Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans

2004 ◽  
Vol 287 (2) ◽  
pp. E199-E206 ◽  
Author(s):  
Jens Juul Holst ◽  
Jesper Gromada
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Response ◽  
Strong Support ◽  
Oral Glucose ◽  
Second Phase ◽  
Incretin Hormones ◽  
Incretin Effect ◽  
Glucagon Like Peptide 1

The available evidence suggests that about two-thirds of the insulin response to an oral glucose load is due to the potentiating effect of gut-derived incretin hormones. The strongest candidates for the incretin effect are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). In patients with type 2 diabetes, however, the incretin effect is lost or greatly impaired. It is hypothesized that this loss explains an important part of the impaired insulin secretion in patients. Further analysis of the incretin effects in patients has revealed that the secretion of GIP is near normal, whereas the secretion of GLP-1 is decreased. On the other hand, the insulintropic effect of GLP-1 is preserved, whereas the effect of GIP is greatly reduced, mainly because of a complete loss of the normal GIP-induced potentiation of second-phase insulin secretion. These two features, therefore, explain the incretin defect of type 2 diabetes. Strong support for the hypothesis that the defect plays an important role in the insulin deficiency of patients is provided by the finding that administration of excess GLP-1 to patients may completely restore the glucose-induced insulin secretion as well as the β-cells' sensitivity to glucose. Because of this, analogs of GLP-1 or GLP-1 receptor activations are currently being developed for diabetes treatment, so far with very promising results.

scholarly journals Inhibition of DPP-4 with Vildagliptin Improved Insulin Secretion in Response to Oral as well as “Isoglycemic” Intravenous Glucose without Numerically Changing the Incretin Effect in Patients with Type 2 Diabetes

2011 ◽  
Vol 96 (4) ◽  
pp. 945-954 ◽  
Author(s):  
Irfan Vardarli ◽  
Michael A. Nauck ◽  
Lars D. Köthe ◽  
Carolyn F. Deacon ◽  
Jens J. Holst ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glycosylated Hemoglobin ◽  
Oral Glucose ◽  
Incretin Effect ◽  
Intravenous Glucose ◽  
Dipeptidyl Peptidase 4 ◽  
Glucagon Like Peptide 1 ◽  
D 12

Abstract Background and Aims: Dipeptidyl peptidase-4 (DPP-4) inhibitors block the degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. The aim of the present study was to quantitatively assess the incretin effect after treatment with the DPP-4 inhibitor vildagliptin (V) or placebo (P) in patients with type 2 diabetes. Materials and Methods: Twenty-one patients (three women, 18 men) with type 2 diabetes previously treated with metformin (mean age, 59 yr; body mass index, 28.6 kg/m2; glycosylated hemoglobin, 7.3%) were studied in a two-period crossover design. They received 100 mg V once daily or P for 13 d in randomized order. The incretin effect was measured on d 12 (75-g oral glucose) and d 13 (“isoglycemic” iv glucose) based on insulin and C-peptide determinations and insulin secretion rates (ISR). Results: V relative to P treatment significantly increased intact incretin concentrations after oral glucose and insulin secretory responses to both oral glucose and isoglycemic iv glucose (e.g. AUCISR oral, by 32.7%, P = 0.0006; AUCISR iv, by 33.1%, P = 0.01). The numerical incretin effect was not changed (IEISR, V vs. P, 35.7 ± 4.9 and 34.6 ± 4.0%, P = 0.80). Conclusions: DPP-4 inhibition augmented insulin secretory responses both after oral glucose and during isoglycemic iv glucose infusions, with no net change in the incretin effect. Thus, slight variations in basal incretin levels may be more important than previously thought. Or, DPP-4 inhibitor-induced change in the incretin-related environment of islets may persist overnight, augmenting insulin secretory responses to iv glucose as well. Alternatively, yet unidentified mediators of DPP-4 inhibition may have caused these effects.

DPP-4 Inhibition as a Newly Emerging Therapy for Type 2 Diabetes

2006 ◽  
Vol 00 (02) ◽  
Author(s):  
Carolyn F Deacon ◽  
Jens Juul Holst
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Progressive Disease ◽  
Incretin Hormones ◽  
New Approach ◽  
Current Therapies ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Emerging Therapy

Type 2 diabetes mellitus (T2DM) is a progressive disease, characterized by insulin resistance, impaired glucose-induced insulin secretion, inappropriately elevated glucagon concentrations, and hyperglycemia. Many patients cannot obtain satisfactory glycemic control with current therapies, and eventually develop microvascular and macrovascular diabetic complications. New and more effective agents, targeted not only at treatment, but also at prevention of the disease, its progression, and its associated complications, are, therefore, required. One new approach focuses on the effects of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which enhance mealinduced insulin secretion.1

Secretion of incretin hormones (GIP and GLP-1) and incretin effect after oral glucose in first-degree relatives of patients with type 2 diabetes

2004 ◽  
Vol 122 (3) ◽  
pp. 209-217 ◽  
Author(s):  
Michael A. Nauck ◽  
Andrea El-Ouaghlidi ◽  
Bartholomäus Gabrys ◽  
Katrin Hücking ◽  
Jens J. Holst ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Oral Glucose ◽  
Incretin Hormones ◽  
Incretin Effect ◽  
First Degree Relatives

scholarly journals Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial

Diabetes Care ◽  
2022 ◽  
Author(s):  
Marta Garaulet ◽  
Jesus Lopez-Minguez ◽  
Hassan S. Dashti ◽  
Céline Vetter ◽  
Antonio Miguel Hernández-Martínez ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Insulin Response ◽  
Area Under The Curve ◽  
Oral Glucose ◽  
Elevated Concentration ◽  
Endogenous Melatonin

OBJECTIVE We tested whether the concurrence of food intake and elevated concentration of endogenous melatonin, as occurs in late eating, results in impaired glucose control, in particular in carriers of the type 2 diabetes–associated G allele in the melatonin receptor-1b gene (MTNR1B). RESEARCH DESIGN AND METHODS In a Spanish natural late-eating population, a randomized, crossover study was performed. Each participant (n = 845) underwent two evening 2-h 75-g oral glucose tolerance tests following an 8-h fast: an early condition scheduled 4 h prior to habitual bedtime (“early dinner timing”) and a late condition scheduled 1 h prior to habitual bedtime (“late dinner timing”), simulating an early and a late dinner timing, respectively. Differences in postprandial glucose and insulin responsesbetween early and late dinner timing were determined using incremental area under the curve (AUC) calculated by the trapezoidal method. RESULTS Melatonin serum levels were 3.5-fold higher in the late versus early condition, with late dinner timing resulting in 6.7% lower insulin AUC and 8.3% higher glucose AUC. In the late condition, MTNR1B G-allele carriers had lower glucose tolerance than noncarriers. Genotype differences in glucose tolerance were attributed to reductions in β-cell function (P for interaction, Pint glucose area under the curve = 0.009, Pint corrected insulin response = 0.022, and Pint Disposition Index = 0.018). CONCLUSIONS Concurrently high endogenous melatonin and carbohydrate intake, as typical for late eating, impairs glucose tolerance, especially in MTNR1B G-risk allele carriers, attributable to insulin secretion defects.

scholarly journals Diabetes and obesity. The role of agonists glucagon-like peptide-1 of in the treatment of type 2 diabetes

2018 ◽  
Vol 21 (4) ◽  
pp. 293-300 ◽  
Author(s):  
Nina A. Petunina ◽  
Milena Е. Telnova
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Response ◽  
Diabetic Patients ◽  
Incretin Effect ◽  
Receptor Agonists ◽  
Number Of Patients ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Diabetes And Obesity

Significant number of patients with type 2 diabetes mellitus are obese. It is known that even glucose intolerance, as well as diabetes, can lead to vascular complications. At the same time, weight loss can reduce the risk of type 2 diabetes in obese and pre-diabetic patients. According to available data, a significant decrease in the incretin effect is observed in patients with type 2 diabetes and obese individuals. Thus, a decrease in the incretin effect leads to a violation of the insulin response to the intake of carbohydrates, and, consequently, an increase in the level of glucose in the blood. It was also found that the decrease in the incretin effect in patients with type 2 diabetes can be associated with a lower secretion of glucagon-like peptide-1. The interest is represented by groups of antidiabetic drugs capable of regulating glycemia by affecting the secretion of insulin and glucagon, depending on its level. Such drugs include glucagon-like peptide-1 receptor agonists. The article shows the advantage of prolonged action in patients with type 2 diabetes and obesity of the glucagon-like peptide 1 receptor agonists (albiglutide, dulaglutide, exenatide with slow release) dosing 1 time a week.

Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes

2007 ◽  
Vol 292 (6) ◽  
pp. E1775-E1781 ◽  
Author(s):  
Kenneth Cusi ◽  
Sangeeta Kashyap ◽  
Amalia Gastaldelli ◽  
Mandeep Bajaj ◽  
Eugenio Cersosimo
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Family History ◽  
Second Phase ◽  
Β Cell ◽  
C Peptide ◽  
Hyperglycemic Clamp ◽  
History Of ◽  
Plasma Ffa

Elevated plasma FFA cause β-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% ( P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or ΔC-peptide/Δglucose AUC (+177%, P = 0.02), an index of improved β-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 ± 5% ( P < 0.04). First- (+19 ± 6%, P = 0.1) and second-phase (+31 ± 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 ± 7 ( P < 0.05) and 41 ± 8% ( P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR ( r2 = 0.31, P < 0.02) and acute (2–4 min) glucose-induced insulin release after acipimox ( r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.

Subcutaneous glucagon-like peptide-1 improves postprandial glycaemic control over a 3-week period in patients with early Type 2 diabetes

1998 ◽  
Vol 95 (3) ◽  
pp. 325-329 ◽  
Author(s):  
Jeannie F. TODD ◽  
C. Mark B. EDWARDS ◽  
Mohammad A. GHATEI ◽  
Hugh M. MATHER ◽  
Stephen R. BLOOM
Keyword(s):  
Type 2 Diabetes ◽  
Glycaemic Control ◽  
Plasma Glucose ◽  
Test Meal ◽  
Insulin Response ◽  
Standard Test ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
First Phase Insulin Response

1.Glucagon-like peptide-1 (7-36) amide (GLP-1) is released into the circulation after meals and is the most potent physiological insulinotropic hormone in man. GLP-1 has the advantages over other therapeutic agents for Type 2 diabetes of also suppressing glucagon secretion and delaying gastric emptying. One of the initial abnormalities of Type 2 diabetes is the loss of the first-phase insulin response, leading to postprandial hyperglycaemia. 2.To investigate the therapeutic potential of GLP-1 in Type 2 diabetes, six patients were entered into a 6-week, double-blind crossover trial during which each received 3 weeks treatment with subcutaneous GLP-1 or saline, self-administered three times a day immediately before meals. A standard test meal was given at the beginning and end of each treatment period. 3.GLP-1 reduced plasma glucose area under the curve (AUC) after the standard test meal by 58% (AUC, 0–240 ;min: GLP-1 start of treatment, 196±141 ;mmol·min-1·l-1; saline start of treatment, 469±124 ;mmol·min-1·l-1; F = 16.4, P< 0.05). The plasma insulin excursions were significantly higher with GLP-1 compared with saline over the initial postprandial 30 ;min, the time period during which the GLP-1 concentration was considerably elevated. The plasma glucagon levels were significantly lower over the 240-min postprandial period with GLP-1 treatment. The beneficial effects of GLP-1 on plasma glucose, insulin and glucagon concentrations were fully maintained for the 3-week treatment period. 4.We have demonstrated a significant improvement in postprandial glycaemic control with subcutaneous GLP-1 treatment. GLP-1 improves glycaemic control partially by restoring the first-phase insulin response and suppressing glucagon and is a potential treatment for Type 2 diabetes.

scholarly journals Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial

2022 ◽  
Author(s):  
Marta Garaulet ◽  
Jesus Lopez-Minguez ◽  
Hassan S Dashti ◽  
Céline Vetter ◽  
Antonio Miguel Hernández-Martínez ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Area Under The Curve ◽  
Serum Levels ◽  
Postprandial Glucose ◽  
Oral Glucose ◽  
Elevated Concentration ◽  
Endogenous Melatonin

<strong>Objective: </strong>We tested whether the concurrence of food intake and elevated concentration of endogenous melatonin, as occurs in late eating, results in impaired glucose control, in particular in carriers of the type 2 diabetes-associated G allele in the melatonin-receptor-1-b gene (<i>MTNR1B</i>).<strong> </strong> <p><strong>Research Design and Methods:</strong> In a Spanish natural late eating population, a randomized, cross-over study design was performed, following an 8-h fast. Each participant <strong>(n=845) </strong>underwent two evening 2-h 75g oral glucose tolerance tests (OGTT): an early condition scheduled 4 hours prior to habitual bedtime <strong>(“early dinner-timing”)</strong>, and a late condition scheduled 1 hour prior to habitual bedtime <strong>(“late dinner-timing”)</strong>, simulating an early and a late dinner timing, respectively.<strong> </strong>Differences in postprandial glucose and insulin responses were determined using incremental area under the curve (AUC) calculated by the trapezoidal method between <strong>early and late dinner-timing.</strong><strong></strong></p> <p><strong>Results:</strong> <strong>Melatonin serum levels were </strong>3.5-fold <strong>higher in the late <i>vs. </i>early condition, with late dinner-timing resulting in </strong>6.7% <strong>lower insulin</strong> <strong>area-under-the-curve (AUC) and </strong>8.3%<strong> higher glucose</strong> <strong>AUC. In the late condition<i> MTNR1B</i> G-allele carriers had lower glucose tolerance than non-carriers. Genotype differences in glucose tolerance were attributed to reductions in </strong>β-cell <strong>function (<i>P<sub>int</sub></i><sub> </sub>AUCgluc=0.009, <i>P<sub>int</sub></i><sub> </sub>CIR=0.022, <i>P<sub>int </sub></i>DI=0.018).</strong></p> <p><strong>Conclusions:</strong> <strong>Concurrently high endogenous melatonin and carbohydrate intake, as typical for late eating, impair glucose tolerance, especially in <i>MTNR1B</i> G-risk-allele carriers<i>, </i>attributable to insulin secretion defects.</strong></p>

scholarly journals Glucagon-Like Peptide 1: A Predictor of Type 2 Diabetes?

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Matthias Ploug Larsen ◽  
Signe Sørensen Torekov
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Fasting Glucose ◽  
Incretin Effect ◽  
Nonesterified Fatty Acids ◽  
Incretin Hormone ◽  
Pubmed Database ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Background. The incretin effect is impaired in patients with type 2 diabetes. Aim. To assess the relation between the incretin hormone GLP-1 and the prediabetic subtypes: impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and the combined IFG/IGT to investigate whether a low GLP-1 response may be a predictor of prediabetes in adults. Method. 298 articles were found using a broad search phrase on the PubMed database and after the assessment of titles and abstracts 19 articles were included. Results and Discussion. Studies assessing i-IFG/IFG and i-IGT/IGT found both increased, unaltered, and reduced GLP-1 levels. Studies assessing IFG/IGT found unaltered or reduced GLP-1 levels. When assessing the five studies with the largest sample size, it clearly suggests a decreased GLP-1 response in IFG/IGT subjects. Several other factors (BMI, glucagon, age, and nonesterified fatty acids (NEFA)), including medications (metformin), may also influence the secretion of GLP-1. Conclusion. This review suggests that the GLP-1 response is a variable in prediabetes possibly due to a varying GLP-1-secreting profile during the development and progression of type 2 diabetes or difference in the measurement technique. Longitudinal prospective studies are needed to assess whether a reduced GLP-1 response is a predictor of diabetes.

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