SUBCUTANEOUS GLUCAGON-LIKE PEPTIDE-I COMBINED WITH INSULIN NORMALIZESPOSTCIBAL 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 empt ying transiently can prevent postcibal hyperglycemia in IDDM without c ausing hypoglycemia when administered with insulin. RESEARCH DESIGN AN D METHODS - The postcibal increase in plasma human pancreatic polypept ide (HPP) was used as a presumptive indicator of arrival of nutrient i n the small intestine. Studies in seven normal human volunteers establ ished 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 re sidual endogenous insulin secretion. The patients received a standard liquid test meal with or without subcutaneous tGLP-I and their usual d ose of regular insulin before the meal. Blood samples collected at tim ed intervals were assayed for plasma concentrations of glucose, C-pept ide (CP), immunoreactive insulin (IRI), HPP, and glucagon (GLN). RESUL TS - In normal subjects after administration of tGLP-I, postcibal plas ma 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 mi n, the excursions of plasma HPP, CP, and IRI were negatively correlate d to the dose of tGLP-I. In subjects with IDDM, the selected dose of t GLP-I given with insulin before the meal delayed the plasma HPP respon se for 30 min and confined excursions of plasma glucose within the ran ge observed in normal subjects receiving saline injections, whereas ad ministration of insulin with saline injections in IDDM was followed by supranormal increases of plasma glucose. In IDDM, this dose of subcut aneous tGLP-I had no effect on plasma CE: IRI, or GLN. CONCLUSIONS - I n normal subjects, transient hypoglycemia after injections of tGLP-I w ith a meal was associated with transient stimulation of insulin secret ion and inhibition of glucagon secretion. These actions together with delayed gastric emptying may account for the hypoglycemia, but other u nidentified mechanisms cannot be excluded. In the subjects with IDDM, the selected relatively low dose of tGLP-I delayed excursions of plasm a HPP as in normal subjects, but did not reduce the plasma glucose bel ow the fasting level and had no effect on plasma CP, IRI, or GLN. Howe ver, 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 wi th regular insulin alone without risk of hypoglycemia, this combinatio n of glucoregulatory peptides has therapeutic potential in insulin-req uiring diabetes.