The contribution of incretin impairment to type 2 diabetes is the focus of ongoing research, and many questions remain to be answered. Preliminary data from several ongoing studies have provided insights into the role of glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase (DPP)-4 in relation to the role of the incretin system in type 2 diabetes. These data were reviewed by Richard Pratley, MD, Medical Director of the Florida Hospital Diabetes Institute and Professor at the Sanford-Burnham Medical Research Institute, Orlando, at the 2012 American Diabetes Association (ADA) annual meeting.
A number of metabolic defects contribute to the complexity of type 2 diabetes and its management. Some of these defects are insulin resistance in adipose tissue and skeletal muscle, decreased insulin secretion from pancreatic beta-cells, overproduction of glucagon (which drives hepatic glucose production), abnormalities in glucose absorption in the kidneys, and effects in the stomach and brain.
Impact of Incretin Impairment in Type 2 Diabetes
GLP-1 is a natural hormone that is secreted in the gut during meals. Food triggers the release of the incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) from the intestines into the blood. GLP-1 has effects on the pancreas to decrease glucagon and increase insulin secretion.
DPP-4 is an enzyme that inactivates GLP-1. The levels of GLP-1 can be enhanced for their beneficial effects by inhibiting the action of DPP-4 through a DPP-4 inhibitor, resulting in enhanced levels of endogenous secretion of GLP-1 and GIP. The use of a GLP receptor agonist bypasses incretin secretion but results in pharmacologic levels of GLP, which works through its receptor in the pancreas to decrease glucagon, increase insulin, and lower blood glucose.
Native GLP-1 increases insulin secretion from the beta-cell in a glucose-dependent fashion. It decreases glucagon secretion from the alpha-cell, and, at pharmacologic levels, it decreases gastric emptying. In contrast, the DPP-4 enzyme inactivates native GLP-1, and this contributes to the regulation of glucose homeostasis by inactivating the incretin hormones GLP-1 and GIP.
The incretin effect is the enhanced glucose-stimulated insulin secretion from the beta-cells in response to an oral glucose challenge compared with an intravenous challenge in patients with type 2 diabetes.
It is not yet known whether an incretin defect in patients with type 2 diabetes is related to impaired incretin secretion or to impaired incretin action. Abnormalities in the incretin system have been shown to contribute to progressive beta-cell failure.
The mechanisms of the incretin defect are not completely understood, and various investigations have shown multiple defects that contribute to this. There are slight decreases in the secretion of GLP-1, a possible reduced insulinogenic response to GLP-1, impaired activity of GLP-1, and beta-cell resistance to GIP.
Strategies to Overcome the Incretin Defect
Increase GLP-1 Levels
One strategy to overcome an impaired incretin effect is to give higher levels of GLP-1. A physiologic infusion of GLP-1 over 2 hours under hyperglycemic conditions resulted in a very robust insulin secretory response in healthy controls, although it was markedly blunted in patients with type 2 diabetes.
In contrast, a higher dose of GLP-1 (double that of the infusion) restored the insulin secretory response in patients with type 2 diabetes to nearly the same level as in the healthy controls who had normal glucose tolerance. Thus, pharmacologic levels of GLP-1 can restore the insulin secretory effect of GLP-1 in patients with type 2 diabetes, as shown in the study discussed by Dr Pratley.
Another study has shown that native GLP-1 stimulates insulin secretion and inhibits glucagon secretion in a glucose-dependent manner. In patients with poorly controlled type 2 diabetes (fasting plasma glucose, 220 mg/dL), the infusion of native GLP-1 markedly decreased the glucose response to a normal fasting glucose level at approximately 4 hours compared with placebo.
The prompt increase in the secretion of insulin and the prompt suppression of glucagon with the GLP-1 infusion were the mechanisms contributing to the improved glucose response. The long-term effect of GLP-1 to improve glucose control and improve beta-cell function was shown in another study.
DPP-4 inhibition relies on an endogenous secretion of GLP-1 and GIP, which enhances insulin secretion and decreases glucagon secretion. But this tends to be with levels in the high physiologic range, which gives clear improvements over baseline in patients with type 2 diabetes, but does not achieve pharmacologic levels.
To obtain the full pharmacologic effect, exogenous GLP-1 must be given through an infusion of a GLP-1 agonist. This provides some additional effects (eg, decreased gastric emptying, increased satiety, decreased energy intake, decreased body weight, and increased nausea and vomiting).
A proof-of-concept study in patients with type 2 diabetes showed that subcutaneous infusion of GLP-1 in 10 patients compared with saline infusion in 9 patients over 6 weeks resulted in an approximate 4-lb reduction of body weight with GLP-1 versus an approximate 1.5-lb loss with saline.
Impaired incretin effect is a key component of dysregulation of glucose in patients with type 2 diabetes, said Dr Pratley. DPP-4, an enzyme found throughout the body, rapidly inactivates GLP-1 and GIP, and modulates endogenous, physiologic GLP-1 activity levels. The effects of GLP-1 when given at pharmacologic levels include restoration of the insulin response and reduced body weight.
LP-1 and DPP-4 interact with the GLP-1 receptor by slightly different mechanisms. These actions are:
- Directly stimulates GLP-1 receptor
- Markedly increases GLP-1 activity
- Markedly decreases glucagon secretion
- Increases insulin response
- Delays gastric emptying
- Decreases appetite and energy intake
- Indirectly stimulates GLP-1 receptor
- Modestly increases endogenous GLP-1 and GIP levels
- Modestly decreases glucagon secretion
- Increases insulin response
- No effect on gastric emptying
- No effect on appetite and energy intake.
The recent ADA and the European Association for the Study of Diabetes Position Statement for managing hyperglycemia in patients with type 2 diabetes calls for initiating treatment with lifestyle changes and metformin, said Dr Pratley. In patients who are not achieving goals within 3 months, the second-line options include sulfonylureas, thiazolidinediones (TZDs), DPP-4 inhibitors, GLP-1 receptor agonists, and insulin.
The next steps in treatment would be the use of 3-drug combinations and more complex insulin strategies.
The clinical question is how to select from these different options. To maintain glycemic control without promoting hypoglycemia, we are limited to TZDs, DPP-4 inhibitors, or GLP-1 receptor agonists, said Dr Pratley.
To avoid weight gain, we want to avoid sulfonylureas, TZDs, and insulin; incretin therapies have the advantages of low rates of hypoglycemia and low or no weight gain.