Progress in Caring for Diabetes: Emerging Treatment Options

Supported by an unrestricted educational grant from Eli Lilly and Company and Amylin Pharmaceuticals
Friday, June 4, 2004
7:00 – 9:30 PM

Chair:
Harold Lebovitz, MD

Faculty:
Steve Edelman, MD
James R Gavin, III, MD, PhD|
Harold Lebovitz, MD

Adipose tissue improves the probability of survival in an environment of uncertain food supply, but modern living conditions make it easy to acquire too much of a good thing. Adipose tissue has endocrine activity, secreting many hormones and other factors, among which are triglycerides, free fatty acids (FFAs), and the recently discovered hormone adiponectin. The metabolic products of FFAs are detrimental to all organs; importantly, high FFA levels essentially poison the pancreatic β cell. Thus, type 2 diabetes can be conceptualized as a lipid disorder that causes hyperglycemia; obesity appears to be the core defect driving insulin resistance; therefore, clinicians should address the modifiable risk factors for developing type 2 diabetes (eg, food intake, exercise) with unflappable resolve. Adiponectin, an adipose-tissue–specific glycoprotein, has antiinflammatory and antiatherosclerotic actions. Decreasing adiponectin levels are associated with increasing insulin resistance.1 Adiponectin also increases hepatic insulin action, suggesting a potential role in the future therapy of type 2 diabetes. In clinical trials, treatment with synthetic exendin-4, a long-acting mimetic of the human incretin GLP-1, administered with oral antihyperglycemic medications, improved glycemic control and resulted in weight loss, a novel combination of benefits.2,3 Another emerging treatment, pramlintide, the synthetic analog of the pancreatic neurohormone amylin, may improve postprandial glucose control when administered in conjunction with insulin.4 Poor metabolic control is associated with increased risk of developing diabetic microvascular complications (DMC), but DMC can develop even in well-controlled patients, suggesting that factors other than glycemia lead to their development. Protein kinase C (PKC) β activation is thought to have a critical role in the development of DMC, including diabetic macular edema (DME). The PKC β inhibitor ruboxistaurin significantly reduced the progression of DME after 18 months of treatment in patients with baseline A1C between 8.0% and 10% in a Phase III clinical trial.5

References

1. Stefan N, Vozarova B, Funahashi T, et al. Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. Diabetes. 2002;51:1884-1888.
2. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824-830.
3. Buse J, Henry R, Han J, Kim DD, Fineman M, Baron AD. Effect of exenatide (exendin-4) on glycemic control and safety over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes. 2004;53(suppl 2):A82.
4. Ratner RE, Want LL, Fineman MS, et al. Adjunctive therapy with the amylin analogue pramlintide leads to a combined improvement in glycemic and weight control in insulin-treated subjects with type 2 diabetes. Diab Tech Ther. 2002;4:51-61.
5. Aiello LP, Davis MD, Milton RC, Sheetz MJ, Arora V, Vignati L. Initial results of the protein kinase C β inhibitor Diabetic Macular Edema Study (PKC-DMES). Diabetologia. 2003;46(suppl 2):A42.