Learn more about the people and groups that further research at the Joslin Diabetes Center  |  Select an application from the list below:  |  Search JoslinResearch.org  |  Learn about JoslinResearch.org and its features  |  Contact us with questions or to let us know about problems  |  Login to use all our features
Joslin Diabetes Center Website
  Harvard Medical School
Joslin Research Home  
Harvard Medical School Joslin Research Home
Welcome to the Joslin Research Website                     
 
  Joslin Investigator:
   
  
Dr. Mary Elizabeth Patti
 
Investigator Specifics:
Professional Details:
Publications
CV

Member of Section:
Cellular and Molecular Physiology

Core Director:

PCR Net

Primary Investigator for DGAP:
 Diabetes Genome Anatomy Project

Current Fellows, Students, or Lab Members:
Sarah Crunkhorn
Elvira Isganaitis, MD, MPH
Wanzhu Jin, PhD
Eun Young Kim, MD, PhD
Hee Jin Kim, M.D.
Melissa Woo, MD

Past Fellows, etc.:
Kirstine Anderson
Kristen Barry
Maura Costello
Farrell Dearie
Ryan Faucette
Hiral Gami
Christine Jensen
Joseph Jiminez-Chillaron
Jennifer Johnson
Justine Lee
Meagan Lizarazo
Carlos Martinez, Ph. D.
Jussi Pihlajamaki
Carolyn Reamer
Stephanie Ruest
Robert Saccone
Andrew Stein
Joyclyn Yee


 
 
Mary Elizabeth  Patti, MD
Investigator
Joslin Diabetes Center
Assistant Professor of Medicine, Harvard Medical School
 
7/1/1995 -  
 
 Understanding Cellular Mechanisms of Insulin Resistance

Mary Elizabeth Patti MD, Assistant Investigator

The Joslin Genomics Core is a core facility for the NIH-sponsored Diabetes Genome Anatomy Project (DGAP) - please visit: www.diabetesgenome.org


Laboratory Colleagues:




Jussi Pihlajamaki, MD, Postdoctoral Fellow
Elvira Isganaitis, MD, Research Fellow
Melissa Woo, MD, Research Fellow
Wanzhu Jin, DVM, PhD, Research Fellow
Eun-Young Kim, MD, Research Fellow
Alice Chow, BS, Genomics Core
Joshua Schroeder, BS, Genomics Core
Tanner Boes, BA, Lab Manager/Research Assistant
Emily Fisher, Administrative Coordinator

The overall goal of my laboratory investigation is to understand the pathophysiology of insulin resistance and type 2 diabetes, with a particular emphasis on defining linkages between classical metabolic/nutritional pathways and insulin signal transduction cascades which ultimately lead to alterations in gene expression and diabetes risk. At present, the major efforts of the laboratory are focused on:

(1) identification of new pathways important in diabetes pathogenesis, utilizing genomics techniques to analyze gene expression in tissues in human subjects at risk for diabetes ("prediabetes"), followed by functional characterization of differentially expressed genes and metabolic pathways

(2) understanding pathogenesis of diabetes associated with low birth weight

Since both genotype and environmental risk factors for diabetes, including obesity, inactivity, and low birth weight, converge to influence cellular function at the level of gene and protein expression, we hypothesize that alterations in gene expression in nondiabetic individuals at high risk for developing diabetes (“prediabetes”) mediate this risk. In our genomics studies of differential gene expression in skeletal muscle from Mexican-American subjects, we identified (1) a pattern of coordinate reduction in expression of multiple nuclear respiratory factor (NRF)-regulated genes of oxidative metabolism and mitochondrial function in insulin resistant and diabetic subjects, and (2) a potential molecular mechanism for these changes: decreased expression of PGC-1, a coactivator of both NRF and PPARγ-dependent transcription, and reduced expression of genes linked to mitochondrial biogenesis and function (Patti ME, Butte AJ, Crunkhorn S et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. PNAS 2003; 100: 8466-8471.) In Mexican-Americans, expression of both PGC1α and β is reduced in insulin resistant and diabetic subjects and correlates with measures of obesity, insulin resistance, and free fatty acid levels. Similar patterns of impairment in expression of genes of oxidative metabolism have also been observed in Caucasian populations. Our more recent studies (Crunkhorn et al 2007)indicate that both genetics and environmental factors, particularly obesity and saturated fatty acids, may contribute to reduced expression of PGC1 and impaired oxidative capacity, leading to the metabolic changes characteristic of insulin resistance and diabetes progression - inabililty to modulate lipid oxidation, intramuscular lipid accumulation, and further insulin resistance (Figure 1).




Conversely, reduced availability of nutrients during critical periods in development may permanently alter gene expression (“programming”) and play a major role in diabetes associated with low birth weight. We have recently developed a mouse model of low birth weight-associated diabetes, in which maternal undernutrition during the final third of gestation results in low birth weight, progressive and severe glucose intolerance, increased adiposity, insulin resistance, insulin secretory defects, and a 5-fold increased risk of diabetes in adult offspring. Ongoing studies are focused on determining the tissue specificity and cellular mechanisms for defects in insulin action and gene expression in low birth weight mice. Moreover, we are studying the role of postnatal diet composition and nutrient partitioning in modulating the development of diabetes in low birth weight mice and evaluating changes in gene expression in low birth weight humans.

It is our hope that these studies will permit identification of genes critical in diabetes pathogenesis and provide new targets for drug development.



Selected Publications (earliest to recent):

Patti ME, Sun XJ, Bruening JC, Araki E, Lipes MA, White MF, Kahn CR. 4PS/Insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient mice. J Biol Chem. 1995; 270:24670-24673.

Patti ME, Kahn CR. Lessons from transgenic and knockout animals about NIDDM. TEM 1996; 7(9):311-319.

Patti ME, Kahn CR. Transgenic animal models: Insights into the pathophysiology of NIDDM. Diab Rev 1997; 19: 149-164.

Smith-Hall J, Pons S, Patti ME, Burks DJ, Yenush L, Sun XJ, Kahn CR, White MF. The 60 kD insulin receptor substrate functions like an IRS protein (pp60IRS) in adipose cells. Biochemistry 1997; 36: 8304-8310.

Patti ME, Brambilla E, Luzi L, Landaker EJ, Kahn CR. Bidirectional modulation of insulin action by amino acids. J Clin Invest 1998; 101: 1519-1529.

Patti ME, Kahn CR. The insulin receptor - a critical link in glucose homeostasis and insulin action. J Basic Clin Physiol Pharmacol 1998, 9: 89-109.

Patti ME, Virkamaki A, Landaker EJ, Kahn CR, Yki-Jarvinen H. Activation of the hexosamine pathway by glucosamine induces insulin resistance of early post-receptor signaling events in skeletal muscle. Diabetes 1999; 48: 1562-1571.

Koval JA, Maezono K, Patti ME, Pendergrass M, DeFronzo RA, Mandarino LJ. Effects of exercise and insulin on insulin signaling proteins in human skeletal muscle. Medicine and Science in Sports and Exercise 1999; 31: 998-1004.

Goldfine AB, Patti ME, Zuberti L, Goldstein BJ, LeBlanc R, Landaker EJ, Jiang ZY, Willsky GR, Kahn CR. Metabolic effects of vanadyl sulfate in humans with non-insulin dependent diabetes mellitus: in vivo and in vitro studies. Metabolism 2000: 49: 1-12.

Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ. Insulin resistance differentially affects the PI 3-kinase and MAP kinase pathways of insulin receptor signaling in human muscle. J Clin Invest 2000; 105: 311-320.

Patti ME. Nutrient modulation of cellular insulin action. Annals of New York Academy of Sciences 1999; 892: 187-203 (invited review).

Orban T, Landaker E, Ruan Z, Cordeman TP, Weitgasser R, Bonner-Weir S, Jackson RA, Patti ME. High fructose diet preserves b-cell mass and prevents DM in NOD mice: A potential role for increased IRS-2. Metabolism 2001, 50: 1369-76.

Fraenkel PG, Rutkove SB, Matheson JK, Fowkes M, Cannon ME, Patti ME, Atkins MB, Gollob JA. Induction of myasthenia gravis, myositis, and IDDM by high-dose interleukin-2. J Immunotherapy 2002; 25: 373-378.

Yechoor VK, Patti ME, Saccone R, Kahn CR. Coordinated patterns of gene expression for substrate and energy metabolism in skeletal muscle of diabetic mice. PNAS 2002; 99: 10587-10592.

Combs TP, Berg AH, Rajala MW, Klebanov S, Iyengar P, Jimenez-Chillaron JC, Patti ME, Klein SL, Weinstein RS, Scherer PE. Sexual differentiation, pregnancy, calorie restriction, and aging affect ACRP30. Diabetes 2003;52:268-276.

Patti ME, Butte AJ, Crunkhorn S et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. PNAS 2003; 100: 8466-8471.

Bluher M, Patti ME, Gesta S, Kahn BB, Kahn CR. Intrinsic heterogeneity in adipose tissue of fat-specific insulin receptor knockout mice is associated with differences in patterns of gene expression. JBC 2004; 279: 31891-31901.

Patti ME. Gene Expression in the Pathophysiology of Diabetes. Current Diabetes Reports 2004;4(3): 176-81.


Patti ME. Gene expression in humans with diabetes and prediabetes: what have we learned about diabetes pathophysiology? Curr Opin Clin Nutr Metab Care 2004; 4: 383-390.

Patti ME and Kahn BB. Nutrient sensor links obesity with insulin resistance. Nature Medicine 2004;10:9-10.


Yechoor VK, Patti ME, Ueki K, Laustsen PG, Saccone R, Rauniyar R, Kahn CR. Distinct pathways of insulin-regulated versus diabetes-regulated gene expression: an in vivo analysis in MIRKO mice. PNAS 2004; 101: 16525-16530.

Gordon LB, Harten IA, Patti ME, Lichtenstein AH. Reduced Adiponectin and HDL Cholesterol Without Elevated C-reactive Protein; Clues to the Biology of Premature Atherosclerosis in Progeria. J Pediatrics 2005; 146: 336-341.

Jimenez-Chillaron JC, Hernandez-Valencia M, Reamer C, Fisher S, Joszi A, Hirshman M, Oge A, Walrond S, Przybyla R, Boozer C, Goodyear LJ, Patti ME. β-cell secretory dysfunction in the pathogenesis of low birth weight-associated diabetes: a murine model. Diabetes 2005; 54: 702-711.

Tseng Y, Butte AJ, Kokkotou E, Yechoor VK, Taniguchi CM, Kriauciunas KM, Niinobe M, Yoshikawa K, Patti ME, Kahn CR. Gene expression profiles in brown preadipocytes predict differentiation: role of insulin receptor substrates, necdin, E2F, and CREB mediated pathways. Nature Cell Biology 2005 Jun;7(6):601-11.


Halperin F, Beckman JA, Patti ME, Trujillo ME, Garvin M, Creager MA, Scherer PE, Goldfine AB. The role of total and high molecular weight complex of adiponectin in vascular function in offspring of two type 2 diabetic parents. Diabetologia 2005 Oct; 48(10):2147-54.

Patti ME, Mun EC, Holst JJ et al. Severe hypoglycemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia 2005: 48: 2236-2240.

Myers MG, Patti ME, Leshan RL. Leptin and perinatal nutrition in the predisposition to obesity. Endocrinology 2005 Oct; 146(10): 4209-10.


Goldfine AB, Crunkhorn S, Costello M, Gami H, Landaker EJ, Niinobe M, Yoshikawa K, Kahn CR, Lo D, Warren A, Jimenez-Chillaron J, Patti ME. Necdin and E2F4 are Modulated by Rosiglitazone Therapy in Diabetic Human Adipose and Muscle Tissue. Diabetes
Diabetes 2006; 55: 640-650.

Pihlajamaki J and Patti ME. 2006. Regulation of PGC-1 in Humans with Insulin Resistance and Type 2 Diabetes: Functional Implications. In: New Transcription Factors and their Role in Diabetes and its Therapy (Friedman JE, eds, Advances in Molecular and Cellular Endocrinology series). Oxford: Elsevier, 233-253.

Kuhl JE, Ruderman NB, Musi N, Goodyear LJ, Patti ME et al. Exercise training decreases the concentration of malonyl CoA and increases the expression and activity of malonyl CoA decarboxylase in human muscle. Am J Phys Endo Metab 2006; 290(6):E1296-303.

Ilany J, Bilan PJ, Kapur S, Caldwell JS, Patti ME, Marette A, Kahn CR. Overexpression of Rad in muscle worsens diet-induced insulin resistance and glucose intolerance and lowers plasma triglyceride level. PNAS 2006; 103: 4481-4486.

Jimenez-Chillaron JC, Hernandez-Valencia M, Lightner A, Faucette RR, Reamer C, Przybyla R, Ruest S, Barry K Barry, Otis JP, and Patti ME. Reductions in caloric intake and early postnatal growth prevent low birth weight-associated glucose intolerance and obesity. Diabetologia 2006; 49: 1974-1984.

Tiffin N, Adie E, Turner F, Brunner HG, van Driel MA, Oti M, Lopez-Bigas N, Ouzounis C, Perez-Iratxeta C, Andrade-Navarro MA, Adeyemo A, Patti ME, Semple CAM, Hide W. Computational disease gene identification: a concert of methods prioritizes type 2 diabetes and obesity candidate genes. Nucleic Acids Research 2006, 34: 3067-3081.

Goldfine AB, Mun EC, Patti ME. Hyperinsulinemic hypoglycaemia following gastric bypass surgery for obesity. Current Opinions in Endocrinology and Diabetes, 2006, 13(5): 419-424.


Crunkhorn, S, Patti ME. Nutrient Sensor Links Obesity with Diabetes Risk. Chapter in Physical Activity and Type 2 Diabetes (book), 2007, in press.

Jimenez-Chillaron JC, Patti ME. To Catch Up or Not to Catch Up: Is This the Question? Current Opinions in Endocrinology and Diabetes 2007, 14: 23-29.

Oge A, Isganaitis E, Jimenez-Chillaron J, Reamer C, Faucette R, Barry K, Przybyla R, Patti ME. In Utero Undernutrition Reduces Diabetes Incidence in NOD Mice. Diabetologia 2007, 50: 1099-1108.

Crunkhorn S, Dearie F, Mantzoros C, Gami H, da Silva W, Espinoza D, Faucette R, Barry K, Bianco AC, Patti ME. PGC-1 expression is reduced in obesity: Potential pathogenic role of saturated fatty acids and p38 MAP kinase activation. Journal of Biological Chemistry 2007; 282: 15439-15450.

Arikawa E, Ma RCW, Isshiki K, Luptak I, He Z, Yasuda Y, Maeno Y, Patti ME, Weir GC, Harris RA, Zammit VA, Tian R, King GL. Effect of insulin replacements, inihibitors of angiotensin and protein kinase C ’s actions to normalize cardiac gene expression and fuel metabolism in diabetic rats. Diabetes 2007, 56(5):1410-20.

Crunkhorn S, Patti ME. Links Between Thyroid Hormone Action, Oxidative Metabolism, and Diabetes Risk? Thyroid, 2007, in press (Special Edition on “Thyroid hormone and metabolic control”).


Biographical Sketch:

Dr. Patti is an Assistant Investigator in the Section on Cellular and Molecular Physiology. She received her M.D. degree from Jefferson Medical College (Philadelphia) in 1985. Following her clinical residency training in internal medicine at the University of Pittsburgh, she joined the internal medicine faculty of Eastern Virginia Medical School, where she was active in medical student and resident teaching. She subsequently moved to Boston to pursue clinical and research training in endocrinology and metabolism in the joint Harvard/Longwood program. Dr. Patti was the recipient of the Mary K. Iacocca Fellowship in 1995 and has been a member of the clinical and research staffs at Joslin since 1995. She received the Marios Balodimos Award of the American Diabetes Association (Massachusetts Affiliate) for her ongoing research in nutritional modulation of insulin action. She is the director of the Joslin Genomics Core Laboratory and a coinvestigator in the NIH-funded Diabetes Genome Anatomy Project (DGAP).