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)

The Snf1/AMP-activated protein kinase (AMPK) family plays fundamental roles in cellular responses to metabolic stress in eukaryotes. In humans, AMPK regulates lipid and glucose metabolism and has been implicated in such metabolic disorders as diabetes and obesity and in cardiac abnormalities. Snf1 and AMPK are the downstream components of kinase cascades, but the upstream kinase(s) have remained elusive. We have here identified three yeast kinases, Pak1p, Tos3p, and Elm1p, that activate Snf1 kinase in vivo. Triple deletion of the cognate genes causes a Snf- mutant phenotype and abolishes Snf1 catalytic activity. All three kinases phosphorylate recombinant Snf1p on the activation-loop threonine. Moreover, Tos3p phosphorylates mammalian AMPK on the equivalent residue and activates the enzyme, suggesting functional conservation of the upstream kinases between yeast and mammals. We further show that the closely related mammalian LKB1 kinase, which is associated with Peutz-Jeghers cancer-susceptibility syndrome, phosphorylates and activates AMPK in vitro. Thus, the identification of the yeast upstream kinases should facilitate identification of the corresponding, physiologically important mammalian upstream kinases.
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PMID:Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases. 1284 91

Adiponectin is an adipocyte-derived hormone, which has been shown to play important roles in the regulation of glucose and lipid metabolism. Eight mutations in human adiponectin have been reported, some of which were significantly related to diabetes and hypoadiponectinemia, but the molecular mechanisms of decreased plasma levels and impaired action of adiponectin mutants were not clarified. Adiponectin structurally belongs to the complement 1q family and is known to form a characteristic homomultimer. Herein, we demonstrated that simple SDS-PAGE under non-reducing and non-heat-denaturing conditions clearly separates multimer species of adiponectin. Adiponectin in human or mouse serum and adiponectin expressed in NIH-3T3 or Escherichia coli formed a wide range of multimers from trimers to high molecular weight (HMW) multimers. A disulfide bond through an amino-terminal cysteine was required for the formation of multimers larger than a trimer. An amino-terminal Cys-Ser mutation, which could not form multimers larger than a trimer, abrogated the effect of adiponectin on the AMP-activated protein kinase pathway in hepatocytes. Among human adiponectin mutations, G84R and G90S mutants, which are associated with diabetes and hypoadiponectinemia, did not form HMW multimers. R112C and I164T mutants, which are associated with hypoadiponectinemia, did not assemble into trimers, resulting in impaired secretion from the cell. These data suggested impaired multimerization and/or the consequent impaired secretion to be among the causes of a diabetic phenotype or hypoadiponectinemia in subjects having these mutations. In conclusion, not only total concentrations, but also multimer distribution should always be considered in the interpretation of plasma adiponectin levels in health as well as various disease states.
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PMID:Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin. 1287 98

The effect of exercise intensity on skeletal muscle AMP-activated protein kinase (AMPK) signaling and substrate metabolism was examined in eight men cycling for 20 min at each of three sequential intensities: low (40 +/- 2% VO(2) peak), medium (59 +/- 1% VO(2) peak), and high (79 +/- 1% VO(2) peak). Muscle free AMP/ATP ratio only increased at the two higher exercise intensities (P < 0.05). AMPK alpha 1 (1.5-fold) and AMPK alpha 2 (5-fold) activities increased from low to medium intensity, with AMPK alpha 2 activity increasing further from medium to high intensity. The upstream AMPK kinase activity was substantial at rest and only increased 50% with exercise, indicating that, initially, signaling through AMPK did not require AMPK kinase posttranslational modification. Acetyl-CoA carboxylase (ACC)-beta phosphorylation was sensitive to exercise, increasing threefold from rest to low intensity, whereas neuronal NO synthase (nNOS) micro phosphorylation was only observed at the higher exercise intensities. Glucose disappearance (tracer) did not increase from rest to low intensity, but increased sequentially from low to medium to high intensity. Calculated fat oxidation increased from rest to low intensity in parallel with ACC beta phosphorylation, then declined during high intensity. These results indicate that ACC beta phosphorylation is especially sensitive to exercise and tightly coupled to AMPK signaling and that AMPK activation does not depend on AMPK kinase activation during exercise.
Diabetes 2003 Sep
PMID:Effect of exercise intensity on skeletal muscle AMPK signaling in humans. 1294 58

The obesity crisis in the United States has been associated with an alarming increase in the prevalence of the metabolic syndrome (MSX) disease cluster. Here we review evidence that the MSX reflects a failure of a system of intracellular lipid homeostasis that prevents lipotoxicity in the organs of overnourished individuals by confining the lipid overload to cells specifically designed to store large quantities of surplus calories, the white adipocytes. Normally, early in obesity, adipocytes increase leptin and adiponectin secretion, hormones that enhance oxidation of surplus liquids in nonadipose tissues by activating AMP-activated protein kinase and reducing the activity and expression of lipogenic enzymes. These events combine to lower malonyl coenzyme A. Deficiency of and/or unresponsiveness to leptin prevents these protective events and results in ectopic accumulation of lipids. Increased de novo ceramide formation is probably the most damaging lipid and is a cause of lipoapoptosis, abetted by a decline in tissue Bcl-2. Pancreatic beta-cells and myocardiocytes are cellular victims of the process, leading to non-insulin-dependent diabetes and lipotoxic cardiomyopathy. The MSX is particularly prevalent in visceral obesity, probably because visceral adipocytes make less leptin than sc adipocytes. Cushing's syndrome, the lipodystrophy associated with protease inhibitor therapy of AIDS, polycystic ovarian disease, as well as diet-induced visceral obesity, all have a high waist/hip ratio, and all exhibit MSX. Increased lipid content in the heart and skeletal muscle organs of such patients is now under study.
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PMID:Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. 1296 11

Accumulation of intracellular lipid by pancreatic islet beta-cells has been proposed to inhibit normal glucose-regulated insulin secretion ('glucolipotoxicity'). In the present study, we determine whether over-expression in rat islets of the lipogenic transcription factor SREBP1c (sterol-regulatory-element-binding protein-1c) affects insulin release, and whether changes in islet lipid content may be reversed by activation of AMPK (AMP-activated protein kinase). Infection with an adenovirus encoding the constitutively active nuclear fragment of SREBP1c resulted in expression of the protein in approx. 20% of islet cell nuclei, with a preference for beta-cells at the islet periphery. Real-time PCR (TaqMan) analysis showed that SREBP1c up-regulated the expression of FAS (fatty acid synthase; 6-fold), acetyl-CoA carboxylase-1 (2-fold), as well as peroxisomal-proliferator-activated receptor-gamma (7-fold), uncoupling protein-2 (1.4-fold) and Bcl2 (B-cell lymphocytic-leukaemia proto-oncogene 2; 1.3-fold). By contrast, levels of pre-proinsulin, pancreatic duodenal homeobox-1, glucokinase and GLUT2 (glucose transporter isoform-2) mRNAs were unaltered. SREBP1c-transduced islets displayed a 3-fold increase in triacylglycerol content, decreased glucose oxidation and ATP levels, and a profound inhibition of glucose-, but not depolarisation-, induced insulin secretion. Culture of islets with the AMPK activator 5-amino-4-imidazolecarboxamide riboside decreased the expression of the endogenous SREBP1c and FAS genes, and reversed the effect of over-expressing active SREBP1c on FAS mRNA levels and cellular triacylglycerol content. We conclude that SREBP1c over-expression, even when confined to a subset of beta-cells, leads to defective insulin secretion from islets and may contribute to some forms of Type II diabetes.
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PMID:Over-expression of sterol-regulatory-element-binding protein-1c (SREBP1c) in rat pancreatic islets induces lipogenesis and decreases glucose-stimulated insulin release: modulation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). 1469 Apr 55

Conserved pairs of CBS sequence motifs (named after cystathionine beta-synthase) found in a wide variety of proteins associate to form Bateman domains. A new study establishes that Bateman domains bind adenosyl compounds and regulate IMP dehydrogenase, CBS, chloride channels, and AMP-activated protein kinase. This discovery reveals how mutations in CBS sequences in these proteins cause hereditary diseases and provides a rich vista of conceptual opportunities for therapies in energy metabolism, obesity, diabetes, cancer, antivirals, and immunosuppression.
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PMID:Bateman domains and adenosine derivatives form a binding contract. 1472 19

CBS domains are defined as sequence motifs that occur in several different proteins in all kingdoms of life. Although thought to be regulatory, their exact functions have been unknown. However, their importance was underlined by findings that mutations in conserved residues within them cause a variety of human hereditary diseases, including (with the gene mutated in parentheses): Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase); retinitis pigmentosa (IMP dehydrogenase-1); congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members); and homocystinuria (cystathionine beta-synthase). AMP-activated protein kinase is a sensor of cellular energy status that is activated by AMP and inhibited by ATP, but the location of the regulatory nucleotide-binding sites (which are prime targets for drugs to treat obesity and diabetes) was not characterized. We now show that tandem pairs of CBS domains from AMP-activated protein kinase, IMP dehydrogenase-2, the chloride channel CLC2, and cystathionine beta-synthase bind AMP, ATP, or S-adenosyl methionine,while mutations that cause hereditary diseases impair this binding. This shows that tandem pairs of CBS domains act, in most cases, as sensors of cellular energy status and, as such, represent a newly identified class of binding domain for adenosine derivatives.
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PMID:CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. 1472 9

It is now generally accepted that activation of AMP-activated protein kinase (AMPK) is involved in the stimulation of glucose transport by muscle contractions. However, earlier studies provided evidence that increases in cytosolic Ca(2+) mediate the effect of muscle contractions on glucose transport. The purpose of this study was to test the hypothesis that both the increase in cytosolic Ca(2+) and the activation of AMPK are involved in the stimulation of glucose transport by muscle contractions. Caffeine causes release of Ca(2+) from the sarcoplasmic reticulum. Incubation of rat epitrochlearis muscles with a concentration of caffeine that raises cytosolic Ca(2+) to levels too low to cause contraction resulted in an approximate threefold increase in glucose transport. Caffeine treatment also resulted in increased phosphorylation of calmodulin-dependent protein kinase (CAMK)-II in epitrochlearis muscle. The stimulation of glucose transport by caffeine was blocked by the Ca(2+)-CAMK inhibitors KN62 and KN93. Activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) also resulted in an approximate threefold increase in glucose transport in the epitrochlearis. The increases in glucose transport induced by AICAR and caffeine were additive, and their combined effect was not significantly different from that induced by maximally effective contractile activity. KN62 and KN93 caused an approximately 50% inhibition of the stimulation of glucose transport by contractile activity. Our results provide evidence that both Ca(2+) and AMPK are involved in the stimulation of glucose transport by muscle contractions. They also suggest that the stimulation of glucose transport by Ca(2+) involves activation of CAMK.
Diabetes 2004 Feb
PMID:Ca2+ and AMPK both mediate stimulation of glucose transport by muscle contractions. 1474 82

AMP-activated protein kinase (AMPK), an energy-sensing enzyme that is activated in response to cellular stress, is a critical signaling molecule for the regulation of multiple metabolic processes. AMPK has recently emerged as an attractive novel target for the treatment of obesity and type 2 diabetes because its activation increases fatty acid oxidation and improves glucose homeostasis. Here we show that pharmacological activation of AMPK by insulin-sensitizing drugs markedly inhibits inducible nitric-oxide synthase (iNOS), a proinflammatory mediator in endotoxic shock and in chronic inflammatory states including obesity-linked diabetes. AMPK-mediated iNOS inhibition was observed in several cell types (myocytes, adipocytes, macrophages) and primarily resulted from post-transcriptional regulation of the iNOS protein. AMPK activation in vivo also blunted iNOS induction in muscle and adipose tissues of endotoxin-challenged rats. Reduction of AMPK expression by small interfering RNA reversed the inhibitory effects of AMPK activators on iNOS expression and nitric oxide production in myocytes. These results indicate that AMPK is a novel anti-inflammatory signaling pathway and thus represents a promising therapeutic target for immune-inflammatory disorders.
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PMID:Inhibition of inducible nitric-oxide synthase by activators of AMP-activated protein kinase: a new mechanism of action of insulin-sensitizing drugs. 1498 44

Adipocyte dysfunction is strongly associated with the development of obesity and insulin resistance. It is accepted that the regulation of adipocytokine secretion or the adipocyte-specific gene expression is one of the most important targets for the prevention of obesity and amelioration of insulin sensitivity. In this study, we demonstrated that anthocyanins (cyanidin or cyanidin 3-glucoside) have the potency of a unique pharmacological function in isolated rat adipocytes. Treated adipocytes with anthocyanins enhanced adipocytokine (adiponectin and leptin) secretion and up-regulated the adipocyte specific gene expression without activation of PPARgamma in isolated rat adipocytes. The gene expression of adiponectin was also up-regulated in white adipose tissue in mice fed an anthocyanin supplemented diet. As one of the possible mechanisms, AMP-activated protein kinase activation would be associated with these changes, nevertheless, the AMP:ATP ratio was significantly decreased by administration of the anthocyanins. These data suggest that anthocyanins have a potency of unique therapeutic advantage and also have important implications for preventing obesity and diabetes.
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PMID:Anthocyanin enhances adipocytokine secretion and adipocyte-specific gene expression in isolated rat adipocytes. 1500 23


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