Impaired beta cell sensitivity to incretins in type 2 diabetes is insufficiently compensated by higher incretin response.

BACKGROUND AND AIMS: The incretin effect is impaired in type 2 diabetes (T2D), but the underlying mechanisms are only partially understood. We investigated the relationships between the time course of the incretin effect and that of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during oral glucose tolerance tests (OGTTs), thereby estimating incretin sensitivity of the beta cell, and its associated factors. METHODS AND RESULTS: Eight patients with T2D and eight matched subjects with normal glucose tolerance (NGT) received 25, 75, and 125 g OGTTs and corresponding isoglycemic glucose infusions (IIGI). The time course of the incretin effect, representing potentiation of insulin secretion by incretins (PINCR), was determined by mathematical modelling as the time-dependent fold increase in insulin secretion during OGTT compared to IIGI. The time course of PINCR was correlated with that of both GIP and GLP-1 in each subject (median r = 0.67 in NGT and 0.45 in T2D). We calculated an individual beta cell sensitivity to incretins (SINCR) using a weighted average of GIP and GLP-1 (pooled incretin concentration, PIC), as the slope of the relationship between PINCR and PIC. SINCR was reduced in T2D (p < 0.01). In the whole group, mean PIC, GIP and GLP-1 concentrations during the OGTT were inversely correlated with SINCR, but T2D had lower PIC, GIP and GLP-1 levels at the same SINCR (p < 0.05). CONCLUSION: Relative incretin insensitivity is partly compensated for by higher incretin secretory responses. However, T2D shows both impairment in incretin sensitivity and abnormal compensation by incretin secretion.

Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake.

Bile acids released postprandially modify the rate and extent of absorption of lipophilic compounds. The present study aimed to predict gastric emptying (GE) rate and gallbladder emptying (GBE) patterns in response to caloric intake. A mechanism-based model for GE, cholecystokinin plasma concentrations, and GBE was developed on data from 33 patients with type 2 diabetes and 33 matched nondiabetic individuals who were administered various test drinks. A feedback action of the caloric content entering the proximal small intestine was identified for the rate of GE. The cholecystokinin concentrations were not predictive of GBE, and an alternative model linking the nutrients amount in the upper intestine to GBE was preferred. Relative to fats, the potency on GBE was 68% for proteins and 2.3% for carbohydrates. The model predictions were robust across a broad range of nutritional content and may potentially be used to predict postprandial changes in drug absorption.

Reduced postprandial GLP-1 responses in women with gestational diabetes mellitus.

AIM: We investigated postprandial glucagon-like peptide-1 (GLP-1) responses in pregnant women with and without gestational diabetes mellitus (GDM) and again following delivery when normal glucose tolerance (NGT) was re-established. METHODS: Eleven women with GDM [plasma glucose (PG) concentration at 120 min after a 75-g oral glucose tolerance test (OGTT): 10.0 ± 0.9 mM (mean ± SD); age: 31 ± 6 years; body mass index (BMI): 31.6 ± 6.4 kg/m(2) ; haemoglobin A1c (HbA1c): 5.6 ± 0.5%] and eight pregnant women with NGT (PG(120 min), OGTT : 5.7 ± 0.7 mM; age: 28 ± 3 years; BMI: 29.7 ± 5.4 kg/m(2) ; HbA1c: 5.4 ± 0.3%) were investigated with a 4-h liquid meal test during third trimester (TT) and 3-4 months postpartum (PP). All patients with GDM re-established NGT following delivery. RESULTS: Pregnancy was associated with low postprandial GLP-1 responses. Patients with GDM exhibited reduced postprandial GLP-1 responses compared to their PP levels [area under curve (AUC): 5.5 ± 1.3 vs. 8.4 ± 3.2 nM × min, p=0.005], but the difference among NGT women (7.3 ± 2.8 vs. 8.8 ± 2.0 nM × min, p=0.066) was not statistically significant. Pregnancy did not influence postprandial responses of the other incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in any of the groups, but GDM patients were characterized by greater postprandial GIP responses during both TT and PP compared to NGT subjects. CONCLUSIONS: Pregnancy is associated with reduced postprandial GLP-1 responses (most pronounced in patients with GDM) that normalize after delivery. In contrast, postprandial GIP responses seem unaffected by pregnancy but is increased in GDM patients.

Glucagon antagonism as a potential therapeutic target in type 2 diabetes.

Glucagon is a hormone secreted from the alpha cells of the pancreatic islets. Through its effect on hepatic glucose production (HGP), glucagon plays a central role in the regulation of glucose homeostasis. In patients with type 2 diabetes mellitus (T2DM), abnormal regulation of glucagon secretion has been implicated in the development of fasting and postprandial hyperglycaemia. Therefore, new therapeutic agents based on antagonizing glucagon action, and hence blockade of glucagon-induced HGP, could be effective in lowering both fasting and postprandial hyperglycaemia in patients with T2DM. This review focuses on the mechanism of action, safety and efficacy of glucagon antagonists in the treatment of T2DM and discusses the challenges associated with this new potential antidiabetic treatment modality.

Reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet impairs the incretin effect in healthy subjects.

AIMS/HYPOTHESIS: The loss of incretin effect in patients with type 2 diabetes mellitus may be secondary to impaired glucose homeostasis. We investigated whether reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet in healthy young males would impair the incretin effect. METHODS: The incretin effect was measured using 75 g oral glucose tolerance test (OGTT) and isoglycemic iv glucose infusion (IIGI) in 10 healthy Caucasian normal glucose-tolerant male subjects without any family history of diabetes [age 24 + or - 3 yr (mean + or - sd); body mass index 23 + or - 2 kg/m(2); glycosylated hemoglobin 5.4 + or - 0.1%] before and at the end of a 12-d period with oral administration of prednisolone (37.5 mg once daily), high-calorie diet, and relative physical inactivity. RESULTS: The 12-d intervention period resulted in significant increases in body weight [79 + or - 5 vs. 80 + or - 6 kg (mean + or - sd), P = 0.03] and fasting plasma glucose (5.1 + or - 0.1 vs. 5.6 + or - 0.2 mm, P = 0.016), whereas insulin sensitivity (Matsuda index 17.6 + or - 1.7 vs. 9.2 + or - 1.0, P = 0.0001) decreased. Glucose tolerance [as assessed by the 120-min plasma glucose value after OGTT (4.9 + or - 1.1 vs. 7.8 + or - 2.5 mm, P < 0.0001) and area under curve (AUC) (152 + or - 45 vs. 384 + or - 53 mm.4 h, P = 0.002)] during the OGTT deteriorated. Also, the incretin effect [incretin effect (percent) = 100% x (AUC(insulin,OGTT) - AUC(insulin,IIGI))/AUC(insulin,OGTT))] deteriorated (72 + or - 5 vs. 43 + or - 7%, P = 0.002). An increase in glucose-dependent insulinotropic polypeptide response during OGTT, but no significant changes in glucagon-like peptide-1 or glucagon responses, was observed after glucose homeostatic dysregulation. CONCLUSIONS/INTERPRETATION: Impairment of the incretin effect can be elicited by a short period of reduced glucose tolerance and insulin resistance in healthy male subjects not disposed for type 2 diabetes.