Impaired endoplasmic reticulum (ER) and mitochondrial function has been implicated in many of the obesity-induced etiology of insulin resistance and type 2 diabetes. However, the underlying molecular mechanisms remain to be fully elucidated. We have identified Disulfide bond A oxidoreductase-like protein or DsbA-L as a critical regulator of adiponectin assembly and secretion in adipocytes (Liu et al (2008) Proc. Nat.Acad. Sci. USA, 105, 18302-07). DsbA-L expression in adipose tissues is significantly reduced in obese human subjects and animal models of obesity.

Over 25% of the US population >65 years of age have type 2 diabetes and 80% of these individuals are overweight or obese. These individuals face shortened lifespans, increased health care needs, greater medical complications, and lower quality of life relative to those of similar age without these conditions. Lifestyle interventions focused on weight loss are recommended for overweight and obese individuals with type 2 diabetes, but whether these interventions meaningfully improve the lives of older individuals with diabetes over extended follow-up is unknown.

Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin action and insulin secretion. Hyperglycemia is the primary pathophysiologic abnormality responsible for the microvascular, and to a lesser extent, macrovascular complications. Much in vivo and in vitro evidence in rodents demonstrates that chronic hyperglycemia can induce insulin resistance and cause beta cell dysfunction.

Major manifestations of diabetic nephropathy are increased enal hypertrophy involving glomeruli and tubules with expansion of matrix proteins, including fibronectin. These changes occur concomitant with increased expression of transforming growth factor-ø?(TGFø) that contributes to the pathogenesis of human and experimental diabetic nephropathy. The mechanisms by which hyperglycemia and/or TGFø ?result in hypertrophy and increased expression of fibronectin are poorly understood.

Abnormal regulation of glycemia ('dysglycemia') has a very long time course, from its earliest stage, labeled pre-diabetes, to the onset of Type 2 diabetes (T2D), to the development of clinically detectable microvascular changes and measurable atherosclerosis, to clinically manifest complications with attendant morbidity and mortality.

This proposal defines a multi-disciplinary postdoctoral research training program to annually support six graduates of medicine, veterinary medicine, or the basic biomedical sciences. The past 29 years of this program document an impressive record of successfully training young scientists; indeed, 87% of completed trainees in the past decade (n=22) remain in research or training, and 10 received independent funding while supported by this program.

Tubulointerstitial fibrosis is a prominent pathological feature of progressive renal disease including diabetic nephropathy. In diabetic nephropathy and other progressive renal diseases, tubular epithelial cells acquire mesenchymal cell characteristics and accumulate matrix proteins that eventuate in fibrosis. Two potential mediators of renal fibrosis in diabetes are high glucose concentrations and transforming growth factor-beta.

Applied Research

This research project will seek to answer if the allosteric site in one subunit regulates the active site in the same subunit. a result that will simplify mechanistic interpretation of structural changes. Detailed understanding of the molecular mechanisms of hL-PYK will facilitate future drug designs to activate (or prevent inhibition of) this enzyme to reduced hepatic glucose secretion and counteract hyperglycemia.In both type 1 and type 2 diabetes. hepatic secretion of glucose is a primary contributor to hyperglycemia. In turn.

The systemic inflammatory response in sepsis has devastating consequences resulting in high morbidity and mortality. Over the past decade. mortality from sepsis alone has remained greater than 25%. despite effective antimicrobial therapy. In particular. the survival rate of the Hispanic population with other complications and combat casualties are often poorer. This highlights lack of understanding of the pathways operative in sepsis and the necessity for improved therapies. One of the major changes that occur during Multi-organ-failure (MOF) in severe sepsis is mitochondrial dysfunction.