Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The response to exercise stress is characterized by an increase in circulating catecholamines and rapid synthesis of the inducible member of the 70 kDa family of heat shock proteins (Hsp70). Cell culture studies indicate that Hsp70 expression is influenced by beta-adrenergic receptor intermediates including cyclic AMP (cAMP) and cAMP dependent protein kinase (PKA). Thus, in the present investigation, the effect of a beta-adrenergic agonist, isoproterenol (ISO; 10 mg/kg) and a beta-adrenergic antagonist, nadolol (NAD; 25 mg/kg), on the in vivo expression of Hsp70 in rodent cardiac and skeletal muscle following moderate (MOD; 17 m/min) and exhaustive (EXH; 30 m/min) exercise was examined. While ISO alone did not induce Hsp70 synthesis, ISO treatment potentiated Hsp70 expression following MOD in the white vastus and heart (395+/-29 and 483+/-29% greater than control respectively, P < 0.05). Furthermore, this effect was reversed with combined beta-adrenergic agonist and antagonist treatment (ISO+NAD) indicating that the isoproterenol induced increase in post-exercise Hsp70 expression was mediated via beta-adrenergic receptor activity. However, there were no differences in Hsp70 levels among treatment groups following EXH. The failure of NAD to attenuate Hsp70 accumulation following EXH suggests that beta-adrenergic receptor activity is not the main signal in the induction of Hsp70 following exercise. Hsp70 induction was dependent on exercise intensity and ISO administration prior to MOD resulted in Hsp70 levels similar to those observed following EXH. The results from the present investigation indicate that beta-adrenergic receptor stimulation does not induce Hsp70 synthesis per se, but may be one factor involved in the complex regulation of the stress response to exercise in vivo.
 ...
PMID:Isoproterenol potentiates exercise-induction of Hsp70 in cardiac and skeletal muscle. 1054 69

Non-insulin-dependent diabetes mellitus is associated with, in addition to impaired insulin release, elevated levels of free fatty acids (FFA) in the blood. Insulin release is stimulated when beta-cells are acutely exposed to FFA, whereas chronic exposure may inhibit glucose-induced insulin secretion. In the present study we investigated the direct effects of long chain acyl-CoA (LC-CoA), the active intracellular form of FFA, on insulin exocytosis. Palmitoyl-CoA stimulated both insulin release from streptolysin-O-permeabilized HIT cells and fusion of secretory granules to the plasma membrane of mouse pancreatic beta-cells, as measured by cell capacitance. The LC-CoA effect was chain length-dependent, requiring chain lengths of at least 14 carbons. LC-CoA needed to be present to stimulate insulin release, and consequently there was no effect following its removal. The stimulatory effect was observed after inhibition of protein kinase activity and in the absence of ATP, even though both kinases and ATP, themselves, modulate exocytosis. The effect of LC-CoA was inhibited by cerulenin, which has been shown to block protein acylation. The data suggest that altered LC-CoA levels, resulting from FFA or glucose metabolism, may act directly on the exocytotic machinery to stimulate insulin release by a mechanism involving LC-CoA protein binding.
 ...
PMID:Acute stimulation with long chain acyl-CoA enhances exocytosis in insulin-secreting cells (HIT T-15 and NMRI beta-cells). 1073 79

The lipolytic reaction in adipocytes is one of the most important reactions in the management of bodily energy reserves, and dysregulation of this reaction may contribute to the symptoms of Type 2 diabetes mellitus. Yet, progress on resolving the molecular details of this reaction has been relatively slow. However, recent developments at the molecular level begin to paint a clearer picture of lipolysis and point to a number of unanswered questions. While HSL has long been known to be the rate-limiting enzyme of lipolysis, the mechanism by which HSL attacks the droplet lipids is not yet firmly established. Certainly, the immunocytochemical evidence showing the movement of HSL to the lipid droplet upon stimulation leaves little doubt that this translocation is a key aspect of the lipolytic reaction, but whether or not HSL phosphorylation contributes to the translocation, and at which site(s), is as yet unresolved. It will be important to establish whether there is an activation step in addition to the translocation reaction. The participation of perilipin A is indicated by the findings that this protein can protect neutral lipids within droplets from hydrolysis, but active participation in the lipolytic reaction is yet to be proved. Again, it will be important to determine whether mutations of serine residues of PKA phosphorylation sites of perilipins prevent lipolysis, and whether such modifications abolish the physical changes in the droplet surfaces that accompany lipolysis.
 ...
PMID:On the control of lipolysis in adipocytes. 1084 61

Insulin regulates the rate of expression of many hepatic genes, including PEPCK, glucose-6-phosphatase (G6Pase), and glucose-6-phosphate dehydrogenase (G6PDHase). The expression of these genes is also abnormally regulated in type 2 diabetes. We demonstrate here that treatment of hepatoma cells with 5-aminoimidazole-4-carboxamide riboside (AICAR), an agent that activates AMP-activated protein kinase (AMPK), mimics the ability of insulin to repress PEPCK gene transcription. It also partially represses G6Pase gene transcription and yet has no effect on the expression of G6PDHase or the constitutively expressed genes cyclophilin or beta-actin. Several lines of evidence suggest that the insulin-mimetic effects of AICAR are mediated by activation of AMPK. Also, insulin does not activate AMPK in H4IIE cells, suggesting that this protein kinase does not link the insulin receptor to the PEPCK and G6Pase gene promoters. Instead, AMPK and insulin may lie on distinct pathways that converge at a point upstream of these 2 gene promoters. Investigation of the pathway by which AMPK acts may therefore give insight into the mechanism of action of insulin. Our results also suggest that activation of AMPK would inhibit hepatic gluconeogenesis in an insulin-independent manner and thus help to reverse the hyperglycemia associated with type 2 diabetes.
 ...
PMID:5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. 1086 40

Type 1 diabetes results from autoimmune destruction of the pancreatic beta-cells. Although viruses have been implicated as etiologic factors, specific pathogenic mechanisms have not been identified. Recently, increased attention has focused on the role of the innate antiviral defense system in directing adaptive immune responses. In this context, the pathogenesis of type 1 diabetes may involve an aberrant response to endogenous or exogenous viruses or their products. The family of 2',5' oligoadenylate synthetases (2', 5' AS) are IFN-alpha-inducible, RNA-dependent effector molecules in the antiviral defense system. We show that lymphocytic 2',5' AS activity is significantly increased in type 1 diabetes, both in recent-onset and in long-standing type 1 diabetes, and in diabetic twins from monozygotic twin pairs. The activity of 2',5' AS was not elevated in patients with type 2 diabetes or multiple sclerosis thus excluding hyperglycemia or autoimmunity per se as inducing upregulation of enzyme activity. In recent-onset diabetic patients, lymphocyte levels of protein kinase p68 and MxA, two other IFN-alpha-inducible antiviral proteins, were similar to control levels. These data suggest that the increased 2',5' AS activity may reflect an aberrant response to viruses or RNA molecules originating from exogenous or endogenous sources.
 ...
PMID:The antiviral 2',5'-oligoadenylate synthetase is persistently activated in type 1 diabetes. 1087 23

Over the past 20 years, it has been clearly documented that 1) polycystic ovary syndrome (PCOS) has major metabolic sequelae related to insulin resistance and 2) insulin resistance plays an important role in the pathogenesis of the reproductive abnormalities of the disorder. Women with PCOS are at significantly increased risk of developing type 2 diabetes mellitus (DM). Studies in isolated adipocytes and in cultured skin fibroblasts from PCOS women have demonstrated intrinsic postbinding defects in insulin-mediated glucose metabolism. In fibroblasts, the mitogenic pathway of insulin action is intact, consistent with a selective defect in insulin signaling. While PCOS skeletal muscle is resistant to insulin in vivo, cultured muscle cells have normal insulin sensitivity, consistent with a major role of extrinsic factors in producing insulin resistance in this tissue. Excessive serine phosphorylation of the insulin receptor or downstream signaling proteins may be involved in the pathogenesis of insulin resistance in PCOS. The putative serine kinase is extrinsic to the insulin receptor but its identity is unknown. The explanations for tissue-specific and signaling pathway-specific differences in insulin action in PCOS are unknown but may involve differential roles of insulin receptor substrate (IRS)-1 and IRS-2 in insulin signal transduction.
 ...
PMID:Insulin resistance in polycystic ovary syndrome: progress and paradoxes. 1123 18

Psammomys obesus is a model of type 2 diabetes that displays resistance to insulin and deranged beta-cell response to glucose. We examined the major signaling pathways for insulin release in P. obesus islets. Islets from hyperglycemic animals utilized twice as much glucose as islets from normoglycemic diabetes-prone or diabetes-resistant controls but exhibited similar rates of glucose oxidation. Fractional oxidation of glucose was constant in control islets over a range of concentrations, whereas islets from hyperglycemic P. obesus showed a decline at high glucose. The mitochondrial substrates alpha-ketoisocaproate and monomethyl succinate had no effect on insulin secretion in P. obesus islets. Basal insulin release in islets from diabetes-resistant P. obesus was unaffected by glucagon-like peptide 1 (GLP-1) or forskolin, whereas that of islets of the diabetic line was augmented by the drugs. GLP-1 and forskolin potentiated the insulin response to maximal (11.1 mmol/l) glucose in islets from all groups. The phorbol ester phorbol myristic acid (PMA) potentiated basal insulin release in islets from prediabetic animals, but not those from hyperglycemic or diabetes-resistant P. obesus. At the maximal stimulatory glucose concentration, PMA potentiated insulin response in islets from normoglycemic prediabetic and diabetes-resistant P. obesus but had no effect on islets from hyperglycemic P. obesus. Maintenance of islets from hyperglycemic P. obesus for 18 h in low (3.3 mmol/l) glucose in the presence of diazoxide (375 pmol/l) dramatically improved the insulin response to glucose and restored the responsiveness to PMA. Immunohistochemical analysis indicated that hyperglycemia was associated with reduced expression of alpha-protein kinase C (PKC) and diminished translocation of lambda-PKC. In summary, we found that 1) P. obesus islets have low oxidative capacity, probably resulting in limited ability to generate ATP to initiate and drive the insulin secretion; 2) insulin response potentiated by cyclic AMP-dependent protein kinase is intact in P. obesus islets, and increased sensitivity to GLP-1 or forskolin in the diabetic line may be secondary to increased sensitivity to glucose; and 3) islets of hyperglycemic P. obesus display reduced expression of alpha-PKC and diminished translocation of lambda-PKC associated with impaired response to PMA. We conclude that low beta-cell oxidative capacity coupled with impaired PKC-dependent signaling may contribute to the animals' poor adaptation to a high-energy diet.
 ...
PMID:Defective stimulus-secretion coupling in islets of Psammomys obesus, an animal model for type 2 diabetes. 1127 41

Imidazoline compounds have been considered for the treatment of type 2 diabetes. We have now investigated the effects of imidazolines on interleukin (IL)-1beta-induced beta-cell apoptosis and the signal transduction pathways involved. Inhibition of Ca2+ influx into beta-cells by D-600, a blocker of voltage-gated L-type Ca2+ channels, suppressed IL-1beta-induced apoptosis. Our data show that calcineurin, Ca2+/calmodulin-dependent serine/threonine protein phosphatase 2B, is responsible for the effect of Ca2+ on beta-cell apoptosis. We also demonstrate that IL-1beta-mediated apoptosis correlates with expression of inducible nitric oxide synthase (iNOS) and the increase in intracellular production of nitric oxide. An inhibitor of cGMP-dependent protein kinase (PKG), KT5823, suppressed IL-1beta-induced apoptosis, suggesting the involvement of a PKG-dependent pathway in the apoptotic process. One of the major findings in this study is that imidazoline compounds RX871024 and efaroxan, suggested as prototypes of a new generation of drugs against type 2 diabetes, can protect against IL-1beta-induced apoptosis in pancreatic beta-cells, possibly by their inhibition of the expression of iNOS, a key element in the IL-1beta-induced apoptotic pathway in pancreatic beta-cells. These data suggest that imidazoline compounds should be explored as a potential therapeutic agent for the treatment of both type 1 and type 2 diabetes.
 ...
PMID:Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis. 1127 6

Prostaglandylinositol cyclic phosphate (cPIP), functionally a cAMP antagonist, is a novel, low-molecular weight mediator of insulin action. Both essential hypertension and type 2 diabetes may be associated with a reduction of cPIP synthesis. In intact cells and in plasma membranes, cPIP synthesis is stimulated by insulin, which activates cPIP synthase by tyrosine phosphorylation. We measured the activities of cPIP synthase in the homogenates of freeze-clamped and then lyophilized liver samples from five insulin-resistant, adult rhesus monkeys, obtained under basal fasting conditions and again under maximal insulin stimulation during a euglycemic hyperinsulinemic clamp. The mean cPIP synthase activity in basal samples (0.33 +/- 0.09 pmol/min/mg protein) was not significantly different at the end of the clamp (0.24 +/- 0.11 pmol/min/mg protein). Basal cPIP synthase activityVoL 12, No. 1, 2001 was directly related to both basal cAMP content and basal fractional activity of cAMP-dependent protein kinase (PKA): r=0.85, p<0.05 and r=0.86, p<0.05, respectively. In turn, insulin-stimulated cPIP synthase activity was inversely related to both the insulin-stimulated fractional activity of PKA (r=0.89, p<0.02) and the insulin-stimulated total PKA activity: r=0.94, p<0.005. The findings suggest that in the liver of insulin-resistant rhesus monkeys, cPIP synthase activity, which leads to the synthesis of the low-molecular weight mediator cPIP, may oppose cAMP synthesis and PKA activity.
 ...
PMID:Prostaglandylinositol cyclic phosphate synthase activity in the liver of insulin-resistant rhesus monkeys before and after a euglycemic hyperinsulinemic clamp. 1141 4

A considerable amount of data have accumulated showing that contraction of muscle has an acute insulin-like effect, triggering the uptake of glucose. Chronic muscle contraction, as seen in endurance training has effects on insulin sensitivity, enhancing the effect of insulin on glucose uptake. Endurance training results in an increase in levels of GLUT4 in the muscle. This increase in GLUT4 is thought to be responsible in part for the enhancement of insulin sensitivity. Recent experiments have demonstrated that acute and chronic effects of muscle contraction on glucose uptake and the increase in GLUT4 may be due to activation of a protein kinase, AMP-activated protein kinase (AMPK). This kinase is activated by the increase in 5'-AMP and the decline in creatine phosphate that occur during muscle contraction. Phosphorylated AMPK then presumably phosphorylates undefined target proteins, which in turn increase glucose uptake and transcription of the GLUT4 gene. Experiments have demonstrated that this kinase, normally activated during exercise, can be activated artificially in muscle by injecting non-exercising rats with 5-aminoimidazole-4-carboxamide-riboside (AICAR), an adenosine analog. AICAR is taken up into muscle and phosphorylated to form an analog of 5'-AMP. Acute (stimulation of glucose uptake into muscle) and chronic (increase in GLUT4) effects of exercise can be reproduced by injection of this drug. These observations open the door to the possibility of treatment of patients with type 2 diabetes with AMPK activators.
 ...
PMID:AMP-activated protein kinase: possible target for treatment of type 2 diabetes. 1146 46


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>