Insulin Sensitizers Modulate IGFBP-1 in EMPOWIR (Enhance the Metabolic Profile of Women with Insulin Resistance) a Randomized Clinical Trial (NCT00618071) of normoglycemic hyperinsulinemic women with midlife weight gain

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 780-806-Determinants of Insulin Resistance & Associated Metabolic Disturbances
Basic/Translational
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-798
Harriette Rosen Mogul1, Ruth G Freeman2, Feras M Hantash3, Namitha Bhat*4 and Michael Frey5
1New York Med Coll, Valhalla, NY, 2Montefiore Med Ctr, Bronx, NY, 3Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, 4Ndw York Medical College, 5New York Medical College, Valhalla, NY
BACKGROUND Hyperinsulinemia is increasingly recognized as a cause as well as a consequence of obesity and diabetes1-3 and strategies to ameliorate hyperinsulinemia are widely advocated.4 Identification of hyperinsulinemia is critical to initiation of early intervention. IGFBP-1 is an acknowledged marker of hyperinsulinemia5-7with a documented role in glucose homeostasis.7,8 Hepatic IGFBP-1 is inhibited by insulin. Low serum IGFBP-1’s correlate with metabolic syndrome (MS), and cardiovascular disease,9,10 and predict impaired glucose tolerance and Type 2 diabetes (T2DM) incidence in prospective studies.5 IGFBP-1 has excellent sensitivity & specificity as a screening test for ↑AUC-insulin11 & could be used to detect and monitor treatment in normoglycemic patients, comparable to Hb A1C in the management of T2DM. Accordingly, we measured IGFBP-1 at baseline & 6 months in EMPOWIR, a double blind, placebo controlled randomized clinical trial of metformin (MF) 2000mg & MF plus rosiglitazone (RSG) in women with Syndrome W—an early manifestation of insulin resistance, defined by the triad of Weight gain (≥20 lbs after the 20´s), Waist gain, & White Coat hypertension in normoglycemic hyperinsulinemic Women.12 The study was conducted to test the hypothesis that insulin sensitizers, along with a novel carbohydrate modified diet, could reduce fasting insulin (FIn) & attenuate related risk factors.13, 14 METHODS We compared FIn, IGFBP-1, BW, HOMA, & MS measures at baseline & 6-months in 46 subjects (mean age 46.6, BMI 30.5kg/m2, Hb A1C 5.4%) meeting inclusion criteria: age 35-55; 20 lb wt gain; normal GTT & AUC-insulin>100μU/ml. Paired t-tests & multivariate models were used (SPSS 19). Participants attended 4 weekly nutrition workshops to introduce the EMPOWIR diet: a flexible food plan (40% carbohydrates-40% protein-20% fat) promoting increased intake of vegetables, low-glycemic index fruits, low-fat protein & dairy products, restriction of all free sugars, & notable postponement of 3 allowable additional carbohydrates (starches) to after 4PM. RESULTS Significant reductions in mean BW were observed in all 3 study arms (P´s=.049, .005, .017). IGFBP-1 increased in all 3 arms (11.6→15.1, 11.2→13.2, & 11.8→19.6 ng/ml), but was only significant in the MF+RSG arm: P’s=.427, .194, .005, and was independent of weight loss. FIn reduction was significant in the MF arm (12.5→8.0µU/ml, P= .011). HOMA decreased in MF & MF+RSG arms (2.5→1.6 &1.9→1.3, P´s=.054 & .013). DISCUSSION IGFBP-1 improvement is reported in studies of women with PCOS.15-17 We believe this is the first demonstration of IGFBP-1 normalization with preventive interventions in midlife women. CONCLUSIONS Significant IGFBP-1 increase was observed in the MF+RSG arm in a diverse cohort of normoglycemic, hyperinsulinemic midlife women. IGFBP-1 may be a valuable test to diagnose and monitor hyperinsulinemia and merits additional study.

1.   Lustig RH. Which comes first? The obesity or the insulin? The behavior or the biochemistry? J Pediatr 2008;152(5):601-602.    2.   Corkey BE. Banting lecture 2011: hyperinsulinemia: cause or consequence? Diabetes 2012;61(1):4-13.    3.   Buettner C. Is hyperinsulinemia required to develop overeating-induced obesity? Cell Metab 2012;16(6):691-692.    4.   Kendall D, Vail A, Amin R et al. Metformin in Obese Children and Adolescents: The MOCA Trial. J Clin Endocrinol Metab 2012.    5.   Holly JM. The physiological role of IGFBP-1. Acta Endocrinol (Copenh) 1991;124 Suppl 2:55-62.    6.   Brismar K, Hall K. Clinical applications of IGFBP-1 and its regulation. Growth Regul 1993;3(1):98-100.    7.   Brismar K, Hilding A, Lindgren B. Regulation of IGFBP-1 in humans. Prog Growth Factor Res 1995;6(2-4):449-456.    8.   Frystyk J. Role of IGFBP-1 in glucose regulation? Acta Paediatr 2000;89(9):1025-1027.    9.   Heald AH, Cruickshank JK, Riste LK et al. Close relation of fasting insulin-like growth factor binding protein-1 (IGFBP-1) with glucose tolerance and cardiovascular risk in two populations. Diabetologia 2001;44(3):333-339. 10.   Heald AH, Siddals KW, Fraser W et al. Low circulating levels of insulin-like growth factor binding protein-1 (IGFBP-1) are closely associated with the presence of macrovascular disease and hypertension in type 2 diabetes. Diabetes 2002;51(8):2629-2636. 11.   Mogul HR, Marshall M, Frey M et al. Insulin like growth factor-binding protein-1 as a marker for hyperinsulinemia in obese menopausal women. J Clin Endocrinol Metab 1996;81(12):4492-4495. 12.   Mogul HR, Weinstein BI, Mogul DB et al. Syndrome W: a new model of hyperinsulinemia, hypertension and midlife weight gain in healthy women with normal glucose tolerance. Heart Dis 2002;4(2):78-85. 13.   Mogul HR, Peterson SJ, Weinstein BI, Zhang S, Southren AL. Metformin and carbohydrate-modified diet: a novel obesity treatment protocol: preliminary findings from a case series of nondiabetic women with midlife weight gain and hyperinsulinemia. Heart Dis 2001;3(5):285-292. 14.   Mogul HR, Peterson SJ, Weinstein BI, Li J, Southren AL. Long-term (2-4 year) weight reduction with metformin plus carbohydrate-modified diet in euglycemic, hyperinsulinemic, midlife women (Syndrome W). Heart Dis 2003;5(6):384-392. 15.   De L, V, La MA, Orvieto R, Morgante G. Effect of metformin on insulin-like growth factor (IGF) I and IGF-binding protein I in polycystic ovary syndrome. J Clin Endocrinol Metab 2000;85(4):1598-1600. 16.   Pawelczyk L, Spaczynski RZ, Banaszewska B, Duleba AJ. Metformin therapy increases insulin-like growth factor binding protein-1 in hyperinsulinemic women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2004;113(2):209-213. 17.   Seibel SA, Chou KH, Capp E, Spritzer PM, von Eye CH. Effect of metformin on IGF-1 and IGFBP-1 levels in obese patients with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2008;138(1):122-124.

Disclosure: HRM: Principal Investigator, GlaxoSmithKline, Clinical Researcher, Eli Lilly & Company. Nothing to Disclose: RGF, FMH, NB, MF

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: EMPOWIR is an unsolicited, investigator-initiated study supported by Glaxo Smith Kline with additional support from a Clinical and Translational Science Award (CTSA) from the National Institutes of Health UL11RR025740 awarded to the GCRC at Einstein.