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ARRA Investments in Insulin Resistance

Public Health Burden
Insulin resistance alters the body’s sugar and fat metabolism and contributes to the onset of type 2 diabetes.  Insulin resistance is associated with aging and with obesity, some liver diseases, and a number of other chronic conditions affecting adults and children.

Development of Novel Therapies for Insulin Resistance and Diabetes
Insulin-sensitizing medications and/or diet and exercise can help reverse or reduce insulin resistance; however, improved approaches are needed.  ARRA funded grants are exploring new molecular pathways and alternate strategies to modify insulin resistance and its effects on metabolism:
  • A project exploring whether nitrate, a molecule found in diets rich in leafy green vegetables, plays a role in preventing or reversing insulin resistance.1
  • A study in animal models investigating the potential therapeutic benefit of a reengineered version of a fat cell molecule (adiponectin) that exerts insulin-sensitizing and cardiovascular- protective effects.2
  • A study in animal models on whether the health benefits of caloric restriction can be mimicked with an “intermittent feeding” strategy that does not necessarily cause weight loss and which may be a more feasible dietary regimen for people.3
  • A project to identify the mechanisms underlying altered fat and sugar metabolism and overall energy balance in mice treated with a drug (ezetimibe) that blocks absorption of dietary cholesterol.4
Maternal-Fetal Environment and Insulin Resistance Pathogenesis
Research suggests that maternal and fetal nutrition and metabolism during pregnancy exert long-term effects on offspring’s risk for obesity, diabetes, and other chronic diseases.  Understanding what influences development of insulin resistance early in life is important to preventing future metabolic dysfunction.  ARRA funded grants are studying a number of factors:
  • A project to study whether maternal-fetal vitamin D deficiency during pregnancy increases child adiposity, insulin resistance, and blood pressure.5
  • A study of a primate animal model on how maternal nutrient restriction affects development and function of fetal skeletal muscle, the major site of fat and sugar metabolism.6
  • A grant investigating the extent to which maternal diet early in pregnancy influences epigenetic chromosomal changes and, in turn, the extent to which these changes predict obesity and cardiovascular disease risk factors in offspring.7
Mitochondria and Insulin Resistance
Abnormalities in mitochondria, the tiny structures that serve as the “powerhouses” of cells, appear to play a central role in the development of insulin resistance and type 2 diabetes.  A number of ARRA grants are studying this aspect of disease development to identify potential therapeutic targets and strategies:
  • A project will explore a potential molecular linkage between oxidative stress, mitochondrial function, and the development of insulin resistance in fat cells.8
  • A project will seek to determine if there is a relationship between increased flux of free fatty acids from fat cells and abnormalities in fat cell mitochondria.9
  • A project will use state-of-the-art proteomics technologies and mouse models to “map out” mitochondrial alterations that occur in skeletal muscle cells during the onset of type 2 diabetes—a framework that could help researchers identify biomarkers for disease.10
Clinical and Epidemiologic Studies of Insulin Resistance and Type 2 Diabetes
Clinical and epidemiologic studies are important both to test the relevance of basic research findings to human disease and to reveal new clues about disease that may be tested in the laboratory.  ARRA funded grants are studying insulin resistance and type 2 diabetes in human populations:
  • A project will use a large, ongoing women’s cohort study to examine the relationship between telomere length (the ends of chromosomes), its regulators, and the risk of type 2 diabetes.11
  • An epidemiologic study will try to identify genetic and environmental factors and their interactions associated with type 2 diabetes and obesity among Mexican Pima Indians.12
  • New findings in mice suggest a bone hormone (undercarboxylated osteocalcin) positively affects insulin resistance and development of diabetes.  A study will assess whether this hormone has similar effects in humans and if lower levels of the hormone predict development of diabetes.13
Insulin Resistance and Diseases other than Diabetes
Insulin resistance is suspected to have a role in cancers, non-alcoholic fatty liver disease, and other diseases.  ARRA funded grants are extending research in these areas:
  • One grant will test whether a protein that appears to influence insulin resistance in the liver (CEACAM1) also plays a key role in the development of non-alcoholic steatohepatitis (NASH).14
  • Another grant will study a possible link between insulin resistance and breast cancer development in response to early life exposure to the chemical bisphenol A (BPA) and diet-induced obesity.15

  1. 1RC1DK085852-01 -- Dietary Nitrate Activation of PPARGamma Improves Insulin Sensitivity -- Freeman, Bruce A; Gladwin, Mark Thomas (PA)
  2. 1R21HL093731-01A1 -- Adiponetin and AMPK Biosensor -- Shyy, John Y-J (CA)
  3. 1R01AG034297-01 -- Response to and Signals of Caloric Restriction and Intermittent Feeding Regimens -- Hellerstein, Marc Kopel (CA)
  4. 1R01DK077170-01A2 -- Role of NPC1l1 In Regulating Energy Metabolism, Nutrient Utilization & Weight Gain -- Howles, Philip N (OH)
  5. 1R21DK082661-01A1 -- Maternal-Fetal Vitamin D Status and Child Adiposity, Insulin Resistance and BP -- Huh, Susanna Y (MA)
  6. 1R03HD060076-01A1 -- Maternal Nutrient Restriction and Nonhuman Primate Fetal Skeletal Muscle Development -- Du, Min (WY)
  7. 1RC1HD063590-01 -- Epidemiology & Epigenetics: Maternal Diet, DNA Methylation, & Offspring Adiposity -- Gillman, Matthew W (MA)
  8. 1R56DK084669-01 -- Mitochondrial Dysfunction And Adipose Insulin Resistance -- Bernlohr, David A (MN)
  9. 1R21DK082820-01A1 -- Adipocyte Mitochondrial Dysfunction In Insulin Resistance -- Meyer, Christian (AZ)
  10. 1RC1DK086410-01 -- Quantitative Mitochondrial Proteomics Of Healthy And Diabetic Mice -- Pagliarini, David (WI)
  11. 1R21DK084452-01 -- Telomere And Its Bio-Regulators As Predictors For Clinical Diabetes In Women -- Liu, Simin (CA)
  12. 1R01DK082568-01A1 -- T2DM, Obesity In Mexican Pimas: Gene-Environment Interactions -- Schulz, Leslie O. (AZ)
  13. 1R21DK082848-01A1 -- Undercarboxylated Osteocalcin, Body Fat, and Diabetes in Older Adults -- Schwartz, Ann V (CA)
  14. 1R01DK083850-01A1 -- Insulin Resistance in the Pathogenesis of NASH -- Najjar, Sonia Michael (OH)
  15. 1R03CA142009-01 -- ERR-Gamma-Dependent Mammary Tumorigenesis In Response To BPA And A High-Fat Diet -- Riggins, Rebecca B (DC)

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