The enthusiasm for potential therapeutic use of GLP-1 derives from studies demonstrating that unlike GIP, the glucose-lowering actions of GLP-1 are preserved in patients with type 2 diabetes, as shown in Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993 Jan;91(1):301-7 and The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects.
Similarly, the actions of GLP-1 on inhibition of gastric emptying are also preserved in subjects with poorly controlled type 2 diabetes, Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab. 1996 Jan;81(1):327-32.
Although the actions of GLP-1 on the b-cell are preserved yet modestly diminished in T2DM, the diabetic a-cell retains near normal responsivity to low dose GLP-1 infusion, with inhibition of glucagon secretion seen to a similar extent in diabetic vs. non-diabetic subjects. Hence, modestly diminished GLP-1 action in diabetic subjects does not likely contribute to the defective glucose-stimulated glucagon suppression that remains a characteristic of diabetic subjects. See Preserved inhibitory potency of GLP-1 on glucagon secretion in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2009 Dec;94(12):4679-87. Epub 2009 Oct 16
Although the total number of diabetic patients treated with native GLP-1 to date remains small, combined analyses of several studies shows uniform responses to GLP-1 with glucose lowering in all diabetic subjects analyzed to date. See Glucagon-like peptide 1 and its potential in the treatment of non-insulin-dependent diabetes mellitus. Horm Metab Res. 1997 Sep;29(9):411-6. Nevertheless, it seems clear that there is a spectrum of GLP-1 responses in subjects with Type 2 diabetes, with the greatest 'GLP-1 effectiveness' observed in short term intravenous infusion studies, in subjects with more modest impairment in fasting hyperglycemia. See Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes. J Clin Endocrinol Metab. 2001 Aug;86(8):3853-60
Similarly, although long term data for GLP-1 treatment of diabetics is currently lacking, treatment of diabetic patients for 3-6 weeks with subcutaneous GLP-1 was efficacious in several small pilot studies, Subcutaneous glucagon-like peptide-1 improves postprandial glycaemic control over a 3-week period in patients with early type 2 diabetes. Clin Sci (Colch). 1998 Sep;95(3):325-9 and Glucagon-like peptide-1 (GLP-1): a trial of treatment in non-insulin -dependent diabetes mellitus. Eur J Clin Invest. 1997 Jun;27(6):533-6.
For results of longer term studies in human subjects, see, GLP-1 analogues and human diabetes
Importantly, GLP-1 lowers blood glucose in the overnight fasting state, and not just after meal ingestion, as shown in Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993 Aug;36(8):741-4 and Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 1 (7-36) amide in patients with NIDDM. Diabetes. 1996 Nov;45(11):1524-30, largely via improvement of β cell function. It seems clear that although the predominant gluose-lowering effects of GLP-1R agonists are during the day, studies examining 16 hr vs 24 hr infusion of GLP-1 in hospitalized patients for 7 days clearly demonstrated better 24 hr glucose control in subjects receiving the continuous 24 hr infusion as shown in Glucagon-like peptide-1 infusion must be maintained for 24 h/day to obtain acceptable glycemia in type 2 diabetic patients who are poorly controlled on sulphonylurea treatment. Diabetes Care. 2001 Aug;24(8):1416-21
The finding that short-term GLP-1 infusion normalized fasting plasma glucose in patients with type 2 diabetes following secondary sulfonylurea failure suggests that activation of GLP-1R signaling may reverse diabetes-associated defects in the failing β cell, as shown in Influence of glucagon-like peptide 1 on fasting glycemia in type 2 diabetic patients treated with insulin after sulfonylurea secondary failure. Diabetes Care. 1998 Nov;21(11):1925-31. Furthermore, the glucose-lowering effects of GLP-1 and sulfonylureas are additive, as shown in Glucagon-like peptide I enhances the insulinotropic effect of glibenclamide in NIDDM patients and in the perfused rat pancreas. Diabetes Care. 1996 Aug;19(8):857-63.
Infusion of GLP-1 for varying periods of time produces different results on β cell function, consistent with the notion that GLP-1R activation sets in motion a large number of molecular events in addition to acute stimulation of exocytosis and insulin secretion. A three hour GLP-1 infusion produced more significant improvement in first phase insulin secretion and second phase insulin release compared to a single acute GLP-1 injection. See Differential Effects of Acute and Extended Infusions of Glucagon-Like Peptide-1 on First- and Second-Phase Insulin Secretion in Diabetic and Nondiabetic Humans. Diabetes Care. 2003 Mar;26(3):791-798
Although numerous studies attest to the effectiveness of GLP-1 in the acute lowering of blood glucose in subjects with type 2 diabetes, graded infusion of varying glucose and GLP-1 concentrations in seven diabetic subjects demonstrates a clearly detectable difference in β cell responsivity to GLP-1 in diabetic subjects. β cell responsivity, as measured by the insulin secretory response, was clearly lower in subjects with Type 2 diabetes compared to normal controls, but improves significantly following even low dose GLP-1 infusion. See The Influence of GLP-1 on Glucose-Stimulated Insulin Secretion: Effects on beta-Cell Sensitivity in Type 2 and Nondiabetic Subjects. Diabetes. 2003 Feb;52(2):380-386. Nevertheless, GLP-1 infusion potentiates the acute β cell secretory response to glucose after meal ingestion in human subjects as shown in Characterization of GLP-1 Effects on beta-Cell Function After Meal Ingestion in Humans. Diabetes Care. 2003 Oct;26(10):2860-4.
Does GLP-1 work additively in the presence of other antidiabetic agents? The answer, at least for metformin, appears to be yes. See Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes. Diabetes Care. 2001 Apr;24(4):720-5
Similarly, addition of 48 hrs of GLP-1 therapy in diabetic subjects previously treated with the thiazolidinedione pioglitazone increased levels of insulin, decreased plasma glucagon and produced further reductions in fasting plasma glucose, 8 hr mean plasma glucose, and levels of free fatty acids. See Additive effects of glucagon-like Peptide 1 and pioglitazone in patients with type 2 diabetes. Diabetes Care. 2004 Aug;27(8):1910-4.
Can GLP-1 be delivered via a non-injectable formulation? Several studies appear promising, however additional refinements in these technologies are eagerly awaited. See GLP-1 tablet in type 2 diabetes in fasting and postprandial conditions. Diabetes Care. 1997 Dec;20(12):1874-9
Does it matter greatly whether GLP-1 is administered prior to or after food intake for the treatment of Type 2 diabetes? At least in the very short term single injection paradigm, the answer is no. Although the mechanism for antidiabetogenic action of GLP-1 may be different (gastric emptying versus effects on glucagon and insulin), some degree of postprandial glycemic control was achieved with various pre and postmeal GLP-1 administration regimens. More long term studies (24h to several days and weeks) are required before these conclusions can be more widely extrapolated. See Antidiabetogenic action of glucagon-like peptide-1 related to administration relative to meal intake in subjects with type 2 diabetes. J Intern Med. 2001 Jul;250(1):81-87
What is the optimum duration of GLP-1 therapy during a 24 h period? Subjects with type 2 diabetes (considered to have failed SU therapy) were randomized to receive continuous subcutaneous GLP-1 infusion for either 16 (8 am-12 am) or 24 h. Patients treated with 24 h GLP-1 infusions exhibited lower glycemic excursion profiles during the night, and lower fasting blood glucose. These findings suggest that maintaining enhanced levels of GLP-1 signaling even during the overnight period is important for optimal glycemic control in Type 2 diabetes. See Glucagon-Like Peptide-1 Infusion Must Be Maintained for 24 h/day to Obtain Acceptable Glycemia in Type 2 Diabetic Patients Who Are Poorly Controlled on Sulphonylurea Treatment. Diabetes Care. 2001 Aug; 24(8): 1416-21