 01/08/2023]
Abstract
BACKGROUND Glucocorticoids are highly effective and widely used anti-inflammatory drugs, but their use is limited by serious side-effects, including glucocorticoid-induced hyperglycaemia and diabetes. AZD9567 is a non-steroidal, selective glucocorticoid receptor modulator that aims to reduce side-effects. We aimed to assess the safety, tolerability, and pharmacokinetics of AZD9567 in healthy volunteers. METHODS Two phase 1 clinical studies were done. First, a randomised, placebo-controlled, single-blind, single-ascending dose study was done in healthy men who received single oral doses of AZD9567 2 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 125 mg, or 155 mg, or prednisolone 60 mg (n=8 per dose group, randomly assigned [6:2] to receive active drug or placebo). Second, a randomised, active-controlled, single-blind, multiple-ascending dose study was done, in which men and women received oral AZD9567 or prednisolone once daily for 5 days. One cohort of volunteers with prediabetes received AZD9567 10 mg (n=7) or prednisolone 20 mg (n=2). All other cohorts comprised healthy volunteers, receiving AZD9567 20 mg, 40 mg, 80 mg, or 125 mg (n=7 per dose group), or prednisolone 5 mg (n=13), 20 mg (n=16), or 40 mg (n=13). Participants and study centre staff were masked to treatment assignment for each cohort, although data were unmasked for safety review between cohorts. The primary outcome of the single-ascending dose study was the safety, tolerability, and pharmacokinetics of single ascending doses of AZD9567; for the multiple-ascending dose study it was the safety and tolerability of AZD9567 following multiple ascending doses. As a secondary outcome, effects on glycaemic control were ascertained with oral glucose tolerance tests (OGTTs) done at baseline and on day 1 of the single-ascending dose study, and at baseline and on day 4 of the multiple-ascending dose study. These trials are registered at ClinicalTrials.gov, NCT02512575 and NCT02760316. FINDINGS In the single-ascending dose study, between Nov 18, 2015, and Sept 26, 2016, 72 healthy white men were enrolled, and all completed the study. In the multiple-ascending dose study, between May 2, 2016, and Sept 13, 2017, 77 predominantly white male volunteers (including nine individuals with prediabetes and eight women) were enrolled and 75 completed the study. All doses of AZD9567 and prednisolone were well tolerated, with no serious adverse events or events suggesting adrenal insufficiency. In the single-ascending dose study, nine adverse events of mild intensity were reported (five with AZD9567 and four with placebo); no adverse event was reported by more than one person. In the multiple-ascending dose study, 44 adverse events of mild or moderate intensity were reported (18 with AZD9567 and 26 with prednisolone). The most common were headache and micturition. Apparent clearance, volume of distribution, and half-life of AZD9567 were consistent across doses and for single versus repeated dosing. In the multiple-ascending dose study, OGTTs showed no significant difference with AZD9567 doses up to 80 mg compared with prednisolone 5 mg in glucose area under the curve from 0 h to 4 h post-OGTT (AUC0-4h) from baseline to day 4; the increase in glucose AUC0-4h from baseline to day 4 was significantly lower with all AZD9567 doses versus prednisolone 20 mg (AZD9567 20 mg p<0·0001, 40 mg p=0·0001, 80 mg p=0·0001, and 125 mg p=0·0237). INTERPRETATION AZD9567 appears to be safe and well tolerated in healthy, predominantly white male volunteers and shows promising initial evidence for improved post-prandial glucose control. Studies of longer duration, with a greater proportion of women and other ethnic groups, and in patients requiring anti-inflammatory treatment are needed to characterise the clinical efficacy and safety profile of AZD9567. FUNDING AstraZeneca.
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Affiliation(s)
| | - Susanne Prothon
- Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Karl Edman
- Structure Biophysics and Fragments, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Jacob Leander
- Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Mahdi Hashemi
- Early Biometrics & Statistical Innovation, Data Science & AI, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Matthew Dearman
- Bioscience, Research and Early Development, Respiratory, Inflammation and Autoimmunity, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Goran Edenro
- Bioscience, Research and Early Development, Respiratory, Inflammation and Autoimmunity, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Petter Svanberg
- Drug Metabolism and Pharmacokinetics, Research and Early Development, Respiratory, Inflammation and Autoimmunity, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Eva-Marie Andersson
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Joachim Almquist
- Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Carina Ämmälä
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Ramon Hendrickx
- Drug Metabolism and Pharmacokinetics, Research and Early Development, Respiratory, Inflammation and Autoimmunity, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Ziad Taib
- Early Biometrics & Statistical Innovation, Data Science & AI, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Kicki A Johansson
- Research and Early Development, Respiratory, Inflammation and Autoimmunity, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Anders R Berggren
- Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Christina M Keen
- Research and Early Development, Respiratory, Inflammation and Autoimmunity, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Ulf G Eriksson
- Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Rainard Fuhr
- PAREXEL Early Phase Clinical Unit, Berlin, Germany
| | - Björn C L Carlsson
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
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Prévost G, Arabo A, Le Solliec MA, Bons J, Picot M, Maucotel J, Berrahmoune H, El Mehdi M, Cherifi S, Benani A, Nédélec E, Coëffier M, Leprince J, Nordqvist A, Brunel V, Déchelotte P, Lefebvre H, Anouar Y, Chartrel N. Neuropeptide 26RFa (QRFP) is a key regulator of glucose homeostasis and its activity is markedly altered in obese/hyperglycemic mice. Am J Physiol Endocrinol Metab 2019; 317:E147-E157. [PMID: 31084498 DOI: 10.1152/ajpendo.00540.2018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Recent studies have shown that the hypothalamic neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and increasing insulin sensitivity. In this study, we further characterized the role of the 26RFa/GPR103 peptidergic system in the global regulation of glucose homeostasis using a 26RFa receptor antagonist and also assessed whether a dysfunction of the 26RFa/GPR103 system occurs in obese hyperglycemic mice. First, we demonstrate that administration of the GPR103 antagonist reduces the global glucose-induced incretin effect and insulin sensitivity whereas, conversely, administration of exogenous 26RFa attenuates glucose-induced hyperglycemia. Using a mouse model of high-fat diet-induced obesity and hyperglycemia, we found a loss of the antihyperglcemic effect and insulinotropic activity of 26RFa, accompanied with a marked reduction of its insulin-sensitive effect. Interestingly, this resistance to 26RFa is associated with a downregulation of the 26RFa receptor in the pancreatic islets, and insulin target tissues. Finally, we observed that the production and release kinetics of 26RFa after an oral glucose challenge is profoundly altered in the high-fat mice. Altogether, the present findings support the view that 26RFa is a key regulator of glucose homeostasis whose activity is markedly altered under obese/hyperglycemic conditions.
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Affiliation(s)
- Gaëtan Prévost
- Normandie University, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N) , Rouen , France
- Normandie University, UNIROUEN, Rouen University Hospital, Department of Endocrinology, Diabetes and Metabolic Diseases, Rouen , France
| | - Arnaud Arabo
- Normandie University, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N) , Rouen , France
| | - Marie-Anne Le Solliec
- Normandie University, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N) , Rouen , France
| | - Justine Bons
- Normandie University, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N) , Rouen , France
- Normandie University, UNIROUEN, Rouen University Hospital, Department of Endocrinology, Diabetes and Metabolic Diseases, Rouen , France
| | - Marie Picot
- Normandie University, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N) , Rouen , France
| | - Julie Maucotel
- Normandie University, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N) , Rouen , France
| | - Hind Berrahmoune
- Normandie University, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N) , Rouen , France
- Normandie University, UNIROUEN, Rouen University Hospital, Department of Endocrinology, Diabetes and Metabolic Diseases, Rouen , France
| | - Mouna El Mehdi
- Normandie University, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N) , Rouen , France
| | - Saloua Cherifi
- Normandie University, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N) , Rouen , France
| | - Alexandre Benani
- Center for Taste and Feeding Behaviour, CNRS (UMR6265), INRA (UMR1324), Université de Bourgogne-Franche Comté , Dijon , France
| | - Emmanuelle Nédélec
- Center for Taste and Feeding Behaviour, CNRS (UMR6265), INRA (UMR1324), Université de Bourgogne-Franche Comté , Dijon , France
| | - Moïse Coëffier
- Normandie University, UNIROUEN, INSERM U1073 Nutrition, Inflammation and dysfunction of gut-brain axis, Rouen , France
- Normandie University, UNIROUEN, Rouen University Hospital, Department of Nutrition , Rouen , France
| | - Jérôme Leprince
- Normandie University, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N) , Rouen , France
| | - Anneli Nordqvist
- Cardiovascular Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Mölndal , Sweden
| | - Valéry Brunel
- Normandie University, UNIROUEN, Rouen University Hospital, Department of Biochemistry , Rouen , France
| | - Pierre Déchelotte
- Normandie University, UNIROUEN, INSERM U1073 Nutrition, Inflammation and dysfunction of gut-brain axis, Rouen , France
- Normandie University, UNIROUEN, Rouen University Hospital, Department of Nutrition , Rouen , France
| | - Hervé Lefebvre
- Normandie University, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N) , Rouen , France
- Normandie University, UNIROUEN, Rouen University Hospital, Department of Endocrinology, Diabetes and Metabolic Diseases, Rouen , France
| | - Youssef Anouar
- Normandie University, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N) , Rouen , France
| | - Nicolas Chartrel
- Normandie University, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N) , Rouen , France
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Deacon CF. Physiology and Pharmacology of DPP-4 in Glucose Homeostasis and the Treatment of Type 2 Diabetes. Front Endocrinol (Lausanne) 2019; 10:80. [PMID: 30828317 PMCID: PMC6384237 DOI: 10.3389/fendo.2019.00080] [Citation(s) in RCA: 236] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 01/30/2019] [Indexed: 12/11/2022] Open
Abstract
Dipeptidyl peptidase-4 (DPP-4), also known as the T-cell antigen CD26, is a multi-functional protein which, besides its catalytic activity, also functions as a binding protein and a ligand for a variety of extracellular molecules. It is an integral membrane protein expressed on cells throughout the body, but is also shed from the membrane and circulates as a soluble protein in the plasma. A large number of bioactive molecules can be cleaved by DPP-4 in vitro, but only a few of these have been demonstrated to be physiological substrates. One of these is the incretin hormone, glucagon-like peptide-1 (GLP-1), which plays an important role in the maintenance of normal glucose homeostasis, and DPP-4 has been shown to be the key enzyme regulating its biological activity. This pathway has been targeted pharmacologically through the development of DPP-4 inhibitors, and these are now a successful class of anti-hyperglycaemic agents used to treat type 2 diabetes (T2DM). DPP-4 may additionally influence metabolic control via its proteolytic effect on other regulatory peptides, but it has also been reported to affect insulin sensitivity, potentially mediated through its non-enzymatic interactions with other membrane proteins. Given that altered expression and activity of DPP-4 are associated with increasing body mass index and hyperglycaemia, DPP-4 has been proposed to play a role in linking obesity and the pathogenesis of T2DM by functioning as a local mediator of inflammation and insulin resistance in adipose and hepatic tissue. As well as these broader systemic effects, it has also been suggested that DPP-4 may be able to modulate β-cell function as part of a paracrine system involving GLP-1 produced locally within the pancreatic islets. However, while it is evident that DPP-4 has the potential to influence glycaemic control, its overall significance for the normal physiological regulation of glucose homeostasis in humans and its role in the pathogenesis of metabolic disease remain to be established.
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Demant M, Bagger JI, Suppli MP, Lund A, Gyldenløve M, Hansen KB, Hare KJ, Christensen M, Sonne DP, Holst JJ, Vilsbøll T, Knop FK. Determinants of Fasting Hyperglucagonemia in Patients with Type 2 Diabetes and Nondiabetic Control Subjects. Metab Syndr Relat Disord 2018; 16:530-536. [PMID: 30325692 DOI: 10.1089/met.2018.0066] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Fasting hyperglucagonemia can be detrimental to glucose metabolism in patients with type 2 diabetes (T2D) and may contribute to metabolic disturbances in obese and/or prediabetic subjects. However, the mechanisms underlying fasting hyperglucagonemia remain elusive. METHODS We evaluated the interrelationship between fasting hyperglucagonemia and demographic and biochemical parameters in 106 patients with T2D (31% female, age: 57 ± 9 years [mean ± standard deviation; body mass index (BMI): 30.1 ± 4.4 kg/m2; fasting plasma glucose (FPG): 9.61 ± 2.39 mM; hemoglobin A1c (HbA1c): 57.1 ± 13.1 mmol/mol] and 163 nondiabetic control subjects (29% female; age: 45 ± 17 years; BMI: 25.8 ± 4.1 kg/m2; FPG: 5.2 ± 0.4 mM; and HbA1c: 35.4 ± 3.8 mmol/mol). Multiple linear regression analysis was applied using a stepwise approach with fasting plasma glucagon as dependent parameter and BMI, waist-to-hip ratio (WHR), blood pressure, hemoglobin A1c, FPG, and insulin concentrations as independent parameters. RESULTS Fasting plasma glucagon concentrations were significantly higher among patients with T2D (13.5 ± 6.3 vs. 8.5 ± 3.8 mM, P < 0.001) together with HbA1c (P < 0.001), FPG (P < 0.001), and insulin (84.9 ± 56.4 vs. 57.7 ± 35.3 mM, P < 0.001). When adjusted for T2D, HbA1c and insulin were significantly positive determinants for fasting plasma glucagon concentrations. Furthermore, WHR comprised a significant positive determinant. CONCLUSIONS We confirm that fasting plasma glucagon concentrations are abnormally high in patients with T2D, and show that fasting plasma glucagon concentrations are influenced by WHR (in addition to glycemic control and fasting plasma insulin concentrations), which may point to visceral fat deposition as an important determinant of increased fasting plasma glucagon concentrations.
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Affiliation(s)
- Mia Demant
- 1 Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Jonatan I Bagger
- 1 Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Malte P Suppli
- 1 Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Asger Lund
- 1 Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Mette Gyldenløve
- 1 Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Katrine B Hansen
- 1 Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Kristine J Hare
- 1 Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Mikkel Christensen
- 1 Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - David P Sonne
- 1 Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Jens J Holst
- 2 Department of Biomedical Sciences and Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark
| | - Tina Vilsbøll
- 1 Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark .,3 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark
| | - Filip K Knop
- 1 Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark .,3 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark .,4 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark
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8
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Deacon CF. Peptide degradation and the role of DPP-4 inhibitors in the treatment of type 2 diabetes. Peptides 2018; 100:150-157. [PMID: 29412814 DOI: 10.1016/j.peptides.2017.10.011] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 10/19/2017] [Accepted: 10/19/2017] [Indexed: 01/17/2023]
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are now a widely used, safe and efficacious class of antidiabetic drugs, which were developed prospectively using a rational drug design approach based on a thorough understanding of the endocrinology and degradation of glucagon-like peptide-1 (GLP-1). GLP-1 is an intestinal hormone with potent insulinotropic and glucagonostatic effects and can normalise blood glucose levels in patients with type 2 diabetes, but the native peptide is not therapeutically useful because of its inherent metabolic instability. Using the GLP-1/DPP-4 system and type 2 diabetes as an example, this review summarises how knowledge of a peptide's biological effects coupled with an understanding of the pathways involved in its metabolic clearance can be exploited in a rational, step-by-step manner to develop a therapeutic agent, which is effective and well tolerated, and any side effects are minor and largely predictable. Other peptides with metabolic effects which can also be degraded by DPP-4 will be reviewed, and their potential role as additional mediators of the effects of DPP-4 inhibitors will be assessed.
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Affiliation(s)
- Carolyn F Deacon
- Department of Biomedical Sciences, University of Copenhagen, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
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9
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Andersen ES, Deacon CF, Holst JJ. Do we know the true mechanism of action of the DPP-4 inhibitors? Diabetes Obes Metab 2018; 20:34-41. [PMID: 28544214 DOI: 10.1111/dom.13018] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 05/18/2017] [Accepted: 05/21/2017] [Indexed: 12/19/2022]
Abstract
The prevalence of type 2 diabetes is increasing, which is alarming because of its serious complications. Anti-diabetic treatment aims to control glucose homeostasis as tightly as possible in order to reduce these complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a recent addition to the anti-diabetic treatment modalities, and have become widely accepted because of their good efficacy, their benign side-effect profile and their low hypoglycaemia risk. The actions of DPP-4 inhibitors are not direct, but rather are mediated indirectly through preservation of the substrates they protect from degradation. The two incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, are known substrates, but other incretin-independent mechanisms may also be involved. It seems likely therefore that the mechanisms of action of DPP-4 inhibitors are more complex than originally thought, and may involve several substrates and encompass local paracrine, systemic endocrine and neural pathways, which are discussed here.
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Affiliation(s)
- Emilie S Andersen
- Department of Internal Medicine F, Hospital Gentofte, Copenhagen University, Copenhagen, Denmark
- Department of Biomedical Sciences, NNF Center of Basic Metabolic Research, The Panum Institute, Copenhagen University, Copenhagen, Denmark
| | - Carolyn F Deacon
- Department of Biomedical Sciences, NNF Center of Basic Metabolic Research, The Panum Institute, Copenhagen University, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, NNF Center of Basic Metabolic Research, The Panum Institute, Copenhagen University, Copenhagen, Denmark
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10
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Lin PJ, Borer KT. Third Exposure to a Reduced Carbohydrate Meal Lowers Evening Postprandial Insulin and GIP Responses and HOMA-IR Estimate of Insulin Resistance. PLoS One 2016; 11:e0165378. [PMID: 27798656 PMCID: PMC5087910 DOI: 10.1371/journal.pone.0165378] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 10/06/2016] [Indexed: 12/28/2022] Open
Abstract
Background Postprandial hyperinsulinemia, hyperglycemia, and insulin resistance increase the risk of type 2 diabetes (T2D) and cardiovascular disease mortality. Postprandial hyperinsulinemia and hyperglycemia also occur in metabolically healthy subjects consuming high-carbohydrate diets particularly after evening meals and when carbohydrate loads follow acute exercise. We hypothesized the involvement of dietary carbohydrate load, especially when timed after exercise, and mediation by the glucose-dependent insulinotropic peptide (GIP) in this phenomenon, as this incretin promotes insulin secretion after carbohydrate intake in insulin-sensitive, but not in insulin-resistant states. Methods Four groups of eight metabolically healthy weight-matched postmenopausal women were provided with three isocaloric meals (a pre-trial meal and two meals during the trial day) containing either 30% or 60% carbohydrate, with and without two-hours of moderate-intensity exercise before the last two meals. Plasma glucose, insulin, glucagon, GIP, glucagon-like peptide 1 (GLP-1), free fatty acids (FFAs), and D-3-hydroxybutyrate concentrations were measured during 4-h postprandial periods and 3-h exercise periods, and their areas under the curve (AUCs) were analyzed by mixed-model ANOVA, and insulin resistance during fasting and meal tolerance tests within each diet was estimated using homeostasis-model assessment (HOMA-IR). Results The third low-carbohydrate meal, but not the high-carbohydrate meal, reduced: (1) evening insulin AUC by 39% without exercise and by 31% after exercise; (2) GIP AUC by 48% without exercise and by 45% after exercise, and (3) evening insulin resistance by 37% without exercise and by 24% after exercise. Pre-meal exercise did not alter insulin-, GIP- and HOMA-IR- lowering effects of low-carbohydrate diet, but exacerbated evening hyperglycemia. Conclusions Evening postprandial insulin and GIP responses and insulin resistance declined by over 30% after three meals that limited daily carbohydrate intake to 30% compared to no such changes after three 60%-carbohydrate meals, an effect that was independent of pre-meal exercise. The parallel timing and magnitude of postprandial insulin and GIP changes suggest their dependence on a delayed intestinal adaptation to a low-carbohydrate diet. Pre-meal exercise exacerbated glucose intolerance with both diets most likely due to impairment of insulin signaling by pre-meal elevation of FFAs.
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Affiliation(s)
- Po-Ju Lin
- School of Kinesiology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Katarina T. Borer
- School of Kinesiology, University of Michigan, Ann Arbor, Michigan, United States of America
- * E-mail:
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11
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A Prospective Study of Renal Transplant Recipients: A Fall in Insulin Secretion Underpins Dysglycemia After Renal Transplantation. Transplant Direct 2016; 2:e107. [PMID: 27826600 PMCID: PMC5096434 DOI: 10.1097/txd.0000000000000618] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 07/25/2016] [Indexed: 02/06/2023] Open
Abstract
Background Dysglycemia (encompassing impaired glucose tolerance and diabetes mellitus) arising after renal transplantation is common and confers a significant cardiovascular mortality risk. Nonetheless, the pathophysiology of posttransplant dysglycemia is not well described. The aim of this study was to prospectively and comprehensively assess glucose handling in renal transplant recipients from before to 12 months after transplantation to determine the underpinning pathophysiology. Materials and Methods Intravenous and oral glucose tolerance testing was conducted before and at 3 and 12 months posttransplantation. An intravenous glucose tolerance test was also performed on day 7 posttransplantation. We followed up 16 transplant recipients for 3 months and 14 recipients for 12 months. Insulin secretion, resistance and a disposition index (DI (IV)), a measure of β cell responsiveness in the context of prevailing insulin resistance, were also determined. Results At 12 months, 50% of renal transplant recipients had dysglycemia. Dysglycemia was associated with a dramatic fall in DI (IV) and this loss in β cell function was evident as early as 3 months posttransplantation (23.5 pretransplant; 6.4 at 3 months and 12.2 at 12 months posttransplant). Differences in the β cell response to oral glucose challenge were evident pretransplant in those destined to develop dysglycemia posttransplant (2-hour blood glucose level 5.6 mmol/L versus 6.8 mmol/L; P < 0.01). Conclusions Dysglycemia after renal transplantation is common, and the loss of insulin secretion is a major contributor. Subclinical differences in glucose handling are evident pretransplant in those destined to develop dysglycemia potentially heralding a susceptible β cell which under the stressors associated with transplantation fails.
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12
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Aulinger BA, Vahl TP, Prigeon RL, D'Alessio DA, Elder DA. The incretin effect in obese adolescents with and without type 2 diabetes: impaired or intact? Am J Physiol Endocrinol Metab 2016; 310:E774-81. [PMID: 26979523 PMCID: PMC4867309 DOI: 10.1152/ajpendo.00496.2015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 03/07/2016] [Indexed: 01/11/2023]
Abstract
The incretin effect reflects the actions of enteral stimuli to promote prandial insulin secretion. Impairment of this measure has been proposed as an early marker of β-cell dysfunction and described in T2D, IGT, and even obesity without IGT. We sought to determine the effects of obesity and diabetes on the incretin effect in young subjects with short exposures to metabolic abnormalities and a few other confounding medical conditions. Subjects with T2D (n = 10; 18.0 ± 0.4 yr) or NGT, either obese (n = 11; 17.7 ± 0.4 yr) or lean (n = 8; 26.5 ± 2.3 yr), had OGTT and iso-iv. The incretin effect was calculated as the difference in insulin secretion during these tests and was decreased ∼50% in both the NGT-Ob and T2D subjects relative to the NGT-Ln group. The T2D group had impaired glucose tolerance and insulin secretion during the OGTT, whereas the lean and obese NGT subjects had comparable glucose excursions and β-cell function. During the iso-iv test, the NGT-Ob subjects had significantly greater insulin secretion than the NGT-Ln and T2D groups. These findings demonstrate that in young subjects with early, well-controlled T2D the incretin effect is reduced, similar to what has been described in diabetic adults. The lower incretin effect calculated for the obese subjects with NGT is driven by a disproportionately greater insulin response to iv glucose and does not affect postprandial glucose regulation. These findings confirm that the incretin effect is an early marker of impaired insulin secretion in persons with abnormal glucose tolerance but suggest that in obese subjects with NGT the incretin effect calculation can be confounded by exaggerated insulin secretion to iv glucose.
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Affiliation(s)
- Benedikt A Aulinger
- Department of Medicine, University of Cincinnati, Cincinnati, Ohio; Department of Internal Medicine II, Ludwig-Maximillian's University, Munich, Germany
| | - Torsten P Vahl
- Department of Medicine, University of Cincinnati, Cincinnati, Ohio; Department of Medicine, Columbia University, New York, New York
| | - Ron L Prigeon
- Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - David A D'Alessio
- Department of Medicine, University of Cincinnati, Cincinnati, Ohio; Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio; and david.d'
| | - Deborah A Elder
- Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, Ohio
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13
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Chon S, Gautier JF. An Update on the Effect of Incretin-Based Therapies on β-Cell Function and Mass. Diabetes Metab J 2016; 40:99-114. [PMID: 27126881 PMCID: PMC4853229 DOI: 10.4093/dmj.2016.40.2.99] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 03/30/2016] [Indexed: 12/31/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a multifactorial disease with a complex and progressive pathogenesis. The two primary mechanisms of T2DM pathogenesis are pancreatic β-cell dysfunction and insulin resistance. Pancreatic β-cell dysfunction is recognized to be a prerequisite for the development of T2DM. Therapeutic modalities that improve β-cell function are considered critical to T2DM management; however, blood glucose control remains a challenge for many patients due to suboptimal treatment efficacy and the progressive nature of T2DM. Incretin-based therapies are now the most frequently prescribed antidiabetic drugs in Korea. Incretin-based therapies are a favorable class of drugs due to their ability to reduce blood glucose by targeting the incretin hormone system and, most notably, their potential to improve pancreatic β-cell function. This review outlines the current understanding of the incretin hormone system in T2DM and summarizes recent updates on the effect of incretin-based therapies on β-cell function and β-cell mass in animals and humans.
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Affiliation(s)
- Suk Chon
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea
| | - Jean François Gautier
- Department of Diabetes and Endocrinology, DHU FIRE, Lariboisière Hospital, University Paris-Diderot Paris-7, Paris, France.
- Clinical Investigation Center, INSERM-CIC9504, Saint-Louis University Hospital, University Paris-Diderot Paris-7, Paris, France
- INSERM UMRS 1138, Cordeliers Research Center, University Pierre et Marie Curie Paris-6, Paris, France
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14
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Halden TAS, Egeland EJ, Åsberg A, Hartmann A, Midtvedt K, Khiabani HZ, Holst JJ, Knop FK, Hornum M, Feldt-Rasmussen B, Jenssen T. GLP-1 Restores Altered Insulin and Glucagon Secretion in Posttransplantation Diabetes. Diabetes Care 2016; 39:617-24. [PMID: 26908914 DOI: 10.2337/dc15-2383] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 02/04/2016] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Development of posttransplantation diabetes (PTDM) is characterized by reduced insulin secretion and sensitivity. We aimed to investigate whether hyperglucagonemia could play a role in PTDM and to examine the insulinotropic and glucagonostatic effects of the incretin hormone glucagon-like peptide 1 (GLP-1) during fasting and hyperglycemic conditions, respectively. RESEARCH DESIGN AND METHODS Renal transplant recipients with (n = 12) and without (n = 12) PTDM underwent two separate experimental days with 3-h intravenous infusions of GLP-1 (0.8 pmol/kg/min) and saline, respectively. After 1 h of infusion, a 2-h hyperglycemic clamp (fasting plasma glucose + 5 mmol/L) was established. Five grams of arginine was given as an intravenous bolus 10 min before termination of the clamp. RESULTS Fasting concentrations of glucagon (P = 0.92) and insulin (P = 0.23) were similar between the groups. In PTDM patients, glucose-induced glucagon suppression was significantly less pronounced (maximal suppression from baseline: 43 ± 12 vs. 65 ± 12%, P < 0.001), while first- and second-phase insulin secretion were significantly lower. The PTDM group also exhibited a significantly lower insulin response to arginine (P = 0.01) but similar glucagon and proinsulin responses compared with control subjects. In the preclamp phase, GLP-1 lowered fasting plasma glucose to the same extent in both groups but reduced glucagon only in PTDM patients. During hyperglycemic clamp, GLP-1 reduced glucagon concentrations and increased first- and second-phase insulin secretion in both groups. CONCLUSIONS PTDM is characterized by reduced glucose-induced insulin secretion and attenuated glucagon suppression during a hyperglycemic clamp. Similar to the case in type 2 diabetes, GLP-1 infusion seems to improve (insulin) or even normalize (glucagon) these pathophysiological defects.
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Affiliation(s)
- Thea A S Halden
- Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Erlend J Egeland
- Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
| | - Anders Åsberg
- Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway Norwegian Renal Registry, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Anders Hartmann
- Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Karsten Midtvedt
- Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Hassan Z Khiabani
- Department of Pharmacology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Mads Hornum
- Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Bo Feldt-Rasmussen
- Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Trond Jenssen
- Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway
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15
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Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the known incretin hormones in humans, released predominantly from the enteroendocrine K and L cells within the gut. Their secretion is regulated by a complex of integrated mechanisms involving direct contact for the activation of different chemo-sensors on the brush boarder of K and L cells and several indirect neuro-immuno-hormonal loops. The biological actions of GIP and GLP-1 are fundamental determinants of islet function and blood glucose homeostasis in health and type 2 diabetes. Moreover, there is increasing recognition that GIP and GLP-1 also exert pleiotropic extra-glycaemic actions, which may represent therapeutic targets for human diseases. In this review, we summarise current knowledge of the biology of incretin hormones in health and metabolic disorders and highlight the therapeutic potential of incretin hormones in metabolic regulation.
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Affiliation(s)
- Tongzhi Wu
- Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000, Australia
| | - Christopher K Rayner
- Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000, Australia.
- Centre of Research Excellence in Translating Nutritional Science into Good Health, The University of Adelaide, Adelaide, Australia.
| | - Michael Horowitz
- Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000, Australia
- Centre of Research Excellence in Translating Nutritional Science into Good Health, The University of Adelaide, Adelaide, Australia
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Langsford D, Dwyer K. Dysglycemia after renal transplantation: Definition, pathogenesis, outcomes and implications for management. World J Diabetes 2015; 6:1132-51. [PMID: 26322159 PMCID: PMC4549664 DOI: 10.4239/wjd.v6.i10.1132] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Revised: 07/06/2015] [Accepted: 08/16/2015] [Indexed: 02/05/2023] Open
Abstract
New-onset diabetes after transplantation (NODAT) is major complication following renal transplantation. It commonly develops within 3-6 mo post-transplantation. The development of NODAT is associated with significant increase in risk of major cardiovascular events and cardiovascular death. Other dysglycemic states, such as impaired glucose tolerance are also associated with increasing risk of cardiovascular events. The pathogenesis of these dysglycemic states is complex. Older recipient age is a consistent major risk factor and the impact of calcineurin inhibitors and glucocorticoids has been well described. Glucocorticoids likely cause insulin resistance and calcineurin inhibitors likely cause β-cell toxicity. The impact of transplantation in incretin hormones remains to be clarified. The oral glucose tolerance test remains the best diagnostic test but other tests may be validated as screening tests. Possibly, NODAT can be prevented by administering insulin early in patients identified as high risk for NODAT. Once NODAT has been diagnosed altering immunosuppression may be acceptable, but creates the difficulty of balancing immunological with metabolic risk. With regard to hypoglycemic use, metformin may be the best option. Further research is needed to better understand the pathogenesis, identify high risk patients and to improve management options given the significant increased risk of major cardiovascular events and death.
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Sato S, Saisho Y, Inaishi J, Kou K, Murakami R, Yamada T, Itoh H. Effects of Glucocorticoid Treatment on β- and α-Cell Mass in Japanese Adults With and Without Diabetes. Diabetes 2015; 64:2915-27. [PMID: 25883114 DOI: 10.2337/db15-0151] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 04/11/2015] [Indexed: 11/13/2022]
Abstract
The aim of this study was 1) to clarify β-cell regenerative capacity in the face of glucocorticoid (GC)-induced insulin resistance and 2) to clarify the change in β- and α-cell mass in GC-induced diabetes in humans. We obtained the pancreases from 100 Japanese autopsy case subjects. The case subjects were classified according to whether or not they had received GC therapy before death and the presence or absence of diabetes. Fractional β-cell area (%BCA) and α-cell area (%ACA) were quantified, and the relationship with GC therapy was evaluated. As a result, in case subjects without diabetes, there was no significant difference in %BCA between case subjects with and without GC therapy (1.66 ± 1.05% vs. 1.21 ± 0.59%, P = 0.13). %ACA was also not significantly different between the two groups. In case subjects with type 2 diabetes, %BCA and %ACA were both significantly reduced compared with control subjects without diabetes; however, neither %BCA nor %ACA was significantly decreased in case subjects with GC-induced diabetes. There was a significant negative correlation between %BCA and HbA1c measured before death; however, this relationship was attenuated in case subjects with GC therapy. In conclusion, the current study suggests that β- and α-cell mass remain largely unchanged in the face of GC-induced insulin resistance in Japanese individuals, implying limited capacity of β-cell regeneration in adult humans. The absence of apparent β-cell deficit in case subjects with GC-induced diabetes suggests that GC-induced diabetes is mainly caused by insulin resistance and/or β-cell dysfunction, but not necessarily a deficit of β-cell mass.
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Affiliation(s)
- Seiji Sato
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yoshifumi Saisho
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Jun Inaishi
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Kinsei Kou
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Rie Murakami
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Taketo Yamada
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Hiroshi Itoh
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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18
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Aulinger BA, Vahl TP, Wilson-Pérez HE, Prigeon RL, D'Alessio DA. β-Cell Sensitivity to GLP-1 in Healthy Humans Is Variable and Proportional to Insulin Sensitivity. J Clin Endocrinol Metab 2015; 100:2489-96. [PMID: 25825945 PMCID: PMC4454808 DOI: 10.1210/jc.2014-4009] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
CONTEXT Glucagon-like peptide-1 (GLP-1) is an insulinotropic factor made in the gastrointestinal tract that is essential for normal glucose tolerance. Infusion of GLP-1 increases insulin secretion in both diabetic and nondiabetic humans. However, the degree to which people vary in their β-cell sensitivity to GLP-1 and the factors contributing to this variability have not been reported. OBJECTIVE The objective was to measure the sensitivity of insulin secretion to GLP-1 in cohorts of lean and obese subjects across a broad range of insulin sensitivity. METHODS Insulin secretion was measured during clamped hyperglycemia (7.2 mmol/L) and graded GLP-1 infusion in young, healthy subjects, and GLP-1 sensitivity was computed from the insulin secretion rate (ISR) during progressive increases in plasma GLP-1. RESULTS All subjects had fasting glucose values <5.2 mm. The obese subjects were insulin resistant compared to the lean group (homeostasis model of assessment 2 for insulin resistance: obese, 2.6 ± 0.5; lean, 0.8 ± 0.1; P < .001). ISR increased linearly in both cohorts with escalating doses of GLP-1, but the slope of ISR in response to GLP-1 was greater in the obese than in the lean subjects (obese, 0.17 ± 0.03 nmol/min/pm; lean, 0.05 ± 0.01 nmol/min/pm; P < .001). There was a significant association of β-cell GLP-1 sensitivity and insulin resistance (r = 0.83; P < .001), and after correction for homeostasis model of assessment 2 for insulin resistance, the slopes of ISR vs GLP-1 concentration did not differ in the two cohorts (obese, 0.08 ± 0.01; lean, 0.08 ± 0.01; P = .98). However, within the entire study group, β-cell GLP-1 sensitivity corrected for insulin resistance varied nearly 10-fold. CONCLUSIONS Insulin secretion in response to GLP-1 is proportional to insulin resistance in healthy subjects. However, there is considerable variability in the sensitivity of the β-cell to GLP-1 that is independent of insulin sensitivity.
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Affiliation(s)
- Benedikt A Aulinger
- Division of Endocrinology, Diabetes, and Metabolism (B.A.A., T.P.V., H.E.W.-P., D.A.D.), Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267; University of Maryland School of Medicine (R.L.P.), and Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201; and Cincinnati Veterans Affairs Medical Center (D.A.D.), Cincinnati, Ohio 45220
| | - Torsten P Vahl
- Division of Endocrinology, Diabetes, and Metabolism (B.A.A., T.P.V., H.E.W.-P., D.A.D.), Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267; University of Maryland School of Medicine (R.L.P.), and Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201; and Cincinnati Veterans Affairs Medical Center (D.A.D.), Cincinnati, Ohio 45220
| | - Hilary E Wilson-Pérez
- Division of Endocrinology, Diabetes, and Metabolism (B.A.A., T.P.V., H.E.W.-P., D.A.D.), Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267; University of Maryland School of Medicine (R.L.P.), and Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201; and Cincinnati Veterans Affairs Medical Center (D.A.D.), Cincinnati, Ohio 45220
| | - Ron L Prigeon
- Division of Endocrinology, Diabetes, and Metabolism (B.A.A., T.P.V., H.E.W.-P., D.A.D.), Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267; University of Maryland School of Medicine (R.L.P.), and Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201; and Cincinnati Veterans Affairs Medical Center (D.A.D.), Cincinnati, Ohio 45220
| | - David A D'Alessio
- Division of Endocrinology, Diabetes, and Metabolism (B.A.A., T.P.V., H.E.W.-P., D.A.D.), Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267; University of Maryland School of Medicine (R.L.P.), and Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201; and Cincinnati Veterans Affairs Medical Center (D.A.D.), Cincinnati, Ohio 45220
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19
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Rajan S, Dickson LM, Mathew E, Orr CMO, Ellenbroek JH, Philipson LH, Wicksteed B. Chronic hyperglycemia downregulates GLP-1 receptor signaling in pancreatic β-cells via protein kinase A. Mol Metab 2015; 4:265-76. [PMID: 25830090 PMCID: PMC4354925 DOI: 10.1016/j.molmet.2015.01.010] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 01/21/2015] [Accepted: 01/26/2015] [Indexed: 02/07/2023] Open
Abstract
Objective Glucagon-like peptide 1 (GLP-1) enhances insulin secretion and protects β-cell mass. Diabetes therapies targeting the GLP-1 receptor (GLP-1R), expressed in numerous tissues, have diminished dose-response in patients with type 2 diabetes compared with healthy human controls. The aim of this study was to determine the mechanistic causes underlying the reduced efficacy of GLP-1R ligands. Methods Using primary mouse islets and the β-cell line MIN6, outcomes downstream of the GLP-1R were analyzed: Insulin secretion; phosphorylation of the cAMP-response element binding protein (CREB); cAMP responses. Signaling systems were studied by immunoblotting and qRT-PCR, and PKA activity was assayed. Cell surface localization of the GLP-1R was studied by confocal microscopy using a fluorescein-tagged exendin-4 and GFP-tagged GLP-1R. Results Rodent β-cells chronically exposed to high glucose had diminished responses to GLP-1R agonists including: diminished insulin secretory response; reduced phosphorylation of (CREB); impaired cAMP response, attributable to chronically increased cAMP levels. GLP-1R signaling systems were affected by hyperglycemia with increased expression of mRNAs encoding the inducible cAMP early repressor (ICER) and adenylyl cyclase 8, reduced PKA activity due to increased expression of the PKA-RIα subunit, reduced GLP-1R mRNA expression and loss of GLP-1R from the cell surface. To specifically examine the loss of GLP-1R from the plasma membrane a GLP-1R-GFP fusion protein was employed to visualize subcellular localization. Under low glucose conditions or when PKA activity was inhibited, GLP-1R-GFP was found at the plasma membrane. Conversely high glucose, expression of a constitutively active PKA subunit, or exposure to exendin-4 or forskolin led to GLP-1R-GFP internalization. Mutation of serine residue 301 of the GLP-1R abolished the glucose-dependent loss of the receptor from the plasma membrane. This was associated with a loss of an interaction between the receptor and the small ubiquitin-related modifier (SUMO), an interaction that was found to be necessary for internalization of the receptor. Conclusions These data show that glucose acting, at least in part, via PKA leads to the loss of the GLP-1R from the cell surface and an impairment of GLP-1R signaling, which may underlie the reduced clinical efficacy of GLP-1R based therapies in individuals with poorly controlled hyperglycemia.
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Affiliation(s)
- Sindhu Rajan
- Kovler Diabetes Center, The University of Chicago, USA ; Department of Medicine, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, The University of Chicago, USA
| | - Lorna M Dickson
- Kovler Diabetes Center, The University of Chicago, USA ; Department of Medicine, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, The University of Chicago, USA
| | - Elizabeth Mathew
- Kovler Diabetes Center, The University of Chicago, USA ; Department of Medicine, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, The University of Chicago, USA
| | - Caitlin M O Orr
- Kovler Diabetes Center, The University of Chicago, USA ; Department of Medicine, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, The University of Chicago, USA ; Committee on Molecular Metabolism and Nutrition, The University of Chicago, USA
| | - Johanne H Ellenbroek
- Kovler Diabetes Center, The University of Chicago, USA ; Department of Medicine, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, The University of Chicago, USA
| | - Louis H Philipson
- Kovler Diabetes Center, The University of Chicago, USA ; Department of Medicine, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, The University of Chicago, USA ; Committee on Molecular Metabolism and Nutrition, The University of Chicago, USA
| | - Barton Wicksteed
- Kovler Diabetes Center, The University of Chicago, USA ; Department of Medicine, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, The University of Chicago, USA ; Committee on Molecular Metabolism and Nutrition, The University of Chicago, USA
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Aaboe K, Akram S, Deacon CF, Holst JJ, Madsbad S, Krarup T. Restoration of the insulinotropic effect of glucose-dependent insulinotropic polypeptide contributes to the antidiabetic effect of dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab 2015; 17:74-81. [PMID: 25243647 DOI: 10.1111/dom.12395] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 09/14/2014] [Accepted: 09/15/2014] [Indexed: 01/31/2023]
Abstract
AIMS To examine whether 12 weeks of treatment with a dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, influences the insulin secretion induced by glucose, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during a hyperglycaemic clamp in patients with type 2 diabetes (T2DM). METHODS A randomized, double-blind, placebo-controlled study was conducted over 12 weeks, during which 25 patients with T2DM completed treatment with either sitagliptin (100 mg once daily) or placebo as add-on therapy to metformin [sitagliptin group (n = 12): mean ± standard error of the mean (s.e.m.) age 54 ± 2.5 years, mean ± s.e.m. HbA1c 7.8 ± 0.2%; placebo group (n = 13): mean ± s.e.m. age: 57 ± 3.0 years, mean ± s.e.m. HbA1c 7.9 ± 0.2 %]. In weeks 1 and 12, the patients underwent three 2-h 15-mM hyperglycaemic clamp experiments with infusion of either saline, GLP-1 or GIP. β-cell function was evaluated according to first-phase, second-phase, incremental and total insulin and C-peptide responses. RESULTS In the sitagliptin group, the mean HbA1c concentration was significantly reduced by 0.9% (p = 0.01). The total β-cell response during GIP infusion improved significantly from week 1 to week 12, both within the sitagliptin group (p = 0.004) and when compared with the placebo group (p = 0.04). The total β-cell response during GLP-1 infusion was significantly higher (p = 0.001) when compared with saline and GIP infusion, but with no improvement from week 1 to week 12. No significant changes in β-cell function occurred in the placebo group. CONCLUSIONS Treatment with the DPP-4 inhibitor sitagliptin over 12 weeks in patients with T2DM partially restored the lost insulinotropic effect of GIP, whereas the preserved insulinotropic effect of GLP-1 was not further improved. A gradual enhancement of the insulinotropic effect of GIP, therefore, possibly contributes to the antidiabetic actions of DPP-4 inhibitors.
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Affiliation(s)
- K Aaboe
- Department of Endocrinology I, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
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Abstract
In normal physiology, glucagon from pancreatic alpha cells plays an important role in maintaining glucose homeostasis via its regulatory effect on hepatic glucose production. Patients with type 2 diabetes suffer from fasting and postprandial hyperglucagonemia, which stimulate hepatic glucose production and, thus, contribute to the hyperglycemia characterizing these patients. Although this has been known for years, research focusing on alpha cell (patho)physiology has historically been dwarfed by research on beta cells and insulin. Today the mechanisms behind type 2 diabetic hyperglucagonemia are still poorly understood. Preclinical and clinical studies have shown that the gastrointestinal hormone glucose-dependent insulinotropic polypeptide (GIP) might play an important role in this pathophysiological phenomenon. Furthermore, it has become apparent that suppression of glucagon secretion or antagonization of the glucagon receptor constitutes potentially effective treatment strategies for patients with type 2 diabetes. In this review, we focus on the regulation of glucagon secretion by the incretin hormones glucagon-like peptide-1 (GLP-1) and GIP. Furthermore, potential advantages and limitations of suppressing glucagon secretion or antagonizing the glucagon receptor, respectively, in the treatment of patients with type 2 diabetes will be discussed.
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Affiliation(s)
- Asger Lund
- Center for Diabetes Research, Department of Medicine, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
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22
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Chon S, Riveline JP, Blondeau B, Gautier JF. Incretin-based therapy and pancreatic beta cells. DIABETES & METABOLISM 2014; 40:411-22. [DOI: 10.1016/j.diabet.2014.05.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 05/19/2014] [Accepted: 05/21/2014] [Indexed: 01/09/2023]
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Plourde CÉ, Grenier-Larouche T, Caron-Dorval D, Biron S, Marceau S, Lebel S, Biertho L, Tchernof A, Richard D, Carpentier AC. Biliopancreatic diversion with duodenal switch improves insulin sensitivity and secretion through caloric restriction. Obesity (Silver Spring) 2014; 22:1838-46. [PMID: 24760439 DOI: 10.1002/oby.20771] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 04/07/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To assess the rapid improvement of insulin sensitivity and β-cell function following biliopancreatic diversion with duodenal switch (BPD-DS) and determine the role played by caloric restriction in these changes. METHODS Standard meals were administrated before and on day 3, 4, and 5 after BPD-DS to measure total caloric intake, glucose excursion, insulin sensitivity, and secretion in matched type 2 diabetes and normoglycemic (NG) subjects. In a second set of study, other subjects with type 2 diabetes had the same meal tests prior to and after a 3-day caloric restriction identical to that observed after BPD-DS and then 3 days after actually undergoing BPD-DS. RESULTS Improvement of HOMA-IR occurred at day 3 after BPD-DS in diabetes and after 3 days of caloric restriction. The disposition index (DI) improved rapidly in diabetes after BPD-DS and to a similar extent after caloric restriction. DI was higher and did not change after BPD-DS in NG. Changes in glucagon-like peptide-1, gastric inhibitory peptide, peptide tyrosine tyrosine, ghrelin, and pancreatic polypeptide levels were not associated with modulation of DI in the participants. CONCLUSIONS Caloric restriction is the major mechanism underlying the early improvement of insulin sensitivity and β-cell function after BPD-DS in type 2 diabetes.
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Affiliation(s)
- Charles-Étienne Plourde
- Department of Medicine, Division of Endocrinology, Centre de recherche clinique Étienne-Le Bel, Université de Sherbrooke, Québec, Canada; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, Canada
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Geographical distribution patterns of iodine in drinking-water and its associations with geological factors in Shandong Province, China. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2014; 11:5431-44. [PMID: 24852390 PMCID: PMC4053898 DOI: 10.3390/ijerph110505431] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Revised: 04/29/2014] [Accepted: 05/04/2014] [Indexed: 11/17/2022]
Abstract
County-based spatial distribution characteristics and the related geological factors for iodine in drinking-water were studied in Shandong Province (China). Spatial autocorrelation analysis and spatial scan statistic were applied to analyze the spatial characteristics. Generalized linear models (GLMs) and geographically weighted regression (GWR) studies were conducted to explore the relationship between water iodine level and its related geological factors. The spatial distribution of iodine in drinking-water was significantly heterogeneous in Shandong Province (Moran's I = 0.52, Z = 7.4, p < 0.001). Two clusters for high iodine in drinking-water were identified in the south-western and north-western parts of Shandong Province by the purely spatial scan statistic approach. Both GLMs and GWR indicated a significantly global association between iodine in drinking-water and geological factors. Furthermore, GWR showed obviously spatial variability across the study region. Soil type and distance to Yellow River were statistically significant at most areas of Shandong Province, confirming the hypothesis that the Yellow River causes iodine deposits in Shandong Province. Our results suggested that the more effective regional monitoring plan and water improvement strategies should be strengthened targeting at the cluster areas based on the characteristics of geological factors and the spatial variability of local relationships between iodine in drinking-water and geological factors.
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Strom Halden TA, Asberg A, Vik K, Hartmann A, Jenssen T. Short-term efficacy and safety of sitagliptin treatment in long-term stable renal recipients with new-onset diabetes after transplantation. Nephrol Dial Transplant 2014; 29:926-33. [DOI: 10.1093/ndt/gft536] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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Alssema M, Rijkelijkhuizen JM, Holst JJ, Teerlink T, Scheffer PG, Eekhoff EMW, Gastaldelli A, Mari A, Hart LM, Nijpels G, Dekker JM. Preserved GLP-1 and exaggerated GIP secretion in type 2 diabetes and relationships with triglycerides and ALT. Eur J Endocrinol 2013; 169:421-30. [PMID: 23864340 DOI: 10.1530/eje-13-0487] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
OBJECTIVE To i) compare incretin responses to oral glucose and mixed meal of diabetic patients with the normoglycaemic population and ii) to investigate whether incretin responses are associated with hypertriglyceridaemia and alanine aminotransferase (ALT) as liver fat marker. DESIGN A population-based study. METHODS A total of 163 persons with normal glucose metabolism (NGM), 20 with intermediate hyperglycaemia and 20 with type 2 diabetes aged 40-65 years participated. Participants received a mixed meal and oral glucose load on separate occasions. Glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon profiles were analysed as total area under the curve (tAUC) and incremental area under the curve. RESULTS In diabetic patients compared with persons with NGM, we found increased GLP-1 secretion (tAUC per hour) following oral glucose (23.2 pmol/l (95% CI 17.7-28.7) vs 18.0 (95% CI 16.9-19.1), P<0.05) but not after the mixed meal. GIP secretion among diabetic patients was increased on both occasions (82.9 pmol/l (55.9-109.8) vs 47.1 (43.8-50.4) for oral glucose and 130.6 (92.5-168.7) vs 83.2 (77.5-88.9) for mixed meal, both P<0.05). After oral glucose, GLP-1 (tAUC per hour) was inversely related to fasting triglycerides. GIP (tAUC per hour) was positively related to fasting and postprandial triglycerides. Higher fasting GIP levels were related to higher fasting and postprandial triglyceride levels and ALT. CONCLUSION This study confirms that in type 2 diabetes, GLP-1 secretion is generally preserved and that GIP secretion is exaggerated. The mechanism underlying the divergent associations of GLP-1 and GIP metabolism with fat metabolism and liver fat accumulation warrants further study.
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Affiliation(s)
- Marjan Alssema
- Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands
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Kosinski M, Knop F, Vedtofte L, Grycewiczv J, Swierzewska P, Cypryk K, Vilsbøll T. Postpartum reversibility of impaired incretin effect in gestational diabetes mellitus. ACTA ACUST UNITED AC 2013; 186:104-7. [DOI: 10.1016/j.regpep.2013.08.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Revised: 07/25/2013] [Accepted: 08/08/2013] [Indexed: 01/23/2023]
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Yuen KCJ, Chong LE, Riddle MC. Influence of glucocorticoids and growth hormone on insulin sensitivity in humans. Diabet Med 2013; 30:651-63. [PMID: 23510125 DOI: 10.1111/dme.12184] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/13/2013] [Indexed: 12/17/2022]
Abstract
The seminal concept proposed by Sir Harold Himsworth more than 75 years ago that a large number of patients with diabetes were 'insulin insensitive', now termed insulin resistance, has now expanded to include several endocrine syndromes, namely those of glucocorticoid excess, and growth hormone excess and deficiency. Synthetic glucocorticoids are increasingly used to treat a wide variety of chronic diseases, whereas the beneficial effects of recombinant growth hormone replacement therapy in children and adults with growth hormone deficiency have now been well-recognized for over 25 years. However, clinical and experimental studies have established that increased circulating levels of glucocorticoids and growth hormone can also lead to worsening of insulin resistance, glucose intolerance, overt diabetes mellitus and cardiovascular disease. Improved understanding of the physiological 24-h rhythmicity of glucocorticoid and growth hormone secretion and its influence on the dawn phenomenon and the Staub-Trauggot effect has therefore led to renewed interest in studies on the mechanisms of insulin resistance induced by exogenous administration of glucocorticoids and growth hormone in humans. In this review, we describe the physiological events that result from the presence of resistance to insulin action at the level of skeletal muscle, adipose tissue, and liver, describe the known mechanisms of glucocorticoid- and growth hormone-mediated insulin resistance, and provide an update of the contributions of glucocorticoids and growth hormone to understanding the pathophysiology of insulin resistance and its effects on several endocrine syndromes.
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Affiliation(s)
- K C J Yuen
- Department of Medicine, Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health and Science University, Portland, OR, USA.
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Incretin dysfunction in type 2 diabetes: Clinical impact and future perspectives. DIABETES & METABOLISM 2013; 39:195-201. [DOI: 10.1016/j.diabet.2013.03.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 03/08/2013] [Accepted: 03/11/2013] [Indexed: 01/21/2023]
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van Raalte DH, Kwa KAA, van Genugten RE, Tushuizen ME, Holst JJ, Deacon CF, Karemaker JM, Heine RJ, Mari A, Diamant M. Islet-cell dysfunction induced by glucocorticoid treatment: potential role for altered sympathovagal balance? Metabolism 2013; 62:568-77. [PMID: 23164480 DOI: 10.1016/j.metabol.2012.10.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Revised: 10/06/2012] [Accepted: 10/10/2012] [Indexed: 11/22/2022]
Abstract
AIM Glucocorticoids impair glucose tolerance by inducing insulin resistance. We investigated the dose-dependent effects of glucocorticoid treatment on islet-cell function in healthy males and studied the role of the autonomic nervous system. DESIGN AND METHODS A randomized, placebo-controlled, double-blind, dose-response intervention study was conducted in 32 healthy males (age: 21±2years; BMI: 21.9±1.7kg/m(2)). Participants were allocated to prednisolone 7.5mg once daily (n=12), prednisolone 30mg once daily (n=12), or placebo (n=8) for two weeks. Beta-cell function was measured by hyperglycemic clamp with arginine stimulation, glucagon levels were measured following a standardized meal test. RESULTS We found that prednisolone treatment dose-dependently reduced C-peptide secretion following arginine stimulation on top of hyperglycemia (ASI-iAUCCP): -2.8 (-5.2;0.2) and -3.1 (-8.8; -1.0) nmolL(-1)min(-1) for prednisolone 7.5mg and prednisolone 30mg, respectively (P=0.035 vs. placebo). Fasting glucagon levels increased dose-dependently (vs. placebo; P=0.001), whereas postprandial glucagon levels were only increased by prednisolone 30mg. Changes in parasympathetic activity related with changes in fasting glucose levels (r=-0.407; P=0.03) and showed a trend towards correlation with fasting glucagon concentrations (r=-0.337; P=0.07). The change in sympathovagal balance was inversely related to ASI-iAUCCP (r=-0.365; P=0.05). CONCLUSION We conclude that in addition to inducing insulin resistance, prednisolone treatment dose-dependently impaired islet-cell function. Altered sympathovagal balance may be related to these effects.
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Affiliation(s)
- Daniël H van Raalte
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, De Boelelaan 1117, 1007MB, PO Box 7057, Amsterdam, The Netherlands.
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Bllaci L, Kjellström S, Eliasson L, Friend JR, Yeo LY, Nilsson S. Fast surface acoustic wave-matrix-assisted laser desorption ionization mass spectrometry of cell response from islets of Langerhans. Anal Chem 2013; 85:2623-9. [PMID: 23384197 DOI: 10.1021/ac3019125] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
A desire for higher speed and performance in molecular profiling analysis at a reduced cost is driving a trend in miniaturization and simplification of procedures. Here we report the use of a surface acoustic wave (SAW) atomizer for fast sample handling in matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) peptide and protein profiling of Islets of Langerhans, for future type 2 diabetes (T2D) studies. Here the SAW atomizer was used for ultrasound (acoustic) extraction of insulin and other peptide hormones released from freshly prepared islets, stimulated directly on a membrane. A high energy propagating SAW atomizes the membrane-bound liquid into approximately 2 μm diameter droplets, rich in cell-released molecules. Besides acting as a sample carrier, the membrane provides a purification step by entrapping cell clusters and other impurities within its fibers. A new SAW-based sample-matrix deposition method for MALDI MS was developed and characterized by a strong insulin signal, and a limit of detection (LOD) lower than 100 amol was achieved. Our results support previous work reporting the SAW atomizer as a fast and inexpensive tool for ultrasound, membrane-based sample extraction. When interfaced with MALDI MS, the SAW atomizer constitutes a valuable tool for rapid cell studies. Other biomedical applications of SAW-MALDI MS are currently being developed, aiming at fast profiling of biofluids. The membrane sampling is a simplistic and noninvasive collection method of limited volume biofluids such as the gingival fluid and the tearfilm.
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Affiliation(s)
- Loreta Bllaci
- Lund University, Center for Chemistry and Chemical Engineering, Pure and Applied Biochemistry, Box 124, 221 00 Lund, Sweden
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Cummings BP, Bremer AA, Kieffer TJ, D'Alessio D, Havel PJ. Investigation of the mechanisms contributing to the compensatory increase in insulin secretion during dexamethasone-induced insulin resistance in rhesus macaques. J Endocrinol 2013; 216:207-15. [PMID: 23151361 DOI: 10.1530/joe-12-0459] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Dexamethasone has well-described effects to induce insulin resistance and increase insulin secretion. Herein, we examined potential contributors to the effect of dexamethasone to increase insulin secretion in rhesus macaques. Six male rhesus macaques received daily injections of either saline or dexamethasone (0.25 mg/kg i.m. for 7 days) in random order with 3 weeks between treatments. At the end of the treatment period, animals were fasted overnight and underwent a feeding study the next day, during which blood samples were taken before and for 60 min after a meal in order to assess islet hormone and incretin secretion. Dexamethasone induced marked increases in fasting plasma insulin, glucagon, leptin, and adiponectin concentrations (P<0.05). Surprisingly, the glycemic response after meal ingestion was decreased twofold during dexamethasone treatment (P<0.05). Dexamethasone-treated animals exhibited a significant increase in both insulin and glucose-dependent insulinotropic polypeptide (GIP) secretion during the feeding study (P<0.05). However, glucagon-like peptide-1 secretion was significantly lower in dexamethasone-treated animals compared with controls (P<0.01). Fasting and meal-stimulated pancreatic polypeptide concentrations (an index of the parasympathetic input to the islet) did not differ between saline and dexamethasone treatments. However, the proinsulin:insulin ratio was decreased throughout the feeding study with dexamethasone treatment suggesting an improvement of β-cell function (P<0.05). In conclusion, the maintenance of euglycemia and reduction of postprandial glycemia with short-term dexamethasone treatment appears to be due to the marked elevations of fasting and meal-stimulated insulin secretion. Furthermore, increases in postprandial GIP secretion with dexamethasone treatment appear to contribute to the effect of dexamethasone treatment to increase insulin secretion.
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Affiliation(s)
- Bethany P Cummings
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, California 95616, USA.
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Herzberg-Schäfer S, Heni M, Stefan N, Häring HU, Fritsche A. Impairment of GLP1-induced insulin secretion: role of genetic background, insulin resistance and hyperglycaemia. Diabetes Obes Metab 2012; 14 Suppl 3:85-90. [PMID: 22928568 DOI: 10.1111/j.1463-1326.2012.01648.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
One major risk factor of type 2 diabetes is the impairment of glucose-induced insulin secretion which is mediated by the individual genetic background and environmental factors. In addition to impairment of glucose-induced insulin secretion, impaired glucagon-like peptide (GLP)1-induced insulin secretion has been identified to be present in subjects with diabetes and impaired glucose tolerance, but little is known about its fundamental mechanisms. The state of GLP1 resistance is probably an important mechanism explaining the reduced incretin effect observed in type 2 diabetes. In this review, we address methods that can be used for the measurement of insulin secretion in response to GLP1 in humans, and studies showing that specific diabetes risk genes are associated with resistance of the secretory function of the β-cell in response to GLP1 administration. Furthermore, we discuss other factors that are associated with impaired GLP1-induced insulin secretion, for example, insulin resistance. Finally, we provide evidence that hyperglycaemia per se, the genetic background and their interaction result in the development of GLP1 resistance of the β-cell. We speculate that the response or the non-response to therapy with GLP1 analogues and/or dipeptidyl peptidase-4 (DPP-IV) inhibitors is critically dependent on GLP1 resistance.
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Affiliation(s)
- S Herzberg-Schäfer
- Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University, Tübingen, Germany
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Ahrén B. Incretin hormones and the up-regulation of insulin secretion in insulin resistance. J Clin Endocrinol Metab 2012; 97:1173-5. [PMID: 22493308 DOI: 10.1210/jc.2012-1420] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
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