Although GLP-1 receptors are not classically thought to be widely expressed in peripheral insulin-sensitive tissues such as muscle, fat, or liver, several studies have suggested that sustained treatment with GLP-1 receptor agonists is associated with improvements in insulin sensitivity.

GLP-1, insulin sensitivity, and human studies

A six week continuous GLP-1 infusion study in human subjects with type 2 diabetes demonstrated modest weight loss (1.9 kg) and an increase in insulin sensitivity at the end of the treatment period as described in Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002 Mar 9;359(9309):824-30

Seghieri and colleagues assess the effects of native GLP-1, infused at rates to produce postprandial levels of GLP-1 (to levels 3-fold highr than basal), in 14 healthy non-diabetic non-obese human volunteers subjected to a pancreatic somatostatin clamp, with replacement of insulin and glucagon levels. Despite the somatostatin clamp, GLP-1-infused subjects did exhibit breakthrough insulin secretion during the last hour of the study. Nevetheless, GLP-1 infusion suppressed endogenous glucose production by 60-180 minutes befoe insulin levels began to rise. Hence, GLP-1 appears to inhibit endogenous Ra under mild hyperglycemic conditions independent of changes in insulin, glucagon, or glucose levels Direct effect of GLP-1 infusion on endogenous glucose production in humans Diabetologia. 2012 Oct 12

Treatment of 8 elderly subjects for 3 months with continuous subcutaneous GLP-1 infusion for 12 weeks was associated with enhanced glucose disposal during a hyperinsulinemic euglycemic clamp as shown in Effects of 3 months of continuous subcutaneous administration of glucagon-like peptide 1 in elderly patients with type 2 diabetes. Diabetes Care. 2003 Oct;26(10):2835-41. These findings are consistent with short term studies in elderly subjects suggesting a role for GLP-1 in the enhancement of glucose disposal in elderly subjects Glucagon-like peptide-1 (7-37) augments insulin-mediated glucose uptake in elderly patients with diabetes. J Gerontol A Biol Sci Med Sci. 2001 Nov;56(11):M681-5 and Effect of glucagon-like peptide 1 on non-insulin-mediated glucose uptake in the elderly patient with diabetes. Diabetes Care. 2001 Nov;24(11):1951-6.

Similar short term infusion studies have demonstrated that GLP-1 infusion enhances glucose disposal to a greater extent than matched levels of insulin in non-diabetic obese subjects Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state. J Clin Endocrinol Metab. 2002 Aug;87 (8): 3768-73. In contrast, GLP-1 had no effect on insulin-stimulated glucose uptake in subjects with type 1 diabetes as described in 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):837-42.

Nevertheless, a majority of these studies fail to completely clamp the levels of insulin and glucagon, as might be achieved with a somatostatin infusion, hence it is sometimes difficult to exclude small effects from these hormones on the study outcome.

Preclinical Studies

Mizuno and colleagues reported an 88% increase in clamp insulin sensitivity and a 2.4-fold increase in muscle glucose uptake in Otsuka Long-Evans Tokushima Fatty (OLETF) rats treated with a 4 week chronic subcutaneous infusion of native GLP-1, whereas no change in hepatic glucose uptake was observed in the same studies Extrapancreatic action of truncated glucagon-like peptide-I in Otsuka Long-Evans Tokushima Fatty rats, an animal model for non-insulin-dependent diabetes mellitus. Metabolism. 1997 Jul;46(7):745-9.

Early studies using exendin-4 demonstrated that chronic treatment of diabetic rodents was associated with both weight loss and increased insulin sensitivity, as described in Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). Diabetes. 1999 May;48(5):1026-34

The effects of exendin-4 on insulin sensitivity were examined in a 6 week study of nondiabetic, insulin-resistant obese fa/fa Zucker rats treated with exendin-4, 3 uk/kg b.i.d. The insulin sensitivity index (ISI; glucose infusion rate to plasma insulin concentration) during a hyperinsulinemic euglycemic clamp was 224% higher in Ex-4-treated rats relative to control  rats  and 61% higher in Ex-4-treated rats relative to pair fed rats  exhibiting comparable HbA1c, fasting glucose, fasting insulin, and daily food consumption between Ex-4 and PF animals. Although the mechanisms mediating enhanced peripheral glucose uptake in Ex-4-treated rats remain uncertain, this study demonstrates that weight loss alone cannot account for the insulin sensitizing effect of exendin-4 treatment. See Exenatide (Exendin-4) Improves Insulin Sensitivity and {beta}-Cell Mass in Insulin-Resistant Obese fa/fa Zucker Rats Independent of Glycemia and Body Weight. sEndocrinology. 2005 Apr;146(4):2069-76

In contrast, short term studies of GLP-1 action in depancreatized dogs demonstrated that GLP-1 potentiates insulin-stimulated glucose utilization as shown in Glucagon-like peptide 1 increases insulin sensitivity in depancreatized dogs. Diabetes. 1999 May;48(5):1045-53


To review data implicating potential actions of GLP-1 in tissues such as liver or muscle that may not express the known GLP-1 receptor, see GLP-1 actions and a second GLP-1 receptor