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Volumn 10, Issue 3, 2010, Pages 192-198

The contribution of enteroinsular hormones to the pathogenesis of type 2 diabetes mellitus

Author keywords

DPP 4; Enteroinsular axis; GIP; GLP 1; Glucagon; Incretins; Insulin; Type 2 diabetes

Indexed keywords

ALOGLIPTIN; ANTIDIABETIC AGENT; EXENDIN 4; GASTRIC INHIBITORY POLYPEPTIDE; GASTROINTESTINAL HORMONE; GLUCAGON LIKE PEPTIDE 1; INCRETIN; LIRAGLUTIDE; PLACEBO; SAXAGLIPTIN; SITAGLIPTIN; TRANSCRIPTION FACTOR 7 LIKE 2; VILDAGLIPTIN;

EID: 77956394651     PISSN: 15344827     EISSN: None     Source Type: Journal    
DOI: 10.1007/s11892-010-0114-6     Document Type: Review
Times cited : (3)

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    • Fifteen nondiabetic individuals participated in euglycemic and hyperglycemic clamps to assess the effects of acute hyperglycemia on the incretin response. It was found that the postprandial increases in GIP and GLP-1 following the administration of a mixed meal were about 50% lower during the experiments with hyperglycemia. Hyperglycemia also elicited a significant delay in gastric emptying
    • Vollmer K, Gardiwal H, Menge BA, et al.: Hyperglycemia acutely lowers the postprandial excursions of glucagon-like peptide-1 and gastric inhibitory polypeptide in humans. J Clin Endocrinol Metab 2009, 94:1379-1385. Fifteen nondiabetic individuals participated in euglycemic and hyperglycemic clamps to assess the effects of acute hyperglycemia on the incretin response. It was found that the postprandial increases in GIP and GLP-1 following the administration of a mixed meal were about 50% lower during the experiments with hyperglycemia. Hyperglycemia also elicited a significant delay in gastric emptying.
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    • Vollmer, K.1    Gardiwal, H.2    Menge, B.A.3
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    • Four weeks of nearnormalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes
    • This study evaluated the incretin effect in eight obese diabetic patients with poor glycemic control before and after 4 weeks of near-normalization of blood glucose levels using insulin treatment. After 4 weeks, it was found that ß-cell responsiveness to both GLP-1 and GIP improved by a factor of 3 to 4
    • Hojberg PV, Vilsboll T, Rabol R, et al.: Four weeks of nearnormalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 2009, 52:199-207. This study evaluated the incretin effect in eight obese diabetic patients with poor glycemic control before and after 4 weeks of near-normalization of blood glucose levels using insulin treatment. After 4 weeks, it was found that ß-cell responsiveness to both GLP-1 and GIP improved by a factor of 3 to 4.
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    • Hojberg, P.V.1    Vilsboll, T.2    Rabol, R.3
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    • Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin effect in type 2 diabetes mellitus
    • Glucagon suppression responses were studied during OGTT and IV glucose infusion in 10 diabetic patients and 10 controls; these were found to be significantly attenuated and delayed only in the diabetic patients after oral ingestion of glucose, suggesting that this phenomenon contributes to both the glucose intolerance and reduced incretin effect observed in patients with type 2 diabetes
    • Knop FK, Vilsboll T, Madsbad S, et al.: Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin effect in type 2 diabetes mellitus. Diabetologia 2007, 50:797-805. Glucagon suppression responses were studied during OGTT and IV glucose infusion in 10 diabetic patients and 10 controls; these were found to be significantly attenuated and delayed only in the diabetic patients after oral ingestion of glucose, suggesting that this phenomenon contributes to both the glucose intolerance and reduced incretin effect observed in patients with type 2 diabetes.
    • (2007) Diabetologia , vol.50 , pp. 797-805
    • Knop, F.K.1    Vilsboll, T.2    Madsbad, S.3
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    • Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals
    • Saxena R, Gianniny L, Burtt NP, et al.: Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes 2006, 55:2890-2895.
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    • This review article focuses on the recent genetic discoveries pertaining to polygenic type 2 diabetes
    • Grant RW, Moore AF, Florez JC: Genetic architecture of type 2 diabetes: recent progress and clinical implications. Diabetes Care 2009, 32:1107-1114. This review article focuses on the recent genetic discoveries pertaining to polygenic type 2 diabetes.
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    • Grant, R.W.1    Moore, A.F.2    Florez, J.C.3
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    • Impaired glucagonlike peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms
    • A total of 1110 nondiabetic German participants were genotyped for polymorphisms in TCF7L2 and underwent an OGTT to assess the incretin response. Two hundred and ten participants also underwent an IV glucose tolerance test. It was found that variants of TCF7L2 specifically impair GLP-1- induced insulin secretion, and this was likely due to a defect in GLP-1 signaling as opposed to a reduction in GLP-1 secretion
    • Schafer SA, Tschritter O, Machicao F, et al.: Impaired glucagonlike peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia 2007, 50:2443-2450. A total of 1110 nondiabetic German participants were genotyped for polymorphisms in TCF7L2 and underwent an OGTT to assess the incretin response. Two hundred and ten participants also underwent an IV glucose tolerance test. It was found that variants of TCF7L2 specifically impair GLP-1- induced insulin secretion, and this was likely due to a defect in GLP-1 signaling as opposed to a reduction in GLP-1 secretion.
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    • Schafer, S.A.1    Tschritter, O.2    Machicao, F.3
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    • The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men
    • In this study, 81 healthy young Danish men underwent genotyping for the T allele of rs7903146 TCF7L2 along with various ß-cell tests. It was found that subjects with this genotype had reduced 24-hour insulin and glucagon concentrations, along with reduced insulin secretion during mixed meal testing and elevated hepatic glucose production
    • Pilgaard K, Jensen CB, Schou JH, et al.: The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men. Diabetologia 2009, 52:1298-1307. In this study, 81 healthy young Danish men underwent genotyping for the T allele of rs7903146 TCF7L2 along with various ß-cell tests. It was found that subjects with this genotype had reduced 24-hour insulin and glucagon concentrations, along with reduced insulin secretion during mixed meal testing and elevated hepatic glucose production.
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    • Pilgaard, K.1    Jensen, C.B.2    Schou, J.H.3
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    • TCF7L2 variant rs7903146 affects the risk of type 2 diabetes by modulating incretin action
    • This study evaluated eight subjects with risk-conferring TCF7L2 genotypes (TT or TC at rs7903146) and 10 matched subjects with wild-type genotype (CC). The incretin effect was assessed from ratios of the insulin secretory rates during oral and isoglycemic glucose infusions. ß- Cell responsivity to oral glucose was 50% lower in the group of subjects with risk-conferring TCF7L2 genotypes compared with control subjects. The incretin effect was also reduced by 30% in the at-risk group, suggesting that this genotypic variant affects the risk of type 2 diabetes, at least in part, by modifying the effect of incretins on insulin secretion
    • Villereal DT, Robertson H, Bell GI, et al.: TCF7L2 variant rs7903146 affects the risk of type 2 diabetes by modulating incretin action. Diabetes 2010, 59:479-485. This study evaluated eight subjects with risk-conferring TCF7L2 genotypes (TT or TC at rs7903146) and 10 matched subjects with wild-type genotype (CC). The incretin effect was assessed from ratios of the insulin secretory rates during oral and isoglycemic glucose infusions. ß- Cell responsivity to oral glucose was 50% lower in the group of subjects with risk-conferring TCF7L2 genotypes compared with control subjects. The incretin effect was also reduced by 30% in the at-risk group, suggesting that this genotypic variant affects the risk of type 2 diabetes, at least in part, by modifying the effect of incretins on insulin secretion.
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    • Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus
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    • Liraglutide once a day versus exenatide twice a day for type 2 diabetes: A 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)
    • This is a 26-week trial comparing once-daily liraglutide with twice-daily exenatide in 233 diabetic patients who were uncontrolled on maximally tolerated doses of metformin, sulfonylurea, or both. This study revealed that liraglutide once a day provided significantly greater improvements in glycemic control than did exenatide twice a day and was generally better tolerated
    • Buse JB, Rosenstock J, Sesti G, et al.: Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009, 374:39-47. This is a 26-week trial comparing once-daily liraglutide with twice-daily exenatide in 233 diabetic patients who were uncontrolled on maximally tolerated doses of metformin, sulfonylurea, or both. This study revealed that liraglutide once a day provided significantly greater improvements in glycemic control than did exenatide twice a day and was generally better tolerated.
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    • Vilsboll T: Liraglutide: a new treatment for type 2 diabetes. Drugs Today (Barc) 2009, 45:101-113.
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    • Liraglutide, a once-daily human GLP-1 analogue, improves pancreatic B-cell function and argininestimulated insulin secretion during hyperglycaemia in patients with type 2 diabetes mellitus
    • Vilsboll T, Brock B, Perrild H, et al.: Liraglutide, a once-daily human GLP-1 analogue, improves pancreatic B-cell function and argininestimulated insulin secretion during hyperglycaemia in patients with type 2 diabetes mellitus. Diabet Med 2008, 25:152-156.
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    • Liraglutide, a longacting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes
    • Vilsboll T, Zdravkovic M, Le-Thi T, et al.: Liraglutide, a longacting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care 2007, 30:1608-1610.
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    • Vilsboll, T.1    Zdravkovic, M.2    Le-Thi, T.3
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    • Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years
    • This randomized openlabel trial showed that adjunctive exenatide treatment for at least 3 years in patients with type 2 diabetes resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction
    • Klonoff DC, Buse JB, Nielsen LL, et al.: Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin 2008, 24:275-286. This randomized openlabel trial showed that adjunctive exenatide treatment for at least 3 years in patients with type 2 diabetes resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.
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    • Klonoff, D.C.1    Buse, J.B.2    Nielsen, L.L.3
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    • Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes
    • This is a 15-week randomized clinical trial that evaluated the effect of lower and higherdose exenatide LAR administered to 45 diabetic subjects with suboptimal glycemic control on metformin and/or diet and exercise. It was found that subjects receiving exenatide LAR had significant reductions in mean HbA1c compared with placebo, and subjects receiving the higher dose of exenatide LAR also had significant reductions in mean weight compared with the other two groups
    • Kim D, MacConell L, Zhuang D, et al.: Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care 2007, 30:1487-1493. This is a 15-week randomized clinical trial that evaluated the effect of lower and higherdose exenatide LAR administered to 45 diabetic subjects with suboptimal glycemic control on metformin and/or diet and exercise. It was found that subjects receiving exenatide LAR had significant reductions in mean HbA1c compared with placebo, and subjects receiving the higher dose of exenatide LAR also had significant reductions in mean weight compared with the other two groups.
    • (2007) Diabetes Care , vol.30 , pp. 1487-1493
    • Kim, D.1    MacConell, L.2    Zhuang, D.3
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    • Clinical results of treating type 2 diabetic patients with sitagliptin, vildagliptin or saxagliptin-diabetes control and potential adverse events
    • This is an excellent current review of the three available DPP-4 inhibitors that summarizes the results of the clinical studies demonstrating the efficacy and safety data for these agents
    • Ahren B: Clinical results of treating type 2 diabetic patients with sitagliptin, vildagliptin or saxagliptin-diabetes control and potential adverse events. Best Pract Res Clin Endocrinol Metab 2009, 23:487-498. This is an excellent current review of the three available DPP-4 inhibitors that summarizes the results of the clinical studies demonstrating the efficacy and safety data for these agents.
    • (2009) Best Pract Res Clin Endocrinol Metab , vol.23 , pp. 487-498
    • Ahren, B.1


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