CDK6 as a Novel Therapeutic Target for Type II Diabetes
Abstract
Topic Area: Diabetes Type II Diabetes: At the present time, 1 out of 11 Americans suffers from diabetes. Diabetes is a disease defined by problems with the hormone insulin, a human hormone responsible for the regulation of blood sugars. About 24 million people live with diabetes in the United States, and at least 90 percent of those people have Type II diabetes (T2D), which is characterized by an inability to use insulin effectively (also called insulin resistance: IR). Millions more are at high risk of developing diabetes. Over time, glucose builds up in the blood because it cannot be absorbed by cells in the body, resulting in prediabetes or diabetes, which ultimately impairs nerves and blood vessels, and can even lead to complications such as heart disease, blindness, amputations, coma, and death. Obesity: Both obesity and a sedentary lifestyle are strongly correlated with the development of T2D. An imbalance between caloric intake and caloric expenditure can lead to obesity, which causes insulin resistance and T2D. Despite recent advantages in the therapy of obesity and its associated metabolic consequences, obesity-related diseases continue to pose a substantial therapeutic challenge and a large economic burden on the national and military health care. Therefore, it is imperative to develop new effective therapies. Significance of White-to-Brown Fat Conversion: There are two different types of body fat in humans: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT stores excess calories that induce obesity, whereas BAT burns calories that defend against obesity. Recent work has demonstrated that WAT can undergo “browning change” to become a brown-like fat under certain conditions such as cold exposure and exercise. This brown-like fat is composed of beige adipocytes. In mice, increases in the number of beige adipocytes in the white fat depots are associated with protection against high-fat diet-induced obesity and diabetes. Thus, pharmacological attempts at stimulating white fat browning opens up intriguing possibilities for the treatment of both obesity and diabetes. CDK6: Cyclin dependent kinase 6 (CDK6) is a type of enzyme that regulates cell proliferation and differentiation, the process of producing fully functional cells from an immature cell. To understand the role of the different functional domains of CDK6 in development and diseases, mice with different Cdk6 mutations were made to re-express normal protein or mutant proteins at desired times and specific tissues. One of the mutations stops cells from making functional CDK6. Thus, these animals therefore serve as useful models for CDK6 function in obesity and its related T2D. Unexpectedly, mice without a functional CDK6 protein are lean. Some of their white fat pads appeared browner compared to their wild-type, or normal counterparts. The mice without a functional CDK6 protein did not become obese when given high-fat diets and had improved blood glucose tolerance and insulin sensitivity when compared with mice with normal CDK6 expression. Moreover, by using our proprietary CDK6-specific inhibitor GD007 (GD), we found that the CDK6-specific inhibitor had the potent ability to reduce fat pad mass without significantly reducing lean mass, forecasting a highly attractive and potentially novel pharmacological intervention for obesity and T2D. Thus, CDK6 may be a promising target for drug development for treatment of obesity/diabetes. Hypothesis: CDK6 is an enzyme crucial in the development of obesity and diabetes. It negatively regulates white-to-brown fat conversion, and systemic treatment with the kinase inhibitors of CDK6 will be an effective therapeutic measure for human obesity and related diabetes. Goals of Studies: (1) By using innovative Cdk6 mouse models I made, we are going to define the mechanism whereby CDK6 positively affects visceral adipose tissue biology and metabolism. (2) By using de-identifie
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910301
Entities
People
- Miaofen Hu
Organizations
- Tufts Medical Center
- United States Army