GIP Affects Hepatic Fat and Brown Adipose Tissue Thermogenesis but Not White Adipose Tissue Transcriptome in Type 1 Diabetes

Context: Glucose-dependent insulinotropic polypeptide (GIP) has been proposed to exert insulin-independent effects on lipid and bone metabolism. Objective: We investigated the effects of a 6-day subcutaneous GIP infusion on circulating lipids, white adipose tissue (WAT), brown adipose tissue (BAT), hepatic fat content, infammatory markers, respiratory exchange ratio (RER), and bone homeostasis in patients with type 1 diabetes. Methods: In a randomized, placebo-controlled, double-blind, crossover study, 20 men with type 1 diabetes underwent a 6-day continuous subcutaneous infusion with GIP (6 pmol/kg/min) and placebo (saline), with an interposed 7-day washout period. Results: During GIP infusion, participants (26[+ or -]8 years [mean[+ or -]SD]; BMI 23.8[+ or -] 1.8 kg/[m.sup.2]; glycated hemoglobin [A.sub.1c] 51 [+ or -]10 mmol/mol [6.8[+ or -] 3.1%]) experienced transiently increased circulating concentrations of nonesterifed fatty acid (NEFA) (P= 0.0005), decreased RER (P= 0.009), indication of increased fatty acid p-oxidation, and decreased levels of the bone resorption marker C-terminal telopeptide (P= 0.000072) compared with placebo. After 6 days of GIP infusion, hepatic fat content was increased by 12.6% (P= 0.007) and supraclavicular skin temperature, a surrogate indicator of BAT activity, was increased by 0.29 [degrees]C (P< 0.000001) compared with placebo infusion. WAT transcriptomic profile as well as circulating lipid species, proteome, markers of infammation, and bone homeostasis were unaffected. Conclusion: Six days of subcutaneous GIP infusion in men with type 1 diabetes transiently decreased bone resorption and increased NEFA and p-oxidation. Further, hepatic fat content, and supraclavicular skin temperature were increased without affecting WAT transcriptomics, the circulating proteome, lipids, or infammatory markers. Key Words: type 1 diabetes, cardiovascular disease, GIP, white adipose tissue, brown adipose tissue, hepatic steatosis Abbreviations: AUC, area under the curve; BAT, brown adipose tissue; bsAUC, baseline-subtracted area under the curve; CAP, controlled attenuation parameter; CTX, C-terminal telopeptide; ET-1, endothelin 1; GIP, glucose-dependent insulinotropic polypeptide; GIPHOT, glucose homeostasis of type 1 diabetes trial; GIPR, glucose-dependent insulinotropic polypeptide receptor; GLP-1, glucagon-like peptide 1; IL, interleukin; NEFA, nonesterifed fatty acid; P1NP, procollagen type 1 N-terminal propeptide; REE, resting ene