Defective regulation of phosphatidylinositol-3-kinase gene expression in skeletal muscle and adipose tissue of non-insulin-dependent diabetes mellitus patients

Abstract

Despite intensive efforts, the nature of the molecular defects leading to the development of Type II (noninsulin-dependent) diabetes mellitus is poorly understood. Whereas both alterations in insulin secretion and action are involved in established diabetes [1,2], it has been suggested that defects in insulin action precede the onset of the disease [3]. There is good evidence that insulin resistance in Type II diabetes is dependent, at least in part, on genetic factors [4,5]. The mutations identified so far in the sequences of candidate genes can, however, explain only a small proportion of the different forms of Type II diabetes [5]. Changes in biological functions in response to environmental factors are also involved in the development of the disease [4]. The modulation of the expression of specific key genes is one of the main mechanisms for changing biological function in response to the environment. Several lines of evidence indicate that the expression of some important genes in insulin action is abnormal in peripheral tissues in the common form of Type II diabetes. For example, the basal concentration of the insulin sensitive glu- Diabetologia (1999) Summary We investigated the regulation of the mRNA expression of the insulin receptor, insulin receptor substrate-1 (IRS-1) and p85a-phosphatidylinositol-3-kinase (PI-3K), three major actors of insulin action, in skeletal muscle from 10 healthy lean volunteers, 13 obese patients with Type II (non-insulindependent) diabetes mellitus and 7 non-diabetic obese subjects. The in vivo regulation by insulin was studied using a 3-h euglycaemic, hyperinsulinaemic clamp. There were no differences in the basal concentrations of the three mRNAs in skeletal muscle between groups. Insulin infusion produced a twofold reduction in insulin receptor substrate-1 mRNA expression in the three groups (p < 0.02). In contrast, insulin increased p85a-phosphatidylinositol-3-kinase mRNA expression in muscle from non-diabetic subjects ( + 98 ± 22 % in lean and + 127 ± 16 % in obese, p < 0.02) but this effect was totally impaired in Type II diabetic patients ( + 5 ± 12 %, NS). A similar defect in insulin action on p85a-phosphatidylinositol-3-kinase mRNA expression was observed in abdominal subcutaneous adipose tissue ( + 138 ± 25 %, p < 0.01 in lean and + 46 ± 14 %, p < 0.02 in obese and + 29 ± 11 %, NS in Type II diabetic patients). The lack of action of insulin on p85a-phosphatidylinositol-3-kinase mRNA in diabetic subjects was probably not due to a deleterious effect of hyperglycaemia since improvement of the glycaemic control for 10 days did not restore the response in muscle or in adipose tissue. This study provides evidence for a defect in the regulation by insulin of PI-3K gene expression in Type II diabetic patients, thus reinforcing the concept that alterations at the gene expression might be involved in the pathogeny of Type II diabetes. [Diabetologia (1999)

Regulation by Insulin of Gene Expression in Human Skeletal Muscle and Adipose Tissue

“…Moreover, it has been reported that the induction of GLUT4 (20,21) and hexokinase II (22) expression in response to hyperinsulinemia is impaired in skeletal muscle of type 2 diabetic patients. Recently, we have demonstrated that the regulation by insulin of the p85␣ regulatory subunit of PI3K (p85␣PI3K) is also altered in muscle and adipose tissue of patients with type 2 diabetes (23). Taken together, these data suggest that the regulation of a cluster of genes involved in insulin action and glucose metabolism may be affected in type 2 diabetes.…”

“…None of the obese subjects had impaired glucose tolerance as assessed by classic oral glucose tolerance test. The metabolic data of some of these subjects (all of the control and type 2 diabetic subjects and six of the nine obese patients) have been presented in a previous study (23). An unrelated group of healthy subjects (seven women and one man, age 25 Ϯ 1 years, BMI 22 Ϯ 1 kg/m 2 ) served as control subjects for a group of type 1 diabetic patients (five women and four men, age 33 Ϯ 3 years, BMI 23 Ϯ 1 kg/m 2 , duration of diabetes 16 Ϯ 3 years, C-peptide Ͻ0.05 ng/ml) with HbA 1c (9.2 Ϯ 0.3%) similar to that in the type 2 diabetic subjects (10.9 Ϯ 0.3%, P ϭ 0.252).…”

“…Moreover, in most of the studies, the regulation of one individual gene was investigated, although we have reported the regulation of three mRNAs (insulin receptor, IRS-1, and p85␣PI3K) in parallel (23). It is thus difficult to conclude whether the same mechanism is involved in the defective regulation of GLUT4, hexokinase II, and p85␣PI3K gene expression.…”

Fatty Aldehyde Dehydrogenase

“…Moreover, altered insulin action, often characterized by a deregulation of the PI3K cascade, is found in both diabetic and obese subjects (17)(18)(19). This pathway mediates also the effects of insulin on glucose and lipid homeostasis by controlling the expression of a series of genes (34).…”

Insulin signal transduction and glucose transport in human adipocytes: effects of obesity and low calorie diet

“…Mice with a targeted disruption of the gene encoding the p85α regulatory subunit of PI 3-kinase show increased insulin sensitivity and hypoglycaemia, due to increased glucose uptake in skeletal muscle and adipocytes via signalling through the p50α alternative splice variant of the p85α gene [26]. The mRNA expression of p85α has been reported to be similar in adipose tissue from lean versus obese humans [27]. However in our study, protein expression of the p85α regulatory subunit of PI 3-kinase was reduced by 55% in adipocytes from obese women.…”