Metabolism and Diabetes Platform — Pilot Grants

Title: A novel pharmacological approach to the management of obesity

Investigator: Laurence J. Miller, M.D.

Central hypothesis: Despite the prevalence and clinical importance of obesity, there are very few tools available to manage this condition. Diet and exercise, mainstays of obesity management, are quite effective acutely, but their impact is generally not durable. Bariatric surgery is quite effective for people with morbid obesity, but this is not scalable and can only be utilized in a small percentage of affected patients. Pharmacotherapy has been disappointing; of the few drugs approved, most have subsequently been withdrawn due to side effects, toxicity or both.

The type 1 cholecystokinin receptor (CCK1R) is a well-recognized target for the noncaloric induction of satiety, which helps reduce meal size and caloric intake. This physiologic effect has been demonstrated in both experimental animal and human studies. However, full agonists of this receptor have been found to exhibit the on-target side effects of nausea, abdominal cramping, diarrhea or all three, and possess the theoretical concern of trophic action on the pancreas.

The goal of this project is to develop positive allosteric modulators of CCK1R that will only enhance the biological response to the natural hormonal agonist, thus inducing satiety while avoiding most on-target side effects.

Potential outcomes and advances: The potential target population, people with obesity, is significant and could require drug administration for extended periods of time. Therefore, the bar for drug approval is quite high, requiring safety, tolerability and efficacy. Positive allosteric modulators have the potential to have good safety and tolerability profiles, potentially opening an entire new area of pharmaceutical treatment for millions of people with obesity.

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Title: Mechanisms of regeneration of insulin-secreting beta cells

Investigative team: Aleksey Matveyenko, Ph.D., Michael F. Romero, Ph.D.

Central hypothesis: Diabetes mellitus is associated with severe health complications that afflict both the quality and the length of life. Loss of pancreatic beta cells (beta cell mass) is a key biological feature precipitating development of hyperglycemia in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM).

Whereas in T1DM, beta cell loss occurs as a result of an autoimmune attack, leading to near-total ablation of beta cell mass, in T2DM beta cell loss is more gradual and manifests as a reduction of beta cell mass of approximately 50 to 65 percent.

Given the critical importance of maintaining appropriate beta cell mass for glycemic control, it is imperative to develop novel therapeutic strategies to replenish the patient's beta cell mass. The goal of this project is to determine how the sodium bicarbonate cotransporter NBCe1 can preserve or promote postnatal beta cell growth by regulating cellular pH.

Potential outcomes and advances: Type 1 and type 2 diabetes mellitus affect tens of millions of people, and there is still no effective and safe treatment to prevent diabetes by preserving or enhancing beta cell mass, thereby increasing insulin secretion. This novel concept has the potential to lead to such treatments.

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Title: A new mechanism of cardiac dysfunction in diabetes

Investigator: Tong Lu, M.D., Ph.D.

Central hypothesis: Diabetes mellitus is strongly associated with both microvascular and macrovascular complications in 50 to 75 percent of patients with diabetes in the U.S., resulting in enormous costs to individuals and society. The activation of large-conductance calcium-activated potassium channels (BK channels) is the key ionic mechanism underlying vasodilatation.

In preclinical studies, this vasodilatation mechanism is diminished in both type 1 and type 2 diabetic vessels. However, there has been no investigation into whether the BK channel abnormality observed in animal studies will be correctly interpreted and applied to people with type 2 diabetes. The goal of this project is to establish the pathological role and therapeutic potential of BK channels in the coronary microvascular dysfunction of patients with type 2 diabetes undergoing cardiac surgery.

Potential outcomes and advances: Vascular complications are the main cause of morbidity and mortality in type 2 diabetes. Although people with diabetes are at increased risk of these complications, there are no treatments that specifically reduce the risk of cardiovascular complications in these patients. This is one of the first projects that would take this particular approach.

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Title: Basic metabolic mechanisms underlying osteoporosis

Investigator: Jennifer Jane (Jennifer) Westendorf, Ph.D.

Central hypothesis: Osteoporosis and diabetes create enormous economic and societal costs in aging Western cultures. More than 50 percent of women and 25 percent of men over age 50 will experience an osteoporotic fracture in their lifetimes. These fractures are most common in older adults and can drastically change their quality of life. In fact, 25 percent of adults who lived independently before experiencing hip fractures remain in nursing homes for at least a year after their injuries.

Diabetes, which affects over 23 million people in the U.S., weakens bones and increases the risk of fracture. As bones become more fragile, they simultaneously harbor more fat because bone-forming osteoblast progenitor cells in the marrow either don't function efficiently or are replaced by fat-storing cells (adipocytes) or both.

The goal of this project is to determine the mechanism by which histone deacetylase 3 (Hdac3) prevents this conversion from osteoblast to adipocyte. The central hypothesis of this project is that the enzymatic (deacetylase) activity of Hdac3 in bone cells is required to promote osteogenesis, inhibit lipid storage and regulate systemic metabolism.

Potential outcomes and advances: Understanding this basic pathway of osteogenesis, and its dysregulation, can provide novel targets for pharmaceutical intervention.

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