Effects of endogenous GLP-1 and GIP on glucose tolerance after Roux-en-Y gastric bypass surgery

Exaggerated secretion of glucagon-like peptide 1 (GLP-1) is important for postprandial glucose tolerance after Roux-en-Y gastric bypass (RYGB), whereas the role of glucose-dependent insulinotropic polypeptide (GIP) remains to be resolved. We aimed to explore the relative importance of endogenously secreted GLP-1 and GIP on glucose tolerance and β-cell function after RYGB. We used DPP-4 inhibition to enhance concentrations of intact GIP and GLP-1 and the GLP-1 receptor antagonist exendin-(9–39) (Ex-9) for specific blockage of GLP-1 actions. Twelve glucose-tolerant patients were studied after RYGB in a randomized, placebo-controlled, 4-day crossover study with standard mixed-meal tests and concurrent administration of placebo, oral sitagliptin, Ex-9 infusion, or combined Ex-9-sitagliptin. GLP-1 receptor antagonism increased glucose excursions, clearly attenuated β-cell function, and aggravated postprandial hyperglucagonemia compared with placebo, whereas sitagliptin had no effect despite two- to threefold increased concentrations of intact GLP-1 and GIP. Similarly, sitagliptin did not affect glucose tolerance or β-cell function during GLP-1R blockage. This study confirms the importance of GLP-1 for glucose tolerance after RYGB via increased insulin and attenuated glucagon secretion in the postprandial state, whereas amplification of the GIP signal (or other DPP-4-sensitive glucose-lowering mechanisms) did not appear to contribute to the improved glucose tolerance seen after RYGB.

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Mechanisms of action of a carbohydrate-reduced, high-protein diet in reducing the risk of postprandial hypoglycemia after Roux-en-Y gastric bypass surgery

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqy310 ◽

2019 ◽

Vol 110 (2) ◽

pp. 296-304 ◽

Cited By ~ 3

Author(s):

Daniel Kandel ◽

Kirstine Nyvold Bojsen-Møller ◽

Maria Saur Svane ◽

Amirsalar Samkani ◽

Arne Astrup ◽

...

Keyword(s):

Gastric Bypass ◽

Insulin Secretion ◽

Cell Function ◽

Gastric Bypass Surgery ◽

High Protein Diet ◽

Glucagon Secretion ◽

Glucose Variability ◽

High Protein ◽

Β Cell Function ◽

Glucagon Like Peptide 1

ABSTRACT Background Postprandial hypoglycemia is a risk after Roux-en-Y gastric bypass (RYGB). Objectives We speculated that a carbohydrate-reduced, high-protein (CRHP) diet might reduce the risk of hypoglycemia and therefore compared the acute effects of a conventionally recommended (CR) diet and CRHP diet [55/30 energy percent (E%) carbohydrate and 15/30 E% protein, respectively] in RYGB patients. Methods Ten individuals (2 males, 8 females, mean ± SD age 47 ± 7 y; stable body mass index 31 ± 6 kg/m2; 6 ± 3 y post-RYGB) with recurrent postprandial hypoglycemia documented by plasma glucose (PG) ≤3.4 mmol/L were examined on 2 d with isoenergetic CRHP or CR diets comprising a breakfast and subsequent lunch meal. Results Peak PG was significantly reduced on the CRHP diet after breakfast and lunch by 11% and 31% compared with the CR diet. Nadir PG increased significantly on CRHP (by 13% and 9%). Insulin secretion was reduced, and glucagon secretion increased on the CRHP diet after both meals. Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide secretion were lower after lunch but unaltered after breakfast on CRHP; β-cell function and insulin clearance were unchanged. Conclusions The CRHP diet lowered glucose excursions and reduced insulin secretion and incretin hormone responses, but enhanced glucagon responses compared with the CR diet. Taken together, the results may explain the decreased glucose variability and lower risk of postprandial hypoglycemia. This study was registered at clinicaltrials.gov as NCT02665715.

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Exaggerated Glucagon-Like Peptide 1 Response Is Important for Improved β-Cell Function and Glucose Tolerance After Roux-en-Y Gastric Bypass in Patients With Type 2 Diabetes

Diabetes ◽

10.2337/db13-0022 ◽

2013 ◽

Vol 62 (9) ◽

pp. 3044-3052 ◽

Cited By ~ 195

Author(s):

Nils B. Jørgensen ◽

Carsten Dirksen ◽

Kirstine N. Bojsen-Møller ◽

Siv H. Jacobsen ◽

Dorte Worm ◽

...

Keyword(s):

Type 2 Diabetes ◽

Gastric Bypass ◽

Glucose Tolerance ◽

Cell Function ◽

Β Cell ◽

Β Cell Function ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Vildagliptin An Oral Dipeptidyl Peptidase-4 Inhibitor for Type 2 Diabetes

US Endocrinology ◽

10.17925/use.2006.00.02.1m ◽

2006 ◽

Vol 00 (02) ◽

Author(s):

Eberhard Standl ◽

Martin Fuchtenbusch ◽

Michael Hummel

Keyword(s):

Type 2 Diabetes ◽

Large Scale ◽

Cell Function ◽

Glucagon Secretion ◽

Postprandial Glucose ◽

Dipeptidyl Peptidase ◽

Β Cell ◽

Dipeptidyl Peptidase 4 ◽

Β Cell Function

Vildagliptin is a member of a new class of oral antidiabetogenic agents known as dipeptidyl peptidase-4 (DDP-4) inhibitors.These drugs enhance islet function by improving α- and β-cell responsiveness to glucose. Mechanism of action studies in patients with type 2 diabetes show that vildagliptin increases plasma levels of active glucagon-like peptide-1, improves glucosedependent insulin secretion and β-cell function, improves insulin sensitivity, reduces inappropriate glucagon secretion, reduces fasting and postprandial glucose, and decreases HbA1c. Large-scale treatment trials with vildagliptin 50mg or 100mg per day as monotherapy or in combination in drug-naïve patients or as add-on therapy to on-going anti-diabetic treatment show that it is effective in reducing HbA1c (with greater decreases occurring in patients with higher initial HbA1c levels), maintains efficacy in glycemic control as monotherapy for at least 1 year, is associated with infrequent hypoglycemia, and does not cause weight gain.

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Upregulated insulin secretion in insulin-resistant mice: evidence of increased islet GLP1 receptor levels and GPR119-activated GLP1 secretion

Endocrine Connections ◽

10.1530/ec-12-0079 ◽

2013 ◽

Vol 2 (2) ◽

pp. 69-78 ◽

Cited By ~ 19

Author(s):

L Ahlkvist ◽

K Brown ◽

B Ahrén

Keyword(s):

Cell Function ◽

Hormone Secretion ◽

Glucagon Secretion ◽

Β Cell ◽

Insulin Resistant ◽

Protein Levels ◽

Islet Hormone ◽

Β Cell Function ◽

Glucagon Like Peptide 1 ◽

Insulin Responses

We previously demonstrated that the overall incretin effect and the β-cell responsiveness to glucagon-like peptide-1 (GLP1) are increased in insulin-resistant mice and may contribute to the upregulated β-cell function. Now we examined whether this could, first, be explained by increased islet GLP1 receptor (GLP1R) protein levels and, secondly, be leveraged by G-protein-coupled receptor 119 (GPR119) activation, which stimulates GLP1 secretion. Female C57BL/6J mice, fed a control (CD, 10% fat) or high-fat (HFD, 60% fat) diet for 8 weeks, were anesthetized and orally given a GPR119 receptor agonist (GSK706A; 10 mg/kg) or vehicle, followed after 10 min with gavage with a liquid mixed meal (0.285 kcal). Blood was sampled for determination of glucose, insulin, intact GLP1, and glucagon, and islets were isolated for studies on insulin and glucagon secretion and GLP1R protein levels. In HFD vs CD mice, GPR119 activation augmented the meal-induced increase in the release of both GLP1 (AUCGLP1 81±9.6 vs 37±6.9 pM×min, P=0.002) and insulin (AUCINS 253±29 vs 112±19 nM×min, P<0.001). GPR119 activation also significantly increased glucagon levels in both groups (P<0.01) with, however, no difference between the groups. By contrast, GPR119 activation did not affect islet hormone secretion from isolated islets. Glucose elimination after meal ingestion was significantly increased by GPR119 activation in HFD mice (0.57±0.04 vs 0.43±0.03% per min, P=0.014) but not in control mice. Islet GLP1R protein levels was higher in HFD vs CD mice (0.8±0.1 vs 0.5±0.1, P=0.035). In conclusion, insulin-resistant mice display increased islet GLP1R protein levels and augmented meal-induced GLP1 and insulin responses to GPR119 activation, which results in increased glucose elimination. We suggest that the increased islet GLP1R protein levels together with the increased GLP1 release may contribute to the upregulated β-cell function in insulin resistance.

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Pathogenetic substantiation and effectiveness of vildagliptin use inpatients with diabetes mellitus type 2

Obesity and metabolism ◽

10.14341/2071-8713-5241 ◽

2009 ◽

Vol 6 (3) ◽

pp. 16-26 ◽

Cited By ~ 1

Author(s):

T I Romantsova

Keyword(s):

Type 2 Diabetes ◽

Cell Function ◽

Glucagon Secretion ◽

Β Cell ◽

Dipeptidyl Peptidase 4 ◽

Glucose Levels ◽

Β Cell Function ◽

Control Of Diabetes ◽

Glucagon Like Peptide 1

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. Now it isrecognized that the β-cell failure occurs much earlier and is more severe than previously thought. As a result, earlier and more aggressive new therapy is needed to achiev e better control of diabetes and to prev ent/slow the progressive B-cell failure that already is w ell established in IGT subjects. One approach is to target the incretin mimetic hormone glucagon-like peptide-1 (GLP-1). When blood glucose levels are elevated, GrP-1 stimulates insulin secretion, decreases glucagon secretion, impro ves β-cell function, and slows gastric emptying. GrP-1 production is reduced in patients with type 2 diabetes. Furthermore, GrP-1 is rapidly degraded by the dipeptidyl peptidase 4 (DPP-4) enzyme. Trials have showed, that new inhibitor DPP-4 vildagliptin (Galvus) hav e been demonstrated to significantly reduce HbA lc, fasting and prandial glucose levels when used as monotherapy and in соmbination with traditional agents. Advantages of vildagliptin include few adverse events, low risk of hypoglycemia, neutral effect on body weight, and a once-daily oral dosing regimen. Inaddition, vildagliptin may preserve the decline in β-cell function. Hence, vildagliptin may modify the natural progressive course of diabetes; this however, must be confirmed with longer-term controlled studies

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Improvement in β-cell function in patients with normal and hyperglycemia following Roux-en-Y gastric bypass surgery

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00405.2010 ◽

2010 ◽

Vol 299 (5) ◽

pp. E706-E712 ◽

Cited By ~ 44

Author(s):

Edward Lin ◽

Zhe Liang ◽

Jennifer Frediani ◽

Scott S. Davis ◽

John F. Sweeney ◽

...

Keyword(s):

Gastric Bypass ◽

Cell Function ◽

Gastric Bypass Surgery ◽

Insulin Response ◽

Model Assessment ◽

Obese Women ◽

Β Cell ◽

Tissue Mass ◽

Intravenous Glucose ◽

Β Cell Function

Glycemic disorders resolve following Roux-en-Y gastric bypass (RYGB) surgery, but early and longer-term mechanisms regarding effects on β-cell dysfunction as well as relationships with decreasing adiposity are not well understood. We evaluated longitudinal changes in peripheral insulin sensitivity (Si), the acute insulin response to glucose (AIRg), and the composite estimate of β-cell function, the disposition index (DI), over 24 mo via frequently sampled intravenous glucose tolerance testing in severely obese women who had fasting normoglycemia ( n = 16) and hyperglycemia ( n = 11) before RYGB surgery; homeostatic model assessment (HOMA-IR) estimated insulin resistance; air displacement plethysmography determined adipose tissue mass. At baseline, subjects with normoglycemia had adequate DI associated with elevated AIRg, but DI was markedly reduced in subjects with hyperglycemia. Within 1–6 mo post-RYGB, glycemic control was normalized in subjects with hyperglycemia related to reduced HOMA-IR (−54% at 1 mo, P < 0.005) and increased DI (23-fold at 6 mo vs. baseline, P < 0.05). Over 24 mo, DI improved in subjects with hyperglycemia (15-fold vs. baseline, P < 0.005) and also modestly in subjects with normoglycemia (58%, P < 0.05), due largely to increased Si. Decreasing adiposity correlated with longer-term HOMA-IR and Si values at 6 and 24 mo, respectively. In patients exhibiting fasting hyperglycemia before surgery, β-cell function improved early following RYGB, due largely to increases in insulin secretion. For both normoglycemic and hyperglycemic subjects, further improvement or stabilization of β-cell function over the 2 yr is due largely to improved Si associated with reduced adiposity.

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