Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM

Abstract

Non-insulin-dependent diabetes mellitus (NIDDM) is characterised by an increase in basal glucose concentrations, upon which are superimposed exaggerated postprandial glucose excursions, induced by a combination of beta-cell dysfunction and impaired insulin sensitivity [1]. Sulphonylurea therapy improves beta-cell function approximately twofold [2], but the marked insulin secretory defect persists in most patients, so that the enhancement is usually insufficient to maintain near-normal glucose concentrations, Diabetologia (1997) 40: 205-211 Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM Summary The gut hormone, glucagon-like peptide-1 (GLP-1) is a potent insulin secretogogue with potential as a therapy for non-insulin-dependent diabetes mellitus (NIDDM). GLP-1 has been shown to reduce glucose concentrations, both basally, and, independently, in response to a single meal. For it to be an effective treatment, it would need to be administered as a long-acting therapy, but this might not be feasible due to the profound delay in gastric emptying induced by GLP-1. In order to assess the feasibility and efficacy of continuous administration of GLP-1 in NIDDM, we determined the effects of continuous intravenous infusion of GLP-1 (7-36) amide, from 22.00-17.00 hours, on glucose and insulin concentrations overnight and in response to three standard meals, in eight subjects with NIDDM. These were compared with responses to 0.9 % NaCl infusion and responses in six non-diabetic control subjects who were not receiving GLP-1. Effects on beta-cell function were assessed in the basal state using homeostasis model assessment (HOMA) and in the postprandial state by dividing incremental insulin responses to breakfast by incremental glucose responses. To assess possible clinical benefit from priming of beta cells by GLP-1 given overnight only, a third study assessed the effect of GLP-1 given from 22.00-07.30 hours on subsequent glucose responses the next day. Continuous GLP-1 infusion markedly reduced overnight glucose concentrations (mean from 24.00-08.00 hours) from median (range) 7.8 (6.1-13.8) to 5.1 (4.0-9.2) mmol/l (p < 0.02), not significantly different from control subjects, 5.6 (5.0-5.8) mmol/l. Daytime glucose concentrations (mean from 08.00-17.00 hours) were reduced from 11.0 (9.3-16.4) to 7.6 (4.9-11.5) mmol/l (p < 0.02), not significantly different from control subjects, 6.7 (6.5-7.0) mmol/l. GLP-1 improved beta-cell function in the basal state from 62 (13-102) to 116 (46-180) %b (p < 0.02) and following breakfast from 57 (19-185) to 113 (31-494) pmol/mmol (p < 0.02). GLP-1 only given overnight did not improve the glucose responses to meals the next day. In conclusion, continuous infusion of GLP-1 markedly reduced diurnal glucose concentrations, suggesting that continuous GLP-1 administration may be a useful therapy in NIDDM. [Diabetologia (1997) 40: 205-211]

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

“…47 GLP-1 has also been recently investigated for its potential benefit in the treatment of type-1 diabetes. Zhang et al 5 have demonstrated that continuous infusion of GLP-1 in pre-diabetic NOD mice results in significant delay in the onset of diabetes as a result of increased beta-cell proliferation coupled with decrease in beta-cell apoptosis.…”

Mechanisms of action of glucagon-like peptide 1 in the pancreas

“…Nonetheless, 7 days of bolus subcutaneous administration of GLP-1 before breakfast, lunch and dinner significantly improved post-prandial glucose levels and decreased plasma lipid levels (Juntti-Berggren et al, 1996). In another study, overnight intravenous GLP-1 lowered fasting and post-prandial plasma glucose levels to nearnormal levels in subjects with T2DM (Rachman et al, 1997). It even reduced fasting and postprandial glucose levels after buccal absorption of a tablet containing 119 nmol of GLP-1 (Gutniak et al, 1997).…”

The incretin system and its role in type 2 diabetes mellitus

“…Subsequent studies in patients with moderate disease showed that plasma glucose concentrations could be near-normalized by an intravenous GLP-1 infusion covering the night time and the next day, including two meals (90). In another study, a continuous intravenous administration of GLP-1 for 7 consecutive days was demonstrated to dramatically lower both fasting and postprandial glucose concentrations with no sign of tachyphylaxis over 7 days (91).…”