2010 - Two Awards

(1) "Neurohormonal & Behavioral Correlates of Obesity"

Jon-Kar Zubieta, M.D., Ph.D., Phil F Jenkins Research Professor of Depression, Professor of Psychiatry, Professor of Radiology and Research Professor, Molecular and Behavioral Neuroscience Institute; and Amy Rothberg, M.D., Assistant Professor of Internal Medicine in the Division of Metabolism, Endocrinology & Diabetes and Clinical Director of the U-M Investigational Weight Management Clinic.

ABSTRACT:

With this project, the investigators plan to study the affective regulation and conditions where physical and emotional stressors play a significant role, most notably mood disorders, pain, substance use disorders and their interfaces. These mechanisms are also implicated in obesity, as these implicate motivational systems that drive behaviors such as overeating. As such, this represents a new research direction.

Excess nutrient intake in obesity results in insulin resistance leading to a continued demand for insulin secretion. In genetically predisposed individuals, it is likely that direct toxic effects of elevated fatty acids along with the excess insulin secretion leads to beta-cell failure and type 2 diabetes. One of the most vexing problems in addressing the epidemic of type 2 diabetes is long-term weight loss with a high 1 and 3 year recidivism rate. Endogenous opioid systems regulate a number of physiological and psychological processes including mood, energy management, and reward. The opioid reward processes may be involved both in the short-term control of eating and hedonic food consumption with the mu-opioid system playing a predominant role.

The present proposal will examine the function of the µ-opioid receptor system in lean and obese individuals following an overnight fast and the change in µ-opioid receptor occupancy following the consumption of a standardized meal using PET imaging with [11C]carfentenil. The obese individuals will be retested in the fasting and fed state following a 15% weight loss with a Very Low Calorie Diet. Further, we will evaluate the function of the µ-opioid receptor system within the context of the individual‘s metabolic and psychological profile including aspects of mood and inhibitory control. This information will provide novel information regarding the role of opioid pathways, previously studied in regards to addition, in the context of obesity and its potential role in weight regain.

(2) "In Vivo Corneal Confocal Microscopy for Non-invasive Assessment of Diabetic Peripheral Neuropathy"

Roni Mintz Shtein, M.D., M.S., Assistant Professor, Ophthalmology and Visual Sciences; and Steve Lentz, Ph.D., Research Assistant Professor, Division of Metabolism, Endocrinology & Diabetes.

Diabetic peripheral neuropathy (DPN), the most common complication of diabetes, is marked by painful sensory dysfunction. DPN is the leading cause of diabetes-related hospital admissions and nontraumatic amputations. The need to find treatments or cures to prevent the progressive nature of DPN are critical to improving the quality of life of diabetic patients and their families.

Despite the fact that DPN is common and debilitating, the underlying mechanisms are not well understood. Current clinical trials use a combination of electrophysiology and skin biopsies to measure nerve fiber density as a marker of DPN. These are invasive procedures with inherent risks including discomfort, bleeding, infection, and difficulty with healing, particularly in diabetic patients. A non-invasive method to assess DPN is currently unavailable; developing such a method would considerably improve the effectiveness of preventive care, especially in the early DPN stages.

The goal of this collaboration is to develop a non-invasive protocol for the evaluation of DPN. The use of in vivo confocal microscopy to study corneal nerve fibers will provide a repeated, non-invasive diagnostic tool for monitoring the onset and progression of DPN in diabetic patients. Extending this technology to a mouse model of diabetes will allow for sophisticated longitudinal studies to improve our understanding of the progression of disease and examine the effectiveness of novel therapeutic options for DPN. The protocol and the tool they seek to develop will ultimately be used in large-scale clinical trials and in clinical practice to assess DPN severity and progression.