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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological studies have revealed a relationship between early growth restriction and the subsequent development of type 2 diabetes. A rat model of maternal protein restriction has been used to investigate the mechanistic basis of this relationship. This model causes insulin resistance and diabetes in adult male offspring. The aim of the present study was to determine the effect of early growth restriction on muscle insulin action in late adult life. Rats were fed either a 20% or an isocaloric 8% protein diet during pregnancy and lactation. Offspring were weaned onto a 20% protein diet and studied at 15 Months of age. Soleus muscle from growth restricted offspring (LP) (of dams fed 8% protein diet) had similar basal glucose uptakes compared with the control group (mothers fed 20% protein diet). Insulin stimulated glucose uptake into control muscle but had no effect on LP muscle. This impaired insulin action was not related to changes in expression of either the insulin receptor or glucose transporter 4 (GLUT 4). However, LP muscle expressed significantly less (P<0.001) of the zeta isoform of protein kinase C (PKC zeta) compared with controls. This PKC isoform has been shown to be positively involved in GLUT 4-mediated glucose transport. Expression levels of other isoforms (betaI, betaII, epsilon, theta) of PKC were similar in both groups. These results suggest that maternal protein restriction leads to muscle insulin resistance. Reduced expression of PKC zeta may contribute to the mechanistic basis of this resistance.
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PMID:Early growth restriction leads to down regulation of protein kinase C zeta and insulin resistance in skeletal muscle. 1274 11

Most obese individuals have elevated plasma levels of free fatty acids (FFA) which are known to cause peripheral (muscle) insulin resistance. They do this by inhibiting insulin-stimulated glucose uptake and glycogen synthesis. The mechanism involves intramyocellular accumulation of diacylglycerol and activation of protein kinase C. FFAs also cause hepatic insulin resistance. They do this by inhibiting insulin-mediated suppression of glycogenolysis. On the other hand, FFAs support between 30 and 50 % of basal insulin secretion and potentiate glucose-stimulated insulin secretion. The insulin stimulatory action of FFAs is responsible for the fact that the vast majority ( approximately 80 %) of obese insulin resistant people do not develop type 2 diabetes. They are able to compensate for their FFA mediated insulin resistance with increased FFA mediated insulin secretion. Individuals who are unable to do this (probably for genetic reasons) eventually develop type 2 diabetes. FFAs have recently been shown to activate the IkappaB/NFkappaB pathway which is involved in many inflammatory processes. Thus, elevated plasma levels of FFAs are not only a major cause of insulin resistance in skeletal muscle and liver but may, in addition, play a role in the pathogenesis of coronary artery disease.
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PMID:Effects of free fatty acids (FFA) on glucose metabolism: significance for insulin resistance and type 2 diabetes. 1278 83

Exposure to high concentrations of glucose and insulin results in insulin resistance of metabolic target tissues, a characteristic feature of type 2 diabetes. High glucose has also been associated with oxidative stress, and increased levels of reactive oxygen species have been proposed to cause insulin resistance. To determine whether oxidative stress contributes to insulin resistance induced by hyperglycemia in vivo, nondiabetic rats were infused with glucose for 6 h to maintain a circulating glucose concentration of 15 mM with and without coinfusion of the antioxidant N-acetylcysteine (NAC), followed by a 2-h hyperinsulinemic-euglycemic clamp. High glucose (HG) induced a significant decrease in insulin-stimulated glucose uptake [tracer-determined disappearance rate (Rd), control 41.2 +/- 1.7 vs. HG 32.4 +/- 1.9 mg. kg-1. min-1, P < 0.05], which was prevented by NAC (HG + NAC 45.9 +/- 3.5 mg. kg-1. min-1). Similar results were obtained with the antioxidant taurine. Neither NAC nor taurine alone altered Rd. HG caused a significant (5-fold) increase in soleus muscle protein carbonyl content, a marker of oxidative stress that was blocked by NAC, as well as elevated levels of malondialdehyde and 4-hydroxynonenal, markers of lipid peroxidation, which were reduced by taurine. In contrast to findings after long-term hyperglycemia, there was no membrane translocation of novel isoforms of protein kinase C in skeletal muscle after 6 h. These data support the concept that oxidative stress contributes to the pathogenesis of hyperglycemia-induced insulin resistance.
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PMID:N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress. 1279 18

Insulin resistance in type 2 diabetes is partly due to impaired glucose transport in skeletal muscle. Atypical protein kinase C (aPKC) and protein kinase B (PKB), operating downstream of phosphatidylinositol (PI) 3-kinase and its lipid product, PI-3,4,5-(PO(4))(3) (PIP(3)), apparently mediate insulin effects on glucose transport. We examined these signaling factors during hyperinsulinemic-euglycemic clamp studies in nondiabetic subjects, subjects with impaired glucose tolerance (IGT), and type 2 diabetic subjects. In nondiabetic control subjects, insulin provoked twofold increases in muscle aPKC activity. In both IGT and diabetes, aPKC activation was markedly (70-80%) diminished, most likely reflecting impaired activation of insulin receptor substrate (IRS)-1-dependent PI 3-kinase and decreased ability of PIP(3) to directly activate aPKCs; additionally, muscle PKC-zeta levels were diminished by 40%. PKB activation was diminished in patients with IGT but not significantly in diabetic patients. The insulin sensitizer rosiglitazone improved insulin-stimulated IRS-1-dependent PI 3-kinase and aPKC activation, as well as glucose disposal rates. Bicycle exercise, which activates aPKCs and stimulates glucose transport independently of PI 3-kinase, activated aPKCs comparably to insulin in nondiabetic subjects and better than insulin in diabetic patients. Defective aPKC activation contributes to skeletal muscle insulin resistance in IGT and type 2 diabetes, rosiglitazone improves insulin-stimulated aPKC activation, and exercise directly activates aPKCs in diabetic muscle.
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PMID:Activation of protein kinase C-zeta by insulin and phosphatidylinositol-3,4,5-(PO4)3 is defective in muscle in type 2 diabetes and impaired glucose tolerance: amelioration by rosiglitazone and exercise. 1288 7

In humans with obesity or type 2 diabetes, insulin target tissues are resistant to many actions of insulin. The atypical protein kinase C (PKC) isoforms lambda and zeta are downstream of phosphatidylinositol-3 kinase (PI3K) and are required for maximal insulin stimulation of glucose uptake. Phosphoinositide-dependent protein kinase-1 (PDK-1), also downstream of PI3K, mediates activation of atypical PKC isoforms and Akt. To determine whether impaired PKClambda/zeta or PDK-1 activation plays a role in the pathogenesis of insulin resistance, we measured the activities of PKClambda/zeta and PDK-1 in vastus lateralis muscle of lean, obese, and obese/type 2 diabetic humans. Biopsies were taken after an overnight fast and after a 3-h hyperinsulinemic-euglycemic clamp. Obese subjects were also studied after weight loss on a very-low-calorie diet. Insulin-stimulated glucose disposal rate is reduced 26% in obese subjects and 62% in diabetic subjects (both comparisons P < 0.001). Insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and PI3K activity are impaired 40-50% in diabetic subjects compared with lean or obese subjects. Insulin stimulates PKClambda/zeta activity approximately 2.3-fold in lean subjects; the increment above basal is reduced 57% in obese and 65% in diabetic subjects. PKClambda/zeta protein amount is decreased 46% in diabetic subjects but is normal in obese nondiabetic subjects, indicating impaired insulin action on PKClambda/zeta. Importantly, weight loss in obese subjects normalizes PKClambda/zeta activation and increases IRS-1 phosphorylation and PI3K activity. Insulin also stimulates PDK-1 activity approximately twofold with no impairment in obese or diabetic subjects. In contrast to our previous data on Akt, reduced insulin-stimulated PKClambda/zeta activity could play a role in the pathogenesis of insulin resistance in muscle of obese and type 2 diabetic subjects.
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PMID:Insulin-stimulated protein kinase C lambda/zeta activity is reduced in skeletal muscle of humans with obesity and type 2 diabetes: reversal with weight reduction. 1288 8

Recent data suggest that plasma leptin may represent a cardiovascular risk factor in diabetic patients. To gain further insight into the role of leptin in atherogenesis associated with diabetes, we investigated in the present study the role of this hormone in the regulation of macrophage lipoprotein lipase (LPL), a proatherogenic cytokine overexpressed in patients with type 2 diabetes. Treatment of human macrophages with leptin (1-10 nmol/l) increased LPL expression, at both the mRNA and protein levels. Pretreatment of these cells with anti-leptin receptor (Ob-R) antibody, protein kinase C (PKC) inhibitors, calphostin C, and GF109203X, or the antioxidant N-acetylcysteine (NAC) blocked the effects of leptin. Similar results were observed in leptin-treated J774 macrophages. In these cells, leptin increased the membrane expression of conventional PKC isoforms and downregulation of endogenous PKC expression abolished the effects of leptin on macrophage LPL expression. In leptin-treated J774 cells, enhanced LPL synthetic rate and increased binding of nuclear proteins to the activated protein-1 (AP-1) consensus sequence of the LPL gene promoter were also observed. This latter effect was abrogated by GF109203X. Overall, these data demonstrate that binding of leptin at the macrophage cell surface increases, through oxidative stress- and PKC-dependent pathways, LPL expression. This effect appears to be exerted at the transcriptional level and to involve AP-1 activation.
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PMID:Leptin increases lipoprotein lipase secretion by macrophages: involvement of oxidative stress and protein kinase C. 1288 31

We recently reported that physical exercise prevents the progression of type 2 diabetes mellitus in Psammomys obesus, an animal model of nutritionally induced type 2 diabetes mellitus. In the present study we characterized the effect of physical exercise on protein kinase C delta (PKC delta) activity, as a mediator of the insulin-signaling cascade in vivo. Three groups of Psammomys obesus were exposed to a 4-week protocol: high-energy diet (HE/C), high-energy diet and exercise (HE/EX), or low-energy diet (LE/C). None of the animals in the HE/EX group became diabetic, whereas all the animals in the HE/C group became diabetic. After overnight fast, intraperitoneal (IP) insulin (1U) caused a greater reduction in blood glucose levels in the HE/EX and LE/C groups compared to the HE/C group. Tyrosine phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and phosphatidylinositol 3 kinase (PI3 kinase) was significantly higher in the HE/EX and LE/C groups compared with the HE/C group. Finally, IR-associated PKC delta was higher in the HE/EX and LE/C groups compared to the HE/C group. Coprecipitation of PKC delta with IR was higher in the HE/EX and LE/C groups compared to the HE/C group. Thus, we suggest that 4 weeks of physical exercise results in improved insulin-signaling response in Psammomys obesus accompanied by a direct connection between PKC delta and IR. We conclude that this mechanism may be involved in the preventive effect of exercise on type 2 diabetes mellitus in Psammomys obesus.
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PMID:Physical exercise enhances protein kinase C delta activity and insulin receptor tyrosine phosphorylation in diabetes-prone psammomys obesus. 1289 68

Obesity is commonly associated with elevated plasma levels of free fatty acids (FFAs). High levels of FFA have emerged as a major link between obesity and insulin resistance/type 2 diabetes (T2DM). Thus, acute and chronic elevations of plasma FFAs produce insulin resistance in skeletal muscle and liver. In skeletal muscle, FFA-induced insulin resistance is associated with accumulation of intramyocellular triglyceride and diacylglycerol, and with activation of protein kinase C (the beta and delta isoforms). It is suggested that FFAs interfere with insulin signalling via PKC-induced serine phosphorylation of the insulin receptor substrate-1. In the liver, FFAs cause insulin resistance by interfering with insulin suppression of glycogenolysis. In beta-cells, FFAs potentiate glucose-stimulated insulin secretion acutely and chronically. It is postulated that this prevents the development of T2DM in most (>80%) obese insulin-resistant people who have FFA-mediated insulin resistance. Elevated levels of FFA also seem to activate a pro-inflammatory and pro-atherogenic pathway (the IkappaB/NFkappaB pathway) and may be responsible, at least in part, for the increase in atherosclerotic vascular disease seen in patients with T2DM. As increased plasma levels account for up to 50% of insulin resistance in obese patients with T2DM, lowering of plasma FFAs could be a new and promising approach to the treatment of T2DM.
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PMID:Nutritional effects of fat on carbohydrate metabolism. 1296 93

Sulfonylureas are drugs widely used in the treatment of patients with type 2 diabetes mellitus. In addition to their pancreatic effect of stimulating insulin secretion, many studies suggest that sulfonylureas also have extrapancreatic actions. We have previously reported that gliclazide, a second-generation sulfonylurea, stimulates the glucose uptake by rat hindquarter skeletal muscle directly and immediately by promoting the translocation of glucose transporter 4 to the plasma membrane. The aim of our study was to approach the gliclazide intracellular signaling pathway. For this purpose, we incubated clamped and isolated soleus muscle from rat with gliclazide. The following results were obtained: 1) gliclazide stimulates insulin receptor substrate (IRS)-1-phosphatidylinositol 3 (PI3)-kinase-associated activity, and this activity is necessary for gliclazide-stimulated glucose transport; 2) gliclazide treatment produces a gradual translocation of the diacylglycerol (DAG)-dependent isoforms protein kinase C (PKC) alpha, theta, and epsilon from cytosolic to membrane fraction that is dependent on PI3-kinase and phospholipase C (PLC)-gamma activation; and 3) PKC and PLC-gamma activation is necessary for gliclazide-stimulated glucose transport. We propose a hypothetical signaling pathway by which gliclazide could stimulate IRS-1 that would allow its association with PI3-kinase, promoting its activation. PI3-kinase products could induce PLC-gamma activation, whose hydrolytic activity could activate the DAG-dependent isoforms PKC alpha, theta, and epsilon.
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PMID:Phosphatidylinositol 3-kinase activation is required for sulfonylurea stimulation of glucose transport in rat skeletal muscle. 1456

Chronic exposure of pancreatic beta-cells to saturated fatty acids leads to loss of viability, an effect that has been implicated in the process of beta-cell 'lipotoxicity' associated with the progression of type 2 diabetes. The mechanisms involved are unknown but recent evidence has implicated the delta isoform of protein kinase C (PKCdelta) in mediating fatty acid toxicity. We have investigated this proposition in the clonal insulin-secreting cell line, BRIN-BD11. BRIN-BD11 cells were found to undergo apoptosis when exposed to palmitate and this response was attenuated by the purportedly selective inhibitor of PKCdelta, rottlerin. However, activation of PKCdelta with the phorbol ester, phorbol-12-myristate-13-acetate (PMA), failed to promote cell death and down-regulation of PKCdelta did not prevent the cytotoxic effects of palmitate. Moreover, rottlerin remained effective as a blocker of the palmitate response in cells depleted of PKCdelta. Since rottlerin can inhibit various other kinases in addition to PKCdelta, a range of additional kinase inhibitors was also tested. Of these, only the putative Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) inhibitor, KN-62, was found to inhibit palmitate-induced cell death. However, this effect was not reproduced by a more selective pseudo-substrate inhibitor of CaM kinase II. Therefore, the present results reveal that palmitate induces cell death in BRIN-BD11 cells and suggest that this may involve the activation of a rottlerin (and KN-62)-sensitive kinase. However, it is clear that PKCdelta is not required for this response.
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PMID:Evidence that protein kinase Cdelta is not required for palmitate-induced cytotoxicity in BRIN-BD11 beta-cells. 1476 4


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