Subcutaneous glucagon-like peptide I combined with insulin normalizes postcibal glycemic excursions in IDDM

OBJECTIVE - To determine whether a subcutaneous injection of truncated glucagon-like peptide I (tGLP-I)(7-36) amide that delays gastric emptying transiently can prevent postcibal hyperglycemia in IDDM without causing hypoglycemia when administered with insulin. RESEARCH DESIGN AND METHODS - The postcibal increase in plasma human pancreatic polypeptide (HPP) was used as a presumptive indicator of arrival of nutrient in the small intestine. Studies in seven normal human volunteers established the dose of tGLP-I that delayed the postcibal rise in HPP by 30 min. This dose was tested in six patients with IDDM with a range of residual endogenous insulin secretion. The patients received a standard liquid test meal with or without subcutaneous tGLP-I and their usual dose of regular insulin before the meal. Blood samples collected at timed intervals were assayed for plasma concentrations of glucose, C-peptide (CP), immunoreactive insulin (IRI), HPP, and glucagon (GLN). RESULTS - In normal subjects after administration of tGLP-I, postcibal plasma glucose concentration at 20 min fell below fasting levels in a dose-dependent manner. At 10 and 20 min, transient increments in plasma CP and IRI, and decrements in GLN, occurred. Subsequently, through 60 min, the excursions of plasma HPP, CP, and IRI were negatively correlated to the dose of tGLP-I. In subjects with IDDM, the selected dose of tGLP-I given with insulin before the meal delayed the plasma HPP response for 30 min and confined excursions of plasma glucose within the range observed in normal subjects receiving saline injections, whereas administration of insulin with saline injections in IDDM was followed by supranormal increases of plasma glucose. In IDDM, this dose of subcutaneous tGLP-I had no effect on plasma CE: IRI, or GLN. CONCLUSIONS - In normal subjects, transient hypoglycemia after injections of tGLP-I with a meal was associated with transient stimulation of insulin secretion and inhibition of glucagon secretion. These actions together with delayed gastric emptying may account for the hypoglycemia, but other unidentified mechanisms cannot be excluded. In the subjects with IDDM, the selected relatively low dose of tGLP-I delayed excursions of plasma HPP as in normal subjects, but did not reduce the plasma glucose below the fasting level and had no effect on plasma CP, IRI, or GLN. However, injection of tGLP-I reduced the postcibal glycemic excursion and confined it within the normal range. Thus, in IDDM, a pharmacological dose of subcutaneous tGLP-I that presumably delays gastric emptying by similar to 30 min can normalize glycemic excursions after a meal when given in combination with insulin. Because this cannot be achieved with regular insulin alone without risk of hypoglycemia, this combination of glucoregulatory peptides has therapeutic potential in insulin-requiring diabetes.