| 1. |
- Huang, Xudong, et al.
(author)
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Down-regulation of insulin receptor substrates (IRS)-1 and IRS-2 and Src homologous and collagen-like protein Shc gene expression by insulin in skeletal muscle is not associated with insulin resistance or type 2 diabetes.
- 2002
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In: Journal of Clinical Endocrinology and Metabolism. - 1945-7197. ; 87:1, s. 255-259
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Journal article (peer-reviewed)abstract
- To examine whether altered gene expression of insulin receptor substrates (IRS)-1 and IRS-2 and Src homologous and collagen-like protein Shc is an inherited trait and is associated with muscle insulin resistance or type 2 diabetes, we measured mRNA levels of these genes by a relative quantitative RT-PCR method in muscle biopsies taken before and after an insulin clamp from 12 monozygotic twin pairs discordant for type 2 diabetes and 12 control subjects. Insulin-stimulated glucose uptake was decreased both in the diabetic and nondiabetic twin, compared with healthy control subjects (5.2 +/- 0.7 and 8.5 +/- 0.8 vs. 11.4 +/- 0.9 mg/kg x min(-1); P < 0.01 and P < 0.02, respectively). Basal mRNA levels of IRS-1, IRS-2, and Shc were similar in the diabetic and nondiabetic twins as well as in the control subjects. Insulin decreased mRNA expression of IRS-1 by 72% (from 0.75 +/- 0.06 to 0.21 +/- 0.04 relative units; P < 0.001), IRS-2 by 71% (from 0.55 +/- 0.10 to 0.16 +/- 0.08 relative units; P < 0.03), and Shc by 25% (from 0.95 +/- 0.04 to 0.71 +/- 0.04 relative units; P < 0.01) vs. baseline as demonstrated in the control subjects. The postclamp Shc mRNA level was slightly higher in the diabetic twins (P = 0.05) but similar in the nondiabetic twins, as compared with the control subjects, whereas postclamp IRS-1 and IRS-2 mRNA levels were similar between the study groups. There was an inverse correlation between postclamp Shc mRNA concentration and glucose uptake (r = -0.53, P = 0.01; n = 22) in the controls and nondiabetic twins. However, the decrease in Shc gene expression by insulin was not significantly different between the study groups. In conclusion, because insulin down-regulates IRS-1, IRS-2, and Shc gene expression in skeletal muscle in diabetic and nondiabetic monozygotic twins and control subjects to the same extent, it is unlikely that expression of these genes is an inherited trait or contributes to skeletal muscle insulin resistance.
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| 2. |
- Huang, Xudong, et al.
(author)
-
Impaired cathepsin L gene expression in skeletal muscle is associated with type 2 diabetes.
- 2003
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 52:9, s. 2411-2418
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Journal article (peer-reviewed)abstract
- To identify abnormally expressed genes associated with muscle insulin resistance or type 2 diabetes, we screened the mRNA populations using cDNA differential display combined with relative RT-PCR analysis from muscle biopsies of diabetes-prone C57BL/6J and diabetes-resistant NMRI mice fed with a high-fat or normal diet for 3 or 15 months. Six abnormally expressed genes were isolated from the mice after a 3-month fat feeding; one of them was cathepsin L. No significant difference in mRNA levels of these genes was observed between fat- and normal-diet conditions in either strains. However, cathepsin L mRNA levels in muscle were higher in normal diet–fed C57BL/6J mice compared with normal diet–fed NMRI mice at 3 months (0.72 ± 0.04 vs. 0.51 ± 0.04 relative units, P < 0.01, n = 8–10) and at 15 months (0.41 ± 0.05 vs. 0.27 ± 0.04 relative units, P = 0.01, n = 9–10). Further, cathepsin L mRNA levels in muscle correlated inversely with plasma glucose in both strains regardless of diets at 3 (r = −0.49, P < 0.01, n = 31) and 15 (r = −0.42, P = 0.007, n = 39) months. To study whether cathepsin L plays a role in human diabetes, we measured cathepsin L mRNA levels in muscle biopsies taken before and after an insulin clamp from 12 monozygotic twin pairs discordant for type 2 diabetes and from 12 control subjects. Basal cathepsin L mRNA levels were not significantly different between the study groups. Insulin infusion increased cathepsin L mRNA levels in control subjects from 1.03 ± 0.30 to 1.90 ± 0.32 relative units (P = 0.03). Postclamp cathepsin L mRNA levels were lower in diabetic twins but similar in nondiabetic twins compared with control subjects (0.66 ± 0.22, 1.16 ± 0.18 vs. 1.38 ± 0.21 relative units, P < 0.02, NS, respectively). Further, postclamp cathepsin L mRNA levels were correlated with insulin-mediated glucose uptake (r = 0.37, P = 0.03), particularly, with glucose oxidation (r = 0.37, P = 0.03), and fasting glucose concentrations (r = −0.45, P < 0.01) across all three study groups. In conclusion, muscle cathepsin L gene expression is increased in diabetes-prone mice and related to glucose tolerance. In humans, insulin-stimulated cathepsin L expression in skeletal muscle is impaired in diabetic but not in nondiabetic monozygotic twins, suggesting that the changes may be secondary to impaired glucose metabolism.
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| 3. |
- Ling, Charlotte, et al.
(author)
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Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins.
- 2004
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In: Journal of Clinical Investigation. - 0021-9738. ; 114:10, s. 1518-1526
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Journal article (peer-reviewed)abstract
- Genetic and environmental factors contribute to age-dependent susceptibility to type 2 diabetes. Recent studies have reported reduced expression of PPAR{gamma} coactivator 1{alpha} (PGC-1{alpha}) and PGC-1ß genes in skeletal muscle from type 2 diabetic patients, but it is not known whether this is an inherited or acquired defect. To address this question we studied expression of these genes in muscle biopsies obtained from young and elderly dizygotic and monozygotic twins without known diabetes before and after insulin stimulation and related the expression to a Gly482Ser variant in the PGC-1{alpha} gene. Insulin increased and aging reduced skeletal muscle PGC-1{alpha} and PGC-1ß mRNA levels. This age-dependent decrease in muscle gene expression was partially heritable and influenced by the PGC-1{alpha} Gly482Ser polymorphism. In addition, sex, birth weight, and aerobic capacity influenced expression of PGC-1{alpha} in a complex fashion. Whereas expression of PGC-1{alpha} in muscle was positively related to insulin-stimulated glucose uptake and oxidation, PGC-1ß expression was positively related to fat oxidation and nonoxidative glucose metabolism. We conclude that skeletal muscle PGC-1{alpha} and PGC-1ß expression are stimulated by insulin and reduced by aging. The data also suggest different regulatory functions for PGC-1{alpha} and PGC-1ß on glucose and fat oxidation in muscle cells. The finding that the age-dependent decrease in the expression of these key genes regulating oxidative phosphorylation is under genetic control could provide an explanation by which an environmental trigger (age) modifies genetic susceptibility to type 2 diabetes.
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| 4. |
- Ridderstråle, Martin, et al.
(author)
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FOXC2 mRNA Expression and a 5' Untranslated Region Polymorphism of the Gene Are Associated With Insulin Resistance.
- 2002
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 51:12, s. 3554-3560
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Journal article (peer-reviewed)abstract
- The human transcription factor FOXC2 has recently been shown to protect against diet-induced insulin resistance in transgenic mice. We investigated the expression of FOXC2 in fat and muscle and performed a genetic analysis in human subjects. FOXC2 mRNA levels were increased in visceral compared with subcutaneous fat from obese subjects (12 ± 4-fold; P = 0.0001), and there was a correlation between whole-body insulin sensitivity and FOXC2 mRNA levels in visceral fat (fS-insulin R = −0.64, P = 0.01, and homeostasis model assessment of insulin resistance [HOMA-IR] R = −0.68, P = 0.007) and skeletal muscle (fS-insulin R = −0.57, P = 0.03, and HOMA-IR R = −0.55, P = 0.04). Mutation screening of the FOXC2 gene identified a common polymorphism in the 5′ untranslated region (C-512T). The T allele was associated with enhanced insulin sensitivity (HOMA-IR P = 0.007) and lower plasma triglyceride levels in females (P = 0.007). Also, the higher expression of FOXC2 in visceral than in subcutaneous fat was restricted to subjects homozygous for the T allele (P = 0.03 vs. P = 0.7). Our data suggest that increased FOXC2 expression may protect against insulin resistance in human subjects and that genetic variability in the gene may influence features associated with the metabolic syndrome.
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