Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the past decade, studies of the human tumour suppressor LKB1 have uncovered a novel signalling pathway that links cell metabolism to growth control and cell polarity. LKB1 encodes a serine-threonine kinase that directly phosphorylates and activates AMPK, a central metabolic sensor. AMPK regulates lipid, cholesterol and glucose metabolism in specialized metabolic tissues, such as liver, muscle and adipose tissue. This function has made AMPK a key therapeutic target in patients with diabetes. The connection of AMPK with several tumour suppressors suggests that therapeutic manipulation of this pathway using established diabetes drugs warrants further investigation in patients with cancer.
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PMID:The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. 1962 71

Estrogen appears to protect against cardiovascular disease in pre-menopausal women. However, these protective effects are absent in women with diabetes. The hyperglycemia and consequent oxidative stress observed in diabetes cause endothelial dysfunction, but specific effects on endothelial estrogen responses are not known. In this study, we hypothesized that high glucose conditions would alter the regulation of the estrogen receptors (ERs), ERalpha and ERbeta, in endothelial cells, possibly through increased oxidative stress. The role of the AMPK activator AICAR was examined on modulating the effects of high glucose. Cultured human endothelial cells were exposed to physiologically relevant doses of 17-beta-estradiol (E2) for 24h in presence of normal (5.5mM) and high (30.5mM) levels of glucose. Protein levels of estrogen receptors, ERalpha and ERbeta, were measured through western blotting. Oxidative stress was measured by the dihydroethidium (DHE) assay for superoxide. Under normal glucose, E2 increased the levels of ERalpha relative ERbeta; however, high glucose reversed the estrogen effects on endothelial ER expression. AMPK activation restored the physiological estrogen responses, likely through amelioration of oxidative stress. Control of oxidative stress by AMPK activation or anti-oxidants could restore normal estrogen responses even in presence of hyperglycemia.
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PMID:High glucose-induced oxidative stress alters estrogen effects on ERalpha and ERbeta in human endothelial cells: reversal by AMPK activator. 1963 57

Diabetic heart disease contributes to the high mortality in diabetics, although effective clinical management is lacking. The protease inhibitor 5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101) was reported to protect the hearts against ischemic injury. This study examined the role of UCF-101 on streptozotocin (STZ)-induced diabetic heart defect. Vehicle or UCF-101 was administrated to STZ diabetic mice, and cardiomyocyte mechanical properties were analyzed. UCF-101 reduced STZ-induced hyperglycemia and alleviated STZ-induced aberration in cardiomyocyte contractile mechanics. Diabetes dramatically decreased AMPK phosphorylation at Thr(172) of catalytic alpha-subunit, which was restored by UCF-101. Neither diabetes nor UCF-101 affected the expression of HtrA2/Omi and XIAP or caspase-3 activity. The AMPK activator resveratrol mimicked the UCF-101-induced beneficial effect against diabetic cardiac dysfunction. Mechanical properties in cardiomyocytes from the AMPK-kinase-dead (KD) mice displayed markedly impaired contractile function reminiscent of diabetes. STZ injection in AMPK-KD mice failed to elicit any additional cardiomyocyte contractile defect. UCF-101 significantly downregulated the AMPK-degrading enzymes PP2A and PP2C, the effect of which was mimicked by resveratrol. Taken together, these results indicate that UCF-101 protects against STZ-induced cardiac dysfunction, possibly through AMPK signaling.
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PMID:UCF-101 mitigates streptozotocin-induced cardiomyocyte dysfunction: role of AMPK. 1969 68

The ginsenoside Rg3 is known to have a protective effect against hyperglycemia, obesity and diabetes in vivo. In this study, we examined the effect of Rg3 on insulin signaling and glucose uptake in cultured L6 myotubes. Rg3 increased glucose uptake both in the basal and insulin-induced states of L6 myotubes. Consistent with the increase in glucose uptake, Rg3 stimulated the phosphorylation of IRS-1 and Akt. Interestingly, Rg3 dramatically increased IRS-1 protein levels, while the protein level of Akt was not affected. Rg3 regulated IRS-1 expression at the transcriptional level and also increased the level of GLUT4 mRNA. Treatment of ginsam, in which Rg3 is the major compound of ginsenosides, increased the IRS-1 protein levels in OLEFT rats. In addition, we found that this effect of Rg3 on insulin signaling was not mediated by the AMPK pathway. In conclusion, these results suggest that Rg3 improves insulin signaling and glucose uptake primarily by stimulating the expression of IRS-1 and GLUT4.
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PMID:The ginsenoside Rg3 has a stimulatory effect on insulin signaling in L6 myotubes. 1969 14

Type-2 diabetes is growing at epidemic proportions world-wide. This report describes the effect of a novel, synthetic, small molecule 2-(3,4-dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), on metabolic abnormalities in genetic and dietary mouse models of type-2 diabetes. DHPO (20mg/kg/d i.p. for 21 days) attenuated fasting blood glucose, improved glucose disposal and corrected dyslipidemia in genetic (leptin deficient, ob/ob) and dietary (high-fat-fed) mouse models of insulin resistance. In addition, DHPO augmented 2-deoxy-d-glucose (2DG) uptake in gastrocnemius muscles of wild-type mice and in cultured myotubes. The increase in 2DG-uptake was associated with an increase in the phosphorylation of AMPK (thr-172) and its downstream effector acetyl-CoA carboxylase without any changes in the phosphorylation of Akt of insulin receptor. The AMPK inhibitor, compound C attenuated DHPO-induced glucose-uptake whereas the PI3-kinase inhibitor Wortmannin was less effective. In addition, DHPO failed to augment glucose-uptake in the gastrocnemius muscle from AMPK-alpha2-transgenic (kinase-dead) mice. Taken together, these results suggest that DHPO is a novel small molecule that alleviates impaired glucose tolerance and lipid abnormalities associated with type-2 diabetes.
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PMID:2-(3,4-Dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), a novel, synthetic small molecule that alleviates insulin resistance and lipid abnormalities. 1976 46

Metformin, a biguanide drug commonly used to treat type-2 diabetes, has been noted to extend healthspan of nondiabetic mice, but this outcome, and the molecular mechanisms that underlie it, have received relatively little experimental attention. To develop a genetic model for study of biguanide effects on healthspan, we investigated metformin impact on aging Caenorhabditis elegans. We found that metformin increases nematode healthspan, slowing lipofuscin accumulation, extending median lifespan, and prolonging youthful locomotory ability in a dose-dependent manner. Genetic data suggest that metformin acts through a mechanism similar to that operative in eating-impaired dietary restriction (DR) mutants, but independent of the insulin signaling pathway. Energy sensor AMPK and AMPK-activating kinase LKB1, which are activated in mammals by metformin treatment, are essential for health benefits in C. elegans, suggesting that metformin engages a metabolic loop conserved across phyla. We also show that the conserved oxidative stress-responsive transcription factor SKN-1/Nrf2 is essential for metformin healthspan benefits in C. elegans, a mechanistic requirement not previously described in mammals. skn-1, which functions in nematode sensory neurons to promote DR longevity benefits and in intestines for oxidative stress resistance lifespan benefits, must be expressed in both neurons and intestines for metformin-promoted healthspan extension, supporting that metformin improves healthy middle-life aging by activating both DR and antioxidant defense longevity pathways. In addition to defining molecular players operative in metformin healthspan benefits, our data suggest that metformin may be a plausible pharmacological intervention to promote healthy human aging.
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PMID:Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1. 2009 Sep 12

AMPK is an evolutionarily conserved fuel-sensing enzyme that is activated in shortage of energy and suppressed in its surfeit. AMPK activation stimulates fatty acid oxidation, enhances insulin sensitivity, alleviates hyperglycemia and hyperlipidemia, and inhibits proinflammatory changes. Thus, AMPK is a well-received therapeutic target for metabolic syndrome and Type 2 diabetes. Recent studies indicate that AMPK plays a role in linking metabolic syndrome and cancer. AMPK is an essential mediator of the tumor suppressor LKB1 and could be suppressed in cancer cells containing loss-of-function mutations of LKB1 or containing active mutations of B-Raf, or in cancers associated with metabolic syndrome. The activation of AMPK reprograms cellular metabolism and enforces metabolic checkpoints by acting on mTORC1, p53, fatty acid synthase and other molecules for regulating cell growth and metabolism. In keeping with in vitro studies, recent epidemiological studies indicate that the incidence of cancer is reduced in Type 2 diabetes treated with metformin, an AMPK activator. Thus, AMPK is emerging as an interesting metabolic tumor suppressor and a promising target for cancer prevention and therapy.
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PMID:AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. 2022 1

Adiponectin is an anti-diabetic adipokine. Its receptors possess a seven-transmembrane topology with the amino terminus located intracellularly, which is the opposite of G-protein-coupled receptors. Here we provide evidence that adiponectin induces extracellular Ca(2+) influx by adiponectin receptor 1 (AdipoR1), which was necessary for subsequent activation of Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta), AMPK and SIRT1, increased expression and decreased acetylation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), and increased mitochondria in myocytes. Moreover, muscle-specific disruption of AdipoR1 suppressed the adiponectin-mediated increase in intracellular Ca(2+) concentration, and decreased the activation of CaMKK, AMPK and SIRT1 by adiponectin. Suppression of AdipoR1 also resulted in decreased PGC-1alpha expression and deacetylation, decreased mitochondrial content and enzymes, decreased oxidative type I myofibres, and decreased oxidative stress-detoxifying enzymes in skeletal muscle, which were associated with insulin resistance and decreased exercise endurance. Decreased levels of adiponectin and AdipoR1 in obesity may have causal roles in mitochondrial dysfunction and insulin resistance seen in diabetes.
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PMID:Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. 2051 15

The yeast Saccharomyces cerevisiae attains energy homeostasis through complex regulatory events that are predominantly controlled by the Snf1 kinase. This master regulator senses the stress and energy starvation and activates the metabolic processes to produce ATP and inhibits biosynthesis. In doing so, Snf1 controls the switch between catabolism and anabolism accordingly, and regulates the cellular growth and development in coordination with other signaling pathways. Since its mammalian ortholog AMPK, a drug target for obesity and type II diabetes, also exerts analogous control of metabolism, there has been extensive interest recently to understand the chemical and biological aspects of Snf1 activation and regulation in yeast to expedite human disease studies as well as fundamental understanding of yeast. This review will focus on how Snf1 regulates lipid metabolism based on the cellular energy status in yeast and drawing parallels with the mammalian system.
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PMID:Systems biology of energy homeostasis in yeast. 2043 64

Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the antidiabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly, we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2 but also in the absence of AMPK. Consistent with these observations, in two distinct preclinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling in an AMPK-independent manner. We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases.
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PMID:Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. 2044 19


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