The gene encoding for transcription factor 7-like 2 () is the strongest type 2 diabetes mellitus (T2DM) candidate gene discovered to date. The TCF7L2 protein is a key transcriptional effector of the Wnt/β-catenin signaling pathway, which is an important developmental pathway that negatively regulates adipogenesis. However, the precise role that TCF7L2 plays in the development and function of adipocytes remains largely unknown. Using a combination of in vitro approaches, we first show that TCF7L2 protein is increased during adipogenesis in 3T3-L1 cells and primary adipocyte stem cells and that TCF7L2 expression is required for the regulation of Wnt signaling during adipogenesis. Inactivation of TCF7L2 protein by removing the high-mobility group (HMG)-box DNA binding domain in mature adipocytes in vivo leads to whole-body glucose intolerance and hepatic insulin resistance. This phenotype is associated with increased subcutaneous adipose tissue mass, adipocyte hypertrophy, and inflammation. Finally, we demonstrate that mRNA expression is downregulated in humans with impaired glucose tolerance and adipocyte insulin resistance, highlighting the translational potential of these findings. In summary, our data indicate that TCF7L2 has key roles in adipose tissue development and function that may reveal, at least in part, how TCF7L2 contributes to the pathophysiology of T2DM.

Highlights d L-lactate triggers ER Mg 2+ release that promotes mitochondrial Mg 2+ uptake d Mg 2+ is a second messenger for metabolic circuits d Limiting Mrs2-mediated Mg 2+ uptake enhances mitochondrial bioenergetics d Inflammation-induced lactate contributes to organ failure via m Mg 2+ surge

The ability to maintain skeletal muscle mass appears to be impaired in insulin resistant conditions. The present study investigated the effect of lipid induced insulin resistance on the rate of muscle protein synthesis. Seven healthy male volunteers (23 ± 1 y, 24 ± 1 kg/m2) underwent a 7 h intravenous infusion of [ring‐2H5]phenylalanine (0.5 mg/kg/h) on two randomised occasions combined with either 0.9% saline or 10% Intralipid (100 mL/h; Fresenius Kabi, Germany). After a 4 h ‘basal’ period, a 21 g bolus of amino acids (except phenylalanine and tyrosine) was administered in a 440 mL solution nasogastrically, and a 3 h euglycaemic (4.5 mmol/L) hyperinsulinemic (50 mU/m2/min) clamp was commenced (‘fed’ period). Muscle biopsies were obtained from the vastus lateralis at 1.5, 4, and 7 h. Lipid infusion resulted in elevated levels of plasma free fatty acids when compared to saline (P<0.001), which reduced fed glucose disposal by 20% (P<0.01) and pyruvate dehydrogenase complex activation by 50% (P<0.05). Furthermore, whereas mixed muscle fractional synthetic rate increased from the basal to fed period during saline infusion (0.040 ± 0.010 to 0.067 ± 0.013 %/h; P<0.05), it did not respond during lipid infusion (0.048 ± 0.013 to 0.038 ± 0.005 %/h), despite the same circulating insulin and leucine concentrations. Thus, lipid induced insulin resistance results in anabolic resistance to amino acid ingestion in healthy young men.

No abstract