Terry P Combs1, Janet K Snell-Bergeon1, David M Maahs1, Bryan C Bergman1, Marie Lamarche1, Laura Iberkleid1, Omar AbdelBaky1, Roland Tisch1, Philipp E Scherer1, Errol B Marliss1. 1. Department of Medicine (T.P.C., L.I., O.A.), Department of Microbiology and Immunology (R.T.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Crabtree Nutrition Laboratories (T.P.C., M.L., E.B.M.), Department of Medicine, McGill University, Montréal, Québec, Canada H4A 3J1; Barbara Davis Center for Childhood Diabetes (J.K.S.-B., D.M.M., B.C.B.), Department of Medicine, University of Colorado, Anschutz Medical Campus, Denver, Colorado 80045; and Touchstone Diabetes Center (P.E.S.), Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
Abstract
CONTEXT: Circulating adiponectin is elevated in human type 1 diabetes (T1D) and nonobese diabetic (NOD) mice without the expected indications of adiponectin action, consistent with tissue resistance. OBJECTIVE: Adiponectin stimulates hepatocyte production of the suppressor of glucose from autophagy (SOGA), a protein that inhibits glucose production. We postulated that due to tissue resistance, the elevation of adiponectin in T1D should fail to increase the levels of a surrogate marker for liver SOGA, the circulating C-terminal SOGA fragment. MAIN OUTCOME MEASURES: Liver and plasma SOGA were measured in NOD mice (n = 12) by Western blot. Serum adiponectin and SOGA were measured in T1D and control (Ctrl) participants undergoing a three-stage insulin clamp for the Coronary Artery Calcification in T1D study (n = 20). Glucose turnover was measured using 6,6[(2)H2]glucose (n = 12). RESULTS: In diabetic NOD mice, the 13%-29% decrease of liver SOGA (P = .003) and the 30%-37% reduction of circulating SOGA (P < .001) were correlated (r = 0.826; P = .001). In T1D serum, adiponectin was 50%-60% higher than Ctrl, SOGA was 30%-50% lower and insulin was 3-fold higher (P < .05). At the low insulin infusion rate (4 mU/m(2)·min), the resulting glucose appearance correlated negatively with adiponectin in T1D (r = -0.985, P = .002) and SOGA in Ctrl and T1D (r = -0.837, P = .001). Glucose disappearance correlated with adiponectin in Ctrl (r = -0.757, P = .049) and SOGA in Ctrl and T1D (r = -0.709, P = .010). At 40 mU/m(2)·min, the lowered glucose appearance was similar in Ctrl and T1D. Glucose disappearance increased only in Ctrl (P = .005), requiring greater glucose infusion to maintain euglycemia (8.58 ± 1.29 vs 3.09 ± 0.87 mg/kg·min; P = .009). CONCLUSIONS: The correlation between liver and plasma SOGA in NOD mice supports the use of the latter as surrogate marker for liver concentration. Reduced SOGA in diabetic NOD mice suggests resistance to adiponectin. The dissociation between adiponectin and SOGA in T1D raises the possibility that restoring adiponectin signaling and SOGA might improve the metabolic response to insulin therapy.
CONTEXT: Circulating adiponectin is elevated in humantype 1 diabetes (T1D) and nonobese diabetic (NOD) mice without the expected indications of adiponectin action, consistent with tissue resistance. OBJECTIVE:Adiponectin stimulates hepatocyte production of the suppressor of glucose from autophagy (SOGA), a protein that inhibits glucose production. We postulated that due to tissue resistance, the elevation of adiponectin in T1D should fail to increase the levels of a surrogate marker for liver SOGA, the circulating C-terminal SOGA fragment. MAIN OUTCOME MEASURES: Liver and plasma SOGA were measured in NOD mice (n = 12) by Western blot. Serum adiponectin and SOGA were measured in T1D and control (Ctrl) participants undergoing a three-stage insulin clamp for the Coronary Artery Calcification in T1D study (n = 20). Glucose turnover was measured using 6,6[(2)H2]glucose (n = 12). RESULTS: In diabetic NOD mice, the 13%-29% decrease of liver SOGA (P = .003) and the 30%-37% reduction of circulating SOGA (P < .001) were correlated (r = 0.826; P = .001). In T1D serum, adiponectin was 50%-60% higher than Ctrl, SOGA was 30%-50% lower and insulin was 3-fold higher (P < .05). At the low insulin infusion rate (4 mU/m(2)·min), the resulting glucose appearance correlated negatively with adiponectin in T1D (r = -0.985, P = .002) and SOGA in Ctrl and T1D (r = -0.837, P = .001). Glucose disappearance correlated with adiponectin in Ctrl (r = -0.757, P = .049) and SOGA in Ctrl and T1D (r = -0.709, P = .010). At 40 mU/m(2)·min, the lowered glucose appearance was similar in Ctrl and T1D. Glucose disappearance increased only in Ctrl (P = .005), requiring greater glucose infusion to maintain euglycemia (8.58 ± 1.29 vs 3.09 ± 0.87 mg/kg·min; P = .009). CONCLUSIONS: The correlation between liver and plasma SOGA in NOD mice supports the use of the latter as surrogate marker for liver concentration. Reduced SOGA in diabetic NOD mice suggests resistance to adiponectin. The dissociation between adiponectin and SOGA in T1D raises the possibility that restoring adiponectin signaling and SOGA might improve the metabolic response to insulin therapy.
Authors: Terry P Combs; Utpal B Pajvani; Anders H Berg; Ying Lin; Linda A Jelicks; Mathieu Laplante; Andrea R Nawrocki; Michael W Rajala; Albert F Parlow; Laurelle Cheeseboro; Yang-Yang Ding; Robert G Russell; Dirk Lindemann; Adam Hartley; Glynn R C Baker; Silvana Obici; Yves Deshaies; Marian Ludgate; Luciano Rossetti; Philipp E Scherer Journal: Endocrinology Date: 2003-10-23 Impact factor: 4.736
Authors: Dana Dabelea; Gregory Kinney; Janet K Snell-Bergeon; John E Hokanson; Robert H Eckel; James Ehrlich; Satish Garg; Richard F Hamman; Marian Rewers Journal: Diabetes Date: 2003-11 Impact factor: 9.461
Authors: Utpal B Pajvani; Xueliang Du; Terry P Combs; Anders H Berg; Michael W Rajala; Therese Schulthess; Jürgen Engel; Michael Brownlee; Philipp E Scherer Journal: J Biol Chem Date: 2002-12-20 Impact factor: 5.157
Authors: Tsu-Shuen Tsao; Eva Tomas; Heather E Murrey; Christopher Hug; David H Lee; Neil B Ruderman; John E Heuser; Harvey F Lodish Journal: J Biol Chem Date: 2003-09-30 Impact factor: 5.157
Authors: Risheng Ye; William L Holland; Ruth Gordillo; Miao Wang; Qiong A Wang; Mengle Shao; Thomas S Morley; Rana K Gupta; Andreas Stahl; Philipp E Scherer Journal: Elife Date: 2014-10-23 Impact factor: 8.140
Authors: Petter Bjornstad; Laura Pyle; Gregory L Kinney; Marian Rewers; Richard J Johnson; David M Maahs; Janet K Snell-Bergeon Journal: J Diabetes Complications Date: 2016-06-14 Impact factor: 2.852