Amino Acid and Fatty Acid Levels Affect Hepatic Phosphorus Metabolite Content in Metabolically Healthy Humans.

Objective: Hepatic energy metabolism negatively relates to insulin resistance and liver fat content in patients with type 2 diabetes, but its role in metabolically healthy humans is unclear. We hypothesized that intrahepatocellular γ-adenosine triphosphate (γATP) and inorganic phosphate (Pi) concentrations exhibit similar associations with insulin sensitivity in nondiabetic, nonobese volunteers. Design: A total of 76 participants underwent a four-point sampling, 75-g oral glucose tolerance test (OGTT), as well as in vivo31P/1H magnetic resonance spectroscopy. In 62 of them, targeted plasma metabolomic profiling was performed. Pearson correlation analyses were performed for the dependent variables γATP and Pi. Results: Adjusted for age, sex, and body mass index (BMI), hepatic γATP and Pi related to 2-hour OGTT glucose (r = 0.25 and r = 0.27, both P < 0.05), and Pi further associated with nonesterified fatty acids (NEFAs; r = 0.28, P < 0.05). However, neither γATP nor Pi correlated with several measures of insulin sensitivity. Hepatic γATP correlated with circulating leucine (r = 0.42, P < 0.001) and Pi with C16:1 fatty acids palmitoleic acid and C16:1w5 (r = 0.28 and 0.30, respectively, P < 0.01), as well as with δ-9-desaturase index (r = 0.33, P < 0.05). Only the association of γATP with leucine remained important after correction for multiple testing. Leucine and palmitoleic acid, together with age, sex, and BMI, accounted for 26% and for 15% of the variabilities in γATP and Pi, respectively. Conclusions: Specific circulating amino acids and NEFAs, but not measures of insulin sensitivity, partly affect hepatic phosphorus metabolites, suggesting mutual interaction between hepatic energy metabolism and circulating metabolites in nondiabetic humans.

Low-energy diets differing in fibre, red meat and coffee intake equally improve insulin sensitivity in type 2 diabetes: a randomised feasibility trial.

AIMS/HYPOTHESIS: Epidemiological studies have found that a diet high in fibre and coffee, but low in red meat, reduces the risk for type 2 diabetes. We tested the hypothesis that these nutritional modifications differentially improve whole-body insulin sensitivity (primary outcome) and secretion. METHODS: Inclusion criteria were: age 18-69 years, BMI ≥ 30 kg/m(2), type 2 diabetes treated with diet, metformin or acarbose and known disease duration of ≤ 5 years. Exclusion criteria were: HbA1c >75 mmol/mol (9.0%), type 1 or secondary diabetes types and acute or chronic diseases including cancer. Patients taking any medication affecting the immune system or insulin sensitivity, other than metformin, were also excluded. Of 59 patients (randomised using randomisation blocks [four or six patients] with consecutive numbers), 37 (54% female) obese type 2 diabetic patients completed this controlled parallel-group 8-week low-energy dietary intervention. The participants consumed either a diet high in cereal fibre (whole grain wheat/rye: 30-50 g/day) and coffee (≥ 5 cups/day), and free of red meat (L-RISK, n = 17) or a diet low in fibre (≤ 10 g/day), coffee-free and high in red meat (≥ 150 g/day) diet (H-RISK, n = 20). Insulin sensitivity and secretion were assessed by hyperinsulinaemic-euglycaemic clamp and intravenous glucose tolerance tests with isotope dilution. Whole-body and organ fat contents were measured by magnetic resonance imaging and spectroscopy. RESULTS: Whole-body insulin sensitivity increased in both groups (mean [95% CI]) (H-RISK vs L-RISK: 0.8 [0.2, 1.4] vs 1.0 [0.4, 1.7]mg kg(-1) min(-1), p = 0.59), while body weight decreased (-4.8% [-6.1%, -3.5%] vs -4.6% [-6.0%, -3.3%], respectively). Hepatic insulin sensitivity remained unchanged, whereas hepatocellular lipid content fell in both groups (-7.0% [-9.6%, -4.5%] vs -6.7% [-9.5%, -3.9%]). Subcutaneous fat mass (-1,553 [-2,767, -340] cm(3) vs -751 [-2,047; 546] cm(3), respectively) visceral fat mass (-206 [-783, 371] cm(3) vs -241 [-856, 373] cm(3), respectively) and muscle fat content (-0.09% [-0.16%, -0.02%] vs -0.02% [-0.10%, 0.05%], respectively) decreased similarly. Insulin secretion remained unchanged, while the proinflammatory marker IL-18 decreased only after the L-RISK diet. CONCLUSIONS/INTERPRETATION: No evidence of a difference between both low-energy diets was identified. Thus, energy restriction per se seems to be key for improving insulin action in phases of active weight loss in obese type 2 diabetic patients, with a potential improvement of subclinical inflammation with the L-RISK diet. TRIAL REGISTRATION: Clinicaltrials.gov NCT01409330. FUNDING: This study was supported by the Ministry of Science and Research of the State of North Rhine-Westphalia (MIWF NRW), the German Federal Ministry of Health (BMG), the Federal Ministry for Research (BMBF) to the Center for Diabetes Research (DZD e.V.) and the Helmholtz Alliance Imaging and Curing Environmental Metabolic Diseases (ICEMED).

Mechanisms underlying the onset of oral lipid-induced skeletal muscle insulin resistance in humans.

Several mechanisms, such as innate immune responses via Toll-like receptor-4, accumulation of diacylglycerols (DAG)/ceramides, and activation of protein kinase C (PKC), are considered to underlie skeletal muscle insulin resistance. In this study, we examined initial events occurring during the onset of insulin resistance upon oral high-fat loading compared with lipid and low-dose endotoxin infusion. Sixteen lean insulin-sensitive volunteers received intravenous fat (iv fat), oral fat (po fat), intravenous endotoxin (lipopolysaccharide [LPS]), and intravenous glycerol as control. After 6 h, whole-body insulin sensitivity was reduced by iv fat, po fat, and LPS to 60, 67, and 48%, respectively (all P < 0.01), which was due to decreased nonoxidative glucose utilization, while hepatic insulin sensitivity was unaffected. Muscle PKCθ activation increased by 50% after iv and po fat, membrane Di-C18:2 DAG species doubled after iv fat and correlated with PKCθ activation after po fat, whereas ceramides were unchanged. Only after LPS, circulating inflammatory markers (tumor necrosis factor-α, interleukin-6, and interleukin-1 receptor antagonist), their mRNA expression in subcutaneous adipose tissue, and circulating cortisol were elevated. Po fat ingestion rapidly induces insulin resistance by reducing nonoxidative glucose disposal, which associates with PKCθ activation and a rise in distinct myocellular membrane DAG, while endotoxin-induced insulin resistance is exclusively associated with stimulation of inflammatory pathways.