Incretin Augmentation of Insulin Secretion

The observation that food ingestion or enteral glucose administration provoked a greater stimulation of insulin release than similar amounts of glucose infused intravenously led to the recognition of gastrointestinal hormones known as incretins. Although a number of neurotransmitters and gut hormones possess incretin-like activity, several lines of evidence (immunoneutralization, administration of antagonists, and knockout studies) suggest that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) represent the dominant peptides responsible for nutrient-augmented stimulation of insulin secretion. Exenatide, the first GLP-1 agonist, has recently received FDA approval for adjuvant therapy in T2DM (see Section 6.19.6.7)

Dipeptidyl peptidase-IV (DPP-IV) is a membrane-associated peptidase that is widely distributed in tissues and also exists as a soluble circulating form. Several DPP-IV inhibitors have been characterized and shown to lower blood glucose via prolongation of circulating GLP-1 and GIP action.87 Animal studies with DPP-IV inhibitors show promising results. Progressive improvement in glycemic control, enhanced insulin secretory response, increased insulin-stimulated muscle glucose uptake, and improved hepatic and peripheral insulin sensitivity have been noted. Vildagliptin (LAF-237), a DPP-IVinhibitor, is in phase III clinical trials forT2DM. It markedly reduces DPP-IVactivity within 30 min and continues to show activity for at least 10 h. In a recently reported trial that compared metformin plus LAF-237 50mgday_ 1 with metformin plus placebo, LAF-237 reduced HbA1C levels by 0.7% in 12 weeks.88 The LAF-237 group also showed significant reductions in FPG levels and improvements in mean prandial glucose. The dipeptidyl peptidase-IV (DPP-IV) inhibitor, sitagliptin was approved as monotherapy for type 2 diabetes in October 2006.

Glucose-dependent insulinotropic polypeptide (GIP), also known as gastric inhibitory polypeptide, is a 42 amino acid peptide released from intestinal cells in response to nutrient absorption. Similarly to GLP-1, GIP undergoes rapid metabolism by DPP-IV via amino-terminal inactivation. GIP promotes b-cell proliferation89 and stimulates glucose-dependent b-cell insulin secretion,90 but has no effect on glucagon secretion or gastric emptying. GIP infusion in normal human subjects did not affect glucose, insulin, or C-peptide at normoglycemia. Although there are no GIP analogs currently in phase III clinical trials, there remains interest in the possibility that GIP analogs resistant to DPP-IV may exhibit therapeutic potential.

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

Get My Free Ebook


Post a comment