Glucagon-Like Peptide-1 (7-37) Augments Insulin Release in Elderly Patients With Diabetes

Glucagon-like peptide-1 (GLP-1) is a potent stimulator of glucose-induced insulin release (1). Unlike glucose-dependent insulinotropic polypeptide (GIP), GLP-1 augments insulin release in middle-aged patients with type 2 diabetes (1) and is therefore a potentially promising agent for the treatment of type 2 diabetes. We undertook the following experiments to determine whether the effects of GLP-1 on glucose-induced insulin release are preserved in elderly patients with diabetes.

These studies were conducted on 8 elderly patients with diabetes (age 77 ± 1 years, BMI 28 ± 1 kg/m²). The mean duration of diabetes was 8 ± 1 years and mean HbA_1c was 7.1 ± 0.2%. All subjects were free of clinically apparent microvascular, macrovascular, or neuropathic complications. Patients with hypertension were not excluded. Three of the subjects were treated with sulfonylurea drugs, and four were being treated with angiotensin-converting enzyme inhibitors for hypertension. All medications were stopped at least 2 weeks before the test. This study was approved by the Committee on Human Investigation at the University of British Columbia. All subjects gave written informed consent before participation.

Each subject underwent two hyperglycemic clamp studies in random order, separated by at least 4 weeks (2). From −20 to 0 min, three blood samples were taken at 10-min intervals to measure basal glucose, insulin, glucagon, C-peptide, and GLP-1. At time 0, glucose was acutely increased to 5.4 mmol/l above basal using the hyperglycemic clamp protocol and was kept at that level for 180 min. In one study, glucose alone was infused. In the other study, GLP-1 was infused in a primed continuous manner at a rate of 1.5 pmol/l · kg^–1 · min^–1 for the duration of the study, as previously described (3). Blood samples were taken every 2 min from 0 to 10 min to measure glucose and insulin values, every 5 min for the rest of the study to measure glucose, and every 15 min to measure hormone levels. Blood samples were collected in heparinized syringes. Plasma glucose was measured immediately at the bedside using a YSI Glucose Analyzer (Yellowsprings Instruments, Yellowsprings, OH). The remaining blood was placed in prechilled test tubes containing diproten A (for measurement of GLP-1), aprotonin (400 KIU/ml), and EDTA (1.5 mg/ml) (for measurement of C-peptide, glucagon, and insulin) and centrifuged at 4°C. Samples were stored in a –70°C freezer until analysis. Insulin, glucagon, C-peptide, and total and active GLP-1 were measured by radioimmunoassays, as previously described (3,4). Differences between studies were evaluated with Student’s paired t test. Except where otherwise indicated, results are presented as mean ± SEM; P < 0.05 was considered significant in all analyses.

Fasting glucose and hormone values did not differ between studies. Plasma glucose, insulin, and C-peptide levels for the hyperglycemic clamp studies are illustrated in Fig. 1. Steady-state (120–180 min) glucose values were similar in each study (control 12.8 ± 0.4 mmol/l and GLP-1 12.6 ± 0.3 mmol/l; P = NS). Steady-state plasma insulin (control 161 ± 22 pmol/l and GLP-1 643 ± 141 pmol/l, P < 0.01) and C-peptide (control 1.1 ± 0.2 nmol/l and GLP-1 4.2 ± 0.7 nmol/l, P < 0.0001) values were substantially higher during the GLP-1 study. Steady-state total (control 7 ± 2 pmol/l and GLP-1 226 ± 25 pmol/l, P < 0.0001) and active GLP-1 values (control 1 ± 1 pmol/l and GLP-1 17 ± 2 pmol/l, P < 0.0001) were substantially higher during the GLP-1 study, whereas glucagon values (control 20 ± 2 pmol/l and GLP-1 13 ± 1 pmol/l, P < 0.001) were lower.

In middle-aged patients with diabetes, glucose-induced insulin responses to GLP-1 are preserved. But GLP-1 does not lead to hypoglycemia, because little or no insulin is secreted at glucose levels <4 mmol/l, even when large doses of GLP-l are given (1). Because older-aged patients with diabetes have an increased risk of severe hypoglycemia when treated with oral hypoglycemic agents or insulin (5), GLP-1 could prove to be a particularly safe therapeutic agent in this patient population. However, although GLP-1 has a similar insulinotropic effect in healthy young and old rats (6,7), the effect of GLP-1 on insulin release is reduced in healthy elderly humans (8). For GLP-1 to be a useful therapy in the elderly, it must maintain its insulinotropic effectiveness in this patient population. In this study, we demonstrated for the first time that the insulin responses to GLP-1 are preserved in elderly patients with diabetes. We also showed that GLP-1 maintains its ability to suppress glucagon levels in elderly patients with diabetes. The levels of active GLP-1 were substantially lower than that of total GLP-1. The biological effect GLP-1 is partly regulated through metabolism by dipeptidyl peptidase IV (DPIV), an enzyme that cleaves the first two amino acids from both GIP and GLP-1 (9). Our data suggest that DPIV inhibitors have the potential to substantially enhance the therapeutic effect of GLP-1 in the elderly.

In conclusion, GLP-1 maintains significant insulinotropic potential in elderly patients with diabetes. The results of this study are the basis for ongoing clinical trials designed to evaluate the usefulness of GLP-1 as a therapeutic agent in elderly patients with diabetes.