Enhanced Basal Activation of Mitogen-Activated Protein Kinases in Adipocytes From Type 2 Diabetes

Abstract

Serine and threonine kinases may contribute to insulin resistance and the development of type 2 diabetes. To test the potential for members of the mitogen-activated protein (MAP) kinase family to contribute to type 2 diabetes, we examined basal and insulin-stimulated Erk 1/2, JNK, and p38 phosphorylation in adipocytes isolated from healthy and type 2 diabetic individuals. Maximal insulin stimulation increased the phosphorylation of Erk 1/2 and JNK in healthy control subjects but not type 2 diabetic patients. Insulin stimulation did not increase p38 phosphorylation in either healthy control subjects or type 2 diabetic patients. In type 2 diabetic adipocytes, the basal phosphorylation status of these MAP kinases was significantly elevated and was associated with decreased IRS-1 and GLUT4 in these fat cells. To determine whether MAP kinases were involved in the downregulation of IRS-1 and GLUT4 protein levels, selective inhibitors were used to inhibit these MAP kinases in 3T3-L1 adipocytes treated chronically with insulin. Inhibition of Erk 1/2, JNK, or p38 had no effect on insulin-stimulated reduction of IRS-1 protein levels. However, inhibition of the p38 pathway prevented the insulin-stimulated decrease in GLUT4 protein levels. In summary, type 2 diabetes is associated with an increased basal activation of the MAP kinase family. Furthermore, upregulation of the p38 pathway might contribute to the loss of GLUT4 expression observed in adipose tissue from type 2 diabetic patients. Diabetes 52:634 -641, 2003

Reduced insulin-stimulated GLUT4 bioavailability in stroke-prone spontaneously hypertensive rats

“…It is unlikely, however, that aberrant insulin-stimulated p38MAPK activity underlies this. Increased expression of p38MAPK has been reported in adipocytes from patients with type 2 diabetes compared with healthy controls [18]. Although there was a tendency for increased p38MAPK expression in SHRSP animals, this did not reach significance in the current study.…”

“…In 3T3-L1 adipocytes, insulin has been demonstrated to stimulate p38MAPK phosphorylation (a measure of activity) [18,19]. However, insulin had no effect on p38MAPK phosphorylation in human adipocytes from healthy subjects or patients with type 2 diabetes [18]. Insulin had no effect on p38MAPK phosphorylation in either rat strain in the current study.…”

“…Furthermore, p38MAPK has been proposed as a candidate that mediates insulin stimulation of GLUT4 intrinsic activity [13]. In 3T3-L1 adipocytes, insulin has been demonstrated to stimulate p38MAPK phosphorylation (a measure of activity) [18,19]. However, insulin had no effect on p38MAPK phosphorylation in human adipocytes from healthy subjects or patients with type 2 diabetes [18].…”

Insulin activates hypoxia-inducible factor-1α in human and rat vascular smooth muscle cells via phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways: impairment in insulin resistance owing to defects in insulin signalling

“…In particular arterial perfusion of the gastrocnemious muscle with insulin induced a significantly greater ERK-2 activation in lean than in obese Zucker rats [36]; in vitro incubation with insulin of the skeletal muscles extensor digitorum longus and soleus induced a significantly greater phosphorylation of ERK-1/2 and JNK in muscle isolated from lean than in muscle from ob/ob mice [29]; and a 15-min insulin stimulation increased ERK-1/2 and JNK phosphorylation in adipocytes isolated from healthy subjects but not in adipocytes from type 2 diabetic patients [37]. The 'selectivity' of insulin resistance, therefore, appears to be specific for some cell types and strictly dependent on the experimental conditions employed, such as the animal model.…”

Hyperinsulinemia and insulin resistance in Wrn null mice fed a diabetogenic diet

“…However, it is unclear what role p38MAPK may play in adipogenesis. It is known that p38MAPK is highly expressed in adipocytes from patients with type 2 diabetes (Carlson et al, 2003). It has also been demonstrated that 3T3-L1 preadipocyte cell cultures treated with a p38MAPK inhibitor (SB203580) do not differentiate, suggesting that p38MAPK may be necessary for the maturation of preadipocytes.…”