Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

Abstract

Objective The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and GLP-1 in patients with type 2 diabetes. Methods Eight obese patients with type 2 diabetes with poor glycaemic control (HbA 1c 8.6±1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4±1.2 mmol/l) using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l) with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. Results Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0-10 min). The late phase C-peptide response (10-120 min) increased during GIP infusion from 33.0±8.5 to 103.9±24.2 (nmol/l)×(110 min)

Effects of Sitagliptin on Glycemia, Incretin Hormones, and Antropyloroduodenal Motility in Response to Intraduodenal Glucose Infusion in Healthy Lean and Obese Humans and Patients With Type 2 Diabetes Treated With or Without Metformin

“…The lack of glucose lowering with sitagliptin in type 2 diabetic subjects, therefore, supports the hypothesis of a defective glucoregulatory capacity of endogenous GIP in this group and is consistent with the marked impairment of glucose lowering by sitagliptin in type 2 diabetic patients after oral glucose during GLP-1 antagonism with exendin-(9-39) (20). Although insulin response to exogenous GIP can be partly restored with strict glycemic control in type 2 diabetes, its insulinotropic effect is not associated with improvement in glucose disposal during hyperglycemic clamp studies (41). In a group of patients with relatively well-controlled type 2 diabetes, exogenous GIP was shown to exert a modest effect on glucose disposal when blood glucose was clamped at ;12 mmol/L, but it had no effect on fasting hyperglycemia (;8 mmol/L), suggesting a glucose-dependent effect of GIP to lower glycemia (42).…”

Bariatric surgery and obesity: influence on the incretins

“…The effect of GIP on insulin secretion can be restored after lowering glycemia. 21 Both GLP-1 and GIP have a trophic effect on the β-cell, as demonstrated in vitro and in vivo in rodent studies. [22][23][24][25] GLP-1 has other important physiological effects, including potentiation of GSIS in the post-prandial setting, suppression of glucagon, slowing of gastric emptying, decrease of body weight and favorable cardiovascular protection, 1,26 that makes it an attractive tool for the treatment of overweight or obese individuals with diabetes.…”

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

“…Near normalisation of blood glucose levels has been shown to restore the insulin-secretory effect of GIP in both animal models of type 2 diabetes [5] and in humans [6] with this condition, providing evidence that defective GIP receptor signalling is reversible. In addition, co-administration of GIP with a sulfonylurea restores pancreatic beta cell sensitivity to GIP [7], although this could be linked to uncoupling of incretin glucose dependency by sulfonylureas [8].…”

“…For GIP, the first 14 N-terminal amino acid residues contain the bioactive domain important for insulin-secretory function [25,26]. Based on this knowledge, we constructed a novel GIP/xenin hybrid peptide, (DAla 2 )GIP/xenin-8-Gln, by linking GIP (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) to xenin-8-Gln, retaining the regions of each peptide known to be important for biological activity (see electronic supplementary material [ESM] Table 1). Importantly, since GIP is a substrate for dipeptidyl peptidase-4 (DPP-4) [27], the hybrid peptide includes substitution of the naturally occurring alanine L isomer residue by a D isomer at position 2 [28,29].…”