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- Nilsson, Emma A, et al.
(författare)
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Genetic and Nongenetic Regulation of CAPN10 mRNA Expression in Skeletal Muscle.
- 2005
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 54:10, s. 3015-3020
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Tidskriftsartikel (refereegranskat)abstract
- The gene encoding calpain-10 (CAPN10) has been identified as a candidate gene for type 2 diabetes. Our aim was to study the impact of genetic (heritability and polymorphisms) and nongenetic (insulin, free fatty acids, and age) factors on CAPN10 mRNA expression in skeletal muscle using two different study designs. Muscle biopsies were obtained before and after hyperinsulinemic-euglycemic clamps from 166 young and elderly monozygotic and dizygotic twins as well as from 15 subjects with normal (NGT) or impaired glucose tolerance (IGT) exposed to an Intralipid infusion. We found hereditary effects on both basal and insulin-exposed CAPN10 mRNA expression. Carriers of the type 2 diabetes–associated single nucleotide polymorphism (SNP)-43 G/G genotype had reduced CAPN10 mRNA levels compared with subjects carrying the SNP-43 A-allele. Age had no significant influence on CAPN10 mRNA levels. Insulin had no significant effect on CAPN10 mRNA levels, neither in the twins nor in the basal state of the Intralipid study. However, after a 24-h infusion of Intralipid, we noted a significant increase in CAPN10 mRNA in response to insulin in subjects with NGT but not in subjects with IGT. In conclusion, we provide evidence that mRNA expression of CAPN10 in skeletal muscle is under genetic control. Glucose-tolerant but not glucose-intolerant individuals upregulate their CAPN10 mRNA levels in response to prolonged exposure to fat.
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| 2. |
- Parikh, Hemang, et al.
(författare)
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TXNIP regulates peripheral glucose metabolism in humans
- 2007
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1676. ; 4:5, s. 868-879
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Tidskriftsartikel (refereegranskat)abstract
- Background Type 2 diabetes mellitus ( T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure. Methods and Findings We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein ( TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM. Conclusions TXNIP regulates both insulin-dependent and insulin- independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic beta-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM.
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| 3. |
- Storgaard, Heidi, et al.
(författare)
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Relationships of plasma adiponectin level and adiponectin receptors 1 and 2 gene expression to insulin sensitivity and glucose and fat metabolism in monozygotic and dizygotic twins.
- 2007
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 92:7, s. 2835-2839
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Tidskriftsartikel (refereegranskat)abstract
- Context: Adiponectin is a key insulin-sensitizing adipokine acting on muscle metabolism via two specific receptors [adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2, respectively)]. Objectives: The aim of the study was to investigate the genetic and nongenetic control of plasma adiponectin and muscle AdipoR1/R2 gene expression and the impact of these components on in vivo glucose and fat metabolism. Design and Participants: Plasma adiponectin and muscle gene expression of AdipoR1/R2 were measured before and during insulin infusion in 89 young and 69 elderly monozygotic and dizygotic twins. Insulin action, and glucose and fat oxidation rates were determined using hyperinsulinemic euglycemic clamps and indirect calorimetry. Results: We demonstrated a genetic component in the control of plasma adiponectin and AdipoR1/R2 gene expression. Furthermore, levels of adiponectin and AdipoR1/R2 were influenced by age, sex, abdominal obesity, and aerobic capacity. Intrapair correlations in monozygotic twins indicated a nongenetic influence of birth weight on plasma adiponectin and AdipoR2 expression. Nonoxidative glucose metabolism was associated with AdipoR1 and plasma adiponectin, in young and elderly twins, respectively. In addition, plasma adiponectin was related to glucose and fat oxidation in younger subjects. Conclusions: Plasma adiponectin and muscle gene expression of its specific receptors are controlled by genetic and several specific nongenetic factors. The data suggest that the "adiponectin axis" plays a role in in vivo insulin action and nonoxidative glucose metabolism.
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