scholarly journals Mechanisms for the Antihyperglycemic Effect of Sitagliptin in Patients with Type 2 Diabetes

2012 ◽  
Vol 97 (8) ◽  
pp. 2818-2826 ◽  
Author(s):  
Elza Muscelli ◽  
Arturo Casolaro ◽  
Amalia Gastaldelli ◽  
Andrea Mari ◽  
Giuseppe Seghieri ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Oral Glucose ◽  
Incretin Effect ◽  
Β Cell ◽  
Endogenous Glucose ◽  
Cell Glucose

Abstract Context: Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, β-cell function, endogenous glucose production) are not well known. Objective: The aim of the study was to examine mechanisms of the antihyperglycemic effect of DPP-4 inhibitors. Design, Setting, and Patients: We administered a mixed meal with glucose tracers ([6,6-2H2]-glucose infused, [1-2H]-glucose ingested), and on a separate day, a glucose infusion matched the glucose responses to the meal (isoglycemic test) in 50 type 2 diabetes patients (hemoglobin A1c = 7.4 ± 0.8%) and seven controls; 47 diabetic completers were restudied after 6 wk. Glucose fluxes were calculated, and β-cell function was assessed by mathematical modeling. The incretin effect was calculated as the ratio of oral to iv insulin secretion. Intervention: We conducted a 6-wk, double-blind, randomized treatment with sitagliptin (100 mg/d; n = 25) or placebo (n = 22). Results: Relative to placebo, meal-induced changes in fasting glucose and glucose area under the curve (AUC) were greater with sitagliptin, in parallel with a lower appearance of oral glucose [difference (post-pre) AUC = −353 ± 915 vs. +146 ± 601 μmol · kg−1 · 5 h] and greater suppression of endogenous glucose production. Insulin sensitivity improved 10%, whereas total insulin secretion was unchanged. During the meal, β-cell glucose sensitivity improved (+19[29] vs. 5[21] pmol · min−1 · m−2 · mm−1; median [interquartile range]) and glucagon AUC decreased (19.6 ± 7.5 to 17.3 ± 7.1 ng · ml−1 · 5 h), whereas intact glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 AUC increased with sitagliptin vs. placebo. The incretin effect was unchanged because sitagliptin increased β-cell glucose sensitivity also during the isoglycemic test. Conclusions: Chronic sitagliptin treatment improves glycemic control by lowering the appearance of oral glucose, postprandial endogenous glucose release, and glucagon response, and by improving insulin sensitivity and β-cell glucose sensing in response to both oral and iv glucose.

scholarly journals Higher Endogenous Glucose Production During OGTT vs Isoglycemic Intravenous Glucose Infusion

2016 ◽  
Vol 101 (11) ◽  
pp. 4377-4384 ◽  
Author(s):  
Asger Lund ◽  
Jonatan I. Bagger ◽  
Mikkel Christensen ◽  
Magnus Grøndahl ◽  
Gerrit van Hall ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Body Mass Index ◽  
Hemoglobin A1c ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Oral Glucose ◽  
Control Subjects ◽  
Nondiabetic Control ◽  
Endogenous Glucose

Context: Oral glucose ingestion elicits a larger insulin response and delayed suppression of glucagon compared to isoglycemic IV glucose infusion (IIGI). Objective: We studied whether these differences translate into effects on endogenous glucose production (EGP) and glucose disposal in patients with type 2 diabetes and nondiabetic control subjects. Design: This was a single-blinded, randomized, crossover study. Setting: The study was conducted at a specialized research unit. Participants: Ten patients with type 2 diabetes (age, [mean ± SD] 57.1 ± 6.7 years; body mass index, 29.0 ± 4.3 kg/m2; hemoglobin A1c, 53.8 ± 11.0 mmol/mol; duration of diabetes, 9.2 ± 5.0 years) and 10 matched nondiabetic control subjects (age, 56.0±10.7 years; body mass index, 29.8 ± 2.9 kg/m2; hemoglobin A1c, 33.8 ± 5.5 mmol/mol) participated. Interventions: Three experimental days: 75 g-oral glucose tolerance test (OGTT), IIGI, and IIGI+glucagon (IIGI with a concomitant IV glucagon infusion [0.8 ng/kg/min from 0 to 25 minutes] designed to mimic portal glucagon concentrations during OGTT in the type 2 diabetic group) were undertaken. Main Outcome Measures: Glucose kinetics were assessed by tracer methodology. Results: Glucose rate of disappearance was higher during the OGTT vs IIGI in the control group, but similar on all days in the diabetic group. Surprisingly, in both groups, EGP was more suppressed during IIGI than during OGTT, and exogenous glucagon infusion during IIGI did not restore EGP to the levels observed during OGTT. Conclusion: EGP was less suppressed during OGTT than during IIGI in both patients with type 2 diabetes and in nondiabetic control subjects. Based on the present experimental design, it was not possible to attribute this difference to the delayed glucagon suppression observed in the initial phase of the OGTT.

Improved tolerance to sequential glucose loading (Staub-Traugott effect): size and mechanisms

2009 ◽  
Vol 297 (2) ◽  
pp. E532-E537 ◽  
Author(s):  
Sandra Bonuccelli ◽  
Elza Muscelli ◽  
Amalia Gastaldelli ◽  
Elisabetta Barsotti ◽  
Brenno D. Astiarraga ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Plasma Glucose ◽  
Cell Function ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Fat Free Mass ◽  
Oral Glucose ◽  
Glucose Response ◽  
Glucose Loading ◽  
Endogenous Glucose

Improved glucose tolerance to sequential glucose loading (Staub-Traugott effect) is an important determinant of day-to-day glycemic exposure. Its mechanisms have not been clearly established. We recruited 17 healthy volunteers to receive two sequential oral glucose tolerance tests (OGTTs), at time 0 min and 180 min ( Study I). The protocol was repeated on a separate day ( Study II) except that plasma glucose was clamped at 8.3 mmol/l between 60 and 180 min. β-Cell function was analyzed by mathematical modeling of C-peptide concentrations. In a subgroup, glucose kinetics were measured by a triple-tracer technique (infusion of [6,6-2H2]glucose and labeling of the 2 glucose loads with [1-2H]glucose and [U-13C]glucose). In both Studies I and II, the plasma glucose response to the second OGTT equaled 84 ± 2% ( P = 0.003) of the response to the first OGTT. Absolute insulin secretion was lower (37.8 ± 4.3 vs. 42.8 ± 5.1 nmol/m2, P = 0.02), but glucose potentiation (i.e., higher secretion at the same glycemia) was stronger (1.08 ± 0.02- vs. 0.92 ± 0.02-fold, P = 0.006), the increment being higher in Study II (+36 ± 5%) than Study I (+19 ± 6%, P < 0.05). In pooled data, a higher glucose area during the first OGTT was associated with a higher potentiation during the second OGTT (rho=0.60, P = 0.002). Neither insulin clearance nor glucose clearance differed between loads, and appearance of glucose over 3 h totalled 60 ± 6 g for the first load and 52 ± 5 g for the second load ( P = not significant). Fasting endogenous glucose production [13.3 ± 0.6 μmol·min−1·kg fat-free mass (FFM)−1] averaged 6.0 ± 3.8 μmol·min−1·kg FFM−1 between 0 and 180 min and 1.7 ± 2.6 between 180 and 360 min ( P < 0.03). Glucose potentiation and stronger suppression of endogenous glucose release are the main mechanisms underlying the Staub-Traugott effect.

Impact of incretin hormones on β-cell function in subjects with normal or impaired glucose tolerance

2006 ◽  
Vol 291 (6) ◽  
pp. E1144-E1150 ◽  
Author(s):  
Elza Muscelli ◽  
Andrea Mari ◽  
Andrea Natali ◽  
Brenno D. Astiarraga ◽  
Stefania Camastra ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Cell Function ◽  
Oral Glucose ◽  
Incretin Effect ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Sensitivity ◽  
Cell Glucose

The mechanisms by which the enteroinsular axis influences β-cell function have not been investigated in detail. We performed oral and isoglycemic intravenous (IV) glucose administration in subjects with normal (NGT; n = 11) or impaired glucose tolerance (IGT; n = 10), using C-peptide deconvolution to calculate insulin secretion rates and mathematical modeling to quantitate β-cell function. The incretin effect was taken to be the ratio of oral to IV responses. In NGT, incretin-mediated insulin release [oral glucose tolerance test (OGTT)/IV ratio = 1.59 ± 0.18, P = 0.004] amounted to 18 ± 2 nmol/m2 (32 ± 4% of oral response), and its time course matched that of total insulin secretion. The β-cell glucose sensitivity (OGTT/IV ratio = 1.52 ± 0.26, P = 0.02), rate sensitivity (response to glucose rate of change, OGTT/IV ratio = 2.22 ± 0.37, P = 0.06), and glucose-independent potentiation were markedly higher with oral than IV glucose. In IGT, β-cell glucose sensitivity (75 ± 14 vs. 156 ± 28 pmol·min−1·m−2·mM−1 of NGT, P = 0.01) and potentiation were impaired on the OGTT. The incretin effect was not significantly different from NGT in terms of plasma glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide responses, total insulin secretion, and enhancement of β-cell glucose sensitivity (OGTT/IV ratio = 1.73 ± 0.24, P = NS vs. NGT). However, the time courses of incretin-mediated insulin secretion and potentiation were altered, with a predominance of glucose-induced vs. incretin-mediated stimulation. We conclude that, under physiological circumstances, incretin-mediated stimulation of insulin secretion results from an enhancement of all dynamic aspects of β-cell function, particularly β-cell glucose sensitivity. In IGT, β-cell function is inherently impaired, whereas the incretin effect is only partially affected.

scholarly journals Functional high-intensity training improves pancreatic β-cell function in adults with type 2 diabetes

2017 ◽  
Vol 313 (3) ◽  
pp. E314-E320 ◽  
Author(s):  
Stephan Nieuwoudt ◽  
Ciarán E. Fealy ◽  
Julie A. Foucher ◽  
Amanda R. Scelsi ◽  
Steven K. Malin ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Body Fat ◽  
High Intensity ◽  
Cell Function ◽  
Oral Glucose ◽  
Β Cell ◽  
High Intensity Training ◽  
Β Cell Function ◽  
Intensity Training

Type 2 diabetes (T2D) is characterized by reductions in β-cell function and insulin secretion on the background of elevated insulin resistance. Aerobic exercise has been shown to improve β-cell function, despite a subset of T2D patients displaying “exercise resistance.” Further investigations into the effectiveness of alternate forms of exercise on β-cell function in the T2D patient population are needed. We examined the effect of a novel, 6-wk CrossFit functional high-intensity training (F-HIT) intervention on β-cell function in 12 sedentary adults with clinically diagnosed T2D (54 ± 2 yr, 166 ± 16 mg/dl fasting glucose). Supervised training was completed 3 days/wk, comprising functional movements performed at a high intensity in a variety of 10- to 20-min sessions. All subjects completed an oral glucose tolerance test and anthropometric measures at baseline and following the intervention. The mean disposition index, a validated measure of β-cell function, was significantly increased (PRE: 8.4 ± 3.1, POST: 11.5 ± 3.5, P = 0.02) after the intervention. Insulin processing inefficiency in the β-cell, expressed as the fasting proinsulin-to-insulin ratio, was also reduced (PRE: 2.40 ± 0.37, POST: 1.78 ± 0.30, P = 0.04). Increased β-cell function during the early-phase response to glucose correlated significantly with reductions in abdominal body fat ( R2= 0.56, P = 0.005) and fasting plasma alkaline phosphatase ( R2= 0.55, P = 0.006). Mean total body-fat percentage decreased significantly (Δ: −1.17 0.30%, P = 0.003), whereas lean body mass was preserved (Δ: +0.05 ± 0.68 kg, P = 0.94). We conclude that F-HIT is an effective exercise strategy for improving β-cell function in adults with T2D.

Effect of Glucagon on Nocturnal Rates of Endogenous Glucose Production in Type 2 Diabetes

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 44-OR
Author(s):  
ANANDA BASU ◽  
HUALING ZHAI ◽  
RICKEY CARTER ◽  
RITA BASU
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Endogenous Glucose

scholarly journals β-Cell Function, Incretin Effect, and Incretin Hormones in Obese Youth Along the Span of Glucose Tolerance From Normal to Prediabetes to Type 2 Diabetes

Diabetes ◽  
2014 ◽  
Vol 63 (11) ◽  
pp. 3846-3855 ◽  
Author(s):  
Sara F. Michaliszyn ◽  
Andrea Mari ◽  
SoJung Lee ◽  
Fida Bacha ◽  
Hala Tfayli ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Incretin Hormones ◽  
Incretin Effect ◽  
Β Cell ◽  
Obese Youth ◽  
Β Cell Function

scholarly journals Exenatide improves β-cell function up to 3 years of treatment in patients with type 2 diabetes: a randomised controlled trial

2016 ◽  
Vol 175 (4) ◽  
pp. 345-352 ◽  
Author(s):  
Daniël H van Raalte ◽  
Mathijs C Bunck ◽  
Mark M Smits ◽  
T Hoekstra ◽  
Anja Cornér ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Treatment Period ◽  
Receptor Agonist ◽  
Cell Function ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Sensitivity ◽  
Cell Glucose

Objective Glucagon-like peptide (GLP)-1 receptor agonist treatment improves β-cell function. In this study, we investigated whether the improvements are sustained during a 3-year treatment period. Research design and methods Sixty-nine metformin-treated type 2 diabetes patients were randomised to the GLP1 receptor agonist, exenatide (EXE) twice daily (BID) or to insulin glargine (GLAR). β-cell function parameters were derived using the Mari model from standardised breakfast and lunch meals that were administered before treatment, and after 1 and 3 years of treatment. EXE was administered before breakfast. Results Fifty-nine (EXE: n = 30; GLAR: n = 29) and thirty-six (EXE: n = 16; GLAR: n = 20) patients completed the meal at 1- and 3-year treatment respectively. After 3 years, groups had comparable glycaemic control (HbA1c: EXE 6.6 ± 0.2% and GLAR 6.9 ± 0.2%; P = 0.216). Compared with GLAR, at 1 and 3 years, EXE induced a stronger reduction in post-breakfast glucose concentrations (P < 0.001), with lower C-peptide levels (P < 0.001). Compared with GLAR, EXE increased insulin secretion at 8 mmol/L glucose throughout the study period (P < 0.01). Both treatments improved β-cell glucose sensitivity after 1-year treatment. However, only EXE treatment sustained this improvement for 3 years. No consistent changes in other β-cell parameters including rate sensitivity and potentiation were observed. Conclusions Compared with GLAR, EXE improved the parameters of β-cell function, especially insulin secretion at 8 mmol/L glucose and β-cell glucose sensitivity, which was sustained during the 3-year treatment period.

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