The overarching research goal is to improve our understanding of the growth and development processes of various organ systems tasked with maintaining glucose tolerance and energy homeostasis. In addition to providing insight into the contribution of individual organ systems, these findings will provide an integrated view of the multi-organ communication as it relates to glucose tolerance and energy homeostasis. Ultimately, this information will be applied to a translational paradigm to inform the pathogenesis of diabetes and obesity.
Cell cycle regulators in pancreatic development and diabetes
Mechanisms of beta cell growth and function and pathways that lead to increases in beta cell mass and its regeneration potential are topics of active debate. We continue to explore further in this area of research using informative mouse models, primary islet cell culture, and established cell lines. In addition, we are investigating the importance of cell cycle regulators in the growth, development, differentiation, and death of cells that comprise organs tasked with maintaining glucose tolerance and energy homeostasis. The aim is to determine how cell cycle molecules and the downstream pathways are deregulated during pathogenesis of obesity and diabetes.
TGF-β superfamily signaling in obesity and diabetes
The transforming growth factor beta (TGF-beta) superfamily, which includes TGF-beta, activin, and BMP, has been implicated in pancreatic development and pancreatic diseases. BMP signaling appears to play a role during early pancreatic development and in regulating mature beta cell function, whereas activin signaling has been shown to play a role in islet morphogenesis and establishment of beta cell mass. Our recent observations are consistent with a complex role for TGF-beta signaling in regulation of beta cell function. Using mouse models, primary cells, established cell lines, and human samples, we are actively studying the role of the TGF-beta superfamily in regulating beta cell mass and function.
Further, we recently illustrated an important role of the TGF-beta/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3-deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3-deficient white adipose tissue, acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3-deficient adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1alpha expression. We observed a significant correlation between TGF-beta1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-beta signaling protected mice from obesity, diabetes, and hepatic steatosis. Together, these results demonstrate that TGF-beta signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-beta activity might be an effective treatment strategy for obesity and diabetes. We continue to examine the mechanistic underpinnings of the above-mentioned observations as they relate to the role of TGF-beta family signaling in diabetes and obesity pathogenesis.
The new information generated via genome-wide association studies of type 2 diabetes has offered many targets. These targets need to be validated by further experimentation. Moreover, type 2 diabetes pathogenesis cannot be fully explained by the findings of the genome-wide association studies, which is possibly due to small effects of multiple targets. An integrated molecular picture of multi-organ dysfunction will enable a better view into disease pathogenesis.