Gene Expression Profile in Skeletal Muscle of Type 2 Diabetes and the Effect of Insulin Treatment

Abstract

Type 2 diabetes is characterized by muscle insulin resistance. Nondiabetic first-degree relatives of type 2 diabetic patients have also been reported to have insulin resistance. A polygenic basis for pathogenesis of type 2 diabetes has been proposed. A gene expression profile was evaluated in the skeletal muscle of patients with type 2 diabetes while not on treatment for 2 weeks and after 10 days of intensive insulin treatment. Comparison of gene expression pattern with age-, sex-, and BMI-matched people with no family history of diabetes was performed using a microarray technique (Hu6800 arrays; Affymetrix, Santa Clara, CA). Only those gene transcripts showing >1.9-fold changes and an average difference in fluorescence intensity of >1,000 in all subjects are reported. Insulin sensitivity (SI) was measured using an intravenous glucose tolerance test. Of 6,451 genes surveyed, transcriptional patterns of 85 genes showed alterations in the diabetic patients after withdrawal of treatment, when compared with patterns in the nondiabetic control subjects. Insulin treatment reduced the difference in patterns between diabetic and nondiabetic control subjects (improved) in all but 11 gene transcripts, which included genes involved in structural and contractile functions, growth and tissue development, stress response, and energy metabolism. These improved transcripts included genes involved in insulin signaling, transcription factors, and mitochondrial maintenance. However, insulin treatment altered the transcription of 29 additional genes involved in signal transduction; structural and contractile functions; growth and tissue development; and protein, fat, and energy metabolism. Type 2 diabetic patients had elevated circulating insulin during the insulin-treated phase, although their blood glucose levels (98.8 ؎ 6.4 vs. 90.0 ؎ 2.9 mg/dl for diabetic vs. control) were similar to those of the control subjects. In contrast, after withdrawal of treatment, the diabetic patients had reduced SI and elevated blood glucose (224.0 ؎ 26.2 mg/dl), although their insulin levels were similar to those of the nondiabetic control subjects. This study identified several candidate genes for muscle insulin resistance, complications associated with poor glycemic control, and effects of insulin treatment in people with type 2 diabetes. Diabetes

Proteome Analysis Reveals Phosphorylation of ATP Synthase β-Subunit in Human Skeletal Muscle and Proteins with Potential Roles in Type 2 Diabetes

“…In addition, HSP 90␤ has been shown to play an important role in maintaining the activity of protein kinase B (47), which seems to be involved in the regulation of insulin-mediated glucose transport and glycogen synthesis, two processes shown to be impaired in T2DM (1). Consistent with our data, mRNA expression of a heat shock protein (HSP 70) was found to be increased in skeletal muscle of patients with T2DM both before and after withdrawal of insulin treatment (31). Further studies are needed to establish what specific roles increased levels of certain stress proteins such as HSP 90␤, GRP78, and HSP 70 play in the pathogenesis of insulin resistance in muscle of patients with T2DM.…”

Age‐related changes in miR‐143‐3p:Igfbp5 interactions affect muscle regeneration

“…Interestingly, increased expression of Igfbp5 and other Igfbps in the muscle has been demonstrated in other than aging scenarios, for example in diabetes also associated with changes in IL‐6 levels (Sreekumar et al ., 2002). miR‐143 expression is, however, not affected in this model.…”

Genes for systemic vascular complications are differentially expressed in the livers of Type 2 diabetic patients

“…For example, up-regulation of Rad (a Ras-oncogene associated with diabetes), heat shock 70kD protein, and receptors for PDGF and endothelin, and down-regulation of general transcription and translation factors, and of cadherin and MHC have been observed in the skeletal muscle of insulin-resistant Pima Indians [7] and in Type 2 diabetic patients [8]. In addition, up-regulation of epidermal growth factor receptor and down-regulation of fatty acid-associated enzymes, fibronectin, VCAM1, MHC, plasminogen, SOD2, FMO5 and complement C3 have been observed in the liver of ob/ob mice [10,11,12].…”

“…We have already used cDNA microarrays, consisting of 1080 human cDNAs, to characterise alterations that occur in various liver diseases [5,6]. More recently, microarray profiling of skeletal muscle tissue of Type 2 diabetic patients [7,8] and of healthy humans treated with insulin [9] has been reported. Although the liver is central for glucose homeostasis, microarray profiling of diabetic liver has been done only in Ob/Ob mice, a genetically obese rodent model of diabetes [10,11,12].…”