Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic steatosis is defined by an increased content of hepatocellular lipids (HCLs) and is frequently observed in insulin-resistant states including type 2 diabetes mellitus. A dietary excess of saturated fat contributes significantly to HCL accumulation. Elevated HCL levels mainly account for hepatic insulin resistance, which is probably mediated by partitioning of free fatty acids to the liver (fat overflow) and by an imbalance of adipocytokines (decreased adiponectin and/or increased proinflammatory cytokines). Both free fatty acids and adipocytokines activate inflammatory pathways that include protein kinase C, the transcription factor nuclear factor kappaB, and c-Jun N-terminal kinase 1 and can thereby accelerate the progression of hepatic steatosis to nonalcoholic steatohepatitis and cirrhosis. Proton magnetic resonance spectroscopy has made it possible to quantify HCL concentrations and to detect even small changes in these concentrations in clinical settings. Moderately hypocaloric, fat-reduced diets can decrease HCL levels by approximately 40-80% in parallel with loss of up to 8% of body weight. Treatment with thiazolidinediones (e.g. pioglitazone and rosiglitazone) reduces HCL levels by 30-50% by modulating insulin sensitivity and endocrine function of adipose tissue in type 2 diabetes. Metformin improves hepatic insulin action without affecting HCL levels, whereas insulin infusion for 67 h increases HCL levels by approximately 18%; furthermore, HCL levels positively correlate with the insulin dosage in insulin-treated type 2 diabetes. In conclusion, liver fat is a critical determinant of metabolic fluxes and inflammatory processes, thereby representing an important therapeutic target in insulin resistance and type 2 diabetes mellitus.
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PMID:Mechanisms of Disease: hepatic steatosis in type 2 diabetes--pathogenesis and clinical relevance. 1693 11

This study examined the effects of glucagon-like peptide-1 (GLP-1) on insulin secretion alone and in combination with sulphonylureas or nateglinide, with particular attention to K(ATP) channel-independent insulin secretion. In depolarised cells, GLP-1 significantly augmented glucose-induced K(ATP) channel-independent insulin secretion in a glucose concentration-dependent manner. GLP-1 similarly augmented the K(ATP) channel-independent insulin-releasing effects of tolbutamide, glibenclamide or nateglinide. Downregulation of protein kinase A (PKA)- or protein kinase C (PKC)-signalling pathways in culture revealed that the K(ATP) channel-independent effects of sulphonylureas or nateglinide were critically dependent upon intact PKA and PKC signalling. In contrast, GLP-1 exhibited a reduced but still significant insulin-releasing effect following PKA and PKC downregulation, indicating that GLP-1 can modulate K(ATP) channel-independent insulin secretion by protein kinase-dependent and -independent mechanisms. The synergistic insulin-releasing effects of combinatorial GLP-1 and sulphonylurea/nateglinide were lost following PKA- or PKC-desensitisation, despite GLP-1 retaining an insulin-releasing effect, demonstrating that GLP-1 can induce insulin release under conditions where sulphonylureas and nateglinide are no longer effective. Our results provide new insights into the mechanisms of action of GLP-1, and further highlight the promise of GLP-1 or similarly acting analogues alone or in combination with sulphonylureas or meglitinide drugs in type 2 diabetes therapy.
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PMID:Actions of glucagon-like peptide-1 on KATP channel-dependent and -independent effects of glucose, sulphonylureas and nateglinide. 1700 89

Ruboxistaurin is a potent and specific inhibitor of the beta isoform of protein kinase C. Overactivation of protein kinase C has been demonstrated in patients with type 2 diabetes, and is postulated to play a major role in the pathogenesis of diabetic microvascular complications, which include diabetic retinopathy, neuropathy and nephropathy. The role of protein kinase C in promoting tissue injury in patients with diabetes, and the pharmacologic and clinical studies illustrating the potential of ruboxistaurin to reduce the burden of diabetic microvascular complications will be discussed in this article.
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PMID:Ruboxistaurin. 1702 67

Long-chain, monounsaturated fatty acids (FAs) stimulate secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1) from the intestinal L cell. Because the atypical protein kinase C (PKC), PKCzeta, is involved in FA signaling in many cells, the role of PKCzeta in FA-induced GLP-1 secretion was investigated, using the murine GLUTag L cell line and primary rat intestinal L cells. GLUTag cells expressed mRNA for several PKC isoforms, including PKCzeta, and PKCzeta protein was localized throughout the cytoplasm in GLUTag and primary L cells as well as normal mouse and rat L cells. Treatment with oleic acid (150-1000 microm) for 2 h increased GLP-1 secretion (P < 0.001), and this was abrogated by the PKCzeta inhibitor ZI (P < 0.05) and PKCzeta small interfering RNA transfection (P < 0.05) but not inhibition of classical/novel PKC isoforms. Although most PKCzeta was localized in the particulate compartment of GLUTag cells, oleate treatment did not alter PKCzeta levels or activity in this cell fraction. GLUTag cells expressed mRNA for the Gq-coupled FA receptor GPR120; however, oleic acid did not induce any changes in Akt, MAPK, or calcium, and pretreatment with LY294002 and PD98059 to inhibit phosphatidylinositol 3-kinase and MAPK, respectively, did not prevent the effects of oleic acid. Finally, GLUTag cells also released GLP-1 in response to arachidonic acid (P < 0.001) but were not affected by other long-chain FAs. These findings demonstrate that PKCzeta is required for oleic acid-induced GLP-1 secretion. This enzyme may therefore serve as a therapeutic target to enhance GLP-1 release in type 2 diabetes.
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PMID:Protein kinase Czeta is required for oleic acid-induced secretion of glucagon-like peptide-1 by intestinal endocrine L cells. 1711 Apr 21

Recent studies using magnetic resonance spectroscopy have shown that decreased insulin-stimulated muscle glycogen synthesis due to a defect in insulin-stimulated glucose transport activity is a major factor in the pathogenesis of type 2 diabetes. The molecular mechanism underlying defective insulin-stimulated glucose transport activity can be attributed to increases in intramyocellular lipid metabolites such as fatty acyl CoAs and diacylglycerol, which in turn activate a serine/threonine kinase cascade, thus leading to defects in insulin signaling through Ser/Thr phosphorylation of insulin receptor substrate (IRS)-1. A similar mechanism is also observed in hepatic insulin resistance associated with nonalcoholic fatty liver, which is a common feature of type 2 diabetes, where increases in hepatocellular diacylglycerol content activate protein kinase C-epsilon, leading to reduced insulin-stimulated tyrosine phosphorylation of IRS-2. More recently, magnetic resonance spectroscopy studies in healthy lean elderly subjects and healthy lean insulin-resistant offspring of parents with type 2 diabetes have demonstrated that reduced mitochondrial function may predispose these individuals to intramyocellular lipid accumulation and insulin resistance. Further analysis has found that the reduction in mitochondrial function in the insulin-resistant offspring can be mostly attributed to reductions in mitochondrial density. By elucidating the cellular and molecular mechanisms responsible for insulin resistance, these studies provide potential new targets for the treatment and prevention of type 2 diabetes.
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PMID:Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. 1713 Jun 51

Endothelial dysfunction is one manifestation of the many changes induced in the arterial wall by the metabolic abnormalities accompanying diabetes and insulin resistance. In type 1 diabetes, endothelial dysfunction is most consistently found in advanced stages of the disease. In other patients, it is associated with nondiabetic insulin resistance and probably precedes type 2 diabetes. In obesity and insulin resistance, increased secretion of proinflammatory cytokines and decreased secretion of adiponectin from adipose tissue, increased circulating levels of free fatty acids, and postprandial hyperglycemia can all alter gene expression and cell signaling in vascular endothelium, cause vascular insulin resistance, and change the release of endothelium-derived factors. In diabetes, sustained hyperglycemia causes increased intracellular concentrations of glucose metabolites in endothelial cells. These changes cause mitochondrial dysfunction, increased oxidative stress, and activation of protein kinase C. Dysfunctional endothelium displays activation of vascular NADPH oxidase, uncoupling of endothelial nitric oxide synthase, increased expression of endothelin 1, a changed balance between the production of vasodilator and vasoconstrictor prostanoids, and induction of adhesion molecules. This review describes how these and other changes influence endothelium-dependent vasodilation in patients with insulin resistance and diabetes. The clinical utility of endothelial function testing and future therapeutic targets is also discussed.
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PMID:Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes. 1717 29

Despite the worldwide epidemic of chronic kidney disease complicating diabetes mellitus, current therapies directed against nephroprogression are limited to angiotensin conversion or receptor blockade. Nonetheless, additional therapeutic possibilities are slowly emerging. The diversity of therapies currently in development reflects the pathogenic complexity of diabetic nephropathy. The three most important candidate drugs currently in development include a glycosaminoglycan, a protein kinase C (PKC) inhibitor and an inhibitor of advanced glycation. In targeting primary mechanisms by which hyperglycaemia contributes to diabetic complications, these drugs could provide risk reduction complementary to the partial reduction proven for ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers). Glycosaminoglycans act to restore glycoproteins present in reduced amounts in the glomerular basement membrane and mesangium of diabetic animal models. Components of the drug sulodexide prevent pathological changes and proteinuria in diabetic rats. Reductions in albuminuria, a hallmark of early diabetic kidney disease, have been reported in initial human trials. In the US, a multicentre phase II study has been completed, with an interim analysis indicating reduction in urinary albumin losses. Pivotal phase II trials have begun in patients with type 2 diabetes. A second metabolic pathway of diabetic complications is overexpression of PKC. Several activators of this family of intracellular kinases have been identified and PKC activation may result in tissue damage through a variety of mechanisms. In animal models, the inhibitor ruboxistaurin reduces albuminuria, diabetic histological changes and kidney injury. Like sulodexide, drug development of ruboxistaurin has reached completion of a phase II evaluation with mixed results. The third metabolic target is the nonenzymatic formulation of advanced glycation end-products (AGEs) through well described biochemical pathways. Multiple pathways lead to AGE accumulation in tissues in diabetes and diverse AGE products are formed. AGE deposition has been implicated in animal models of diabetic nephropathy. The leading AGE inhibitor currently in development is pyridoxamine, which has multiple actions that inhibit glycation. Pyridoxamine is an efficient AGE inhibitor in experimental diabetes. A phase II study in diabetic patients with nephropathy reported mixed efficacy results and a favourable safety profile. Phase III evaluation of pyridoxamine has not begun. These three classes of potential therapies, if successfully developed, will confirm that diabetic kidney disease has entered the era of biochemical treatments.
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PMID:New potential agents in treating diabetic kidney disease: the fourth act. 1718 72

To determine mechanisms underlying the transgenerational presence of metabolic perturbations in the intrauterine growth-restricted second-generation adult females (F2 IUGR) despite normalizing the in utero metabolic environment, we examined in vivo glucose kinetics and in vitro skeletal muscle postinsulin receptor signaling after embryo transfer of first generation (F1 IUGR) to control maternal environment. Female F2 rats, procreated by F1 pre- and postnatally nutrient- and growth-restricted (IUGR) mothers but embryo transferred to gestate in control mothers, were compared with similarly gestating age- and sex-matched control (CON) F2 progeny. Although there were no differences in birth weight or postnatal growth patterns, the F2 IUGR had increased hepatic weight, fasting hyperglycemia, hyperinsulinemia, and unsuppressed hepatic glucose production, with no change in glucose futile cycling or clearance, compared with F2 CON. These hormonal and metabolic aberrations were associated with increased skeletal muscle total GLUT4 and pAkt concentrations but decreased plasma membrane-associated GLUT4, total pPKCzeta, and PKCzeta enzyme activity, with no change in total SHP2 and PTP1B concentrations in IUGR F2 compared with F2 CON. We conclude that transgenerational presence of aberrant glucose/insulin metabolism and skeletal muscle insulin signaling of the adult F2 IUGR female offspring is independent of the immediate intrauterine environment, supporting nutritionally induced heritable mechanisms contributing to the epidemic of type 2 diabetes mellitus.
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PMID:Transgenerational inheritance of the insulin-resistant phenotype in embryo-transferred intrauterine growth-restricted adult female rat offspring. 1721 72

Lipocalin-type prostaglandin D(2) synthase (L-PGDS) is a highly glycosylated protein found in several body fluids. Elevated L-PGDS levels have been observed in the serum of patients with renal impairment, diabetes mellitus, and hypertension. Recently, we demonstrated the ability of L-PGDS to induce apoptosis in a variety of cell types including epithelial cells, neuronal cells, and vascular smooth muscle cells (VSMCs). The aim of this study was to investigate the effect several site-directed mutations had on L-PGDS-induced apoptosis in order to identify potential sites of regulation. Point mutations created in a glycosylation site (Asn51), a protein kinase C phosphorylation site (Ser106), and the enzymatic active site (Cys65) all inhibited L-PGDS-induced apoptosis as determined by both terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) and caspase3 activity. We also compared the L-PGDS isoforms present in GK rat serum to WKY control serum using two-dimensional gel electrophoresis and observed distinct differences which vanished after PNGase F glycolytic digestion. We conclude that post-translational modification of L-PGDS, by either glycosylation or phosphorylation, enhances its apoptotic activity and inhibits VSMC hyperproliferation and postulate that this process is altered in type 2 diabetes.
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PMID:Post-translational modification regulates prostaglandin D2 synthase apoptotic activity: characterization by site-directed mutagenesis. 1725 69

Nonalcoholic fatty liver disease is strongly associated with hepatic insulin resistance and type 2 diabetes mellitus, but the molecular signals linking hepatic fat accumulation to hepatic insulin resistance are unknown. Three days of high-fat feeding in rats results specifically in hepatic steatosis and hepatic insulin resistance. In this setting, PKCepsilon, but not other isoforms of PKC, is activated. To determine whether PKCepsilon plays a causal role in the pathogenesis of hepatic insulin resistance, we treated rats with an antisense oligonucleotide against PKCepsilon and subjected them to 3 days of high-fat feeding. Knocking down PKCepsilon expression protects rats from fat-induced hepatic insulin resistance and reverses fat-induced defects in hepatic insulin signaling. Furthermore, we show that PKCepsilon associates with the insulin receptor in vivo and impairs insulin receptor kinase activity both in vivo and in vitro. These data support the hypothesis that PKCepsilon plays a critical role in mediating fat-induced hepatic insulin resistance and represents a novel therapeutic target for type 2 diabetes.
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PMID:Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. 1731 60


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