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1. Circulating sex hormone binding globulin levels are modified with intensive lifestyle intervention, but their changes did not independently predict diabetes risk in the Diabetes Prevention Program

Author

Mike Reidy, Christine Lee, Michael Brändle, Sherita Hill Golden, Samuel Dagogo-Jack, David Kessler, Elizabeth Barrett-Connor, Steve Jones, Ling Chen, Judith Wylie-Rosett, Ping Zhang, Paula Williamson, Carlos Lorenzo, Leigh Perreault, Dana Dabelea, Santica Marcovina, Rachel Williams, Marie Smith, Carmen Pal, Patricia Katz, William H. Herman, Sharon L Edelstein, Yong Ma, Vanita R Aroda, Costas A Christophi, Catherine Kim, Sherita H Golden, Edward Horton, Kieren J Mather, George A. Bray, Kishore Gadde, Iris W. Culbert, Jennifer Arceneaux, Annie Chatellier, Amber Dragg, Catherine M. Champagne, Crystal Duncan, Barbara Eberhardt, Frank Greenway, Fonda G. Guillory, April A. Herbert, Michael L. Jeffirs, Betty M. Kennedy, Erma Levy, Monica Lockett, Jennifer C. Lovejoy, Laura H. Morris, Lee E. Melancon, Donna H. Ryan, Deborah A. Sanford, Kenneth G. Smith, Lisa L. Smith, Julia A. St, Richard T. Tulley Amant, Paula C. Vicknair, Donald Williamson, Jeffery J. Zachwieja, Kenneth S. Polonsky, Janet Tobian, David A. Ehrmann, Margaret J. Matulik, Bart Clark, Kirsten Czech, Catherine DeSandre, Ruthanne Hilbrich, Wylie McNabb, Ann R. Semenske, Jose F. Caro, Kevin Furlong, Barry J. Goldstein, Pamela G. Watson, Kellie A. Smith, Jewel Mendoza, Wendi Wildman, Renee Liberoni, John Spandorfer, Constance Pepe, Richard P. Donahue, Ronald B. Goldberg, Ronald Prineas, Jeanette Calles, Juliet Ojito, Patricia Rowe, Paul Cassanova-Romero, Sumaya Castillo-Florez, Hermes J. Florez, Anna Giannella, Lascelles Kirby, Carmen Larreal, Olga Lara, Valerie McLymont, Jadell Mendez, Arlette Perry, Patrice Saab, Beth Veciana, Steven M. Haffner, Helen P. Hazuda, Maria G. Montez, Kathy Hattaway, Arlene Martinez, Tatiana Walker, Richard F. Hamman, Patricia V. Nash, Sheila C. Steinke, Lisa Testaverde, Denise R. Anderson, Larry B. Ballonoff, Alexis Bouffard, Brian Bucca, B. Ned Calonge, Lynne Delve, Martha Farago, James O. Hill, Shelley R. Hoyer, Tonya Jenkins, Bonnie T. Jortberg, Dione Lenz, Marsha Miller, David W. Price, Judith G. Regensteiner, Helen Seagle, Carissa M. Smith, Brent VanDorsten, Edward S. Horton, Kathleen E. Lawton, Catherine S. Poirier, Kati Swift, Ronald A. Arky, Marybeth Bryant, Jacqueline P. Burke, Enrique Caballero, Karen M. Callaphan, Barbara Fargnoli, Therese Franklin, Om P. Ganda, Ashley Guidi, Mathew Guido, Sharon D. Jackson, Alan M. Jacobsen, Lori Lambert, Sarah Ledbury, Margaret Kocal, Lyn M. Kula, Maureen A. Malloy, Maryanne Nicosia, Cathryn F. Oldmixon, Jocelyn Pan, Marizel Quitingon, Stacy Rubtchinsky, Jessica Sansoucy, Dana Schweizer, Ellen W. Seely, Donald Simonson, Fannie Smith, Caren G. Solomon, Jeanne Spellman, James Warram, Steven E. Kahn, Brenda K. Montgomery, Wilfred Fujimoto, Robert H. Knopp, Edward W. Lipkin, Michelle Marr, Ivy Morgan-Taggart, Anne Murillo, Dace Trence, Lonnese Taylor, April Thomas, Elaine C. Tsai, Abbas E. Kitabchi, Mary E. Murphy, Laura Taylor, Jennifer Dolgoff, William B. Applegate, Michael Bryer-Ash, Debra Clark, Sandra L. Frieson, Uzoma Ibebuogu, Raed Imseis, Helen Lambeth, Lynne C. Lichtermann, Hooman Oktaei, Harriet Ricks, Lily M.K. Rutledge, Amy R. Sherman, Clara M. Smith, Judith E. Soberman, Beverly Williams-Cleaves, Boyd E. Metzger, Mark E. Molitch, Mariana K. Johnson, Daphne T. Adelman, Catherine Behrends, Michelle Cook, Marian Fitzgibbon, Mimi M. Giles, Deloris Heard, Cheryl K.H. Johnson, Diane Larsen, Anne Lowe, Megan Lyman, David McPherson, Samsam C. Penn, Thomas Pitts, Renee Reinhart, Susan Roston, Pamela A. Schinleber, David M. Nathan, Charles McKitrick, Heather Turgeon, Mary Larkin, Kathy Abbott, Ellen Anderson, Laurie Bissett, Kristy Bondi, Enrico Cagliero, Jose C. Florez, Kali D’Anna, Linda Delahanty, Valerie Goldman, Peter Lou, Alexandra Poulos, Elyse Raymond, Christine Stevens, Beverly Tseng, Jerrold M. Olefsky, Mary Lou Carrion-Petersen, Madeline Beltran, Lauren N. Claravall, Jonalle M. Dowden, Steven V. Edelman, Robert R. Henry, Javiva Horne, Marycie Lamkin, Simona Szerdi Janesch, Diana Leos, Sunder Mudaliar, William Polonsky, Jean Smith, Jennifer Torio-Hurley, Karen Vejvoda, F. Xavier Pi-Sunyer, Jane E. Lee, David B. Allison, Nnenna Agharanya, Nancy J. Aronoff, Maria Baldo, Jill P. Crandall, Sandra T. Foo, Susan Hagamen, Jose A. Luchsinger, Kathy Parkes, Mary Beth Pena, Ellen S. Rooney, Gretchen E.H. Van Wye, Kristine A. Viscovich, David G. Marrero, Kieren J. Mather, Melvin J. Prince, Susie M. Kelly, Marcia A. Jackson, Gina McAtee, Paula Putenney, Ronald T. Ackermann, Carolyn M. Cantrell, Yolanda F. Dotson, Edwin S. Fineberg, Megan Fultz, John C. Guare, Angela Hadden, James M. Ignaut, Marion S. Kirkman, Erin O’Kelly Phillips, Beverly D. Porter, Paris J. Roach, Nancy D. Rowland, Madelyn L. Wheeler, Vanita Aroda, Robert E. Ratner, Gretchen Youssef, Sue Shapiro, Catherine Bavido-Arrage, Geraldine Boggs, Marjorie Bronsord, Ernestine Brown, Wayman W. Cheatham, Susan Cola, Cindy Evans, Peggy Gibbs, Tracy Kellum, Renee Wiggins, Milvia Lagarda, Lilia Leon, Claresa Levatan, Milajurine Lindsay, Asha K. Nair, Maureen Passaro, Angela Silverman, Gabriel Uwaifo, Debra Wells-Thayer, Mohammed F. Saad, Karol Watson, Maria Budget, Sujata Jinagouda, Medhat Botrous, Khan Akbar, Claudia Conzues, Perpetua Magpuri, Kathy Ngo, Amer Rassam, Debra Waters, Kathy Xapthalamous, Julio V. Santiago, Neil H. White, Angela L. Brown, Samia Das, Prajakta Khare-Ranade, Tamara Stich, Ana Santiago, Edwin Fisher, Emma Hurt, Tracy Jones, Michelle Kerr, Lucy Ryder, Cormarie Wernimont, Christopher D. Saudek, Vanessa Bradley, Emily Sullivan, Tracy Whittington, Caroline Abbas, Adrienne Allen, Frederick L. Brancati, Sharon Cappelli, Jeanne M. Clark, Jeanne B. Charleston, Janice Freel, Katherine Horak, Alicia Greene, Dawn Jiggetts, Deloris Johnson, Hope Joseph, Kimberly Loman, Henry Mosley, John Reusing, Richard R. Rubin, Alafia Samuels, Thomas Shields, Shawne Stephens, Kerry J. Stewart, LeeLana Thomas, Evonne Utsey, David S. Schade, Karwyn S. Adams, Janene L. Canady, Carolyn Johannes, Claire Hemphill, Penny Hyde, Leslie F. Atler, Patrick J. Boyle, Mark R. Burge, Lisa Chai, Kathleen Colleran, Ysela Gonzales, Doris A. Hernandez-McGinnis, Carolyn King, Sofya Rubinchik, Willette Senter, Jill Crandall, Harry Shamoon, Janet O. Brown, Gilda Trandafirescu, Elsie Adorno, Liane Cox, Helena Duffy, Samuel Engel, Allison Friedler, Angela Goldstein, Crystal J. Howard-Century, Jennifer Lukin, Stacey Kloiber, Nadege Longchamp, Helen Martinez, Dorothy Pompi, Jonathan Scheindlin, Elissa Violino, Elizabeth A. Walker, Elise Zimmerman, Joel Zonszein, Trevor Orchard, Rena R. Wing, Susan Jeffries, Gaye Koenning, M. Kaye Kramer, Susan Barr, Catherine Benchoff, Miriam Boraz, Lisa Clifford, Rebecca Culyba, Marlene Frazier, Ryan Gilligan, Stephanie Guimond, Susan Harrier, Louann Harris, Andrea Kriska, Bonny Rockette-Wagner, Qurashia Manjoo, Monica Mullen, Alicia Noel, Amy Otto, Jessica Pettigrew, Debra Rubinstein, Linda Semler, Cheryl F. Smith, Elizabeth Venditti, Valarie Weinzierl, Katherine V. Williams, Tara Wilson, Richard F. Arakaki, Renee W. Latimer, Narleen K. Baker-Ladao, Mae K. Isonaga, Ralph Beddow, Nina E. Bermudez, Lorna Dias, Jillian Inouye, Marjorie K. Mau, John S. Melish, Kathy Mikami, Pharis Mohideen, Sharon K. Odom, Raynette U. Perry, Robin E. Yamamoto, William C. Knowler, Norman Cooeyate, Mary A. Hoskin, Carol A. Percy, Alvera Enote, Camille Natewa, Kelly J. Acton, Vickie L. Andre, Rosalyn Barber, Shandiin Begay, Peter H. Bennett, Mary Beth Benson, Evelyn C. Bird, Brenda A. Broussard, Brian C. Bucca, Marcella Chavez, Sherron Cook, Jeff Curtis, Tara Dacawyma, Matthew S. Doughty, Roberta Duncan, Charlotte Dodge, Cyndy Edgerton, Jacqueline M. Ghahate, Justin Glass, Martia Glass, Dorothy Gohdes, Wendy Grant, Robert L. Hanson, Ellie Horse, Louise E. Ingraham, Merry Jackson, Priscilla Jay, Roylen S. Kaskalla, Kathleen M. Kobus, Jonathan Krakoff, Jason Kurland, Catherine Manus, Cherie McCabe, Sara Michaels, Tina Morgan, Yolanda Nashboo, Julie A. Nelson, Steven Poirier, Evette Polczynski, Christopher Piromalli, Jeanine Roumain, Debra Rowse, Robert J. Roy, Sandra Sangster, Janet Sewenemewa, Miranda Smart, Darryl Tonemah, Charlton Wilson, Michelle Yazzie, Raymond Bain, Sarah Fowler, Marinella Temprosa, Michael D. Larsen, Tina Brenneman, Sharon L. Edelstein, Solome Abebe, Julie Bamdad, Melanie Barkalow, Joel Bethepu, Tsedenia Bezabeh, Nicole Butler, Jackie Callaghan, Caitlin E. Carter, Costas Christophi, Gregory M. Dwyer, Mary Foulkes, Yuping Gao, Robert Gooding, Adrienne Gottlieb, Kristina L. Grimes, Nisha Grover-Fairchild, Lori Haffner, Heather Hoffman, Kathleen Jablonski, Tara L. Jones, Richard Katz, Preethy Kolinjivadi, John M. Lachin, Pamela Mucik, Robert Orlosky, Qing Pan, Susan Reamer, James Rochon, Alla Sapozhnikova, Hanna Sherif, Charlotte Stimpson, Ashley Hogan Tjaden, Fredricka Walker-Murray, Elizabeth M. Venditti, Andrea M. Kriska, Valerie Weinzierl, Jessica Harting, F. Alan Aldrich, John Albers, Greg Strylewicz, R. Eastman, Judith Fradkin, Sanford Garfield, Edward Gregg, Morton B. Brown, David Altshuler, Liana K. Billings, Maegan Harden, Toni I. Pollin, Alan R. Shuldiner, Paul W. Franks, and Marie-France Hivert

Subjects
Male, Aging, Endocrinology, Diabetes and Metabolism, primary prevention, Overweight, Cardiovascular, Medical and Health Sciences, lcsh:Diseases of the endocrine glands. Clinical endocrinology, law.invention, Impaired glucose tolerance, 0302 clinical medicine, Sex hormone-binding globulin, Randomized controlled trial, law, Sex Hormone-Binding Globulin, polycyclic compounds, skin and connective tissue diseases, reproductive and urinary physiology, biology, DPP Research Group, Diabetes, Metformin, type 2, 030220 oncology & carcinogenesis, diabetes mellitus, Female, Clinical care/Education/Nutrition, medicine.symptom, hormones, hormone substitutes, and hormone antagonists, medicine.drug, medicine.medical_specialty, Diabetes risk, hormone, Clinical Trials and Supportive Activities, Clinical Sciences, 030209 endocrinology & metabolism, Placebo, 03 medical and health sciences, Clinical Research, Internal medicine, Diabetes mellitus, Health Sciences, Glucose Intolerance, Diabetes Mellitus, medicine, Humans, Obesity, Life Style, Metabolic and endocrine, Nutrition, lcsh:RC648-665, business.industry, Prevention, life style, medicine.disease, Estrogen, Diabetes Mellitus, Type 2, biology.protein, 3.1 Primary prevention interventions to modify behaviours or promote wellbeing, sense organs, business
Abstract

IntroductionSex hormone binding globulin (SHBG) levels are reported to be inversely associated with diabetes risk. It is unknown whether diabetes prevention interventions increase SHBG and whether resultant changes in SHBG affect diabetes risk. The purpose of this analysis was to determine whether intensive lifestyle intervention (ILS) or metformin changed circulating SHBG and if resultant changes influenced diabetes risk in the Diabetes Prevention Program (DPP).Research design and methodsThis is a secondary analysis from the DPP (1996–2001), a randomized trial of ILS or metformin versus placebo on diabetes risk over a mean follow-up of 3.2 years. The DPP was conducted across 27 academic study centers in the USA. Men, premenopausal and postmenopausal women without hormone use in the DPP were evaluated. The DPP included overweight/obese persons with elevated fasting glucose and impaired glucose tolerance. Main outcomes measures were changes in SHBG levels at 1 year and risk of diabetes over 3 years.ResultsILS resulted in significantly higher increases (postmenopausal women: pConclusionsLifestyle intervention may be associated with favorable changes in circulating SHBG, which is largely due to changes in adiposity. Changes in circulating SHBG do not independently predict reductions in diabetes incidence.

Published
2020

2. Genetic Modulation of Lipid Profiles following Lifestyle Modification or Metformin Treatment: The Diabetes Prevention Program

Author

James M. Ignaut, Kathy Ngo, Yuping Gao, Roylen S. Kaskalla, Kellie Smith, Margaret Kocal, Patrick J. Boyle, Peggy Gibbs, Lorna Dias, Richard P. Donahue, Deloris Heard, Javiva Horne, Jewel Mendoza, Samia Das, Cheryl F. Smith, Stacy Rubtchinsky, Susie M. Kelly, Kathleen A. Jablonski, Richard Arakaki, Elise Zimmerman, Kenneth S. Polonsky, Toni I. Pollin, Judith E. Soberman, Mary Beth Benson, Jeanine Roumain, Justin Glass, Mary Lou Carrion-Petersen, Jill P. Crandall, Wilfred Y. Fujimoto, Wendy Grant, Rosalyn Barber, Khan Akbar, Catherine Behrends, Roberta Duncan, Jose C. Florez, David M. Nathan, Ping Zhang, Claresa Levatan, Pentti Rautaharju, Steven Poirier, Cathryn F. Oldmixon, Carolyn Johannes, Patricia Katz, Patrice G. Saab, Maria Budget, Pamela Mucik, Jeanne M. Clark, Mark E. Molitch, Alexandra Poulos, Sharon L. Edelstein, Sheila Steinke, Valerie Goldman, Enrico Cagliero, Kristin David, Maureen Passaro, Yabing Li, Marizel Quitingon, Robert Moran, Louise E. Ingraham, Elizabeth M. Venditti, Evette Polczynski, Marsha Miller, Marie Smith, Caren G. Solomon, Anne Lowe, Maryanne Nicosia, Farida Rautaharju, Elizabeth Barrett-Connor, Shandiin Begay, Sharon D. Jackson, Tara L. Jones, James H. Warram, Tina Brenneman, Margaret J. Matulik, Lisa Testaverde, Marjorie K. Mau, George A. Bray, Rena R. Wing, Lisa Clifford, Andrew W. Taylor, Elissa Violino, Paul Cassanova-Romero, William B. Applegate, Fannie E. Smith, Kristine A. Viscovich, Alicia Noel, Barbara Eberhardt, Edward W. Gregg, Ellie Horse, Sofya M Rubinchik, Cormarie Wernimont, Patricia Rowe, Donna H. Ryan, Doris A. Hernandez-McGinnis, Janet Sewenemewa, Mary Beth Pena, Sara Michaels, Linda Semler, Amy D. Otto, Donald A. Williamson, David D. McPherson, Kieren J. Mather, Kirsten Czech, Hermes Florez, Jonathan Scheindlin, Charles Campbell, Evelyn C. Bird, Tracy Jones, Nancy D. Rowland, Linda M. Delahanty, Vickie L. Andre, Donald C. Simonson, Angela L. Brown, Michelle Kerr, Edward S. Horton, Zhu Ming Zhang, Margaret Mills, Alla Sapozhnikova, Edward W. Lipkin, Marion S. Kirkman, Ellen S. Rooney, Robert Orlosky, Julio V. Santiago, Emily Sullivan, Jeanette Calles, Mike Reidy, Lascelles Kirby, William C. Knowler, Catherine Manus, Paula C. Vicknair, Elizabeth J. Mayer-Davis, Willette Senter, Samuel S. Engel, Ysela Gonzales, Sandra Foo, Dorothy Pompi, Steve Jones, Sharon Hall, Robert R. Henry, Sujata Jinagouda, Beverly D. Porter, Fredricka Walker-Murray, Mary A. Hoskin, Iris W. Culbert, Michelle Cook, Steven E. Kahn, H. Shamoon, Frank L. Greenway, Enrique Caballero, Valerie McLymont, Marian L. Fitzgibbon, Carolyn King, David W. Price, Leslie F. Atler, Christopher D. Saudek, Frederick L. Brancati, Judith Wylie-Rosett, Brent VanDorsten, Marcella Chavez, Ronald J. Prineas, N. Grover, Beverly Williams-Cleaves, Catherine DeSandre, Mohammed F. Saad, Ronald A. Arky, Ronald B. Goldberg, Raed E. Imseis, Alexis Bouffard, Jerrold M. Olefsky, Joel Zonszein, Carissa M. Smith, Marinella Temprosa, Greg Strylewicz, Maria G. Montez, Gretchen Youssef, David A. Ehrmann, Janice Freel, Dace L. Trence, Robert E. Ratner, Susan Jeffries, Richard C. Eastman, Andrea M. Kriska, Dione Lenz, Kathleen E. Lawton, Cindy Evans, Neil H. White, Henry Mosley, Susan Cola, William H. Herman, Jean Smith, Alafia Samuels, Larry B. Ballonoff, Yolanda F. Dotson, Merry Jackson, Ann R. Semenske, Diane Larsen, Janet O. Brown, Tina Morgan, Simona Szerdi Janesch, Kerry J. Stewart, Jacqueline M. Ghahate, Ernestine Brown, Kathy Xapthalamous, Narleen K. Baker-Ladao, Maureen Malloy, Richard T. Tulley, Constance Pepe, Mary E. Murphy, Solome Abebe, Jill Crandall, Tracy Kellum, Lucy Ryder, David B. Allison, Samuel Dagogo-Jack, Steven V. Edelman, Ted Ganiats, Jeanne Charleston, James O. Hill, Renee W. Latimer, Sandra L. Frieson, Robert L. Hanson, F. Alan Aldrich, Barry J. Goldstein, Denise R. Anderson, Om P. Ganda, Helen M. Seagle, Gretchen E H van Wye, Monica Mullen, David S. Schade, Santica M. Marcovina, Jeffery J. Zachwieja, Mimi M. Giles, Janene L. Canady, Liane Cox, Madelyn L. Wheeler, John C. Guare, Helen Lambeth, Cheryl K H Johnson, Lynne Lichtermann, Alan R. Shuldiner, Susan Roston, Geraldine Boggs, Bonnie T. Jortberg, Paris Roach, Elsie Adorno, Arlene Martinez, Qing Pan, Pamela A. Schinleber, Jillian Inouye, Kathy Parkes, Katherine Horak, Elizabeth A. Walker, Carol Percy, Perpetua Magpuri, Michelle Yazzie, Cyndy Edgerton, Melvin J. Prince, Ralph Beddow, Sandra Sangster, Laura H. Morris, Carlos Lorenzo, Carmen A. Larreal, Richard J. Katz, Claudia Conzues, Gabriel Uwaifo, Juliet Ojito, Lynne Delve, William H. Polonsky, Julie A. Nelson, Raymond P. Bain, Mark R. Burge, Anna Giannella, Bart Clark, Renee Reinhart, Nancy Pemberton, Norman Cooeyate, Ryan Gilligan, Wayman W. Cheatham, Alan M. Jacobsen, Crystal J. Howard-Century, Sue Shapiro, Louann Harris, Jarred McAteer, Helena Duffy, Trevor J. Orchard, Marcia L. Jackson, Heather Turgeon, Sanford A. Garfield, Jonathan Krakoff, Debra Rowse, Jocelyn Pan, Patricia V. Nash, Kathy Abbott, Pamela G. Watson, James Rochon, M. Kaye Kramer, Paula Williamson, Betty M. Kennedy, Susan Harrier, Jose F. Caro, Richard R. Rubin, Megan Lyman, Kristina L. Grimes, Boyd E. Metzger, Priscilla Jay, Paul W. Franks, Ruthanne Hilbrich, Ellen W. Seely, B. Ned Calonge, Sundar R. D. Mudaliar, Tara Dacawyma, Marybeth Bryant, Abbas E. Kitabchi, Deborah A. Sanford, Renee Liberoni, Angela M. Hadden, Allison Friedler, Charlton Wilson, Valarie A. Weinzierl, Martia Glass, Michael L. Jeffirs, F. Xavier Pi-Sunyer, Elizabeth R. Stamm, John Spandorfer, Wylie L. McNabb, Janet Tobian, Yolanda Nashboo, Edwin S. Fineberg, Caroline Abbas, Amer Rassam, Hooman Oktaei, Robert H. Knopp, Vanessa Bradley, Charlotte Stimpson, Qurashia Manjoo, Marlene Frazier, Dorothy Gohdes, David Kessler, Gaye Koenning, Raynette U. Perry, Lily M K Rutledge, Amy R. Sherman, Catherine M. Champagne, Therese Franklin, Ellen J. Anderson, Arlette C. Perry, Lori Haffner, Darryl Tonemah, Charles McKitrick, Rebecca Culyba, Jennifer C. Lovejoy, Nancy J. Aronoff, Laurie Bissett, Jane E. Lee, Richard F. Hamman, Hanna Sherif, Julia A. St. Amant, Diana Leos, Judith E. Fradkin, David G. Marrero, Mariana K. Johnson, Michael Bryer-Ash, Lisa Chai, Deloris Johnson, Teresa Alexander, Jacqueline P. Burke, Edwin B. Fisher, Miriam A. Boraz, Jarred B. McAteer, Paul I.W. de Bakker, Tracy Whittington, Pharis Mohideen, John M. Lachin, Peter H. Bennett, Karen M. Callaphan, Kenneth G. Smith, Kimberly Loman, Sharon K. Odom, Karen Vejvoda, Susan Barr, L. Delahanty, Catherine Bavido-Arrage, Brenda A. Broussard, Daniel H. O'Leary, Dawn Jiggetts, Helen Martinez, Brenda Montgomery, Debra Waters, Carmen Pal, Tara Wilson, Nadege Longchamp, Lyn M. Kula, Katherine V. Williams, Martha Farago, Judith G. Regensteiner, Asha K. Nair, Karwyn S. Adams, Hope Joseph, Ana Santiago, Marjorie Bronsord, Emma Hurt, Lee E. Melancon, Michelle Marr, Jackie Callaghan, Dana Schweizer, Kathleen M. Kobus, Matthew S. Doughty, Shelley R. Hoyer, Stacey Kloiber, Steven M. Haffner, Sarah E. Fowler, Julie A. Bamdad, Lisa L. Smith, Clara Smith, David Altshuler, Fonda G. Guillory, Jadell Mendez, Thomas Pitts, April A. Herbert, Kathy Mikami, Kelly J. Acton, Andrew J. Sarkin, Tamara Isakova, and Allison, David B

Subjects
Male, Cancer Research, Magnetic Resonance Spectroscopy, 030204 cardiovascular system & hematology, Cardiovascular, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Weight loss, Risk Factors, Genetics (clinical), 0303 health sciences, medicine.diagnostic_test, Diabetes, Single Nucleotide, Middle Aged, Metformin, 3. Good health, Cholesterol, Cardiovascular Diseases, Medicine, Female, medicine.symptom, Type 2, medicine.drug, Research Article, Adult, medicine.medical_specialty, Drugs and Devices, HDL, lcsh:QH426-470, Lipoproteins, Biology, Endocrinology and Diabetes, Polymorphism, Single Nucleotide, LDL, 03 medical and health sciences, Clinical Research, Internal medicine, Diabetes mellitus, Weight Loss, Diabetes Mellitus, Genetics, medicine, Humans, Hypoglycemic Agents, Polymorphism, Allele, Molecular Biology, Life Style, Metabolic and endocrine, Ecology, Evolution, Behavior and Systematics, Genetic Association Studies, Triglycerides, Nutrition, 030304 developmental biology, Dyslipidemias, Diabetic Endocrinology, Prevention, Cholesterol, HDL, Lipid metabolism, Cholesterol, LDL, Diabetes Mellitus Type 2, medicine.disease, Lipid Metabolism, Diabetes Prevention Program Research Group, lcsh:Genetics, chemistry, Diabetes Mellitus, Type 2, Pharmacogenetics, Lipid profile, Developmental Biology, Lipoprotein
Abstract

Weight-loss interventions generally improve lipid profiles and reduce cardiovascular disease risk, but effects are variable and may depend on genetic factors. We performed a genetic association analysis of data from 2,993 participants in the Diabetes Prevention Program to test the hypotheses that a genetic risk score (GRS) based on deleterious alleles at 32 lipid-associated single-nucleotide polymorphisms modifies the effects of lifestyle and/or metformin interventions on lipid levels and nuclear magnetic resonance (NMR) lipoprotein subfraction size and number. Twenty-three loci previously associated with fasting LDL-C, HDL-C, or triglycerides replicated (P = 0.04–1×10−17). Except for total HDL particles (r = −0.03, P = 0.26), all components of the lipid profile correlated with the GRS (partial |r| = 0.07–0.17, P = 5×10−5–1×10−19). The GRS was associated with higher baseline-adjusted 1-year LDL cholesterol levels (β = +0.87, SEE±0.22 mg/dl/allele, P = 8×10−5, P interaction = 0.02) in the lifestyle intervention group, but not in the placebo (β = +0.20, SEE±0.22 mg/dl/allele, P = 0.35) or metformin (β = −0.03, SEE±0.22 mg/dl/allele, P = 0.90; P interaction = 0.64) groups. Similarly, a higher GRS predicted a greater number of baseline-adjusted small LDL particles at 1 year in the lifestyle intervention arm (β = +0.30, SEE±0.012 ln nmol/L/allele, P = 0.01, P interaction = 0.01) but not in the placebo (β = −0.002, SEE±0.008 ln nmol/L/allele, P = 0.74) or metformin (β = +0.013, SEE±0.008 nmol/L/allele, P = 0.12; P interaction = 0.24) groups. Our findings suggest that a high genetic burden confers an adverse lipid profile and predicts attenuated response in LDL-C levels and small LDL particle number to dietary and physical activity interventions aimed at weight loss., Author Summary The study included 2,993 participants from the Diabetes Prevention Program, a randomized clinical trial of intensive lifestyle intervention, metformin treatment, and placebo control. We examined associations between 32 gene variants that have been reproducibly associated with dyslipidemia and concentrations of lipids and NMR lipoprotein particle sizes and numbers. We also examined whether genetic background influences a person's response to cardioprotective interventions on lipid levels. Our analysis, which focused on determining whether common genetic variants impact the effects of cardioprotective interventions on lipid and lipoprotein particle size, shows that in persons with a high genetic risk score the benefit of intensive lifestyle intervention on LDL and small LDL particle levels is substantially diminished; this information may be informative for the targeted prevention of dyslipidemia, as it suggests that genetics might help identify persons in whom lifestyle intervention is likely to be an effective treatment for elevated lipids and lipoproteins. The NMR subfraction analyses provide novel insight into the biology of dyslipidemia by illustrating how numerous genetic variants that have previously been associated with lipid levels also modulate NMR lipoprotein particle sizes and number. This information may be informative for the targeted prevention of cardiovascular disease.

Published
2012

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