Kristensen 2024 Nat Metab

Kristensen JM, Kjøbsted R, Larsen TJ, Carl CS, Hingst JR, Onslev J, Birk JB, Thorup A, Steenberg DE, Knudsen JR, Henriksen NS, Needham EJ, Halling JF, Gudiksen A, Rundsten CF, Hanghøj KE, Stinson SE, Hoier B, Hansen CC, Jensen TE, Hellsten Y, Pilegaard H, Grarup N, Olesen J, Humphrey SJ, James DE, Pedersen ML, Richter EA, Hansen T, Jørgensen ME, Wojtaszewski JFP (2024) Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise. Nat Metab [Epub ahead of print]. https://doi.org/10.1038/s42255-024-01153-1

» PMID: 39482542 Open Access

Kristensen Jonas M, Kjoebsted Rasmus, Larsen Trine J, Carl Christian S, Hingst Janne R, Onslev Johan, Birk Jesper B, Thorup Anette, Steenberg Dorte E, Knudsen Jonas R, Henriksen Nicolai S, Needham Elise J, Halling Jens F, Gudiksen Anders, Rundsten Carsten F, Hanghoej Kristian E, Stinson Sara E, Hoier Birgitte, Hansen Camilla C, Jensen Thomas E, Hellsten Ylva, Pilegaard Henriette, Grarup Niels, Olesen Jesper, Humphrey Sean J, James David E, Pedersen Michael L, Richter Erika A, Hansen Torben, Joergensen Marit E, Wojtaszewski Joergen FP (2024) Nat Metab

Abstract: In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes. Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls. An extended glucose tolerance test reveals prolonged hyperglycaemia followed by reactive hypoglycaemia in the carriers. Whole-body glucose disposal is impaired during euglycaemic-hyperinsulinaemic clamp conditions and associates with severe insulin resistance in skeletal muscle only. Notably, a marked reduction in muscle glucose transporter GLUT4 and associated proteins is observed. While metabolic regulation during exercise remains normal, the insulin-sensitizing effect of a single exercise bout is compromised. Thus, loss of the muscle-specific isoform of TBC1D4 causes severe skeletal muscle insulin resistance without baseline hyperinsulinaemia. However, physical activity can ameliorate this condition. These observations offer avenues for personalized interventions and targeted preventive strategies.

• Bioblast editor: Plangger M • O2k-Network Lab: DK Copenhagen Larsen S, DK Copenhagen Pilegaard H

Labels: MiParea: Respiration, nDNA;cell genetics  Pathology: Diabetes 

Organism: Human  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 

Coupling state: ET, LEAK, OXPHOS  Pathway: N, S, NS  HRR: Oxygraph-2k 

2024-11