Intestinal Ketogenic Inhibition of the Incretin GLP-1

It has been shown in man that a fatty diet in people with obesity stimulated the release of ketone bodies (KB) in the small intestinal mucosa. This observation was partly explained by an increased level of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) in the jejunum of the obese people.

Glucagon-like peptide 1 (GLP-1) is a peptide that is released from the intestinal mucosa and mediates among other things, satiation, as well as insulin-secretion and insulin-sensitivity. In patients with obesity, GLP-1 response to food is attenuated, but it increases following bariatric surgery.

The question arose if the increased KB could be linked to the decreased level of meal-induced GLP-1. Indeed, in mice and rats the increased production of KB could be related to a decreased level of GLP-1. However, such a close relationship has never been shown in man.

The present study tests, therefore, if release of the ketone body beta-hydroxybutyric acid into the intestine on two levels (stomach/duodenum and ileum/colon) of healthy volunteers influences the blood concentration of GLP-1 following an oral glucose tolerance test (OGTT). Glucose, insulin and KB are determined in peripheral plasma according to OGTT-routine.

KB are lipid-derived organic molecules that can serve a circulating energy source during starvation/fasting (or pronged exercise). Beta-hydroxybutyrate (BHB), acetoacetate (AcAc) and acetone ("ketone bodies") are products of acetyl-CoA derived from fatty acids converted to via hepatic mitochondria. The three KB are connected to each by proteolytic interconnection. BHB is the most important source of energy, while AcAc is approximately 25-30% of BHB. Acetone is gas-soluble and is exhaled if ketonemia increases.