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 stimulatory G protein Gsalpha transmits signals from activated beta-adrenergic receptors via the cyclic AMP-PKA pathway, targeting the key regulatory protein phospholamban. We hypothesized that mice with intrinsic activation of cardiac Gsalpha are resistant to the development of the diabetic cardiomyopathy phenotype. Accordingly, streptozotocin (STZ)-diabetes mellitus was induced in genetically engineered mice with cardiac-specific Gsalpha overexpression and in nontransgenic (NTG) littermates. At 8 weeks, Gsalpha diabetic mice showed no impairment of LV contractility nor increase in myocyte apoptosis, whereas NTG diabetic mice showed a 30% decrease in +dP/dt and -dP/dt with sustained (3-fold) myocyte loss by apoptosis. To assess the level of myocardial reactive oxygen species, we measured malondialdehyde, a surrogate marker of oxidative stress, which was increased in the hearts of NTG and Gsalpha diabetic mice. In addition, chronic hyperglycemia also increased the activity of catalase and superoxide dismutase in the hearts of NTG and Gsalpha diabetic mice. Hearts of NTG diabetic mice, but not Gsalpha mice, showed increased expression of proapoptosis Bax, downregulation in Bcl2, and an increase in the Bax/Bcl2 ratio. Hearts of NTG diabetic mice showed 60% reduction in phosphorylation at the critical Ser16 residue of phospholamban, whereas phosphorylation at Ser16 was restored in hearts of Gsalpha-diabetic mice. We conclude that cardiac-specific overexpression of Gsalpha compensates for the loss of cardiac function in diabetes mellitus.
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PMID:Overexpression of Gsalpha compensates for myocyte loss in diabetic cardiomyopathy. 1841 39

Hyperglycemia causes endothelial dysfunction due to its effect on increasing reactive oxygen species (ROS). Adiponectin (Adp) has been reported to suppress hyperglycemia-associated ROS generation. It was hypothesized that administering globular adiponectin (gAdp) via injectable biodegradable thermosensitive triblock copolymer might effectively reduce ROS generation in endothelial cells. In this study, gAdp was incorporated into and released from the polymer gel. The released gAdp was further investigated by comparing it with the intact gAdp with regard to the efficiency in reducing ROS and activating cAMP. The released gAdp effectively suppressed excess ROS production in the in vitro endothelial cell culture model under high-glucose condition via cAMP/PKA pathway. These data provide a rationale for developing controlled release dosage form of gAdp as a therapeutic tool for oxidative stress-related pathology in patients with diabetes.
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PMID:Reversal of oxidative stress in endothelial cells by controlled release of adiponectin. 1861 3

The present study was undertaken to assess the effects of exercise training (ExT) initiated after the onset of diabetes on cardiac ryanodine receptor expression and function. Type 1 diabetes was induced in male Sprague-Dawley rats using streptozotocin (STZ). Three weeks after STZ injection, diabetic rats were divided into two groups. One group underwent ExT for 4 wk while the other group remained sedentary. After 7 wk of sedentary diabetes, cardiac fractional shortening, rate of rise of left ventricular pressure, and myocyte contractile velocity were reduced by 14, 36, 44%, respectively. Spontaneous Ca(2+) spark frequency increased threefold, and evoked Ca(2+) release was dyssynchronous with diastolic Ca(2+) releases. Steady-state type 2 ryanodine receptor (RyR2) protein did not change, but its response to Ca(2+) was altered. RyR2 also exhibited 1.8- and 1.5-fold increases in phosphorylation at Ser(2808) and Ser(2814). PKA activity was reduced by 75%, but CaMKII activity was increased by 50%. Four weeks of ExT initiated 3 wk after the onset of diabetes blunted decreases in cardiac fractional shortening and rate of left ventricular pressure development, increased the responsiveness of the myocardium to isoproterenol stimulation, attenuated the increase in Ca(2+) spark frequency, and minimized dyssynchronous and diastolic Ca(2+) releases. ExT also normalized the responsiveness of RyR2 to Ca(2+) activation, attenuated increases in RyR2 phosphorylation at Ser(2808) and Ser(2814), and normalized CaMKII and PKA activities. These data are the first to show that ExT during diabetes normalizes RyR2 function and Ca(2+) release from the sarcoplasmic reticulum, providing insights into mechanisms by which ExT during diabetes improves cardiac function.
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PMID:Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation. 1913 75

Glucose is the preferred carbon and energy source in prokaryotes, unicellular eukaryotes, and metazoans. However, excess of glucose has been associated with several diseases, including diabetes and the less understood process of aging. On the contrary, limiting glucose (i.e., calorie restriction) slows aging and age-related diseases in most species. Understanding the mechanism by which glucose limits life span is therefore important for any attempt to control aging and age-related diseases. Here, we use the yeast Schizosaccharomyces pombe as a model to study the regulation of chronological life span by glucose. Growth of S. pombe at a reduced concentration of glucose increased life span and oxidative stress resistance as reported before for many other organisms. Surprisingly, loss of the Git3 glucose receptor, a G protein-coupled receptor, also increased life span in conditions where glucose consumption was not affected. These results suggest a role for glucose-signaling pathways in life span regulation. In agreement, constitutive activation of the Galpha subunit acting downstream of Git3 accelerated aging in S. pombe and inhibited the effects of calorie restriction. A similar pro-aging effect of glucose was documented in mutants of hexokinase, which cannot metabolize glucose and, therefore, are exposed to constitutive glucose signaling. The pro-aging effect of glucose signaling on life span correlated with an increase in reactive oxygen species and a decrease in oxidative stress resistance and respiration rate. Likewise, the anti-aging effect of both calorie restriction and the Deltagit3 mutation was accompanied by increased respiration and lower reactive oxygen species production. Altogether, our data suggest an important role for glucose signaling through the Git3/PKA pathway to regulate S. pombe life span.
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PMID:Pro-aging effects of glucose signaling through a G protein-coupled glucose receptor in fission yeast. 1926 76

Calcitonin gene related peptide (CGRP) is a vasodilator; its plasma levels are altered in several human diseases, including migraine, hypertension and diabetes. CGRP is locally released by motor neurons, and is overexpressed in response to surgical or pharmacological blockage of neuromuscular transmission. Additionally to a brief discussion with regard to the clinical relevance of CGRP, this review focuses on the effects of CGRP on skeletal muscle excitation-contraction (EC) coupling, as well as the corresponding pathophysiological consequences. EC coupling involves activation of 2 different types of calcium channels: dihydropyridine receptors (DHPRs) located at the sarcolemma, and ryanodine receptors (RyR1s) located at the sarcoplasmic reticulum (SR). In response to electrical depolarization, DHPRs activate nearby and physically bound RyR1s, allowing Ca(2+) from the SR to move into the cytosol (termed voltage-gated Ca(2+) release, or VGCR). We recently found that CGRP stimulates VGCR by 350 % in as short as 1h. This effect, which lasts for at least 48 h, is due to activation of the CGRP receptor, and requires activation of the cAMP/PKA signaling pathway. CGRP also increases the amplitude of caffeine-induced Ca(2+) release (400 %); suggesting increased SR Ca(2+) content underlies stimulation of VGCR. Interestingly, in the long-term CGRP also increases the density of sarcolemmal DHPRs (up to 30%, within 24-48 h). We propose that these CGRP effects may contribute to prevent and/or restore symptoms in central core disease (CCD); a congenital myopathy that is linked to mutations in the gene encoding RyR1.
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PMID:CGRP, a vasodilator neuropeptide that stimulates neuromuscular transmission and EC coupling. 1948 22

In this review, the pathological alteration and clinical relevance of voltage-gated K(+) (Kv) channels and their specific regulation by protein kinase-dependent signaling in vascular smooth muscle cells are described, particularly focusing on the pulmonary vasculature. The physiological relevance, channel characteristics, pharmacological modulation, and expression of Kv channels vary between different arterial beds and between subdivisions of arteries within those vascular beds. Although detailed signaling cascades regulating Kv channels are not clearly elucidated, it is known that the Kv channels in vascular smooth muscle cells can be tightly regulated by protein kinases C (PKC) and A (PKA). Alterations in Kv channel expression and function has been noted in pathological and pathophysiological conditions including hypertension (pulmonary and systemic), in diabetes and in individuals subjected to prolonged hypoxia (high altitude living). Vascular Kv channels are potential therapeutic targets in diseases such as pulmonary arterial hypertension and, therefore, it is important to understand the specific pharmacological modulation of Kv channel isoforms in different vascular beds.
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PMID:Pathophysiology of voltage-gated K+ channels in vascular smooth muscle cells: modulation by protein kinases. 1983 7

Ca(+) sparklets are subcellular Ca(2+) signals produced by the opening of L-type Ca(2+) channels (LTCCs). In cerebral arterial myocytes, Ca(2+) sparklet activity varies regionally, resulting in low and high activity, "persistent" Ca(2+) sparklet sites. Although increased Ca(2+) influx via LTCCs in arterial myocytes has been implicated in the chain of events contributing to vascular dysfunction during acute hyperglycemia and diabetes, the mechanisms underlying these pathological changes remain unclear. Here, we tested the hypothesis that increased Ca(2+) sparklet activity contributes to higher Ca(2+) influx in cerebral artery smooth muscle during acute hyperglycemia and in an animal model of non-insulin-dependent, type 2 diabetes: the dB/dB mouse. Consistent with this hypothesis, acute elevation of extracellular glucose from 10 to 20 mM increased the density of low activity and persistent Ca(2+) sparklet sites as well as the amplitude of LTCC currents in wild-type cerebral arterial myocytes. Furthermore, Ca(2+) sparklet activity and LTCC currents were higher in dB/dB than in control myocytes. We found that activation of PKA contributed to higher Ca(2+) sparklet activity during hyperglycemia and diabetes. In addition, we found that the interaction between PKA and the scaffolding protein A-kinase anchoring protein was critical for the activation of persistent Ca(2+) sparklets by PKA in cerebral arterial myocytes after hyperglycemia. Accordingly, PKA inhibition equalized Ca(2+) sparklet activity between dB/dB and wild-type cells. These findings suggest that hyperglycemia increases Ca(2+) influx by increasing Ca(2+) sparklet activity via a PKA-dependent pathway in cerebral arterial myocytes and contributes to vascular dysfunction during diabetes.
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PMID:Elevated Ca2+ sparklet activity during acute hyperglycemia and diabetes in cerebral arterial smooth muscle cells. 1990 15

Patients with diabetes tend to have an increased incidence of osteoporosis that may be related to hyperglycemia. In this study, we investigated the effects of high glucose on differentiation of human osteoblastic MG-63 cells and involved intracellular signal transduction pathways. Here, we showed that high glucose suppressed the cell growth, mineralization, and expression of osteogenic markers including Runx2, collagen I, osteocalcin, osteonectin, but inversely promoted expression of adipogenic markers including PPARgamma, aP2, resistin, and adipsin. Moreover, high glucose significantly increased the intracellular cAMP level in a time-dependent manner and induced ERK1/2 activation. Meanwhile, supplementation of H89, a specific inhibitor of PKA, and PD98059, a specific inhibitor of MAPK/ERK kinase, reversed the cell growth inhibition, the down-regulation of osteogenic markers and the up-regulation of adipogenic markers as well as the activation of ERK under high glucose. These results indicate that high glucose can increase adipogenic and inhibit osteogenic differentiation by activating cAMP/PKA/ERK pathway in MG-63 cells, thereby providing further insight into the molecular mechanism of diabetic osteoporosis.
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PMID:High glucose stimulates adipogenic and inhibits osteogenic differentiation in MG-63 cells through cAMP/protein kinase A/extracellular signal-regulated kinase pathway. 1994 37

The AGC kinase subfamily of protein kinases contains 60 members, including PKA, PKG and PKC. The family comprises some intensely examined protein kinases (such as Akt, S6K, RSK, MSK, PDK1 and GRK) as well as many less well-studied enzymes (such as SGK, NDR, LATS, CRIK, SGK494, PRKX, PRKY and MAST). Research has shed new light onto the architecture and regulatory mechanisms of these kinases. In addition, AGC kinases mediate diverse and important cellular functions, and their mutation and/or dysregulation contributes to the pathogenesis of many human diseases, including cancer and diabetes.
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PMID:The nuts and bolts of AGC protein kinases. 2002 84

Metformin use in diabetes can cause acidosis and might be linked to pancreatitis. Here, we mechanistically focus on this relationship via a point mutation in the cystic fibrosis transmembrane conductance regulator (CFTR; ABCC7). CFTR is an ATP-hydrolyzing, cAMP/PKA-activated anion channel regulating pancreatic bicarbonate/chloride secretion across duct-facing apical membranes in epithelia. CFTR has two nucleotide binding domains (NBD1/2) which clamp two ATP molecules across their opposed, inverted interfacial surfaces which generates anion-conductance after ATP hydrolysis. Notably, CFTR mutations not causal for classical cystic fibrosis segregate with unexplained pancreatitis and one of these lies in NBD1 near its ATP-clamp (S573C; close to the Walker B aspartate D572). We recently showed that after raising [cAMP], wt-CFTR chloride-conductance, when expressed in Xenopus oocytes, remains elevated despite the presence of metformin. Yet here, we find that S573C-CFTR manifests a metformin-inhibitable whole cell chloride-conductance after cAMP elevation. In the absence of metformin, cAMP-activated S573C-CFTR also displays a reduced anion-conductance relative to wt-CFTR. Furthermore, intra-oocyte acidification inhibited wt-CFTR and abolished S573C-CFTR conductance. We conclude that defective S573C-CFTR remains both poorly conducting and inhibited by metformin and intracellular acidosis. This might explain the propensity to pancreatitis with this rare CF mutation.
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PMID:Metformin treatment of diabetes mellitus increases the risk for pancreatitis in patients bearing the CFTR-mutation S573C. 2033 19


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