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1. Effects of TM6SF2 rs58542926 polymorphism on hepatocellular lipids and insulin resistance in early type 2 diabetes

Author

Bódis, Kálmán, Bombrich, Maria, Schön, Martin, Knebel, Birgit, Zaharia, Oana Patricia, Bönhof, Gidon, Karusheva, Yanislava, Strassburger, Klaus, Kupriyanova, Yuliya, Kotzka, Jörg, Guthoff, Rainer, Schrauwen-Hinderling, Vera, Al-Hasani, Hadi, Burkart, Volker, Szendroedi, Julia, Wagner, Robert, Markgraf, Daniel F., Roden, Michael, GDS study group, Bódis, Kálmán, Bombrich, Maria, Schön, Martin, Knebel, Birgit, Zaharia, Oana Patricia, Bönhof, Gidon, Karusheva, Yanislava, Strassburger, Klaus, Kupriyanova, Yuliya, Kotzka, Jörg, Guthoff, Rainer, Schrauwen-Hinderling, Vera, Al-Hasani, Hadi, Burkart, Volker, Szendroedi, Julia, Wagner, Robert, Markgraf, Daniel F., Roden, Michael, and GDS study group

Abstract

Background and aims: Increased hepatocellular lipid content (HCL) is linked to insulin resistance, risk of type 2 diabetes and related complications. Conversely, a single-nucleotide polymorphism (TM6SF2EK; rs58542926) in the transmembrane 6 superfamily member 2-gene has been associated with nonalcoholic fatty liver disease (NAFLD), but lower cardiovascular risk. This case-control study tested the role of this polymorphism for tissue-specific insulin sensitivity during early course of diabetes. Methods and results: Males with recent-onset type 2 diabetes with (TM6SF2EK: n = 16) or without (TM6SF2EE: n = 16) the heterozygous TM6SF2-polymorphism of similar age and body mass index, underwent Botnia-clamps with [6,6-2H2]glucose to measure whole-body-, hepatic- and adipose tissue-insulin sensitivity. HCL was assessed with 1H-magnetic-resonance-spectroscopy. A subset of both groups (n = 24) was re-evaluated after 5 years. Despite doubled HCL, TM6SF2EK had similar hepatic- and adipose tissue-insulin sensitivity and 27% higher whole-body-insulin sensitivity than TM6SF2EE. After 5 years, whole-body-insulin sensitivity, HCL were similar between groups, while adipose tissue-insulin sensitivity decreased by 87% and 55% within both groups and circulating triacylglycerol increased in TM6SF2EE only. Conclusions: The TM6SF2-polymorphism rs58542926 dissociates HCL from insulin resistance in recent-onset type 2 diabetes, which is attenuated by disease duration. This suggests that diabetes-related metabolic alterations dominate over effects of the TM6SF2-polymorphism during early course of diabetes and NAFLD.

Published
2023

2. Intramyocellular Triglyceride Content During the Early Course of Type 1 and Type 2 Diabetes.

Author

Schön, Martin, Zaharia, Oana P., Strassburger, Klaus, Kupriyanova, Yuliya, Bódis, Kálmán, Heilmann, Geronimo, Strom, Alexander, Bönhof, Gidon J., Michelotti, Filippo, Yurchenko, Iryna, Möser, Clara, Huttasch, Maximilian, Bombrich, Maria, Kelm, Malte, Burkart, Volker, Schrauwen-Hinderling, Vera B., Wagner, Robert, Roden, Michael, GDS Group, and Roden, M.

Subjects
GLUCOSE clamp technique, TYPE 1 diabetes, TYPE 2 diabetes, DISEASE risk factors, INSULIN sensitivity, PHYSICAL fitness, HYPERGLYCEMIA
Abstract

Intramyocellular lipid content (IMCL) is elevated in insulin-resistant humans, but it changes over time, and relationships with comorbidities remain unclear. We examined IMCL during the initial course of diabetes and its associations with complications. Participants of the German Diabetes Study (GDS) with recent-onset type 1 (n = 132) or type 2 diabetes (n = 139) and glucose-tolerant control subjects (n = 128) underwent 1H-MRS to measure IMCL and muscle volume, whole-body insulin sensitivity (hyperinsulinemic-euglycemic clamps; M-value), and cycling spiroergometry (VO2max). Subgroups underwent the same measurements after 5 years. At baseline, IMCL was ∼30% higher in type 2 diabetes than in other groups independently of age, sex, BMI, and muscle volume. In type 2 diabetes, the M-value was ∼36% and ∼62% lower compared with type 1 diabetes and control subjects, respectively. After 5 years, the M-value decreased by ∼29% in type 1 and ∼13% in type 2 diabetes, whereas IMCL remained unchanged. The correlation between IMCL and M-value in type 2 diabetes at baseline was modulated by VO2max. IMCL also associated with microalbuminuria, the Framingham risk score for cardiovascular disease, and cardiac autonomic neuropathy. Changes in IMCL within 5 years after diagnosis do not mirror the progression of insulin resistance in type 2 diabetes but associate with early diabetes-related complications. Article Highlights: Intramyocellular lipid content (IMCL) can be elevated in insulin-resistant humans, but its dynamics and association with comorbidities remain unclear. Independently of age, sex, body mass, and skeletal muscle volume, IMCL is higher in recent-onset type 2, but not type 1 diabetes, and remains unchanged within 5 years, despite worsening insulin resistance. A degree of physical fitness modulates the association between IMCL and insulin sensitivity in type 2 diabetes. Whereas higher IMCL associates with lower insulin sensitivity in people with lower physical fitness, there is no association between IMCL and insulin sensitivity in those with higher degree of physical fitness. IMCL associates with progression of microalbuminuria, cardiovascular disease risk, and cardiac autonomic neuropathy. [ABSTRACT FROM AUTHOR]

Published
2023
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