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)

The lipid kinase phosphoinositide 3-kinase (PI3K) is activated in response to various extracellular signals including peptide growth factors such as insulin and insulin-like growth factors (IGFs). Phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P(3)] generated by PI3K is central to the diverse responses elicited by insulin, including glucose homeostasis, proliferation, survival and cell growth. The actions of lipid phosphatases have been considered to be the main means of attenuating PI3K signalling, whereby the principal 3-phosphatase - phosphatase and tensin homologue deleted on chromosome 10 (PTEN) - dephosphorylates PtdIns(3,4,5)P(3), reversing the action of PI3K. Recently, however, another pathway of regulation of PI3K has been identified in which activation of PI3K itself is prevented. This finding, together with earlier work, strongly suggests that a major form of negative feedback inhibition of PI3K results from activated growth signalling via mammalian target of rapamycin (mTOR) and the p70 S6 kinase (S6K) - a pathway that could have consequences for the development of type 2 diabetes and tuberous sclerosis complex.
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PMID:Restraining PI3K: mTOR signalling goes back to the membrane. 1565 24

Phosphoinositides are membrane-bound signaling molecules that recruit, activate and localize target effectors to intracellular membranes regulating apoptosis, cell proliferation, insulin signaling and membrane trafficking. The SH2 domain containing inositol polyphosphate 5-phosphatase-2 (SHIP2) hydrolyzes phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) generating phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2). Overexpression of SHIP2 inhibits insulin-stimulated phosphoinositide 3-kinase (PI3K) dependent signaling events. Analysis of diabetic human subjects has revealed an association between SHIP2 gene polymorphisms and type 2 diabetes mellitus. Genetic ablation of SHIP2 in mice has generated conflicting results. SHIP2 knockout mice were originally reported to show lethal neonatal hypoglycemia resulting from insulin hypersensitivity, but in addition to inactivating the SHIP2 gene, the Phox2a gene was also inadvertently deleted. Another SHIP2 knockout mouse has now been generated which inactivates the SHIP2 gene but leaves Phox2a intact. These animals show normal insulin and glucose tolerance but are highly resistant to weight gain on high fat diets, exhibiting an obesity-resistant phenotype. Therefore, SHIP2 remains a significant therapeutic target for the treatment of both obesity and type 2 diabetes.
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PMID:The SH2 domain containing inositol polyphosphate 5-phosphatase-2: SHIP2. 1596 36

The evolutionarily conserved phosphoinositide 3-kinase (PI3K) signaling pathway mediates both the metabolic effects of insulin and the growth-promoting effects of insulin-like growth factor-1 (IGF-1). We have generated mice deficient in both the p85alpha/p55alpha/p50alpha and the p85beta regulatory subunits of class I(A) PI3K in skeletal muscles. PI3K signaling in the muscle of these animals is severely impaired, leading to a significant reduction in muscle weight and fiber size. These mice also exhibit muscle insulin resistance and whole-body glucose intolerance. Despite their ability to maintain normal fasting and fed blood glucose levels, these mice show increased body fat content and elevated serum free fatty acid and triglyceride levels. These results demonstrate that in vivo p85 is a critical mediator of class I(A) PI3K signaling in the regulation of muscle growth and metabolism. Our finding also indicates that compromised muscle PI3K signaling could contribute to symptoms of hyperlipidemia associated with human type 2 diabetes.
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PMID:Loss of class IA PI3K signaling in muscle leads to impaired muscle growth, insulin response, and hyperlipidemia. 1667 93

Although many studies using rodent islets and insulinoma cell lines have been performed to determine the role of insulin in the regulation of islet function, the autocrine effect of insulin on insulin gene expression is still controversial, and no consensus has yet been achieved. Because very little is known about the insulin signaling pathway in human islets, we used single-cell RT-PCR to profile the expression of genes potentially involved in the insulin signaling cascade in human beta-cells. The detection of mRNAs for insulin receptor (IR)A and IRB; insulin receptor substrate (IRS)-1 and IRS-2; phosphoinositide 3-kinase (PI3K) catalytic subunits p110alpha, p110beta, PI3KC2alpha, and PI3KC2gamma; phosphoinositide-dependent protein kinase-1; protein kinase B (PKB)alpha, PKBbeta, and PKBgamma in the beta-cell population suggests the presence of a functional insulin signaling cascade in human beta-cells. Small interfering RNA-induced reductions in IR expression in human islets completely suppressed glucose-stimulated insulin gene expression, suggesting that insulin regulates its own gene expression in human beta-cells. Defects in this regulation may accentuate the metabolic dysfunction associated with type 2 diabetes.
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PMID:Identification of insulin signaling elements in human beta-cells: autocrine regulation of insulin gene expression. 1700 50

Phosphoinositide-dependent kinase-1 (PDK1) is implicated in the metabolic effects of insulin as a key mediator of phosphoinositide 3-kinase-dependent signaling. Here we show that mice with liver-specific PDK1 deficiency manifest various defects in the metabolic actions of insulin in the liver as well as a type 2 diabetes-like phenotype characterized by marked hyperinsulinemia and postprandial hyperglycemia. The hepatic abundance of glucokinase, an important determinant of glucose flux and glucose-evoked signaling in hepatocytes, was substantially reduced in these mice. Restoration of hepatic glucokinase expression, with the use of an adenoviral vector, induced insulin-like effects in the liver and almost completely normalized the fasting hyperinsulinemia and postprandial hyperglycemia in these animals. These results indicate that, if the hepatic abundance of glucokinase is maintained, ingested glucose is normally disposed of even in the absence of acute activation of proximal insulin signaling, such as the activation of Akt, in the liver.
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PMID:Restoration of glucokinase expression in the liver normalizes postprandial glucose disposal in mice with hepatic deficiency of PDK1. 1726 63

Insulin resistance is a defining feature of type 2 diabetes and the metabolic syndrome. While the molecular mechanisms of insulin resistance are multiple, recent evidence suggests that attenuation of insulin signaling by c-Jun N-terminal kinase (JNK) may be a central part of the pathobiology of insulin resistance. Here we demonstrate that the p85alpha regulatory subunit of phosphoinositide 3-kinase (PI3K), a key mediator of insulin's metabolic actions, is also required for the activation of JNK in states of insulin resistance, including high-fat diet-induced obesity and JNK1 overexpression. The requirement of the p85alpha regulatory subunit for JNK occurs independently of its role as a component of the PI3K heterodimer and occurs only in response to specific stimuli, namely, insulin and tunicamycin, a chemical that induces endoplasmic reticulum stress. We further show that insulin and p85 activate JNK by via cdc42 and MKK4. The activation of this cdc42/JNK pathway requires both an intact N terminus and functional SH2 domains within the C terminus of the p85alpha regulatory subunit. Thus, p85alpha plays a dual role in regulating insulin sensitivity and may mediate cross talk between the PI3K and stress kinase pathways.
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PMID:The p85alpha regulatory subunit of phosphoinositide 3-kinase potentiates c-Jun N-terminal kinase-mediated insulin resistance. 1728 57

The associations of five SNPs (SNPs1-5: A-5468G, A-3333G, C-1794T, C437T and T9148C) of the class II phosphoinositide 3-kinase gamma-subunit (PIK3C2G) gene with type 2 diabetes were examined using a population of the Takahata Study (n (M/W): 2930 (1328/1602); age: 63.3+/-10.2 years), a Japanese community-based study. Quantitative association study of the SNPs with HbA1c levels showed significant association for SNPs 2 and 4 (p=0.018 and 0.004, respectively). A case-control association study of SNP 4 with diabetes by multiple logistic regression analysis showed a significant association of the genotype TT of the SNP with an odds ratio of 2.21 (p=0.001) independently of age, gender and BMI. In the NGT subjects, serum fasting insulin levels in the at-risk genotype group of SNP 4 were significantly lower than those in the others (TT, TC, and CC, 4.9+/-2.6, 5.4+/-3.0, and 5.6+/-3.4muU/ml, respectively; p=0.029).
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PMID:Association of the PIK3C2G gene polymorphisms with type 2 DM in a Japanese population. 1799 25

Therapeutics based on the actions of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), have recently been introduced for the treatment of type 2 diabetes mellitus. The serine/threonine kinase Akt is a major mediator of incretin action on the pancreatic islet, increasing beta-cell mass and function and promoting beta-cell survival. The mechanisms underlying incretin activation of Akt are thought to involve an essential phosphoinositide 3-kinase-mediated phosphorylation of threonine 308, similar to the prototypical Akt activator, insulin-like growth factor-I (IGF-I). In this study, using activity assays on immunoprecipitated Akt, we discovered that GIP and GLP-1 were capable of stimulating Akt in the INS-1 beta-cell line and isolated mouse islets via a mechanism that did not require phosphoinositide 3-kinase or phosphorylation of Thr(308) and Ser(473), and this pathway involved the production of cAMP. Furthermore, we found that GIP stimulated anti-apoptotic signaling via this alternate mode of Akt activation. We conclude that incretins can activate Akt via a novel noncanonical mechanism that may provide an alternative therapeutic target for the treatment of type 2 diabetes mellitus and have broader implications for Akt physiology in human health and disease.
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PMID:Noncanonical activation of Akt/protein kinase B in {beta}-cells by the incretin hormone glucose-dependent insulinotropic polypeptide. 1923 42

The capacity of pancreatic beta-cells to adapt to insulin resistance is crucial for glucose homeostasis and is a factor in the development of type 2 diabetes. The insulin receptor substrate (insulin receptor 2/phosphoinositide 3-kinase [PI3K]) pathway plays a crucial part in regulating beta-cell mass and function. The serine-threonine kinase Akt, also known as protein kinase B, is one of the major downstream targets of the PI3K pathway and is negatively regulated by phosphatase and tensin homologue deleted on chromosome 10. This Akt signaling pathway has recently been implicated in cell-cycle progression and survival of pancreatic beta-cells. Understanding the mechanisms that link Akt to modulation of beta-cell mass, function and plasticity will positively affect treatment of human diabetes.
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PMID:Akt and PTEN: beta-cell mass and pancreas plasticity. 1954 99

Insulin resistance is central to the pathogenesis of type 2 diabetes mellitus. Previous studies have demonstrated that compounds that cause adipogenesis and improve glucose uptake in 3T3-L1 cells are potential insulin sensitizers. Therefore, we evaluated one such compound, 18F9, for (1) adipogenesis in human subcutaneous preadipocyte (SQ) cells, (2) glucose uptake in human skeletal muscle myotubes and SQ cells, and (3) antidiabetic activity in db/db mice. We also investigated its effect on ex vivo glucose uptake in soleus muscle isolated from continuously treated db/db mice. Gene expression profiling in soleus muscle and epididymal fat of db/db mice was performed to understand its effect on glucose metabolism, lipid metabolism, and thermogenesis. 18F9 enhanced adipogenesis in SQ cells and increased glucose uptake in SQ and human skeletal muscle myotubes cells. In db/db mice, 18F9 exhibited dose-dependent reduction in plasma glucose and insulin level. Interestingly, 18F9 was as efficacious as rosiglitazone but did not cause body weight gain and hepatic adverse effects. In addition, 18F9 demonstrated no change in plasma volume in Wistar rats. Furthermore, it enhanced ex vivo glucose uptake in soleus muscles in these mice, which substantiates our in vitro findings. Human peroxisome proliferator activated receptor-gamma transactivation assay revealed a weak peroxisome proliferator activated receptor-gamma transactivation potential (44% of rosiglitazone at 10 mumol/L) of 18F9. Gene expression profiling indicated that 18F9 increased insulin sensitivity mainly through a phosphoinositide 3-kinase-dependent mechanism. 18F9 also up-regulated genes involved in lipid transport and synthesis at par with rosiglitazone. Unlike rosiglitazone, 18F9 elevated the expression of Pdk4. In addition, 18F9 elevated the expression of glycogen synthase and adiponectin significantly higher than rosiglitazone. Taken together, these observations suggest that 18F9 is a safer and potent insulin sensitizer that demonstrates promising antidiabetic activity and is worth further development.
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PMID:18F9 (4-(3,6-bis (ethoxycarbonyl)-4,5,6,7-tetrahydrothieno (2,3-c) pyridin-2-ylamino)-4-oxobutanoic acid) enhances insulin-mediated glucose uptake in vitro and exhibits antidiabetic activity in vivo in db/db mice. 1960 7


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