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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of insulin-dependent diabetes mellitus is thought to be dependent on either the autoimmunity or the interaction of environmental agents with the pancreatic beta cells, or both in a genetically susceptible host. As environmental factors affecting the induction of type I diabetes, diabetogenic chemicals and viruses are likely candidates as primary injurious agents for pancreatic beta cells in man and animal. A number of structurally diverse chemicals including alloxan, streptozotocin, chlorozotocin, vacor, and cyproheptadine are diabetogenic mainly in rodents and sometimes in man. The possible mechanisms for the beta cell destruction by these chemicals include (a) generation of oxygen free radicals and alteration of endogenous scavengers of these reactive species; (b) breakage of DNA and consequent increase in the activity of poly ADP ribose synthetase, and enzyme depleting NAD in beta cells; and (c) inhibition of active calcium transport and calmodulin-activated protein kinase activity. Regarding viruses, a number of different viruses including encephalomyocarditis virus, Mengovirus, Coxsackie B viruses, and Reoviruses can infect and destroy pancreatic beta cells mainly in rodents and sometimes in humans. In the murine model, the development of encephalomyocarditis and Coxsackie B virus-induced diabetes is dependent on the genetic background of the host and the genetic makeup of the virus. Mengo-2T virus has caused diabetes in strains of mice resistant to encephalomyocarditis virus-induced diabetes. In contrast to encephalomyocarditis virus, Coxsackie B viruses, and Mengovirus, reovirus type 1 seems to be somewhat associated with an autoimmune response in the induction of diabetes. In addition to the murine model, cotton rats become diabetic when inoculated with Mengovirus 2T. Furthermore, cumulative environmental insults with Coxsackie B viruses and chemicals result in diabetes in non-human primates. In man, there may be 2 possible roles for viruses in the pathogenesis of insulin-dependent diabetes mellitus. The one is acute cytolytic infection of beta cells (e.g., Coxsackie B viruses), which may sometimes induce diabetes in genetically predisposed individuals, and the other one is slow and persistent infection (e.g., congenital cytomegalovirus and Rubella), which may induce autoimmunity, leading to type I diabetes.
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PMID:Effects of environmental factors on the development of insulin-dependent diabetes mellitus. 331 67

Contractile responses to calcium were examined in the K+-depolarized duodenum from normal and alloxan-diabetic rats. In addition, verapamil and trifluoperazine which are well-known calcium channel blocker and calmodulin inhibitor respectively were used as tools in order to approach to the mechanism of changes resulting from diabetes. Decreased contractile responses to calcium were observed in the alloxan diabetic rat duodenum compared to normals. Trifluoperazine-induced non-competitive inhibition was significantly affected depending on diabetes, while verapamil-induced competitive inhibition was not changed. The non-competitive inhibition affinity constant for trifluoperazine was significantly elevated in the K+-depolarized duodenum from alloxan-diabetic rats. On the basis of findings obtained in this study, possible mechanism of the effect of experimental diabetes on the calcium-induced contraction is discussed.
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PMID:Altered responses to calcium and trifluoperazine in K+-depolarized duodenum from alloxan diabetic rats. 343 25

We studied insulin binding to cultured differentiating muscle cell line L6. Insulin binding to the cells reached a plateau after incubation with 125I-insulin for 4 h at 22 degrees C, and was at an optimum at pH 7.8. Preincubation with 10 microM of hydrocortisone for 36 h at 37 degrees C resulted in significantly increased insulin binding (1.73 +/- 0.12 ng/mg protein for treated cells vs. 1.13 +/- 0.025 ng/mg protein for control cells, mean +/- SD, P less than 0.001). Preincubation with 1 microM of hydrocortisone or 1 microM of dexamethasone also led to increased binding. The number of insulin-binding sites per cell increased 2.5-fold in glucocorticoid-treated cells (9.7 X 10(3) sites/cell for treated vs. 3.8 X 10(3) sites/cell for control cells). Preincubation with trifluoperazine (5 microM), a calmodulin inhibitor, did not affect insulin binding to the cells. These results indicate that glucocorticoid might have some important role in regulating the number of insulin receptors in L6 muscle cells.
Diabetes Res Clin Pract
PMID:Insulin binding to differentiating muscle cell line L6. 353 69

Using several experimental approaches, we have studied simultaneously the effect of glucose upon insulin, arachidonic acid and prostaglandin E2 release by rat pancreatic islets. A 16.6 mmol/l glucose concentration stimulated the release of insulin, arachidonic acid and prostaglandins. All these effects were significantly reduced either by calmodulin and phospholipase A2 inhibitors, or by the omission of calcium in the incubation medium. Phospholipase A2 inhibitors do not modify the glucose-induced net 45Ca2+ uptake by isolated islets. Our results would suggest that activation of phospholipases, particularly A2, is involved in the mechanism by which glucose stimulates insulin release. This activation increases the intracellular concentration of arachidonic acid, prostaglandins and probably phospholipid degradation products, that could act as messengers for the stimulus-secretion coupling of insulin. The calcium-calmodulin complex would take part in this effect. Conversely, the glucose-induced net calcium uptake by the islets might either be preceded by phospholipase activation or not significantly affected by the blockade of its activity.
Diabetes Res Clin Pract
PMID:Role of phospholipase and calmodulin inhibitors on insulin, arachidonic acid and prostaglandin E2 release. 393 19

We have identified two different species of inhibitors of calmodulin-dependent cAMP phosphodiesterase: 1) a low molecular weight (LMW) and 2) a high molecular weight (HMW) form. These inhibitors are extracted from rat liver. Both LMW and HMW inhibitors are heat-stable, acidic in nature and lose activity with prolonged storage and/or repeated freezing and thawing. The low molecular weight inhibitor has been purified to about 7,000-fold with 300% recovery. LMW inhibits calmodulin-dependent cAMP phosphodiesterase regardless of the source of calmodulin (e.g. fat, brain, heart, erythrocytes). LMW appears to be lipid in nature with a molecular weight of 1,500-5,000. The role of these inhibitors in diabetes and mechanism of action of insulin is presented.
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PMID:Properties and characterization of low molecular weight inhibitor of calmodulin-dependent cAMP phosphodiesterase from rat liver. 609 16

Levels of calmodulin and activities of calcium and magnesium ATPases were determined in renal tissues of age-matched male rats after increasing durations of the following conditions: untreated streptozotocin (STZ) induced diabetes; STZ-diabetic rats which received daily insulin (NPH) treatment beginning 24 hours after STZ administration; and STZ-diabetic rats which began receiving NPH after having endured untreated diabetes for 1, 2, and 3 weeks. Results were compared with those of age-matched control animals. Calmodulin levels were the same in renal tissues from all groups of rats as were magnesium-ATPase activities. Calcium-ATPase activities were significantly higher than control activities after 2 weeks of untreated STZ-diabetes and in tissues from all rats that received insulin treatment which was instituted after 1, 2 and 3 weeks of STZ-diabetes. Calcium ATPase activities of tissues from rats which received insulin treatment 24 hrs after STZ injections were no different from control values. The data indicate that prolonged deficiency of insulin results in insufficient passive transport of calcium from urine into tubular cells. Thus, the increased activity of calcium-ATPase on the contraluminal membrane of kidney cells represents a futile attempt to conserve calcium.
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PMID:Calmodulin levels and divalent cation pump activities in kidneys of streptozotocin-diabetic rats. 613 28

It may now be possible to identify certain intracellular events that impact specifically on secretion-granule fusion to the plasma membrane or on granule lysis. Secretion vesicles in isolated rat islets appear to translocate somatostatin (SRIF) receptors from the Golgi apparatus to the plasma membrane. We have proposed that secretion granule fusion to the plasma membrane can be determined by measuring recruitment of SRIF receptors to the surface membrane. Granule lysis can be assessed by measuring insulin release. To activate cyclic AMP (cAMP)-dependent pathways, we employed isobutylmethylxanthine (IBMX, 400 microM), glucagon (10 microM), and forskolin (20 microM), a diterpene activator of adenylate cyclase. These agents evoked rapid release of insulin (from 0.41 +/- 0.02 to 1.88 +/- 0.02; 0.41 +/- 0.02 to 1.93 +/- 0.08; and 0.41 +/- 0.02 to 1.66 +/- 0.03 microU/islet/min, respectively, P less than 0.001). There was no concomitant recruitment of SRIF receptors. Somatostatin (10 micrograms/ml), which inhibits cAMP-stimulated protein phosphorylation, suppresses insulin release evoked by IBMX, glucagon, or forskolin (inhibition: 80, 75, or 82%, respectively). In contrast, trifluoperazine (10 microM), an inhibitor of calmodulin, did not suppress insulin release induced through cAMP-dependent pathways. Trifluoperazine suppresses glucose-induced insulin release and the recruitment of SRIF receptors to the surface membrane, suggesting the possible role of calmodulin in promoting secretion-granule fusion with the plasma membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1984 Apr
PMID:Calmodulin and cyclic AMP. Possible different sites of action of these two regulatory agents in exocytotic hormone release. 620 Mar 77

The effect of Ca2+ and calmodulin has been studied on adenylate cyclase activity in homogenates of rat islets of Langerhans. EGTA had a stimulatory effect on the enzyme in accord with the known inhibitory effect of Ca2+. In contrast, the addition of Ca2+ together with calmodulin is stimulatory and demonstrates the existence of a Ca2+-dependent adenylate cyclase in islets of Langerhans. It is suggested that the glucose-induced increase in cyclic AMP concentrations in intact islets is a secondary consequence of the glucose-induced increase in cytosol free-Ca2+ concentrations which, with calmodulin, causes an increase in the activity of adenylate cyclase.
Diabetes 1980 Jan
PMID:Stimulation of adenylate cyclase by Ca2+ and calmodulin in rat islets of langerhans: explanation for the glucose-induced increase in cyclic AMP levels. 624 30

Pancreatic islets contain enzyme activity which catalyzes the phosphorylation by MgATP of cardiac, skeletal, or smooth muscle myosin light chains. The enzyme is activated by calcium (Ka = 10 microM) and calmodulin (Ka = 2 nM) and inhibited by trifluoperazine (Ki = 10 microM), a known inhibitor of calmodulin and of insulin secretion. The enzyme binds to a calmodulin affinity column when Ca2+ is present and is eluted when Ca2+ is omitted. These are the properties of myosin light chain kinase. Since phosphorylation of smooth muscle myosin is necessary for its activation by actin, the kinase may have a key role in coupling stimuli that increase intracellular calcium to the contractile processes involved in insulin secretion.
Diabetes 1982 Jun
PMID:Calcium-calmodulin-dependent myosin phosphorylation by pancreatic islets. 629 60

Calmodulin concentrations were measured in isolated hamster islets or in a cloned rat insulin-secreting cell line RIN-m-5F treated with high glucose. There was no change in the cellular calmodulin content of either islets or RIN-m-5F cells despite increases of insulin concentrations in the media. Treatment of cells with the anti-calmodulin drug W13 inhibited insulin-stimulated glucose release, whereas a small effect on insulin accumulation in the media was observed with W12, the dechlorinated, less active analogue of W13. At the lowest dose tested (30 microM) the effect of W13 on insulin accumulation in the media was completely reversible. To further investigate the possible role of calmodulin in insulin secretion, calmodulin-binding proteins in subcellular fractions of the RIN-m-5F cells were identified using a gel overlay technique. Ca2+-dependent binding of 125I-calmodulin was observed to cytosolic proteins with apparent Mr = 125, 110, 56, 52, and 34 k (kilodalton). This binding was completely displaceable with unlabeled calmodulin, whereas only partial displacement was observed when the homologous Ca2+ binding protein of skeletal muscle, troponin C, was used. Four proteins with Mr similar to the histones bind calmodulin in a Ca2+-independent manner. 125I-calmodulin:calmodulin binding protein interactions were inhibited in a dose-dependent manner by the anti-calmodulin drug, W13. Little effect was observed with the analogue W12.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1983 Dec
PMID:Calmodulin-binding proteins in a cloned rat insulinoma cell line. 631 98


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