The 2ND Century of Caring for Diabetes: Emerging Treatment Options

Supported by an unrestricted educational grant from Eli Lilly and Company and the Amylin-Lilly Alliance
Tuesday, June 15, 2004
6:30-9:30 PM

Chair:
Jane Reusch, MD

Faculty:
Guenther Boden, MD
Kathleen Wyne, MD, PhD, FACE
David D’Alessio, MD
Aaron Vinik, MD, PhD

Reviewed by Joelle Escoffery, PhD

The primary goals of this symposium were to gain an understanding of the pathophysiology of diabetes, to review current treatment strategies to optimize glycemic control, and to examine emerging therapies in the treatment of diabetes and diabetic microvascular complications.  In terms of the pathophysiology of type 2 diabetes, obesity is a known risk factor, as it promotes insulin resistance. Obesity is associated with elevations in free fatty acids (FFAs), which in turn are associated with both peripheral and hepatic insulin resistance, inhibition of insulin signaling, and both proinflammatory and proatherogenic effects. In terms of treatment for type 2 diabetes, the treatment algorithm has shifted to treat the underlying pathophysiology of the disease and to meet more stringent glycemic goals. Specifically, earlier use of combination therapy and simultaneous therapy (as opposed to sequential therapy) represent an attempt to address the underlying pathophysiologic deficits associated with type 2 diabetes. Combinations of oral medications have a greater effect than would be expected by simply summing the effects of the individual agents, allowing for greater glycemic control.  In terms of emerging therapies, GLP-1 has been shown to stimulate insulin secretion, inhibit glucagon secretion, slow gastric emptying, and may stimulate β-cell growth. However, naturally-occurring GLP-1 is rapidly degraded by dipeptidyl peptidase IV (DPP-IV). Two therapeutic approaches to increasing GLP-1 are being explored: the use of DPP-IV-resistant GLP-1 analogs and the use of DPP-IV inhibitors. Phase III clinical trials of one GLP-1 agonist showed a dose-dependent improvement in A1C that was maintained at 30 weeks, without increasing hypoglycemia. The DPP-IV inhibitor LA237 has been shown to significantly decrease A1C, and the effect was maintained over the course of a year.  In terms microvascular complications, animal data have demonstrated that protein kinase C (PKC), specifically the PKC-β isoform, plays a major role in the development of diabetic microvascular complications. PKC- β inhibition has been shown to improve both nerve function and symptoms of peripheral neuropathy.