Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance of skeletal muscle is fundamental to both syndrome X and its frequent sequel, type II diabetes. In these disorders, excessive exposure of muscle to free fatty acids (FFAs) and their metabolic derivatives appears to play a prominent role in the induction of insulin resistance. Recent evidence suggests that activation of novel isoforms of protein kinase C (PKC) by diacylglycerol may mediate at least part of the adverse impact of FFAs on muscle insulin sensitivity. Vitamin E and fish oil omega-3s, by promoting the activity of diacylglycerol kinase and inhibiting that of phosphatidate phosphohydrolase, should reduce diacylglycerol levels, thus accounting for their documented favorable impact on insulin sensitivity. Thiazolidinediones such as troglitazone, on the other hand, appear to intervene in the signaling pathway whereby PKC down-regulates insulin function. The insulin-sensitizing activity of chromium picolinate may be attributable, at least in part, to increased expression of insulin receptors. In combination with lifestyle modifications which reduce FFA exposure--weight loss, very-low-fat eating, excessive training--these measures can be expected to work in a complementary way to promote increased numbers of insulin receptors that are more functionally competent. As these measures appear to be safe and well-tolerated, they may have utility for the prevention of diabetes as well as its therapy. When they do not prove sufficient to achieve optimal glycemic control, excessive hepatic glucose output and impaired cell response to glucose can be addressed with metformin and sulfonylureas, respectively. The prospects for a rational medical management of type II diabetes, obviating the need for injectible insulin, have never been brighter.
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PMID:Complementary measures for promoting insulin sensitivity in skeletal muscle. 1005 64

There is now much interest in the mechanisms by which altered lipid metabolism might contribute to insulin resistance as is found in Syndrome X or in Type II diabetes. This review considers recent evidence obtained in animal models and its relevance to humans, and also likely mechanisms and strategies for the onset and amelioration of insulin resistance. A key tissue for development of insulin resistance is skeletal muscle. Animal models of Syndrome X (eg high fat fed rat) exhibit excess accumulation of muscle triglyceride coincident with development of insulin resistance. This seems to also occur in humans and several studies demonstrate increased muscle triglyceride content in insulin resistant states. Recently magnetic resonance spectroscopy has been used to demonstrate that at least some of the lipid accumulation is inside the muscle cell (myocyte). Factors leading to this accumulation are not clear, but it could derive from elevated circulating free fatty acids, basal or postprandial triglycerides, or reduced muscle fatty acid oxidation. Supporting a link with adipose tissue metabolism, there appears to be a close association of muscle and whole body insulin resistance with the degree of abdominal obesity. While causal relationships are still to be clearly established, there are now quite plausible mechanistic links between muscle lipid accumulation and insulin resistance, which go beyond the classic Randle glucose-fatty acid cycle. In animal models, dietary changes or prior exercise which reduce muscle lipid accumulation also improve insulin sensitivity. It is likely that cytosolic accumulation of the active form of lipid in muscle, the long chain fatty acyl CoAs, is involved, leading to altered insulin signalling or enzyme activities (eg glycogen synthase) either directly or via chronic activation of mediators such as protein kinase C. Unless there is significant weight loss, short or medium term dietary manipulation does not alter insulin sensitivity as much in humans as in rodent models, and there is considerable interest in pharmacological intervention. Studies using PPARgamma receptor agonists, the thiazolidinediones, have supported the principle that reduced muscle lipid accumulation is associated with increased insulin sensitivity. Other potent systemic lipid-lowering agents such as PPARalpha receptor agonists (eg fibrates) or antilipolytic agents (eg nicotinic acid analogues) might improve insulin sensitivity but further work is needed, particularly to clarify implications for muscle metabolism. In conclusion, evidence is growing that excess muscle and liver lipid accumulation causes or exacerbates insulin resistance in Syndrome X and in Type II diabetes; development of strategies to prevent this seem very worthwhile.
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PMID:Triglycerides, fatty acids and insulin resistance--hyperinsulinemia. 1145 39

Non-alcoholic steatohepatitis (NASH) is one of the most common liver disorders. This is highly prevalent in obese and diabetic subjects. Persons with central obesity are at particular risk. Other clinical predictors are age more than 40-50 years and hyperlipidemias, but none of these factors is invariable for causation of NASH. Other reported associations are, celiac disease, Wilson's Disease and few other metabolic diseases. Drugs, particularly amiodarone, tamoxifen, nucleoside analogues and methotrxate have also been linked to NASH. The disease is evenly distributed in both sexes but advanced disease is more common in women. Ethnic variation exists and African Americans are less affected than Hispanic Americans. Specific clinical features of NASH are infrequent. Patients usually come to clinical attention by elevated liver enzymes found on routine evaluation but on history, about two third of patients will admit to have mild fatigue and about half will report right upper quadrant pain. Rarely, patient may present with a complication of cirrhosis. Physical examination may reveal hepatomegaly and splenomegaly. Research in last few years has stressed that development of steatosis, stetohepatitis, fibrosis with subsequent cirrhosis are most probably the result of insulin resistance. Therefore, clinical features may reflect existence of insulin resistance. Obesity, particularly central obesity is most important of these. Patients may have sleep apnea syndrome. Hypertension and manifestations of diabetes mellitus like polyuria, polydypsia, and neurological deficits may occur. Patients may have varying combination of obesity, diabetes, hyperlipidemia, hypertension and impaired fibrinolysis (syndrome X). Children with insulin resistance may show acanthosis nigricance. Patients with polycystic ovary syndrome, which consists of insulin resistance, diabetes, obesity, hirsutism, oligo or polymenorrha and hyperlipidemia may have NASH. Other rare manifestations of insulin resistance, which can be seen in patients of NASH are lipomatosis, lipoatrophy/lipodystrophy and panniculitis. Most other rare conditions known to cause NASH like peroxisomal diseases, mitochondialpathies, Weber-Christian disease, Mauriac syndrome, Madelung's lipomatosis and abetaliopprotenemia also have insulin resistance. This is believed that primary defect underlying insulin resistance is impairment in postreceptor pathways (through tyrosine kinase activity) of insulin action. Primary defect in insulin receptors appear uncommon. This results in down regulation of insulin receptor substance 1 (IRS-1) signaling by excess free fatty acids. In muscle, activated IRS-1 promotes translocation of glucose transporter protein 4 (GLUT4) to cell membrane. As a result, monocyte glucose uptake by GLUT4 increases glucose disposal from blood and reduced need for insulin. PKC-0 is a likely candidate as serine kinase in muscle regulated by fatty acids that can impair the activation of IRS-1. Insulin resistance is usually evaluated by fasting insulin levels, Quantitative Insulin Check Index (QUICKI) and Homeostasis Model Assessment of Insulin Resistance (HOMA), C-peptid/insulin ratio oral glucose tolerance test and hyper insulinemic euglycemic clamp. The clamp technique is considered the gold standard.
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PMID:Insulin resistance and clinical aspects of non-alcoholic steatohepatitis (NASH). 1619 20