The Effect of the GLP-1 Analogue Exenatide on Glucose Metabolism in the CNS and Heart During Hyperglycemia in Type-2 Diabetic Patients Assessed by PET

Background Type 2 diabetes (T2D) is epidemically increasing throughout the world. T2D is frequently associated with multiple complications, where particularly the macrovascular complications in the form of myocardial infarction with its possible complication of death or heart failure, cerebral infarction and limb amputation are responsible for a vast increase in morbidity and mortality in this group of patients. Apart from the individual burden on the patient, T2D puts massive pressure on national health economies.

It is well established that blood glucose lowering drugs, antihypertensive as well as lipid lowering drugs all play a pivotal role in the treatment of the type 2 diabetic subjects. Regarding glycemia, there are frequently side effects with the 'classic' drugs such as hypoglycemia, weight gain, heart failure, and so forth. Another important caveat is that employing the anti-hyperglycemic drugs either as monotherapy or in combination does not lower blood glucose to the targets as defined by the ADA. In other words novel anti-diabetic drugs are urgently required. However, the incretin concept has recently been inaugurated in the pharmacological scenario.

Glucagon-like peptide-1-receptors (GLP-1R) are abundant on alpha- and beta-cells in the pancreas, but are also present in the heart and CNS, especially in hypothalamic and hippocampal regions. A wide range of extrapancreatic effects of GLP-1 have been observed such as slowed gastric emptying and satiety-stimulating effects through hypothalamic mechanisms. Recent studies have showed interesting results regarding protection of the heart during ischemia, and protection of the brain in the acute phases of stroke have been proposed. Over-all GLP-1 seems to display effects in heart, brain, vessels, kidneys, muscles and liver(7).

To our knowledge, our group has in a very recent study been the first, by sophisticated metabolic techniques, together with Positron Emission Tomography (PET), to demonstrate that GLP-1 per se reduces cerebral glucose transport in total cerebral grey matter as well as individual grey matter regions, thereby suggesting that GLP-1 may protect the brain by limiting intracerebral glucose fluctuation when plasma glucose is increased. In other words, GLP-1 regulates blood brain barrier (BBB) glucose transfer at normal glycemia and presumably also during hyperglycemia(19).

GLP-1 is believed to have cardioprotective actions. A recent study has shown improved preservation of cardiac function in patients with acute myocardial infarctions when GLP-1-infusion is supplemented to conventional treatment compared to conventional treatment alone. Ejection fraction was improved by 10 % in both diabetic and non-diabetic patients(15) in the GLP-1 group. It has been shown in animal models by the same research-team that the extend of myocardial injury is smaller during coronary occlusion when treated with GLP-1(16).