Aucune remarque pour cette diapositive
DISCUSSION The development of type 2 diabetes involves defects in multiple organ systems which can be exacerbated by a number of factors, including diet and lifestyle, genetic causes and dysregulation of lipid and carbohydrate metabolism. Initially, insulin resistance is associated with hyperinsulinaemia and normal glucose tolerance. β -cell dysfunction manifests as impaired insulin production and failure to secrete sufficient insulin to compensate for insulin resistance. Eventually, demand for insulin outweighs β -cell capacity, leading to impaired glucose tolerance, escalating hyperglycaemia, and type 2 diabetes. Ramlo-Halsted BA, et al. Prim Care 1999;26:771–789.
DISCUSSION GLP-1 and GIP represent the dominant peptides responsible for the ‘incretin effect’. Bioactive forms of both GLP-1 and GIP are short-lived, with active plasma half-lives of ~2–7 minutes. Degradation is by dipeptidyl peptidase IV (DPP-IV). Drucker DJ. Diabetes Care 2003;26:2929–2940.
DISCUSSION The β -cell secretory response to glucose ingestion, as measured by increases in plasma insulin, was reduced in patients with type 2 diabetes. Patients with type 2 diabetes exhibited a greater β -cell secretory response than control subjects, as indicated by higher insulin secretion levels, during the 180-minute course of intravenous glucose infusion. BACKGROUND Differences in insulin response to oral and intravenous glucose administration, which are attributed to factors other than glucose itself, describe the incretin effect; the incretin effect appears to be reduced in patients with type 2 diabetes. Measured insulin and C-peptide responses to a 50 g oral glucose load and an isoglycaemic intravenous infusion. Additionally, an attempt was made to correlate incretin effects to GIP responses. Insulin measurements are shown here. Plasma insulin responses were studied for 14 patients with type 2 diabetes in this study and 8 metabolically healthy control subjects. Nauck MA, et al. Diabetologia 1986;29:46–52
DISCUSSION In patients with type 2 diabetes, GLP-1, in contrast to GIP, retains much of its insulinotropic activity. Both GIP and GLP-1 augmented insulin secretion in a dose-dependent fashion. With GLP-1 infusion, the maximum insulin effect in patients with type 2 diabetes approached 71% of the maximum insulin effect in subjects without diabetes (no statistical difference). With GIP infusion, the maximum insulin effect in patients with type 2 diabetes was 46% of the maximum insulin effect in subjects without diabetes ( P < 0.05). BACKGROUND The graphs represent immunoreactive insulin plotted against time (minutes) during hyperglycaemic clamp experiments with and without the infusion of synthetic human GIP or GLP-1. The data for the graphs of this slide were derived from a study of the insulinotropic effect of intravenously administered synthetic human GLP-1 and GIP (N = 9 for each patient group). Nauck MA, et al. J Clin Invest 1993;91:301–307
DISCUSSION Decreased GLP-1 secretion is found in patients with type 2 diabetes 1 ; however, it’s ability to stimulate glucose-dependent insulin secretion is preserved 1,2 . Another hormone, glucagon, is secreted by the α - cells of the pancreas and is elevated in type 2 diabetes. Glucagon stimulates hepatic glucose release. GLP-1 suppresses glucagon secretion from pancreatic α - cells in a glucose-dependent manner 3 , suppressing hepatic glucose output 4 . Therefore, incretin hormones, specifically GLP-1, have sparked interest in the treatment of type 2 diabetes 5 . 1 Nauck MA, et al. J Clin Invest 1993;91:301–307 2 Nauck M, et al. Diabetologia 1986;29:46–52 3 Nauck MA, et al. Diabetologia 1993;36:741–744 4 Larsson H, et al. Acta Physiol Scand 1997;160:413–422 5 Drucker DJ. Diabetes Care 2003;26:2929–2940 .
DISCUSSION This diagram demonstrates the GLP-1 effects in humans and the role these effects play in normal physiology. Upon the ingestion of food, plasma glucose levels increase postprandially. GLP-1 is secreted from intestinal L cells and provides a stimulus to the β -cells to release insulin in a glucose-dependent manner. When plasma glucose levels return to normal, the action of GLP-1 decreases 1 . GLP-1 also suppresses glucagon levels that are inappropriately elevated in patients with type 2 diabetes 1 . Lower glucagon levels leads to decreased hepatic glucose output 2 . In the stomach, GLP-1 slows the rate of gastric emptying, which reduces the rate at which meal-derived glucose appears in the circulation 3 . In the brain, GLP-1 promotes satiety and reduces appetite, which leads to a feeling of fullness and a reduction in food intake 4,5 . All these actions help maintain overall glucose homeostasis. 1 Nauck MA, et al. Diabetologia 1993;36:741–744 2 Larsson H, et al. Acta Physiol Scand 1997;160:413–422 3 Nauck MA, et al. Diabetologia 1996;39:1546–1553 4 Flint A, et al. J Clin Invest 1998;101:515–520 5 Zander et al. Lancet 2002;359:824–830.
DISCUSSION Progressive, dose-dependent reduction in weight was seen in exenatide-treated patients. At Week 30, weight changes from baseline were -2.8 ± 0.5 kg (10 µg), -1.6 ± 0.4 kg (5 µg) for exenatide treated patients ( P < 0.001 vs placebo 10 μ g and P < 0.001 vs placebo 5 μ g). No special weight loss programmes, exercise programmes, or standardised diets were used in the study. STUDY BACKGROUND A 30-week triple-blind, phase III study; patients with type 2 diabetes randomised to placebo, exenatide 5 or 10 µg BD with metformin, ITT, N = 336.
DISCUSSION Reduction in weight was seen in both exenatide arms, but greater weight loss was observed in the exenatide 10 µg BD arm. At Week 30, weight changes from baseline were -1.6 ± 0.3 kg (10 µg), -0.9 ± 0.3 kg (5 µg; not significantly different vs placebo) and -0.6 ± 0.3 kg (placebo). No special weight loss programmes, exercise programmes, or standardised diets were used in the study. STUDY BACKGROUND A 30-week triple-blind, phase III study; patients with type 2 diabetes randomised to placebo or exenatide 5 or 10 µg BD with sulphonylurea, ITT, N = 377.