To date, almost all of the actions reported for GLP-1 in animal studies have been validated in several dozen human studies of both normal and diabetic subjects. The glucose-lowering actions of GLP-1 in studies of diabetic patients are secondary to inhibition of gastric emptying and glucagon secretion, and stimulation of insulin secretion. GLP-1 also lowers appetite in short term studies of patients with type 2 diabetes, however the long terms effects of GLP-1 or exendin-4 on body weight in diabetic subjects have not yet been reported.
Enhanced interest in the potential use of GLP-1 for the treatment of diabetes followed the NEJM publication demonstrating that GLP-1 lowered blood glucose in both patients with Type 2 and Type 1 diabetes Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus. N Engl J Med. 1992 May 14;326(20):1316-22.
Although the majority of interest in GLP-1 as a therapeutic agent is focused on Type 2 diabetes, several studies have shown modest glucose-lowering effects of GLP-1 administration in Type 1 diabetes, likely due to effects on gastric emptying and inhibition of glucagon secretion. See:
Although there has been some controversy about whether GLP-1 stimulates insulin-independent glucose uptake, studies of GLP-1 infusion in normal human subjects or patients with Type 1 diabetes do not consistently show any significant stimulation on glucose disappearance and insulin-mediated glucose uptake. See Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans. Diabetologia. 2002 Oct;45(10):1410-5 and Effect of Glucagon-Like Peptide 1 (7-36 Amide) on Insulin-Mediated Glucose Uptake in Patients With Type 1 Diabetes. Diabetes Care. 2003 Mar;26(3):837-842 and Effect of glucagon-like peptide 1(7-36) amide on glucose effectiveness and insulin action in people with type 2 diabetes. Diabetes. 2000 Apr;49(4):611-7
Nevertheless, some studies have
suggested GLP-1 promotes insulin or
glucagon-independent glucose clearance and/or suppression of glucose production.
Studies of endogenous glucose production (Ra) and glucose disposal (Rd) in 8
human volunteers were carried out with fixed insulin and glucagon concentrations
(octreotide infusion) while glucose was maintained at the fasting level and
insulin and glucagon were replaced to maintain blood glucose near fasting
levels. A 60 minute infusion of GLP-1 (30
pmol/kg/h) decreased plasma glucose in all 8 subjects which was accounted for by
a significant,17 % decrease in Ra, with no significant change in Rd. Hence, GLP-1may
lower fasting blood glucose in normal individuals through effects on the liver,
possibly through portal neural mechanisms. See Suppression
of endogenous glucose production by glucagon-like peptide 1 independent of islet
hormones: An extrapancreatic effect of an incretin hormone. Am J Physiol
Endocrinol Metab. 2003 May 28
GLP-1 functions as an incretin in human subjects, as infusion of the GLP-1 antagonist exendin (9-39) blocked the insulinotropic and glucagonostatic effects of exogenous GLP-1, and also increased plasma glucagon during euglycemia and hyperglycemia. Exendin (9-39 also increased insulin during hyperglycemia. Similarly, human GLP-1 is essential for control of anteroduodenal motility, as demonstrated in studies using exendin(9-39). These findings agree with similar studies in rodent "loss of function" models, and demonstrate the physiological importance of GLP-1 action for glucose regulation in normal human subjects. See Endogenous GLP-1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans. Gut. 2005 Jun 28; [Epub ahead of print] and Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans. J Clin Invest. 1998 Apr 1;101(7):1421-30. Similarly, blockade of endogenous GLP-1 with Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. Diabetes. 1999 Jan;48(1):86-93
To review safety issues surrounding use of GLP-1R agonists to treat diabetes, see GLP-1: Adverse Events