Prevention of Diabetes with Nutritional Supplements

Summary

Principal Investigator: Peter Havel
Abstract: [unreadable] DESCRIPTION (provided by applicant): The prevalence of Type 2 Diabetes Mellitus (T2DM), a serious and costly disease, has increased dramatically in the past 2 decades. Current therapies for diabetes are expensive and are unable to prevent the long-term complications of the disease. New strategies to prevent or delay the onset of type 2 diabetes would prevent or delay the onset of diabetic complications, and therefore decrease patient suffering and save the health care system billions of dollars. We have recently developed a new rat model of type 2 diabetes that exhibits both adult-onset obesity induced insulin resistance and an impairment of pancreatic Beta-cell function. This model is more relevant to type-2 diabetes in humans and therefore an appropriate animal model for testing new approaches for diabetes prevention. We propose to determine the efficacy of several widely used nutritional supplements known to activate PPARs and/or target lipid dysregulation, inflammation, and oxidative stress to prevent or delay the onset of T2DM in this rat model. We will pursue the following specific aims: Specific Aim 1: We hypothesize that supplementation with omega 3 fatty acid eicosapentaenoic acid (EPA) will activate PPARalpha, gamma and delta and prevent or delay the onset of T2DM. We will also determine whether purified EPA will attenuate the development of diabetes more effectively than fish oil supplements. Specific Aim 2: We hypothesize that supplementation with a-lipoic acid will reduce oxidative stress, thereby preventing or delaying onset of T2DM. We will also investigate whether a-lipoic acid in combination with the marine oil PPAR activators (EPA & DMA) will be more effective than a-lipoic acid alone in preventing diabetes. Further studies to investigate the mechanism(s) of action of the supplements or the supplement combinations that are effective in preventing/delaying diabetes onset of diabetes in this model are proposed. [unreadable] [unreadable]
Funding Period: 2005-09-01 - 2008-12-30
more information: NIH RePORT

Top Publications

  1. pmc Maternal ileal interposition surgery confers metabolic improvements to offspring independent of effects on maternal body weight in UCD-T2DM rats
    Bethany P Cummings
    Department of Biomedical Sciences, College of Veterinary Medicine, T7 022A Veterinary Research Tower Box 17, Cornell University, Ithaca, NY, 14853, USA
    Obes Surg 23:2042-9. 2013
  2. pmc Loss of coupling between calcium influx, energy consumption and insulin secretion associated with development of hyperglycaemia in the UCD-T2DM rat model of type 2 diabetes
    A M Rountree
    Diabetes and Obesity Center of Excellence, University of Washington, 850 Republican Street, Seattle, WA 98109 8055, USA
    Diabetologia 56:803-13. 2013
  3. pmc Bile-acid-mediated decrease in endoplasmic reticulum stress: a potential contributor to the metabolic benefits of ileal interposition surgery in UCD-T2DM rats
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA
    Dis Model Mech 6:443-56. 2013
  4. ncbi Investigation of the mechanisms contributing to the compensatory increase in insulin secretion during dexamethasone-induced insulin resistance in rhesus macaques
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, California 95616, USA
    J Endocrinol 216:207-15. 2013
  5. pmc Vertical sleeve gastrectomy improves glucose and lipid metabolism and delays diabetes onset in UCD-T2DM rats
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, One Shields Avenue, Davis, California 95616, USA
    Endocrinology 153:3620-32. 2012
  6. pmc Maternal influence of prolyl endopeptidase on fat mass of adult progeny
    C H Warden
    Rowe Program in Genetics, University of California, Davis, CA 95616, USA
    Int J Obes (Lond) 33:1013-22. 2009
  7. pmc Dietary fructose accelerates the development of diabetes in UCD-T2DM rats: amelioration by the antioxidant, alpha-lipoic acid
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, One Shields Ave, Davis, CA 95616, USA
    Am J Physiol Regul Integr Comp Physiol 298:R1343-50. 2010
  8. pmc Ileal interposition surgery improves glucose and lipid metabolism and delays diabetes onset in the UCD-T2DM rat
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, California 95616, USA
    Gastroenterology 138:2437-46, 2446.e1. 2010
  9. pmc Chronic administration of the glucagon-like peptide-1 analog, liraglutide, delays the onset of diabetes and lowers triglycerides in UCD-T2DM rats
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, California, USA
    Diabetes 59:2653-61. 2010
  10. ncbi Supplementation with EPA or fish oil for 11 months lowers circulating lipids, but does not delay the onset of diabetes in UC Davis-type 2 diabetes mellitus rats
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
    Br J Nutr 104:1628-34. 2010

Scientific Experts

  • Jon Ramsey
  • C Warden
  • Peter Havel
  • Mario Kratz
  • Katsuyuki Nakajima
  • Kimber L Stanhope
  • Bethany P Cummings
  • James L Graham
  • Michael M Swarbrick
  • Steven C Griffen
  • Denis G Baskin
  • Michael L Chouinard
  • Jennifer Lee
  • K L Stanhope
  • Andrew A Bremer
  • Nancy L Keim
  • A M Rountree
  • J L Graham
  • Ahmed Bettaieb
  • Mark Kowala
  • S C Griffen
  • Fawaz G Haj
  • C L Cox
  • Ri Yao Yang
  • A Wei
  • Helen E Raybould
  • Anna V Goropashnaya
  • Ronald M Krauss
  • Ravi Retnakaran
  • Sean H Adams
  • Sridevi Devaraj
  • Erin L Streiff
  • P Pérez-Matute
  • Jaehyoung Kim
  • R L Hull
  • Timothy J Kieffer
  • I R Sweet
  • Cecilia Giulivi
  • Fangrui Ma
  • S R Jung
  • Noreene Shibata
  • B P Cummings
  • David D'Alessio
  • B J Reed
  • Jacob Jelsing
  • Niels Vrang
  • Frederik Hansen
  • L Berglund
  • A A Bremer
  • James W Sharp
  • B Hatcher
  • Elizabeth Martin
  • J M Schwarz
  • J P McGahan
  • N L Keim
  • Fu Tong Liu
  • A S Green
  • A J Fascetti
  • Lan Yu
  • C Villaverde
  • K C Kent Lloyd
  • Daniel K Hsu
  • K J Liu
  • E G Manzanilla
  • Joseph L Evans
  • Lotte B Knudsen
  • Cecilia Nilsson
  • Anette Sams
  • Kirsten Raun
  • April D Strader
  • Arthur A Levin
  • Sally Chiu
  • Wei Zhang
  • Anthony Seibert
  • Sheri L Booten
  • Bert B Boyer
  • Jean Marc Schwarz
  • John P McGahan
  • Mary Sexton
  • Sanjay Bhanot
  • Takamitsu Nakano
  • Masumi Ai
  • Chad L Cox
  • Robert A McKay
  • Artem Dyachenko
  • Rosemarie Plaetke
  • Ernst J Schaefer
  • Carine Beysen
  • Lars Berglund
  • Seiko Otokozawa

Detail Information

Publications30

  1. pmc Maternal ileal interposition surgery confers metabolic improvements to offspring independent of effects on maternal body weight in UCD-T2DM rats
    Bethany P Cummings
    Department of Biomedical Sciences, College of Veterinary Medicine, T7 022A Veterinary Research Tower Box 17, Cornell University, Ithaca, NY, 14853, USA
    Obes Surg 23:2042-9. 2013
    ....
  2. pmc Loss of coupling between calcium influx, energy consumption and insulin secretion associated with development of hyperglycaemia in the UCD-T2DM rat model of type 2 diabetes
    A M Rountree
    Diabetes and Obesity Center of Excellence, University of Washington, 850 Republican Street, Seattle, WA 98109 8055, USA
    Diabetologia 56:803-13. 2013
    ..The aim of the study was to test whether impairment of the CMCP could play a role in the development of type 2 diabetes...
  3. pmc Bile-acid-mediated decrease in endoplasmic reticulum stress: a potential contributor to the metabolic benefits of ileal interposition surgery in UCD-T2DM rats
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA
    Dis Model Mech 6:443-56. 2013
    ..These results suggest that postoperative increases in circulating cholic acid concentration contribute to improvements in glucose homeostasis after IT surgery by ameliorating ER stress...
  4. ncbi Investigation of the mechanisms contributing to the compensatory increase in insulin secretion during dexamethasone-induced insulin resistance in rhesus macaques
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, California 95616, USA
    J Endocrinol 216:207-15. 2013
    ..Furthermore, increases in postprandial GIP secretion with dexamethasone treatment appear to contribute to the effect of dexamethasone treatment to increase insulin secretion...
  5. pmc Vertical sleeve gastrectomy improves glucose and lipid metabolism and delays diabetes onset in UCD-T2DM rats
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, One Shields Avenue, Davis, California 95616, USA
    Endocrinology 153:3620-32. 2012
    ..This is potentially mediated by increases of circulating bile acids, adiponectin, and nutrient-stimulated GLP-1 secretion and decreased circulating ghrelin concentrations...
  6. pmc Maternal influence of prolyl endopeptidase on fat mass of adult progeny
    C H Warden
    Rowe Program in Genetics, University of California, Davis, CA 95616, USA
    Int J Obes (Lond) 33:1013-22. 2009
    ..Prolyl endopeptidase (PREP) is a serine protease with putative substrates that regulate appetite or milk production...
  7. pmc Dietary fructose accelerates the development of diabetes in UCD-T2DM rats: amelioration by the antioxidant, alpha-lipoic acid
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, One Shields Ave, Davis, CA 95616, USA
    Am J Physiol Regul Integr Comp Physiol 298:R1343-50. 2010
    ..In conclusion, dietary fructose accelerates the onset of T2DM in UCD-T2DM rats, and LA ameliorates the effects of fructose by improving glucose homeostasis, possibly by preserving beta-cell function...
  8. pmc Ileal interposition surgery improves glucose and lipid metabolism and delays diabetes onset in the UCD-T2DM rat
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, California 95616, USA
    Gastroenterology 138:2437-46, 2446.e1. 2010
    ..In this study we investigated effects of IT surgery on glucose tolerance and diabetes onset in UCD-T2DM (University of California at Davis type 2 diabetes mellitus) rats, a polygenic obese animal model of type 2 diabetes...
  9. pmc Chronic administration of the glucagon-like peptide-1 analog, liraglutide, delays the onset of diabetes and lowers triglycerides in UCD-T2DM rats
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, California, USA
    Diabetes 59:2653-61. 2010
    ..The efficacy of liraglutide, a human glucagon-like peptide-1 (GLP-1) analog, to prevent or delay diabetes in UCD-T2DM rats, a model of polygenic obese type 2 diabetes, was investigated...
  10. ncbi Supplementation with EPA or fish oil for 11 months lowers circulating lipids, but does not delay the onset of diabetes in UC Davis-type 2 diabetes mellitus rats
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
    Br J Nutr 104:1628-34. 2010
    ..01). In conclusion, EPA and fish oil supplementation lowers circulating lipid concentrations, but does not delay the onset of T2DM in UCD-T2DM rats...
  11. ncbi Influence of a high-protein diet on energy balance in obese cats allowed ad libitum access to food
    A Wei
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
    J Anim Physiol Anim Nutr (Berl) 95:359-67. 2011
    ..However, energy expenditure was increased in the HP diet group and it is possible that this effect of HP might help promote weight loss when energy intake is restricted...
  12. pmc Consumption of fructose-sweetened beverages for 10 weeks reduces net fat oxidation and energy expenditure in overweight/obese men and women
    C L Cox
    Department of Nutrition, University of California, Davis, Davis, CA, USA
    Eur J Clin Nutr 66:201-8. 2012
    ....
  13. pmc Ablation of a galectin preferentially expressed in adipocytes increases lipolysis, reduces adiposity, and improves insulin sensitivity in mice
    Ri Yao Yang
    Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA
    Proc Natl Acad Sci U S A 108:18696-701. 2011
    ..These findings add to the significant functions exhibited by intracellular galectins, and have important therapeutic implications for human metabolic disorders...
  14. pmc Glucose sensing by gut endocrine cells and activation of the vagal afferent pathway is impaired in a rodent model of type 2 diabetes mellitus
    Jennifer Lee
    Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis, California 95616, USA
    Am J Physiol Regul Integr Comp Physiol 302:R657-66. 2012
    ..01, P < 0.001, respectively) in RD and 3MD. These data suggest that glucose sensing in enteroendocrine and enterochromaffin cells and activation of neural pathways is markedly impaired in UCD-T2DM rats...
  15. pmc Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans
    Kimber L Stanhope
    Department of Molecular Biosciences, UCD, Davis, California 95616, USA
    J Clin Invest 119:1322-34. 2009
    ..These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults...
  16. pmc The correlation between TG vs remnant lipoproteins in the fasting and postprandial plasma of 23 volunteers
    Katsuyuki Nakajima
    School of Health Sciences, Faculty of Medicine, Gunma University, Maebashi, Gunma, Japan
    Clin Chim Acta 404:124-7. 2009
    ....
  17. ncbi Fructose consumption and moderate zinc deficiency influence growth and adipocyte metabolism in young rats prone to adult-onset obesity
    Erin L Streiff
    Department of Nutrition, University of California at Davis, One Shields Avenue, Davis, CA, USA
    Biol Trace Elem Res 118:53-64. 2007
    ..The mesenteric adipocytes from the animals in the LZF group utilized more glucose. Thus, the addition of fructose to a LZ diet reduced energy intake and growth and altered adipocyte fuel metabolism in young growing rats...
  18. pmc Fructose consumption: potential mechanisms for its effects to increase visceral adiposity and induce dyslipidemia and insulin resistance
    Kimber L Stanhope
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616, USA
    Curr Opin Lipidol 19:16-24. 2008
    ..From these results and a review of the current literature, we present two potential sequences of events by which fructose consumption may contribute to metabolic syndrome...
  19. pmc Effect of dietary n-3 polyunsaturated fatty acids on plasma total and high-molecular-weight adiponectin concentrations in overweight to moderately obese men and women
    Mario Kratz
    Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA
    Am J Clin Nutr 87:347-53. 2008
    ..Recent studies indicated that dietary n-3 polyunsaturated fatty acids (PUFAs) increase circulating adiponectin concentrations in rodents...
  20. pmc Metabolic and endocrine profiles in response to systemic infusion of fructose and glucose in rhesus macaques
    Sean H Adams
    US Department of Agriculture Agricultural Research Service Western Human Nutrition Research Center, University of California, Davis, Davis, California 95616, USA
    Endocrinology 149:3002-8. 2008
    ..e. limited post-fructose insulin excursions and/or hexose-specific differences in adipocyte metabolism) are likely to underlie disparate effects of fructose and glucose to increase circulating leptin concentrations...
  21. pmc Consumption of fructose-sweetened beverages for 10 weeks increases postprandial triacylglycerol and apolipoprotein-B concentrations in overweight and obese women
    Michael M Swarbrick
    Department of Nutrition, University of California, Davis, CA 95616, USA
    Br J Nutr 100:947-52. 2008
    ....
  22. ncbi Correlation of circulating full-length visfatin (PBEF/NAMPT) with metabolic parameters in subjects with and without diabetes: a cross-sectional study
    Ravi Retnakaran
    Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, ON, Canada
    Clin Endocrinol (Oxf) 69:885-93. 2008
    ..Here we use a novel ELISA that is specific for full-length visfatin (PBEF/NAMPT), compare it with the existing C-terminal based assay and use it to investigate associations of visfatin with metabolic parameters...
  23. pmc CRP and adiponectin and its oligomers in the metabolic syndrome: evaluation of new laboratory-based biomarkers
    Sridevi Devaraj
    Laboratory for Atherosclerosis and Metabolic Research, University of California, Davis, Medical Center, Sacramento, CA 95817, USA
    Am J Clin Pathol 129:815-22. 2008
    ..5; 95% CI, 1.3-4.5), its oligomers, or the adiponectin/ hsCRP ratio (OR, 2.6; 95% CI, 1.5, 4.8). Thus, measurements of CRP, adiponectin, or its oligomers provide robust biomarkers for predicting MetS...
  24. pmc Twenty-four-hour endocrine and metabolic profiles following consumption of high-fructose corn syrup-, sucrose-, fructose-, and glucose-sweetened beverages with meals
    Kimber L Stanhope
    Department of Molecular Biosciences, School of Veterinary Medicine, Davis, CA 95616 8669, USA
    Am J Clin Nutr 87:1194-203. 2008
    ..However, pure fructose and glucose are not commonly used as sweeteners. High-fructose corn syrup (HFCS) has replaced sucrose as the predominant sweetener in beverages in the United States...
  25. pmc Physiological, pharmacological, and nutritional regulation of circulating adiponectin concentrations in humans
    Michael M Swarbrick
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA
    Metab Syndr Relat Disord 6:87-102. 2008
    ....
  26. pmc Development and characterization of a novel rat model of type 2 diabetes mellitus: the UC Davis type 2 diabetes mellitus UCD-T2DM rat
    Bethany P Cummings
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, One Shields Ave, Davis, CA 95616, USA
    Am J Physiol Regul Integr Comp Physiol 295:R1782-93. 2008
    ..Thus diabetes in the UC Davis-T2DM rat is more similar to clinical T2DM in humans than in other existing rat models and provides a useful model for future studies of the pathophysiology, treatment, and prevention of T2DM...
  27. pmc Relationships between plasma adiponectin and body fat distribution, insulin sensitivity, and plasma lipoproteins in Alaskan Yup'ik Eskimos: the Center for Alaska Native Health Research study
    Anna V Goropashnaya
    Center for Alaska Native Health Research, Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK 99775 7000, USA
    Metabolism 58:22-9. 2009
    ....
  28. pmc Endocrine and metabolic effects of consuming beverages sweetened with fructose, glucose, sucrose, or high-fructose corn syrup
    Kimber L Stanhope
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
    Am J Clin Nutr 88:1733S-1737S. 2008
    ....
  29. pmc Inhibition of protein tyrosine phosphatase-1B with antisense oligonucleotides improves insulin sensitivity and increases adiponectin concentrations in monkeys
    Michael M Swarbrick
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616, USA
    Endocrinology 150:1670-9. 2009
    ....
  30. ncbi Conjugated linoleic acid inhibits glucose metabolism, leptin and adiponectin secretion in primary cultured rat adipocytes
    P Pérez-Matute
    Department of Physiology and Nutrition, University of Navarra, 31008 Pamplona, Spain
    Mol Cell Endocrinol 268:50-8. 2007
    ..Furthermore, the inhibition of leptin and adiponectin production induced by CLA may contribute to insulin resistance observed in CLA-treated animals and humans...