Despite extensive physiologic investigation, the primary causes of type 2 diabetes mellitus remain unknown. In addition, the metabolic syndrome comprising hypertension, insulin resistance and dyslipidemia has increasingly been recognized as a major public health problem of unknown cause. Genetic and genomic approaches have the capacity to identify these elusive primary causes, thereby defining the pathophysiology of these diseases and identifying new opportunities for therapeutic intervention. Recent studies have implicated loss of mitochondrial function as a factor underlying type 2 diabetes mellitus. In this project, wei will pursue several distinct lines of investigation that bear on this point. First, we will investigate the possibility that impaired mitochondrial function can contribute not only to diabetes but to the other component of the metabolic syndrome. This will be accomplished by the investigation of rare families with known functional mitochondrial mutations, and by the investigation of patients with metabolic syndrome for mitochondrial defects. Second, we will investigate gene expression in the young offspring of diabetics to determine whether early insulin resistance is correlated with altered expression of genes involved in mitochondrial oxidative phosphorylation and mitochondrial copy number. Third, because mitochondria are one of the major sources of reactive oxygen species one possible explanation for loss of mitochondrial function in insulin resistance is acquire damage of mitochondrial DNA. We will investigate this possibility by comparing mitochondrial damage in insulin sensitive and resistant offspring of diabetic parents. Finally, the ability to obtain in vivo biochemical phenotypes of mitochondrial function by MRS provides a new opportunity to define intermediate phenotypes that may be closely related to the primary defect underlying the disease. These can markedly increase the power of genetic linkage studies. We will ascertain kindreds from Project 1 that are segregating extreme biochemical phenotypes, extend these kindreds and map the responsible lenes by analysis of linkage, with an aim to positionally clone these novel susceptibility genes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
New Haven
United States
Zip Code
Madiraju, Anila K; Qiu, Yang; Perry, Rachel J et al. (2018) Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med 24:1384-1394
Lee, Hui-Young; Gattu, Arijeet K; Camporez, João-Paulo G et al. (2014) Muscle-specific activation of Ca(2+)/calmodulin-dependent protein kinase IV increases whole-body insulin action in mice. Diabetologia 57:1232-41
Jornayvaz, François R; Shulman, Gerald I (2012) Diacylglycerol activation of protein kinase C? and hepatic insulin resistance. Cell Metab 15:574-84
Samuel, Varman T; Shulman, Gerald I (2012) Mechanisms for insulin resistance: common threads and missing links. Cell 148:852-71
Samuel, Varman T; Petersen, Kitt Falk; Shulman, Gerald I (2010) Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375:2267-77
Petersen, Kitt Falk; Dufour, Sylvie; Hariri, Ali et al. (2010) Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 362:1082-9
Boumezbeur, Fawzi; Mason, Graeme F; de Graaf, Robin A et al. (2010) Altered brain mitochondrial metabolism in healthy aging as assessed by in vivo magnetic resonance spectroscopy. J Cereb Blood Flow Metab 30:211-21
Boumezbeur, Fawzi; Petersen, Kitt F; Cline, Gary W et al. (2010) The contribution of blood lactate to brain energy metabolism in humans measured by dynamic 13C nuclear magnetic resonance spectroscopy. J Neurosci 30:13983-91
Mitchell, Catherine S; Savage, David B; Dufour, Sylvie et al. (2010) Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia. J Clin Invest 120:1345-54
Befroy, Douglas E; Falk Petersen, Kitt; Rothman, Douglas L et al. (2009) Assessment of in vivo mitochondrial metabolism by magnetic resonance spectroscopy. Methods Enzymol 457:373-93

Showing the most recent 10 out of 30 publications