GLP-1 Agonists and DPP-4 Inhibitors How do they work? Part 1

Overview Discuss normal GLP-1 physiology Examine the actions of DPP-4 inhibitors and GLP-1R agonists Review the tissue-specific differences in the mechanisms of action of GLP-1 analogs, DPP-4 inhibitors, and GLP-1R agonists

GLP-1 GLP-1 (1-37) is synthesized as a 37-amino-acid peptide Predominant circulating bioactive form of GLP-1 is GLP-1 (7-36)amide, but GLP-1 (7-37) is equipotent Native peptide undergoes rapid cleavage by DPP-4 and inactivation within minutes in vivo, thus limiting the effectiveness of the native peptide for the treatment of type 2 diabetes

Pleiotropic Actions of GLP-1 Heart Brain Neuroprotection Appetite Stomach Gastric Emptying Cardioprotection Cardiac Output GLP-1 _ Liver GLP-1 multiple actions. In humans it stimulates insulin secretion in a glucose-dependent manner and inhibits glucagon secretion, leading to a reduction in hepatic glucose production (HGP). The decline in basal HGP leads to a decrease in the FPG concentration, while the enhanced suppression of HGP after a meal results in a decrease in postprandial hyperglycemia. In rodents, GLP-1 augments islet neogenesis, stimulates beta-cell replication, and inhibits beta cell apoptosis. It is unclear whether these effects will be observed in humans. The effect of GLP-1 to augment insulin secretion leads to enhanced muscle glucose uptake and increased suppression of lipolysis in adipocytes. GLP-1 inhibits gastric emptying leading to a decline in postprandial hyperglycemia. GLP-1 receptors are present in appetite center in the hypothalamus and their stimulation leads to reduced food intake and weight loss. GLP-1 and its metabolites augment cardiac output and coronary blood flow in animals. GI Tract Insulin Secretion β-Cell Neogenesis β-Cell Apoptosis Glucagon Secretion Glucose Production + Glucose Uptake Muscle Drucker DJ. Cell Metab. 2006;3:153-165.

Incretins In response to equivalent hyperglycemic stimuli, oral glucose elicits a greater insulin response than intravenus glucose The term “incretin” was introduced by La Barre to describe gut humoral activity that stimulated pancreatic endocrine secretion La Barre J, Still EU. Studies on the physiology of secretion. Am J Physiol. 1930;91:649-653. La Barre J, et al. Am J. Physiol. 1930;91:649-653.

When healthy participants receive an intravenous glucose infusion to mimic the plasma glucose response observed with oral glucose (left), the plasma insulin response is one-third of that observed with ingested glucose. Thus, oral glucose ingestion has a major effect on augmenting insulin secretion. This is the incretin effect. Nauck MA, Homberger E, Siegel EG, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63(2):492-498

GLP-1 and Glucose-Dependent Insulinotropic Polypeptide (GIP) Account for ~90% of the Incretin Effect

GIP, which is secreted by the K cells in the proximal part of the small intestine, stimulates insulin secretion. GLP-1, which is secreted by the L cells in the distal small intestine, augments insulin secretion, inhibits glucagon secretion, delays gastric emptying, and suppresses the appetite. GIP and GLP-1 are secreted within minutes after meal ingestion in response to activation of neural circuits that connect the gastrointestinal tract with the hypothalamus. Activation of these neural arcs requires transport of nutrients though the intestinal mucosal cells.

After subcutaneous injection of GLP-1, 10 µg (or ingestion of a mixed meal to endogenously augment plasma GLP-1 levels), native GLP-1 is rapidly cleared. The active intact GLP-1 represents only 1% to 2% of the total GLP-1 measured in plasma and reaches a peak of concentration of ~50-60 pmol/L. GLP-1 levels are reduced in study participants with T2DM.   Deacon CF, Nauck MA, Toft-Nielsen M, et al. Both subcutaneously and intrave-nously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes.1995;44(9):1126-1131.

Native GLP-1 Is Rapidly and Constantly Degraded and Cleared by the Kidney After subcutaneous injection of GLP-1, 10 µg (or ingestion of a mixed meal to endogenously augment plasma GLP-1 levels), native GLP-1 is rapidly cleared. The active intact GLP-1 represents only 1% to 2% of the total GLP-1 measured in plasma and reaches a peak of concentration of ~50-60 pmol/L. GLP-1 levels are reduced in study participants with T2DM.   Deacon CF, Nauck MA, Toft-Nielsen M, et al. Both subcutaneously and intrave-nously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes.1995;44(9):1126-1131.