Awardees 2007

PI: Sheri-Ann M. Burnett-Bowie, M.D., MPH
Abstract:The United States is experiencing a significant increase in the prevalence of Type 2 diabetes mellitus.  Communities of color are especially affected by this epidemic. Vitamin D deficiency, also more prevalent in minority populations, appears to contribute to both impaired insulin secretion and insulin resistance.  However, there are no large clinical trials of the impact of treating vitamin D deficiency on insulin production or handling.  We hypothesize that treatment of vitamin D deficiency will decrease insulin resistance.  We will recruit 100 vitamin D deficient (25 hydroxyvitamin D < 20 ng/mL), healthy multiracial men and women and randomize them to vitamin D (ergocalciferol) 50,000 international units, or placebo, QWK for 12 weeks.  Daily calcium will be 1,000-1,500 mg.  Subjects will be stratified as glucose tolerant or intolerant based on an OGTT; subjects will be stratified by degree of vitamin D deficiency.  The primary endpoint will be the change in insulin resistance as assessed by a modified IVGTT at weeks 0 and 12; we have 80% power to detect a 30% change in insulin resistance at the 2-sided significance level.  Secondary endpoints will include change in blood pressure, BMI, HOMA-IR, cholesterol and CRP.  Given the ongoing diabetes epidemic, a multi-faceted approach to managing this disease is essential.  Such an initiative should focus on both disease treatment and prevention.  If treatment of vitamin D deficiency decreases insulin resistance, the simple act of repleting this common deficiency could have major public health implications for the prevention of Type 2 diabetes mellitus.

The US is an experiencing an alarming increase in the rates of type 2 diabetes mellitus. Currently, exercise and ideal weight maintenance are the primary lifestyle measures used to prevent developing type 2 diabetes mellitus.  Treatment of vitamin D deficiency is another possible preventive measure.  We are studying how treating vitamin D deficiency affects insulin resistance.  If treatment of vitamin D deficiency decreases insulin resistance, the simple act of repleting this common vitamin deficiency could have major public health implications for the prevention of Type 2 diabetes mellitus.

 

PI: Gerald V. Denis, M.Sc., Ph.D.
Abstract:Brd2, a BET (Bromodomains and Extra Terminal domain) family protein, binds to acetylated promoter histones, recruits transcription factors and co-activators/co-repressors, and helps remodel chromatin to regulate the transcription activity of many genes. Brd2 evinces either transcriptional activator or repressor functions, depending on the context. Interestingly, from zebrafish to humans, the Brd2 gene is located in the major histocompatibility gene cluster, but its physiological function remains unclear. Knockout of Brd2 homologs in yeast or flies is lethal. Surprisingly, mice with whole-animal knockdown of Brd2 became extremely obese with 100% penetrance; their body weights reached 90g on an ad libitum diet of regular chow by the time they were 14 months old. These “brd2 lo“ mice have enlarged adipocytes, fatty liver and more and enlarged pancreatic islets; Brd2 expression was confirmed to be very low in these tissues. Obese brd2 lo mice are also hyperinsulinemic, but unexpectedly, hypoglycemic with better glucose tolerance than wild type. These preliminary results suggest that Brd2 plays an important and novel role in energy homeostasis. We hypothesize that knockdown of Brd2 causes failure of transcriptional regulation of key genes involved in energy metabolism, particularly insulin 1 and/or 2, leading directly to hyperinsulinemia and weight gain. We propose to investigate the role of Brd2 in regulation of insulin production, insulin sensitivity and adipogenesis. The predicted findings will deepen understanding of the maintenance of body energy balance and the etiology of obesity and diabetes.

 

PI:Mark A. Herman, M.D
Abstract:During fasting and in insulin resistant states, expression of the GLUT 4 glucose transporter is down-regulated in adipocytes, but not in muscle.  The Kahn lab developed transgenic mice with constitutive overexpression (AG4OX) or knockout (AG4KO) of GLUT4 selectively in adipocytes.  These mice display reciprocal metabolic phenotypes with improved and impaired glucose tolerance, respectively.  Despite the fact that adipose tissue is thought to account for only a small fraction of glucose disposal, adipose-specific overexpression of GLUT4 (AG40X) results in a mouse susceptible to fasting induced hypoglycemia.  Preliminary evidence indicates that a similar glycemia AG40X adipose tissue is capable of disposing 5 fold more glucose than control adipose tissue. Evidence also indicates that adipose-specific overexpression of GLUT4 results in coordinate up regulation of enzymes of fatty acid synthesis at both mRNA and protein levels.  Additionally, expression of carbohydrate responsive element binding protein (ChREBP) a putative glucose sensing transcription factor is increased in adipose tissue from AG40X mice.  These data suggest that disposal of glucose intoadipose tissue may regulate its own metabolism, and this regulation may be mediated by ChREBP.  Our aim in this proposal is to begin to investigate how adipose tissue may sense changes in glucose flux and how this glucose sensing may alter glucose metabolism in adipose tissue and at the whole-body level. We will use anti-ChREBP antisense oligonucleotides to down-regulate adipose tissue ChREBP to assess the importance of ChREBP in glucose sensing and glucose metabolism.  These studies will provide novel insights into the role of adipose tissue in glucose homeostastis.


PI:Vladimir Marshansky, Ph.D.
Abstract:This proposal is driven by our recent novel discoveries that: i) the vacuolar-H+-ATPase (V-ATPase) is an endosomal pH-sensor that directly interacts with the Arf-family GTPase exchange factor ARNO (ADPribosylation factor nucleotide site opener); ii) this interaction regulates the endosomal/lysosomal protein degradative pathway in kidney proximal tubule (PT) epithelial cells (Nature Cell Biology, 2006); iii) ARNO also interacts with aldolase, the crucial enzyme of the glycolytic pathway (Proteomics, 2007). We propose that this novel V-ATPase/ARNO/aldolase association plays a crucial role in the glucose-dependent regulation of V-ATPase. This is predicted to have profound consequences in diabetes, a disease associated with the generation of pathophysiologically high levels of glucose. While the late stages of diabetes (months/years) leading to diabetic nephropathy and end-stage renal disease (ESRD) are well studied, the important early (1-2 weeks) events that trigger this pathophysiological process remain unknown.

Our main hypothesis is that high glucose during the early stages of diabetes triggers the up-regulation of V-ATPase and over-acidification of the endosomal/lysosomal compartments, which in turn causes malfunctioning of this pathway leading to aberrant vesicular trafficking and abnormal protein degradation.
Thus, the main goal of this proposal is to elucidate the molecular basis and cell biological significance of the V-ATPase in regulation of the protein degradative pathway during early stages of Type I diabetes. This novel function of the V-ATPase coupled to the interaction with small GTPases (ARNO) and glycolytic enzymes (aldolase) is a testable paradigm which may extend to acidic endosomal/lysosomal compartments of the protein degradation pathway of variety of cell and tissues, with possible important implications in the pathophysiology of diabetes in general and in development of early stages of diabetic nephropathy in particular. These studies will be performed using non-obese diabetic (NOD) mice as a model of human Type I diabetes. Our goal will be achieved using novel experimental approaches and taking advantage of powerful tools available within the Microscopy Core of the Program in Membrane Biology (MGH) as well as extensive collaboration with the Harvard Proteomic/Genomic core facility.

 

PI:Corrine K. Welt, M.D.
Abstract:Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive aged women.  Its health threatening consequences include a very high rate of type 2 diabetes, impaired glucose tolerance and metabolic syndrome out of proportion to controls matched for body mass index.  In addition, obesity and other cardiovascular risk factors are most prevalent in women with PCOS compared to controls. Twin studies and family studies suggest a genetic basis for this disorder, and the pattern of inheritance is consistent with that of a complex disease.  We have identified a preliminary linkage peak for PCOS in collaboration decode in Icelandic subjects. We will now use a case control approach with our Boston cohort to search for candidate genes within this region.  With the genetic basis in hand, the phenotypes of PCOS can be mapped onto genotypes to further our understanding and hopefully treatment of PCOS in several populations.

 

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