491-P: Severe Muscle Insulin Resistance in Inuit Homozygous Carriers of the Common Greenlandic P.Arg684Ter TBC1D4 Variant Is Improved by a Single Bout of Exercise

In the Greenlandic Inuit population a common nonsense TBC1D4 p.Arg684Ter variant in muscle is found with an allele frequency of 17%. Homozygous carriers of this variant have impaired glucose tolerance, and a 10-fold increased risk of type 2 diabetes. Here we investigate whether the TBC1D4 p.Arg684Ter affects regulation of skeletal muscle glucose uptake during exercise and during insulin stimulation in the post exercise period. Inuits carrying zero (n=8) or two (n=8) alleles of TBC1D4 p.Arg684Ter were recruited from population surveys in Greenland. Glucose tolerance was measured during a 6 hour oral glucose tolerance test (OGTT). Skeletal muscle glucose uptake was measured by applying arterial-venous balance technique across the legs during one-legged exercise and during subsequent euglycemic hyperinsulinemic clamp. Glucose uptake was measured in both the rested and the exercised leg. During the OGTT blood glucose was similar at fasting but markedly elevated (by 4.4 mM) in TBC1D4 p.Arg684Ter carriers compared to matched controls at 2 hours, and variants became hypoglycemic at 4 hours (3.3 vs. 4.7 mM) and similar to controls at 6 hours. During exercise, TBC1D4 variant carriers and controls displayed similar glucose uptake in skeletal muscle. During insulin clamp, glucose uptake in the previously rested leg was lower (~50%) in TBC1D4 variant carriers compared to controls. In the prior exercised leg, glucose uptake during the insulin clamp was higher in both groups compared to the rested leg. However, glucose uptake in the previously exercised leg from TBC1D4 variant carriers was comparable to the previously rested leg in controls and thus still markedly lower than controls. In conclusion: TBC1D4 p.Arg684Ter carriers have impaired insulin stimulated but normal exercise stimulated glucose uptake in skeletal muscle. A single bout of exercise improves muscle glucose uptake in carriers to levels seen in non-exercise muscle of controls. Disclosure J. M. Kristensen: None. T. Hansen: None. M. E. Jorgensen: Research Support; Self; Boehringer Ingelheim International GmbH, Sanofi-Aventis, Stock/Shareholder; Self; Novo Nordisk A/S. J. F. P. Wojtaszewski: None. T. L. J. Larsen: None. C. S. Carl: None. A. Thorup: None. J. Hingst: None. J. Onslev: None. J. S. Olesen: None. M. L. Pedersen: None. E. A. Richter: None. Funding Novo Nordisk Foundation (NNF14OC0013057, NNF17OC0028136); Independent Research Fund Denmark (FSS802000288B5855628)