Pleotropic effects of leptin to reverse insulin resistance and diabetic ketoacidosis

In this review we discuss the mechanisms for the pleotropic effects of leptin replacement therapy to reverse liver and muscle insulin resistance in lipodystrophic individuals, as well as insulin-independent effects of leptin replacement therapy to suppress white adipose tissue lipolysis, hepatic gluconeogenesis and fasting hyperglycaemia in rodent models of poorly controlled diabetes. On the basis of these studies we conclude with a view of the potential therapeutic applications of leptin replacement therapy in humans. This review summarises a presentation given at the ‘Is leptin coming back?’ symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.1007/s00125-016-3898-3, and by Christoffer Clemmensen and colleagues, DOI: XXX) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7)

Regulation of net hepatic glycogenolysis and gluconeogenesis by epinephrine in humans

The relative contributions of net hepatic glycogenolysis (NHG) and gluconeogenesis to rates of glucose production during a physiological increment in plasma epinephrine concentrations, independent of changes in plasma insulin concentrations, were determined in seven fasting, healthy young subjects. Plasma insulin concentrations were kept constant by infusing somatostatin (0.1 μg·kg−1·min−1) and replacing basal insulin (24 pmol·m−2·min−1). Epinephrine (1.2 μg·m−2·min−1) was infused for 90 min while NHG was assessed directly by 13C magnetic resonance spectroscopy. The rate of glucose production was assessed using [6,6-2H2]glucose, and gluconeogenesis was calculated as the difference between the rate of glucose production and NHG. Plasma epinephrine concentrations increased rapidly from ∼100 to ∼2,000 pmol/l (P < 0.00001) accompanied by an increase in plasma glucose concentrations from 4.3 ± 0.2 to 13.3 ± 0.3 mmol/l at 90 min (P = 0.00001). This increase in plasma epinephrine concentration resulted in a 2.5-fold increase in glucose production (from 14.4 ± 1.0 μmol·kg−1·min−1 to 35.7 ± 2.0 μmol·kg−1·min−1, P < 0.0001), which lasted for ∼60 min (phase 1), after which glucose production decreased to 31.2 ± 1.9 μmol·kg−1·min−1 (P < 0.0001 vs. basal) during the last 30 min of the epinephrine infusion (phase 2). Hepatic glycogen concentrations decreased almost linearly during phase 1, and rates of NHG were 19.9 ± 3.0 μmol·kg−1·min−1 (P = 0.005 vs. basal), which could account for ∼60% of glucose production. During phase 2, NHG decreased to 7.3 ± 2.8 μmol·kg−1·min−1 (P = 0.02 vs. peak), accounting for only ∼20% of glucose production. In conclusion, in the presence of basal plasma insulin and glucagon concentrations, a physiological increase in plasma epinephrine concentrations stimulates glucose production with an initial, 60-min transient phase caused by stimulation of NHG and a second phase that can mostly be attributed to a twofold increase in rates of gluconeogenesis

Ethnic and sex differences in hepatic lipid content and related cardiometabolic parameters in lean individuals

BACKGROUND: Nonalcoholic fatty liver affects 25% to 30% of the US and European populations; is associated with insulin resistance (IR), type 2 diabetes, and increased cardiovascular risk; and is defined by hepatic triglyceride (HTG) content greater than 5.56%. However, it is unknown whether HTG content less than 5.56% is associated with cardiometabolic risk factors and whether there are ethnic (Asian Indian, AI, versus non-AI) and/or sex differences in these parameters in lean individuals. METHODS: We prospectively recruited 2331 individuals and measured HTG, using (1)H magnetic resonance spectroscopy, and plasma concentrations of triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, and uric acid. Insulin sensitivity was assessed using Homeostatic Model Assessment of Insulin Resistance and the Matsuda Insulin Sensitivity Index. RESULTS: The 95th percentile for HTG in lean non-AI individuals was 1.85%. Plasma insulin, triglycerides, total cholesterol, LDL-cholesterol, and uric acid concentrations were increased and HDL-cholesterol was decreased in individuals with HTG content > 1.85% and ≤ 5.56% compared with those individuals with HTG content ≤ 1.85%, and these altered parameters were associated with increased IR. Mean HTG was lower in lean non-AI women compared with lean non-AI men, whereas lean AI men and women had a 40% to 100% increase in HTG when compared with non-AI men and women, which was associated with increased cardiometabolic risk factors. CONCLUSION: We found that the 95th percentile of HTG in lean non-AI individuals was 1.85% and that HTG concentrations above this threshold were associated with IR and cardiovascular risk factors. Premenopausal women were protected from these changes whereas young, lean AI men and women manifested increased HTG content and associated cardiometabolic risk factors. FUNDING: Grants from the United States Department of Health and Human Resources (NIH/National Institute of Diabetes and Digestive and Kidney Diseases): R01 DK113984, P30 DK45735, U24 DK59635, and UL1 RR024139; and the Novo Nordisk Foundation (NNF18CC0034900)