Abstract
BackgroundGlucagon-like peptide-1 (GLP-1) and its agonists are under assessment in treatment of type 2 diabetes, by virtue of their antidiabetic actions, which include stimulation of insulin secretion, inhibition of glucagon release, and delay of gastric emptying. We examined the potential of GLP-1 to improve glycemic control in type 1 diabetes with no endogenous insulin secretion.MethodsDose-finding studies were carried out to establish mid range doses for delay of gastric emptying indicated by postponement of pancreatic polypeptide responses after meals. The selected dose of 0.63 micrograms/kg GLP-1 was administered before breakfast and lunch in 8-hour studies in hospital to establish the efficacy and safety of GLP-1. In outside-hospital studies, GLP-1 or vehicle was self-administered double-blind before meals with usual insulin for five consecutive days by five males and three females with well-controlled C-peptide-negative type 1 diabetes. Capillary blood glucose values were self-monitored before meals, at 30 and 60 min after breakfast and supper, and at bedtime. Breakfast tests with GLP-1 were conducted on the day before and on the day after 5-day studies. Paired t-tests and ANOVA were used for statistical analysis.ResultsIn 8-hour studies time-averaged incremental (delta) areas under the curves(AUC) for plasma glucose through 8 hours were decreased by GLP-1 compared to vehicle (3.2 ± 0.9, mean ± se, vs 5.4 ± 0.8 mmol/l, p < .05), and for pancreatic polypeptide, an indicator of gastric emptying, through 30 min after meals (4.0 ± 3.1 vs 37 ± 9.6 pmol/l, p < .05) with no adverse effects. Incremental glucagon levels through 60 min after meals were depressed by GLP-1 compared to vehicle (-3.7 ± 2.5 vs 3.1 ± 1.9 ng/l, p < .04). In 5-day studies, AUC for capillary blood glucose levels were lower with GLP-1 than with vehicle (-0.64 ± 0.33 vs 0.34 ± 0.26 mmol/l, p < .05). No assisted episode of hypoglycaemia or change in insulin dosage occurred. Breakfast tests on the days immediately before and after 5-day trials showed no change in the effects of GLP-1.ConclusionWe have demonstrated that subcutaneous GLP-1 can improve glucose control in type 1 diabetes without adverse effects when self-administered before meals with usual insulin during established intensive insulin treatment programs.
Highlights
Glucagon-like peptide-1 (GLP-1) and its agonists are under assessment in treatment of type 2 diabetes, by virtue of their antidiabetic actions, which include stimulation of insulin secretion, inhibition of glucagon release, and delay of gastric emptying
Acute studies with subcutaneous injections of GLP-1 in non-insulin-treated type 2 diabetes showed that the peptide can reduce glucose excursions after meals, and longer-term studies showed that administration of subcutaneous injections of GLP-1 before meals through periods up to several weeks can reduce the mean blood glucose levels in patients with type 2 diabetes in suboptimal blood glucose control, without clinical adverse effects [2,3]
We suggest that GLP-1 agonists as potential congeners with insulin in treatment of diabetes may improve glycemic control beyond the level safely achieved with insulin therapy
Summary
Glucagon-like peptide-1 (GLP-1) and its agonists are under assessment in treatment of type 2 diabetes, by virtue of their antidiabetic actions, which include stimulation of insulin secretion, inhibition of glucagon release, and delay of gastric emptying. The pharmacological actions of truncated glucagon-like peptide-1 (GLP-1), including stimulation of insulin release, suppression of glucagon release, and inhibition of gastric emptying, have provided the rationale for its assessment as a therapeutic agent for diabetes, with (page number not for citation purposes). In a further study of type 1 diabetes, virtually complete suppression of glycemic excursions was produced with intravenous infusion of GLP-1 during and after breakfast in volunteers who did not take their premeal insulin injection; this effect was attributed largely to inhibition of gastric emptying [5]. We studied the effects of subcutaneous injection of GLP-1 in volunteers with type 1 diabetes, some of whom had residual insulin secretion [7]. After ingestion of a standard liquid test meal preceded by subcutaneous injection of GLP-1 and the usual insulin dose, glycemic excursions were reduced in volunteers with negligible residual insulin secretion as well as in those with measurable responses of plasma C-peptide to the meal
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