Glucagon-like peptide 1 improved glycemic control in type 1 diabetes

Abstract

BACKGROUND: 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. We examined the potential of GLP-1 to improve glycemic control in type 1 diabetes with no endogenous insulin secretion. METHODS: Dose-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. RESULTS: In 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 PlusMinus; 0.9, mean PlusMinus; se, vs 5.4 PlusMinus; 0.8 mmol/l, p <.05), and for pancreatic polypeptide, an indicator of gastric emptying, through 30 min after meals (4.0 PlusMinus; 3.1 vs 37 PlusMinus; 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 PlusMinus; 2.5 vs 3.1 PlusMinus; 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 PlusMinus; 0.33 vs 0.34 PlusMinus; 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. CONCLUSION: We 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.

Figures

Figure 1

Dose-effect of glucagon-like peptide 1. Plasma glucose, pancreatic polypeptide(HPP), and incremental glucagon responses to breakfast with subcutaneous injection of varying doses of GLP-1 with usual insulin in volunteers with type 1 diabetes.

Figure 2

Eight-hour studies with glucagon-like peptide 1. Plasma glucose, pancreatic polypeptide(HPP), incremental glucagon, free immunoreactive insulin, and lactate responses to breakfast and lunch with subcutaneous injection of 0.63 μg/kg GLP-1 (closed circles) or vehicle (open circles) immediately before meals in volunteers with type 1 diabetes, n = 9.

Figure 3

Five-day studies with glucagon-like peptide 1. Capillary blood glucose values, mean ± SE, before meals (ac), at 30 and 60 min after breakfast and supper, and at night (HS), over five days with self-administered subcutaneous GLP-1 and usual insulin before meals (closed circles) and over five days with vehicle before meals (open circles) in volunteers with type 1 diabetes, n = 8. *P <.05 for time points, paired t-tests.