Normalization of fasting glycaemia by intravenous GLP-1 ([7-36 amide] or [7-37]) in Type 2 diabetic patients

Abstract

Intravenous GLP-1 [7-36 amide] can normalize fasting hyperglycaemia in Type 2 diabetic patients. Whether GLP-1 [7-37] has similar effects and how quickly plasma glucose concentrations revert to hyperglycaemia after stopping GLP-1 is not known. Therefore, 8 patients with Type 2 diabetes (5 female, 3 male; 65+/-6 years; BMI 34.3+/-7.9 kg m(-2); HbA1c 9.6+/-1.2%; treatment with diet alone (n=2), sulphonylurea (n=5), metformin (n=1)) were examined twice in randomized order. GLP-1 [7-36 amide] or [7-37] (1 pmol kg(-1)min(-1) were infused intravenously over 4 h in fasted subjects. Plasma glucose (glucose-oxidase), insulin and C-peptide (ELISA) was measured during infusion and for 4 h thereafter. Indirect calorimetry was performed. Fasting hyperglycaemia was 11.7+/-0.9 [7-36 amide] and 11.3+/-0.9 mmol l(-1) [7-37]. GLP-1 infusions stimulated insulin secretion approximately 3-fold (insulin peak 168+/-32 and 156+/-47 pmol l(-1), p<0.0001 vs basal; C-peptide peak 2.32+/-0.28 and 2.34+/-0.43 nmol l(-1), p<0.0001, respectively, with GLP-1 [7-36 amide] and [7-37]). Four hours of GLP-1 infusion reduced plasma glucose (4.8+/-0.4 and 4.6+/-0.3 mmol l(-1), p<0.0001 vs basal values), and it remained in the non-diabetic fasting range after a further 4 h (5.1+/-0.4 and 5.3+/-0.4 mmol l(-1), for GLP [7-36 amide] and [7-37], respectively). There were no significant differences between GLP-1 [7-36 amide] and [7-37] (glucose, p=0.99; insulin, p=0.99; C-peptide, p=0.99). Neither glucose oxidation nor lipid oxidation (or any other parameters determined by indirect calorimetry) changed during or after the administration of exogenous GLP-1. In conclusion, GLP-1 [7-36 amide] and [7-37] normalize fasting hyperglycaemia in Type 2 diabetic patients. Diabetes therapy (diet, sulphonyl ureas or metformin) does not appear to influence this effect. In fasting and resting patients, the effect persists during administration of GLP-1 and for at least 4 h thereafter, without rebound. Significant changes in circulating substrate concentrations (e.g. glucose) are not accompanied by changes in intracellular substrate metabolism.

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

“…When administered by intravenous infusion to type 2 diabetic subjects, GLP-1 stimulates pancreatic insulin secretion and blunts the postprandial hyperglycemic excursion that is typically observed following ingestion of a meal [10][11][12]. Short term or continuous infusion of GLP-1 restores fasting glycemia in type 2 diabetic subjects [13][14][15][16][17][18][19], and available evidence indicates that GLP-1 remains an effective blood glucose lowering agent under conditions in which subjects are not responsive to administered sulfonylureas such as tolbutamide, glyburide, or glipizide [20][21][22]. Antidiabetogenic actions of GLP-1 in type 2 diabetic subjects are manifest as an improvement of pancreatic b-cell function, as measured by a clear restoration of the missing first phase component of glucose-dependent insulin secretion [10,15,19,23].…”

The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases β-cell mass in diabetic mice

“…incretin hormones; diabetes; animal models; glucagon-like peptide-1 GLUCAGON-LIKE PEPTIDE-1 (GLP-1), an incretin hormone secreted from the intestinal L cells (23,16), is highly effective in lowering blood glucose in type 2 diabetic patients (12,21,22,28). The antihyperglycemic effects of GLP-1 are multifactorial, involving the pancreas, gastrointestinal tract, and brain.…”

Dipeptidyl Peptidase IV Inhibitor NVP-DPP728 Ameliorates Early Insulin Response and Glucose Tolerance in Aged Rats but Not in Aged Fischer 344 Rats Lacking Its Enzyme Activity

“…Another conceivable explanation is that the contribution of endogenous incretin may increase with aging, but its physiological bioactivity would be very low because of the fast degradation by plasma DPP-IV (9, 10). Consistent with this hypothesis, recent clinical studies have demonstrated that intravenous administration of GLP-1 improved the fasting hyperglycemia and islet dysfunction in elderly patients (65-to 74-year-old) with Type 2 diabetes (29,30). In addition, our study demonstrated that the DPP-IV inhibitor NVP-DPP728 improved glucose tolerance in aged rats by inhibiting plasma DPP-IV activity, presumably in association with the endogenous incretin bioactivity.…”