Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:021133 (ATP)
 132,114 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ion channels in beta cells regulate electrical and secretory activity in response to metabolic, pharmacologic, or neural signals by controlling the permeability to K+ and Ca2+. The ATP-sensitive K+ channels act as a switch that responds to fuel secretagogues or sulfonylureas to initiate depolarization. This depolarization opens voltage-dependent calcium channels (VDCC) to increase the amplitude of free cytosolic Ca2+ levels ([Ca2+]i), which triggers exocytosis. Acetyl choline and vasopressin (VP) both potentiate the acute effects of glucose on insulin secretion by generating inositol 1,4,5-trisphosphate to release intracellular Ca2+; VP also potentiates sustained insulin secretion by effects on depolarization. In contrast, inhibitors of insulin secretion decrease [Ca2+]i by either hyperpolarizing the beta cell or by receptor-mediated, G-protein-coupled effects to decrease VDCC activity. Repolarization is initiated by voltage- and Ca(2+)-activated K+ channels. A human insulinoma voltage-dependent K+ channel cDNA was recently cloned and two types of alpha 1 subunits of the VDCC have been identified in insulin-secreting cell lines. Determining how ion channels regulate insulin secretion in normal and diabetic beta cells should provide pathophysiologic insight into the beta cell signal transduction defect characteristic of non-insulin dependent diabetes (NIDDM).
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PMID:The role of ion channels in insulin secretion. 138 42

The aim of this study was to determine whether exercise training produces a myocardium intrinsically more tolerant to ischemic-reperfusion injury. Male Fischer 344 rats were treadmill trained for 11-16 wk at one of the following intensities: LOW (20 m/min, 0% grade, 60 min/day), moderate (MOD; 30 m/min, 5% grade, 60 min/day) or intensive (INT; 10 bouts of alternating 2-min runs at 16 and 60 m/min, 5% grade). Cardiac function was evaluated both before and after 25 min of global, zero-flow ischemia in the isolated, working heart model. Compared to hearts from sedentary (SED) rats, postischemic cardiac output (CO) and work were significantly higher in all trained groups. Percent recovery of CO (relative to preischemia) was 36.0 +/- 7.1 in SED and 61.2 +/- 6.5, 68.1 +/- 9.3, and 73.2 +/- 5.0 in LOW, MOD, and INT, respectively. Postischemic increases in stroke volume with increased preload and cardiac work at high work load were significantly higher in INT compared with SED. Coronary flow during initial retrograde reperfusion was significantly enhanced with training and correlated with subsequent recovery of CO (R2 = 0.613). Furthermore, trained hearts had higher phosphocreatine (P less than 0.05) and ATP (P less than 0.01) contents after 45 min reperfusion. It is concluded that exercise training results in an intrinsic myocardial adaptation, allowing greater recovery of cardiac pump function after global ischemia in the isolated rat heart.
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PMID:Exercise training improves cardiac function after ischemia in the isolated, working rat heart. 141 6

Aldose reductase (EC 1.1.1.21) is implicated in the pathophysiology of diabetic complications. In this paper we determined the activities of aldose reductase and ATPases of the erythrocytes in 17 patients with Type 2 (non-insulin-dependent) diabetes mellitus (NIDDM). In the aldose reductase assay we used fluorometric method to avoid the disturbance of hemoglobin. With dihydronicotinamide adenine dinucleotide (NADH), we verified it was aldose reductase but not aldehyde reductase II that was activated in the erythrocytes of the patients with NIDDM. The aldose reductase activity of the erythrocytes in the patients was significantly higher (P less than 0.01) than that in the controls. The activity of Na+/K(+)-ATPase of the patients was significantly lower (P less than 0.01) than that of the controls. The activities of Ca(2+)-ATPase and Mg(2+)-ATPase on the erythrocyte membranes of the patients were similar to those of the controls. At the same time we measured the seven nucleotide concentrations in the erythrocytes of the patients. In this experiment we used ultrafiltration method, instead of acid precipitation to make it possible to determine dihydronicotinamide adenine dinucleotide phosphate (NADPH) and NADH. The concentrations of ATP, ADP and AMP were similar to those of the controls. The concentrations of NADPH, NAD+ and NADH in the erythrocytes of the patients were significantly lower (P less than 0.01, 0.05 and 0.05 respectively) than those of controls. The concentration of nicotinamide adenine dinucleotide phosphate (NADP+) in the patients was significantly higher (P less than 0.01) than that of controls.
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PMID:Activities of aldose reductase, ATPases, and nucleotide concentrations of erythrocytes in patients with type 2 (non-insulin-dependent) diabetes mellitus. 166 Dec 22

Knowledge of the metabolic changes that occur in insulin-resistant type 2 diabetes is relatively lacking compared to insulin-deficient type 1 diabetes. This paper summarizes the importance of the C57BL/KsJ-db/db mouse as a model of type 2 diabetes, and illustrates the effects that insulin-deficient and insulin-resistant states have on hepatic glycogen metabolism. A longitudinal study of db/db mice of ages 2-15 weeks revealed that significant changes in certain parameters of hepatic glycogen metabolism occur during this period. The liver glycogen levels were similar between diabetic and control mice. However, glycogen particles from db/db mice were on average smaller in mass and had shorter exterior and interior chain lengths. Total phosphorylase and phosphorylase a activities were elevated in the genetically diabetic mice. This was primarily due to an increase in the amount of enzymic protein apparently the result of a decreased rate of degradation. It was not possible to find a consistent alteration in glycogen activity in the db/db mice. Glycogen synthase and phosphorylase from diabetic liver revealed some changes in kinetic properties in the form of a decrease in Vmax and altered sensitivity to inhibitors like ATP. The altered glycogen structure in db/db mice may have contributed to changes in the activities and properties of glycogen synthase and phosphorylase. The exact role played by hormones (insulin and glucagon) in these changes is not clear but further studies should reveal their contributions. The db/db mouse provides a good model for type 2 diabetes and for fluctuating insulin and glucagon ratios.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hepatic glycogen metabolism in the db/db mouse. 240 41

The tyrosine kinase activity of the insulin receptor was examined with partially-purified insulin receptors from adipocytes obtained from 13 lean nondiabetics, 14 obese nondiabetics, and 13 obese subjects with non-insulin-dependent diabetes (NIDDM). Incubation of receptors at 4 degrees C with [gamma-32P]ATP and insulin resulted in a maximal 10-12-fold increase in autophosphorylation of the 92-kDa beta-subunit of the receptor with a half maximal effect at 1-3 ng/ml free insulin. Insulin receptor kinase activity in the three experimental groups was measured by means of both autophosphorylation and phosphorylation of the exogenous substrate Glu4:Tyr1. In the absence of insulin, autophosphorylation and Glu4:Tyr1 phosphorylation activities, measured with equal numbers of insulin receptors, were comparable among the three groups. In contrast, insulin-stimulated kinase activity was comparable in the control and obese subjects, but was reduced by approximately 50% in the NIDDM group. These findings indicate that the decrease in kinase activity in NIDDM resulted from a reduction in coupling efficiency between insulin binding and activation of the receptor kinase. The insulin receptor kinase defects observed in NIDDM could be etiologically related to insulin resistance in NIDDM and the pathogenesis of the diabetic state.
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PMID:Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic subjects. 354 10

ATP-regulated potassium channels play a key role in regulating insulin secretion. We have isolated cDNA clones from a RINm5F insulinoma cell cDNA library that encode a protein, KATP-2, whose sequence shows 72% identity with the rat heart potassium channel KATP. RNA blotting showed that KATP-2 mRNA was present at high levels in brain and undetectable in heart, spleen, lung, liver, skeletal muscle, kidney and testis. A quantitative RT-PCR assay indicated that there were 1.85 +/- 0.32 x 10(5) molecules of KATP-2 mRNA per microgram of total RNA in pancreatic islets from nondiabetic rats. The levels of KATP-2 mRNA were reduced by 34% in islets from diabetic Zucker diabetic fatty male rats, a model of non-insulin dependent diabetes mellitus, compared to their lean nondiabetic littermates (p < 0.05), suggesting that decreased expression of KATP-2 may contribute to beta-cell dysfunction in this animal model.
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PMID:Cloning of rat KATP-2 channel and decreased expression in pancreatic islets of male Zucker diabetic fatty rats. 762 27

A decreased insulin response, preferentially to glucose, has been considered a hallmark of non-insulin dependent diabetes mellitus (Type 2) in humans. Syndromes resembling human diabetes occur spontaneously in many animal species and can also be induced by treating animals with drugs or viruses, excising their pancreases or manipulating their diet. Among these models, rat diabetes induced by neonatal streptozotocin administration (n-STZ models) has been first recognized as an adequate tool to study the long-term consequences of a gradually reduced beta-cell mass. More recently, the GK (Goto Kakisaki) Wistar rat has become available and is now considered as a promising spontaneous rat model of non-insulin dependent diabetes. We and others have found that defects in insulin secretion and action develop in the n-STZ and the GK models, which in many ways resemble those described in human non-insulin dependent diabetes. This review is aimed to sum up with a comparative approach, the informations so far collected in the n-STZ and GK models concerning the cellular mechanisms leading to the desensitization of their beta-cells to glucose. Taken together, the data reinforce the view that the impairment of glucose-induced insulin release in n-STZ and GK rats is clearly related to a defect in oxidative glycolysis. This leads to a severe decrease in the mitochondrial oxidative catabolism of glucose-derived pyruvate. Its coincides with a lower ATP/ADP ratio in glucose-stimulated islets and a subsequent alteration of ionic events tightly coupled to the fuel function of the hexose in islet cells, i.e. the decrease in K+ conductance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glucose refractoriness of pancreatic beta-cells in rat models of non-insulin dependent diabetes. 780 48

The molecular genetics of mitochondria relevant to NIDDM is described, because the mutations in mitochondrial DNA cause diabetes. The non-Mendelian genetics, including maternal inheritance, heteroplasmy, stochastic segregation are characteristic of mitochondrial gene. Since aging causes rapid loss of mitochondrial function, which results in the retardation of insulin secretion via ATP-sensitive K-channel. This loss is not caused by the age-dependent mutation in the mitochondrial DNA, but by a nuclear aging, perhaps accompanied by the shortening of telomere. This was shown by the cybrid experiment. The aged mitochondria in cytoplasts are transferred to immortal rho = cells (cells devoid of mitochondrial DNA) and restored its oxidative and transcriptional activities (J. Biol. Chem. 269:6878, 1994). Thus, the control mechanism of transcription in mitochondria has been analyzed. The genes for mitochondrial transcription factor (mtTF1) an MRP-RNA have been sequenced and their regulatory elements are found (BBRC 194:544, 1993 etc.) The mutations in mitochondrial DNA that cause diabetes have been found, and from the stochastic segregation of the heteroplasmic mutated mitochondrial DNA, we could explain why the MELAS mutation is concentrated in some tissue (J. Neurol. Sci. 120:174, 1993). Although there have been many reports on the mitochondrial mutations found in diabetic patients, we have to be careful on polymorphism (J. Biol. Chem. in press).
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PMID:[Molecular genetics of mitochondria and diabetes]. 798 85

Non-insulin-dependent diabetes mellitus (NIDDM) is a metabolic disease associated with abnormal insulin secretion, the underlying mechanisms of which are unknown. Glucose-dependent signal transduction pathways were investigated in pancreatic islets derived from the db/db mouse, an animal model of NIDDM. After stimulation with glucose (4-12 mM), the changes in intracellular Ca2+ concentration ([Ca2+]i) were different; unlike control islets, db/db islets lacked an initial reduction of [Ca2+]i and the subsequent [Ca2+]i oscillations following stimulation with 12 mM glucose. The severity of these defects in Ca2+ signaling correlated with the age-dependent development of hyperglycemia. Similarly defective glucose-induced Ca2+ signaling were reproduced in control islets by pre-exposure to thapsigargin, a selective inhibitor of endoplasmic reticulum (ER) Ca(2+)-ATPase. Estimation of ATPase activities from rates of ATP hydrolysis and by immunoblot hybridization with an antiserum directed against the sarco/endoplasmic reticulum Ca(2+)-ATPase both demonstrated that the ER Ca(2+)-ATPase was almost entirely absent from db/db islets. The effects of inhibition of ER Ca(2+)-ATPase on insulin secretion were also examined; a 4-day exposure of control islets to 1 microM thapsigargin resulted in basal and glucose-stimulated insulin secretion levels similar to those found in db/db islets. These results suggest that aberrant ER Ca2+ sequestration underlies the impaired glucose responses in the db/db mouse and may play a role in defective insulin secretion associated with NIDDM.
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PMID:Defective glucose-dependent endoplasmic reticulum Ca2+ sequestration in diabetic mouse islets of Langerhans. 803 70

The plasma membrane enzyme (Ca2+ + Mg2+)-adenosine triphosphatase (ATPase) is hormonally regulated and may participate in Ca2+ signaling by removing excess Ca2+ from the cell. Therefore, observations of a hormone-specific loss of insulin stimulation of ATPase in kidney membranes from non-insulin-dependent diabetic (NIDDM) rats may reflect their insulin-resistant state. Consequently, to evaluate whether additional insulin-resistant conditions are associated with impaired function of ATPase and with loss of regulation of the enzyme by insulin, studies were extended to investigate (Ca2+ + Mg2+)-ATPase activities and hormonal regulation of the enzyme in kidney basolateral membranes from obese and lean Zucker rats. (Ca2+ + Mg2+)-ATPase activity was lower in membranes from obese rats compared with lean rats. Maximal velocity (Vmax) of the enzyme activity was 29.2 +/- 2.6 nmol Pi/mg/min in obese rats versus 57.2 +/- 6.5 in lean rats (P < .05). However, the affinity of the enzyme for Ca2+ was similar in obese and lean rats (Km Ca2+, 0.23 +/- 0.025 v 0.23 +/- 0.032 mumol/L Ca2+). Also, the Km for ATP of the enzyme was similar in membranes from obese and lean rats. Insulin, parathyroid hormone (PTH), and cyclic adenosine monophosphate (cAMP) stimulated the ATPase activity in membranes from lean rats in a dose-dependent manner (15% to 28%). Also, the protein kinase C (PKC) stimulator 12-O-tetradecanoyl phorbol-13-acetate (TPA) increased the ATPase activity in membranes from lean rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased activity of (Ca2+ + Mg2+)-adenosine triphosphatase (ATPase) and a hormone-specific defect in insulin regulation of ATPase in kidney basolateral membranes from obese fa/fa rats. 805 47


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