Metabolomic Analysis of the Effects of Leptin Replacement Therapy in Patients with Lipodystrophy.

CONTEXT AND OBJECTIVE: Leptin treatment has dramatic clinical effects on glucose and lipid metabolism in leptin-deficient patients with lipodystrophy. Further elucidation of metabolic effects of exogenous leptin therapy will shed light on understanding leptin physiology in humans. Our objective was to utilize metabolomic profiling to examine the changes associated with administration of short-term metreleptin therapy in patients with lipodystrophy. STUDY DESIGN: We conducted a pre-post-treatment study in 19 patients (75% female) with varying forms of lipodystrophy (congenital generalized lipodystrophy, n = 10; acquired generalized lipodystrophy, n = 1; familial partial lipodystrophy, n = 8) who received daily subcutaneous metreleptin injections for a period of 16 to 23 weeks. A 3-hour oral glucose tolerance test and body composition measurements were conducted before and after the treatment period, and fasting blood samples were used for metabolomic profiling. The study outcome aimed at measuring changes in physiologically relevant metabolites before and after leptin therapy. RESULTS: Metabolomic analysis revealed changes in pathways involving branched-chain amino acid metabolism, fatty acid oxidation, protein degradation, urea cycle, tryptophan metabolism, nucleotide catabolism, vitamin E, and steroid metabolism. Fold changes in pre- to post-treatment metabolite levels indicated increased breakdown of fatty acids, branched chain amino acids proteins, and nucleic acids. CONCLUSIONS: Leptin replacement therapy has significant effects on important metabolic pathways implicated in patients with lipodystrophy. Continued metabolomic studies may provide further insight into the mechanisms of action of leptin replacement therapy and provide novel biomarkers of lipodystrophy.Abbreviations: 1,5-AG, 1,5-anhydroglucitol; 11ßHSD1, 11-ß hydroxysteroid dehydrogenase 1; BCAA, branched-chain amino acid; FFA, free fatty acid; GC-MS, gas chromatography mass spectrometry; IDO, indoleamine 2,3-dioxygenase; IFN-γ, interferon-γ; m/z, mass to charge ratio; OGTT, oral glucose tolerance test; TDO, tryptophan 2,3-dioxygenase; TNF-α, tumor necrosis factor-α; UPLC-MS/MS, ultra-performance liquid chromatography-tandem mass spectrometry.

Reduced Insulin Clearance and Insulin-Degrading Enzyme Activity Contribute to Hyperinsulinemia in African Americans.

BACKGROUND: African Americans (AAs) are at a higher risk for developing type 2 diabetes compared with non-Hispanic whites (NHWs). The causal role of ß-cell glucose sensitivity (ß-GS) and insulin clearance in hyperinsulinemia in AA adults is unclear. OBJECTIVE: Using a cross-sectional study design, we compared ß-cell function and insulin clearance in nondiabetic AAs (n = 36) and NHWs (n = 47) after a mixed meal test (MMT). METHODS: Insulin secretion rate, glucose sensitivity, rate sensitivity, and insulin sensitivity during MMT were derived from a mathematical model. Levels of insulin-degrading enzyme (IDE) and carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1), key players in insulin clearance, were measured (by enzyme-linked immunosorbent assay) in hepatic cytosolic fractions from age-, sex-, and body mass index-matched AA and NHW cadaveric donors (n = 10). RESULTS: Fasting and mean postprandial plasma glucose levels were similar in both ethnic groups. AAs had significantly higher fasting and mean postprandial plasma insulin levels. However, fasting ISR, total insulin output, and insulin sensitivity during MMT were not different between the groups. ß-GS and rate sensitivity were higher in AAs. Fasting and meal plasma insulin clearance were lower in AAs. Hepatic levels of IDE and CEACAM-1 were similar in AAs and NHWs. Hepatic IDE activity was significantly lower in AAs. CONCLUSIONS: In this study, lower insulin clearance contributes to higher plasma insulin levels in AAs. Reduced insulin clearance may be explained by lower IDE activity levels in AAs. Further confirmatory studies are needed to investigate diminished insulin clearance in AAs as a result of lower IDE activity levels.

Effects of growth hormone on hepatic insulin sensitivity and glucose effectiveness in healthy older adults.

PURPOSE: Growth hormone (GH) replacement decreases insulin sensitivity in healthy individuals. However, the effects of GH on organ-specific insulin sensitivity and glucose effectiveness are not well characterized. The purpose of this study was to evaluate the effects of GH administration for 26 weeks on muscle and hepatic insulin sensitivity and glucose effectiveness in healthy older individuals. METHODS: This report is from a 26-week randomized, double-blind, placebo-controlled parallel-group trial in healthy, ambulatory, community-dwelling older women and men. We compared surrogate indices of insulin sensitivity [quantitative insulin-sensitivity check index (QUICKI), muscle insulin sensitivity index (MISI), hepatic insulin resistance index (HIRI)] and glucose effectiveness [oral glucose effectiveness index (oGE)] derived from oral glucose tolerance tests (OGTTs) in subjects before and after 26 weeks of administration of GH (n = 17) or placebo (n = 15) as an exploratory outcome. RESULTS: GH administration for 26 weeks significantly increased fasting insulin concentrations and HIRI but did not significantly change MISI or oGE compared to placebo. CONCLUSIONS: GH administration for 26 weeks in healthy older subjects impairs insulin sensitivity in the liver but not skeletal muscle and does not alter glucose effectiveness.