Graydon S. Meneilly

The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7–37) in normal and diabetic subjects

Despite similar glycemic profiles, higher insulin levels are achieved following oral versus intravenous administration of glucose. This discrepancy is due to the incretin effect and is believed to be mediated via stimulation of beta-cells by hormone(s) released from the gut. The leading gut hormone candidates are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1). To determine the relative insulinotropic activity of these peptides, we infused GLP-1(7-37) and GIP into normal subjects and patients with non-insulin dependent diabetes mellitus (NIDDM). In normal subjects during euglycemia, GLP-1(7-37) stimulated insulin release, whereas GIP did not. Using the Andres clamp technique, we established stable hyperglycemia for 2 h (5.4 mmol/l above the basal level). During the second hour, either GIP, GLP-1(7-37), or both were infused in normal healthy volunteers and in patients with NIDDM. In normal subjects, at a glucose level of 10.4 mmol/l, the 90-120 min insulin response was 279 pmol/l. GIP at a dose of 1, 2 or 4 pmol/kg/min augmented the 90-120 min insulin response by 69, 841 and 920 pmol/l, while GLP-1(7-37), at a dose of 1.5 pmol/kg/min augmented the insulin response by 2106 pmol/l. When both hormones were administered simultaneously, the augmentation was additive--2813 pmol/l. In the diabetic subjects, GIP had no effect, while GLP-1(7-37) augmented the insulin response by 929 pmol/l. We conclude that in normal healthy subjects, GLP-1(7-37), on a molar basis, is several times more potent than GIP at equivalent glycemic conditions. The additive insulinotropic effect suggests that more than one incretin may be responsible for the greater insulin levels observed following oral administration of glucose compared to the intravenous route. In NIDDM, GIP had no insulinotropic effect, while GLP-1(7-37) had a marked effect. This suggests that GLP-1(7-37) may have therapeutic potential as a hypoglycemic agent in NIDDM patients.

The Extrapancreatic Effects of Glucagon-Like Peptide-1 and Related Peptides

CONTEXT Glucagon-like peptide-1 (GLP-1) 7-36 amide, an insulinotropic hormone released from the intestinal L cells in response to nutrient ingestion, has been extensively reviewed with respect to beta-cell function. However GLP-1 receptors are abundant in many other tissues. Thus, the function of GLP-1 is not limited to the islet cells, and it has regulatory actions on many other organs. EVIDENCE ACQUISITION A review of published, peer-reviewed medical literature (1987 to September 2008) on the extrapancreatic actions of GLP-1 was performed. EVIDENCE SYNTHESIS The extrapancreatic actions of GLP-1 include inhibition of gastric emptying and gastric acid secretion, thereby fulfilling the definition of GLP-1 as an enterogastrone. Other important extrapancreatic actions of GLP-1 include a regulatory role in hepatic glucose production, the inhibition of pancreatic exocrine secretion, cardioprotective and cardiotropic effects, the regulation of appetite and satiety, and stimulation of afferent sensory nerves. The primary metabolite of GLP-1, GLP-1 (9-36) amide, or GLP-1m, is the truncated product of degradation by dipeptidyl peptidase-4. GLP-1m has insulinomimetic effects on hepatic glucose production and cardiac function. Exendin-4 present in the salivary gland of the reptile, Gila monster (Heloderma suspectum), is a high-affinity agonist for the mammalian GLP-1 receptor. It is resistant to degradation by dipeptidyl peptidase-4, and therefore has a prolonged half-life. CONCLUSION GLP-1 and its metabolite have important extrapancreatic effects particularly with regard to the cardiovascular system and insulinomimetic effects with respect to glucose homeostasis. These effects may be particularly important in the obese state. GLP-1, GLP-1m, and exendin-4 therefore have potential therapeutic roles because of their diffuse extrapancreatic actions.

Counterregulatory Hormone Responses to Hypoglycemia in the Elderly Patient with Diabetes

In patients with non-insulin-dependent diabetes mellitus (NIDDM), the risk of severe or fatal hypoglycemia associated with the use of oral agents or insulin increases exponentially with age. We conducted this study with the hypothesis that this increased susceptibility to hypoglycemia is caused by alterations in release of counterregulatory hormones and psychomotor performance during hypoglycemia. Ten healthy nonobese elderly subjects (74 ± 1 years of age; body mass index, 24.5 ± 0.6 kg/m2) and 10 nonobese elderly NIDDM subjects (72 ± 1 years of age; body mass index, 25.6 ± 0.9 kg/m2) underwent two hyperinsulinemic glucose clamp studies (insulin infusion, 60 mU·m₋2 · min₋1). In the control study, glucose was maintained at 5 mM for 5 h; in the hypoglycemic study, glucose was kept at 5 mM for 1 h and then lowered in a stepwise fashion to 4.4, 3.8, 3.3, and 2.8 mM in each subsequent hour. At regular intervals in each study, neuropsychological tests were performed, counterregulatory hormones were measured, and a hypoglycemic symptom questionnaire was administered. At a glucose level of 2.8 mM, NIDDM patients had reduced incremental glucagon (normal subjects, 114 ± 18 ng/l; NIDDM subjects, 63 ± 9 ng/l; P < 0.05) and growth hormone responses (normal subjects, 13.8 ± 1.0 micrograms/l; NIDDM subjects, 7.0 ± 2.0 micrograms/l; P < 0.01) and increased epinephrine (normal subjects, 925 ± 198 pM; NIDDM subjects, 4175 ± 824 pM; P < 0.001) and cortisol responses (normal subjects, 291 ± 49 nM; NIDDM subjects, 524 ± 92 mM; P < 0.05). Symptom scores were similar in both groups at all levels of glycemia. at all levels of glycemia. At a glucose level of 2.8 mM, NIDDM patients had a greater impairment on the simple (normal subjects, ₋ 10 ± 24 ms; NIDDM subjects, 108 ± 18 ms; P < 0.001) and choice (normal subjects, 20 ± 18 ms; NIDDM subjects, 111 ± 18 ms; P < 0.01) reaction time tests. We conclude that the elderly NIDDM patients have altered release of counterregulatory hormones and altered psychomotor performance during hypoglycemia.

Short-Term Aerobic Exercise Reduces Arterial Stiffness in Older Adults With Type 2 Diabetes, Hypertension, and Hypercholesterolemia

OBJECTIVE The relationship between increased arterial stiffness and cardiovascular mortality is well established in type 2 diabetes. We examined whether aerobic exercise could reduce arterial stiffness in older adults with type 2 diabetes complicated by comorbid hypertension and hyperlipidemia. RESEARCH DESIGN AND METHODS A total of 36 older adults (mean age 71.4 ± 0.7 years) with diet-controlled or oral hypoglycemic–controlled type 2 diabetes, hypertension, and hypercholesterolemia were recruited. Subjects were randomly assigned to one of two groups: an aerobic group (3 months vigorous aerobic exercise) and a nonaerobic group (no aerobic exercise). Exercise sessions were supervised by a certified exercise trainer three times per week, and a combination of cycle ergometers and treadmills was used. Arterial stiffness was measured using the Complior device. RESULTS When the two groups were compared, aerobic training resulted in a decrease in measures of both radial (−20.7 ± 6.3 vs. +8.5 ± 6.6%, P = 0.005) and femoral (−13.9 ± 6.7 vs. +4.4 ± 3.3%, P = 0.015) pulse-wave velocity despite the fact that aerobic fitness as assessed by Vo2max did not demonstrate an improvement with training (P = 0.026). CONCLUSIONS Our findings indicate that a relatively short aerobic exercise intervention in older adults can reduce multifactorial arterial stiffness (type 2 diabetes, aging, hypertension, and hypercholesterolemia).

Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy.

Background. The effect of islet cell transplantation (ICT) on the progression of diabetic microvascular complications is not well understood. Methods. We have conducted a prospective, crossover, cohort study comparing ICT with intensive medical therapy on the progression of diabetic nephropathy, retinopathy, and neuropathy. Results. The rate of decline in glomerular filtration rate is slower after ICT than on medical therapy. There was significantly more progression of retinopathy in medically treated patients than post-ICT. There was a nonsignificant trend for improved nerve conduction velocity post-ICT. Conclusions. ICT is associated with less progression of microvascular complications than intensive medical therapy. Multicenter, randomized trials are needed to further study the role of ICT in slowing the progression of diabetic complications.

Effect of exenatide on beta cell function after islet transplantation in type 1 diabetes.

Background. Islet transplantation can reduce or eliminate the need for insulin in patients with type 1 diabetes. Exenatide is a long acting analogue of Glucagon-like peptide-1 (GLP-1) that augments glucose induced insulin secretion, and may increase &bgr; cell mass. We evaluated the effect of exenatide on insulin secretion after islet transplantation. Methods. Eleven C-peptide positive islet cell recipients with elevated glucose levels were treated with exenatide for three months. Response was assessed by insulin requirements, meal tolerance tests, and hyperglycemic glucose clamps. Results. Ten patients responded to exenatide. Two patients who had not restarted insulin achieved good glycemic control and one patient who had received 5500 IE/kg in first islet infusion was able to stop insulin. Seven other patients decreased their insulin dose by 39% on exenatide. Hyperglycemic clamp studies showed a rise in second phase insulin release (before exenatide: 246±88 pM; during exenatide: 644±294 pM, P<0.01). Meal tolerance studies before and one month after stopping exenatide did not show a difference in glucose or C-peptide values. Nausea and vomiting were the major side effects. Conclusions. Exenatide stimulates insulin secretion in islet transplant recipients. It reduces insulin dose in some patients and may delay the need to resume insulin in others. We did not find any evidence of a trophic effect on islets.

Glibenclamide vs Gliclazide in Type 2 Diabetes of the Elderly

The objective of this study was to compare the effect of two sulphonylureas on the frequency of hypoglycaemic events and glycaemic control in elderly patients with Type 2 diabetes. Twenty‐two untreated elderly patients were treated with glibenclamide or gliclazide in a randomized double‐blind fashion. Prior to treatment, a biochemical profile, an oral glucose tolerance test, and a 2‐h hyperglycaemic glucose clamp (glucose 5.4 mmol I‐zs‐1 above baseline) were performed. Patients were seen regularly over 6 months to assess glycaemic control and the frequency of hypoglycaemic reactions. Hyperglycaemic clamp studies and oral glucose tolerance tests were repeated at 1 and 6 months. The area under the curve for the oral glucose tolerance test (glibenclamide: 15.5 ± 0.7; gliclazide: 14.9 ± 0.8 mmol I−1 ((p = NS)) and the haemoglobin A1C (glibenclamide: 7.4 ± 0.2%; gliclazide: 7.9 ± 0.5% (p = NS)) were similar at 6 months. Hypoglycaemic reactions were significantly more frequent with glibenclamide than with gliclazide: 17 vs 4 (p < 0.01). Insulin sensitivity index (ml kg−1 min−1 pmol −1 × 100) was increased significantly by glibenclamide but not gliclazide (glibenclamide: 0.284 ± 0.116 (baseline) vs 0.518 ± 0.102 (6 months) (p < 0.05), gliclazide: 0.260 ± 0.048 (baseline) vs 0.358 ± 0.048 (6 months) (p = NS)). We conclude that glycaemic control was equivalent with the two drugs but the incidence of hypoglycaemic reactions was significantly greater with glibenclamide probably because this drug increases insulin sensitivity to a greater degree.

GLP-1 (9–36) Amide, Cleavage Product of GLP-1 (7–36) Amide, Is a Glucoregulatory Peptide

Objective: Glucagon‐like peptide‐1 (GLP‐1) (7–36) amide is a glucoregulatory hormone with insulinotropic and insulinomimetic actions. We determined whether the insulinomimetic effects of GLP‐1 are mediated through its principal metabolite, GLP‐1 (9–36) amide (GLP‐1m).

Metabolic Alterations in Middle-Aged and Elderly Lean Patients With Type 2 Diabetes

Numerous studies (1–6) have systematically examined the metabolic alterations that occur in middleaged patients with type 2 diabetes. These studies have found that when compared with ageand weight-matched control subjects, patients with type 2 diabetes have increased fasting hepatic glucose production, impaired glucose-induced release, and resistance to insulinmediated glucose disposal. Diabetes is common in the elderly (7), but few studies (8–10) have examined the metabolic changes that occur in elderly subjects with diabetes. Recently, we compared metabolic changes in obese middle-aged and elderly control subjects and patients with diabetes (10). We now report our findings in lean middle-aged and elderly control subjects and patients with diabetes.

Alterations in Glucose Metabolism in Patients with Alzheimer's Disease

Objective: To determine the alterations in glucose metabolism that occur in patients with Alzheimers Disease (AD).