The presentation slides will not post here, so go to the link below to view the graphics:
Clinical Impact of Therapies Directed at Beta-cell Preservation
Robert R. Henry, MD
Preserving and Regenerating Beta Cells
Slide 23. GLP-1 Stimulates Beta-cell Regeneration and Mass
Going on to the preservation or regeneration of beta cells, you heard from Dr. Drucker about the potential of the GLP-1 analogs and the DPP-4 inhibitors to have beneficial effects on the beta cell by enhancing beta-cell neogenesis/proliferation, beta-cell hypertrophy, and the ability to inhibit apoptosis. So the GLP-1 analogs and the DPP-4 inhibitors have significant potential to not only maintain beta-cell function, but in fact, to possibly increase beta-cell secretion in people prone to developing diabetes, or those who have diabetes with loss of beta-cell function.
Slide 24. Effects of Exenatide on the Beta Cell
You heard earlier from Dr. Drucker about in vitro preclinical data on exenatide. Exenatide in cell cultures and in animals increases the expression of key beta-cell genes. It increases insulin synthesis and processing; it also increases beta-cell mass with increases in neogenesis and proliferation, and reductions in apoptosis. In humans to date, exenatide improves the insulin/proinsulin ratio consistent with improved insulin secretion. It restores first-phase insulin secretion (I will show you that in the next slide). It also augments insulin secretion at lower prevailing glucose concentrations.
Slide 25. Exenatide Restores First-Phase Insulin Secretion
in Type 2 Diabetes
These are the effects of exenatide on first-phase insulin secretion; again, you saw preclinical data about this potential earlier. This is insulin secretion, shown on the vertical axis, to an IV bolus of glucose or an IV glucose tolerance test. There are 3 groups of subjects: healthy controls; untreated type 2 diabetics; and type 2 diabetics treated with exenatide. Following an IV bolus of glucose in nondiabetic subjects, there is normal first-phase insulin secretion, and then a second-phase tail appears. People with type 2 diabetes have lost their first-phase insulin secretion. However, following acute treatment with exenatide, you see a recovery of first-phase and second-phase insulin secretion -- a substantial improvement in the ability of the beta cell to respond to a standard IV glucose load.
Slide 26. Sustained A1C Reduction
: Exenatide-Treated Patients
In the exenatide controlled trials -- the so-called Diabetes Management for Improving Glucose Outcomes (AMIGO) studies -- hemoglobin A1C was reduced by more than 1% over 26 weeks. As with glitazones, the open-label studies demonstrate sustained and durable glycemic control consistent with a persistent effect to sustaining insulin secretion, at least in these individuals with type 2 diabetes.
Slide 28. Summary
To summarize, increased beta-cell function and mass will occur in response to increased beta-cell demand. There is a gradual decrease in beta-cell function and mass that may occur in individuals at high risk of developing type 2 diabetes. To prevent loss of beta-cell function and mass, beta-cell work must decrease and/or beta-cell stabilization or regeneration occurs.
Section 18 of 18