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Activation of GIP (glucose-dependent insulinotropic peptide) receptor (GIPR) in combination with GLP-1 receptor has demonstrated reduced adiposity and bodyweight in mice. Although the incretin action of GIP in pancreatic beta cells is well characterized, its regulation of adipose tissue metabolism are incompletely understood. Using differentiated human adipocytes we demonstrated GIP suppression of insulin stimulated [14C] glucose and [14C] acetate incorporation into the cellular lipid fraction suggesting GIP/insulin co-regulation of de novo lipogenesis. To further investigate these findings, we employed an NMR and mass spec strategy. Briefly, human adipocytes were differentiated then incubated with [13C] glucose or [13C] acetate overnight in the presence GIP, insulin, GIP + insulin, or control followed by lysate preparation for mass spec and NMR analysis. Isotope label incorporation in lysate fatty acids were determined by HPLC-MS detection of base-hydrolyzed lipids. GIP significantly reduced incorporation of labeled acetate and labeled glucose in fatty acids, both in the presence and absence of insulin. Sample analysis by NMR demonstrated a GIP regulated increase in glycerol production from labeled glucose both in the presence and absence of insulin with little to no acetate incorporation into glycerol under all conditions tested. These findings demonstrate GIP signaling in adipocytes reduces de novo fatty acid synthesis while increasing glycerol formation. This suggests a model whereby GIP suppresses generation of new fatty acids from substrate but enhances appropriate storage capacity of dietary fatty acids by increasing production of glycerol required for triglyceride generation. Further studies will be required to elucidate this potential benefit of GIP to improve nutrient partitioning. Disclosure P.L. Milligan: Employee; Self; Eli Lilly and Company. K.D. Roth: Employee; Self; Eli Lilly and Company. H. Hu: None. J. Moyers: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. X. Ruan: Employee; Self; Eli Lilly and Company. W.C. Roell: Employee; Self; Eli Lilly and Company. A. Regmi: Employee; Self; Eli Lilly and Company.

Serum lipids and sphingolipids circulate in plasma and are linked with insulin resistance and increased cardiovascular disease risk. We previously reported that dihydroceramides (DHCer) are elevated in people with insulin resistance compared to individuals with obesity and trained athletes. Despite associations with insulin resistance, little is known whether insulin sensitizing lifestyle interventions can improve sphingolipid profiles. Twenty-one individuals with obesity and prediabetes (18F; 46± 2y; 35.0± 0.9 kg/m2; fasting glucose: 113.8± 9.4 mg/dl, 2h OGTT: 143.0± 19.4 mg/dl) participated in a 3-month lifestyle intervention of combined weight loss and exercise. Insulin sensitivity (SI) was assessed by hyperinsulinemic-euglycemic clamps and both targeted and shotgun lipidomics were conducted before and after intervention. BMI and body fat percentage were reduced by 11+1% (mean± SEM) and 9± 1% after intervention (p These data show that serum sphingolipids species previously linked to insulin resistance in humans can be improved with insulin sensitizing lifestyle interventions. Decreases in serum sphingolipids may explain increased SI and decreased cardiovascular disease risk associated with weight loss and exercise training. Disclosure J.L. Broussard: Advisory Panel; Self; National Institutes of Health. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, Sleep Research Society, Society in Science-The Branco Weiss Fellowship. D.E. Kahn: None. S.A. Newsom: None. J.T. Brozinick: Employee; Self; Eli Lilly and Company. H. Bui: Employee; Self; Eli Lilly and Company. K.D. Roth: Employee; Self; Eli Lilly and Company. L. Perreault: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. B.C. Bergman: Advisory Panel; Spouse/Partner; AstraZeneca, Merck & Co., Inc., Novo Nordisk Inc. Funding American Diabetes Association (1-14-CE-05 to B.B.); National Institutes of Health (RR-00036, K01DK110138); Colorado Nutrition Obesity Research Center (P30DK048520)

Nonalcoholic fatty liver disease (NAFLD) affects a significant number of patients with T2DM and places them at an increased risk of steatohepatitis (NASH) and cirrhosis. However, it is widely underdiagnosed due to lack of a simple, non-invasive test for its diagnosis. The aim of this study was to establish a plasma biomarker profile to identify NAFLD and NASH in patients with T2DM. We recruited 220 patients with T2DM (59±8 years; BMI: 33.6±4.8 kg/m2; A1c: 7.1±1.2%) and screened them for NAFLD by liver magnetic resonance spectroscopy (No NAFLD: n=76; NAFLD: n=144). If positive, a liver biopsy was performed (Isolated steatosis: n=73; NASH: n=71). All patients underwent untargeted plasma metabolomics and lipidomics. To account for multiple comparisons, a Bonferroni’s adjusted p-value Conclusion: Metabolomics/lipidomics may hold promise to non-invasively diagnose NAFLD in patients with T2DM, although its ability to identify those with NASH remains to be established. Disclosure F. Bril: None. S. Kalavalapalli: None. K.L. Duffin: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Pfizer Inc. M.L. Hartman: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Y. Chen: None. Q. Yang: None. J.V. Haas: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. P.L. Milligan: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. K.D. Roth: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. K. Cusi: Consultant; Self; Janssen Global Services, LLC., Eli Lilly and Company. Research Support; Self; Cirius Therapeutics. Other Relationship; Self; Nordic Bioscience. Research Support; Self; Novartis Pharmaceuticals Corporation, Novo Nordisk Inc.. Other Relationship; Self; Quest Diagnostics. Research Support; Self; Zydus Pharmaceuticals (USA) Inc.. Other Relationship; Self; OWL metabolomics, Echosens. Research Support; Self; Janssen Global Services, LLC.. Consultant; Self; Tobira Therapeutics, Pfizer Inc..