SUMMARY
Loss of pancreatic beta cells (beta cell mass) and their respective function (insulin secretion) is a key pathological feature precipitating development of hyperglycemia in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Whereas in T1DM, beta cell loss and dysfunction occurs as a result of an autoimmune attack, in T2DM, loss of beta cell mass and function is more gradual and occurs as a result of a complex interplay between numerous genetic and environmental factors.
The work in the laboratory of Aleksey Matveyenko, Ph.D., is focused on understanding physiological and molecular mechanisms underlying the decline in beta cell function and mass in patients with diabetes. To accomplish these research goals, the laboratory uses an integrative approach ranging from cellular and molecular level studies in vitro to translational studies in vivo. The underlying goals of the research program are to develop novel therapeutic and preventive approaches to attenuate beta cell dysfunction and loss in patients with diabetes.
Focus areas
- Understanding mechanisms of association between circadian disruption and type 2 diabetes mellitus. Conditions associated with circadian disruption (for example, from shift work, sleep loss, and so on) are becoming commonplace in today's society and greatly increase susceptibility for development of T2DM. The mechanisms driving this association, however, are still largely unknown. The work in Dr. Matveyenko's laboratory is focused on elucidating physiological and molecular links driving the association between circadian disruption and loss of glycemic control, with particular focus on regulation of beta cell function and survival.
- Role of circadian clocks in regulation of beta cell function, survival and regeneration. Intracellular circadian clocks, also known as clock genes, are a highly conserved set of core genes that exert circadian control over numerous essential cellular functions, such as glucose metabolism, proliferation, mitochondrial function, and so on. Dr. Matveyenko's research group is exploring the role of clock genes in regulation of beta cell function, survival and regeneration in health and in pathological conditions such as T2DM. Therapeutic regulation of beta cell clock gene expression potentially presents a novel therapeutic approach to combat beta cell pathology in T2DM.
- Role of T2DM-associated genetic loci in pathophysiology of beta cell failure. Recent genome-wide association studies have identified numerous genetic loci associated with the development of T2DM. However, molecular underpinnings of described associations remain largely unknown. In collaboration with Adrian Vella, M.D., Dr. Matveyenko's laboratory is studying how genetic variations in the TCF7L2 and MTNR1B loci impact islet cell morphology, turnover and cellular physiology.
- Elucidation of mechanisms underlying induction of pancreatic cancer-induced diabetes. Pancreatic cancer is the fourth-leading cause of cancer-related deaths in the U.S. The majority of patients with pancreatic cancer also exhibit hyperglycemia, which often occurs a few years prior to the cancer diagnosis. The mechanisms driving development of cancer-induced hyperglycemia are unknown and may provide important insights into pancreatic cancer development and progression. In collaboration with Suresh T. Chari, M.D., Dr. Matveyenko's laboratory is studying molecular mechanisms that mediate induction of hyperglycemia in pancreatic cancer with specific focus on cancer-related effects on insulin-producing beta cells.
Significance to patient care
The incidence of T2DM has demonstrated a consistent rise, reaching to epidemic proportions worldwide. Thus, advanced understanding of molecular mechanisms responsible for development of T2DM is essential for development of therapeutic and preventive approaches to combat the rising epidemic of diabetes. Specifically, development of treatment approaches targeting beta cell loss and dysfunction in T2DM will provide a directed therapeutic approach to permit more-specialized and efficient treatment of patients with T2DM.
Professional highlights
- Innovation Accelerator Award, Office of Translation to Practice, Mayo Clinic, 2023, 2024.
- J. W. Kieckhefer Professor of Regenerative Medicine to Support Research in Type 1 Diabetes, Mayo Clinic, 2023.