Mechanism of the mitogenic influence of hyperinsulinemia

Either endogenous or exogenous hyperinsulinemia in the setting of insulin resistance promotes phosphorylation and activation of farnesyltransferase, a ubiquitous enzyme that farnesylates Ras protein. Increased availability of farnesylated Ras at the plasma membrane enhances mitogenic responsiveness of cells to various growth factors, thus contributing to progression of cancer and atherosclerosis. This effect is specific to insulin, but is not related to the type of insulin used. Stimulatory effect of hyperinsulinemia on farnesyltransferase in the presence of insulin resistance represents one potential mechanism responsible for mitogenicity and atherogenicity of insulin

Early responses of insulin signaling to high-carbohydrate and high-fat overfeeding

<p>Abstract</p> <p>Background</p> <p>Early molecular changes of nutritionally-induced insulin resistance are still enigmatic. It is also unclear if acute overnutrition alone can alter insulin signaling in humans or if the macronutrient composition of the diet can modulate such effects.</p> <p>Methods</p> <p>To investigate the molecular correlates of metabolic adaptation to either high-carbohydrate (HC) or high-fat (HF) overfeeding, we conducted overfeeding studies in 21 healthy lean (BMI < 25) individuals (10 women, 11 men), age 20-45, with normal glucose metabolism and no family history of diabetes. Subjects were studied first following a 5-day eucaloric (EC) diet (30% fat, 50% CHO, 20% protein) and then in a counter balanced manner after 5 days of 40% overfeeding of both a HC (20% fat, 60% CHO) diet and a HF (50% fat, 30% CHO) diet. At the end of each diet phase, <it>in vivo </it>insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp technique. <it>Ex vivo </it>insulin action was measured from skeletal muscle tissue samples obtained 15 minutes after insulin infusion was initiated.</p> <p>Results</p> <p>Overall there was no change in whole-body insulin sensitivity as measured by glucose disposal rate (GDR, EC: 12.1 ± 4.7; HC: 10.9 ± 2.7; HF: 10.8 ± 3.4). Assessment of skeletal muscle insulin signaling demonstrated increased tyrosine phosphorylation of IRS-1 (p < 0.001) and increased IRS-1-associated phosphatidylinositol 3 (PI 3)-kinase activity (p < 0.001) following HC overfeeding. In contrast, HF overfeeding increased skeletal muscle serine phosophorylation of IRS-1 (p < 0.001) and increased total expression of p85α (P < 0.001).</p> <p>Conclusion</p> <p>We conclude that acute bouts of overnutrition lead to changes at the cellular level before whole-body insulin sensitivity is altered. On a signaling level, HC overfeeding resulted in changes compatible with increased insulin sensitivity. In contrast, molecular changes in HF overfeeding were compatible with a reduced insulin sensitivity.</p

Increasing Dietary Fat Elicits Similar Changes in Fat Oxidation and Markers of Muscle Oxidative Capacity in Lean and Obese Humans

In lean humans, increasing dietary fat intake causes an increase in whole-body fat oxidation and changes in genes that regulate fat oxidation in skeletal muscle, but whether this occurs in obese humans is not known. We compared changes in whole-body fat oxidation and markers of muscle oxidative capacity differ in lean (LN) and obese (OB) adults exposed to a 2-day high-fat (HF) diet. Ten LN (BMI = 22.5±2.5 kg/m2, age = 30±8 yrs) and nine OB (BMI = 35.9±4.93 kg/m2, 38±5 yrs, Mean±SD) were studied in a room calorimeter for 24hr while consuming isocaloric low-fat (LF, 20% of energy) and HF (50% of energy) diets. A muscle biopsy was obtained the next morning following an overnight fast. 24h respiratory quotient (RQ) did not significantly differ between groups (LN: 0.91±0.01; OB: 0.92±0.01) during LF, and similarly decreased during HF in LN (0.86±0.01) and OB (0.85±0.01). The expression of pyruvate dehydrogenase kinase 4 (PDK4) and the fatty acid transporter CD36 increased in both LN and OB during HF. No other changes in mRNA or protein were observed. However, in both LN and OB, the amounts of acetylated peroxisome proliferator-activated receptor γ coactivator-1-α (PGC1-α) significantly decreased and phosphorylated 5-AMP-activated protein kinase (AMPK) significantly increased. In response to an isoenergetic increase in dietary fat, whole-body fat oxidation similarly increases in LN and OB, in association with a shift towards oxidative metabolism in skeletal muscle, suggesting that the ability to adapt to an acute increase in dietary fat is not impaired in obesity

1254-1262 interact with particulate PSPases

Abstract We have examined the regulation of GLUT4 phosphorylation in adipocytes isolated from diabetic rats. Despite progressive (40-70%) reductions in GLUT4 protein contents on the 2nd, 7th, and 14th day of diabetes, the phosphorylation of GLUT4 was increased two-to fourfold. These alterations were accompanied by concomitant reductions (40-66%) in the insulin-stimulated 2-deoxyglucose transport. Insulin treatment of diabetic animals for 5 d restored glucose transport activity, GLUT4 protein, and GLUT4 phosphorylation to control levels whereas vanadate and phlorizin were ineffective. In control adipocytes, insulin promoted GLUT4 translocation from the low density microsomal (LDM) pool to the plasma membranes (PM) and decreased the state of GLUT4 phosphorylation. In adipocytes isolated from the diabetic rats, insulin failed to stimulate GLUT4 translocation and to decrease GLUT4 phosphorylation. To explore the mechanism of the diabetes-induced increases in the GLUT4 phosphorylation, we investigated phosphoserine phosphatase (PSPase) activities using 32P-labeled GLUT4 and phosphorylase &quot;a&quot; as substrates. Diabetes resulted in 50-60% increase in the particulate PSPase activity and concomitant reductions in cytosolic PSPase activities. Although reduced cytosolic PSPase activity correlated with an inadequate dephosphorylation of LDM GLUT4, the existence of highly phosphorylated PM GLUT4 in the presence of increased particulate PSPase activity required additional explanation. To address this problem, we used PM GLUT4 from diabetic rats as a substrate of particulate PSPase. Highly active diabetic particulate PSPase, which dephosphorylated control GLUT4 and phosphorylase a, failed to dephosphorylate PM GLUT4 from diabetic rats. These data suggest that PM GLUT4 from diabetic rats is unable to interact with PSPase or that its phosphorylation sites are not accessible to PSPase action. In summary, an induction of diabetes with streptozotocin resulted in significant increases in GLUT4 phosphorylation. In contrast to normal cells, insulin failed to promote GLUT4 recruitment to the plasma membranes and its dephosphorylation in diabetic adipocytes. At the same time, diabetes appears to induce redistribution of PSPases, resulting in lower cytosolic activity and higher particulate activity. It also appears that the existence of highly phosphorylated GLUT4 in the plasma membranes of diabetic adipocytes resulted from its inability t

A Century of Diabetes Success: The Past as Prologue

On the anniversary of the discovery of insulin, experts reflect on how much progress has been made to treat and manage diabetes—and how much more is necessary

A Unique Control Mechanism in the Regulation of Insulin Secretion Secretagogue-induced Somatostatin Receptor Recruitment

In this study, we have correlated the translocation of somatostatin (SRIF) receptors from the cell interior to the plasma membrane with the ability of SRIF to inhibit insulin release