Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

S6K1, like other serine and threonine kinases activated by insulin (such as mTOR and PKCzeta), has recently been shown to participate in negative feedback mechanisms aimed at terminating insulin signaling through IRS (insulin receptor substrate) phosphorylation. Such homeostatic mechanisms can also be activated by excess nutrients or inducers of insulin resistance (such as fatty acids and proinflammatory cytokines) to produce an insulin-resistant state that often leads to the development of diabetes. Identification of the specific kinases involved in such insulin resistance pathways can help lead to the rational design of novel therapeutic agents for treating insulin resistance and type 2 diabetes.
 ...
PMID:Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. 1567 81

In recent years, recombinant DNA technology has been used to design insulin molecules that overcome the limitations of regular insulin in mealtime supplementation. However, safety issues have been raised with these alternatives, as the alteration of the three-dimensional structure may alter the interaction with the insulin and/or IGF-I receptors and therefore lead to the activation of alternate metabolic as well as mitogenic signaling pathways. It is therefore essential to carefully study acute and long-term effects in a preclinical state, as insulin therapy is meant to be a lifelong treatment. In this study, we determined in vivo the insulin receptor signaling characteristics activated by insulin glulisine (Lys(B3), Glu(B29)) at the level of insulin receptor phosphorylation, insulin receptor substrate phosphorylation, and downstream signaling elements such as phosphatidylinositol (PI) 3-kinase, AKT, and mitogen-activated protein kinase. C57BL/6 mice were injected with insulin glulisine or regular insulin and Western blot analysis was performed for liver and muscle tissue. The extent and time course of insulin receptor phosphorylation and activation of downstream signaling elements after insulin glulisine treatment was similar to that of human regular insulin in vivo. Moreover, insulin signaling in hypothalamic tissue determined by PI 3-kinase activity was comparable. Therefore, insulin glulisine may be a useful tool for diabetes treatment.
Diabetes 2005 Feb
PMID:Insulin glulisine: insulin receptor signaling characteristics in vivo. 1567 93

The neurodegeneration that occurs in sporadic Alzheimer's disease (AD) is consistently associated with a number of characteristic histopathological, molecular, and biochemical abnormalities, including cell loss, abundant neurofibrillary tangles and dystrophic neurites, amyloid-beta deposits, increased activation of pro-death genes and signaling pathways, impaired energy metabolism/mitochondrial function, and evidence of chronic oxidative stress. The general inability to convincingly link these phenomena has resulted in the emergence and propagation of various heavily debated theories that focus on the role of one particular element in the pathogenesis of all other abnormalities. However, the accumulating evidence that reduced glucose utilization and deficient energy metabolism occur early in the course of disease, suggests a role for impaired insulin signaling in the pathogenesis of AD. The present work demonstrates extensive abnormalities in insulin and insulin-like growth factor type I and II (IGF-I and IGF-II) signaling mechanisms in brains with AD, and shows that while each of the corresponding growth factors is normally made in central nervous system (CNS) neurons, the expression levels are markedly reduced in AD. These abnormalities were associated with reduced levels of insulin receptor substrate (IRS) mRNA, tau mRNA, IRS-associated phosphotidylinositol 3-kinase, and phospho-Akt (activated), and increased glycogen synthase kinase-3beta activity and amyloid precursor protein mRNA expression. The strikingly reduced CNS expression of genes encoding insulin, IGF-I, and IGF-II, as well as the insulin and IGF-I receptors, suggests that AD may represent a neuro-endocrine disorder that resembles, yet is distinct from diabetes mellitus. Therefore, we propose the term, "Type 3 Diabetes" to reflect this newly identified pathogenic mechanism of neurodegeneration.
 ...
PMID:Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? 1575 Feb 15

Mitochondrial dysfunction contributes to a number of human diseases, such as hyperlipidemia, obesity, and diabetes. The mutation and reduction of mitochondrial DNA (mtDNA) have been suggested as factors in the pathogenesis of diabetes. To elucidate the association of cellular mtDNA content and insulin resistance, we produced L6 GLUT4myc myocytes depleted of mtDNA by long term treatment with ethidium bromide. L6 GLUT4myc cells cultured with 0.2 mug/ml ethidium bromide (termed depleted cells) revealed a marked decrease in cellular mtDNA and ATP content, concomitant with a lack of mRNAs encoded by mtDNA. Interestingly, the mtDNA-depleted cells showed a drastic decrease in basal and insulin-stimulated glucose uptake, indicating that L6 GLUT4myc cells develop impaired glucose utilization and insulin resistance. The repletion of mtDNA normalized basal and insulin-stimulated glucose uptake. The mRNA level and expression of insulin receptor substrate (IRS)-1 associated with insulin signaling were decreased by 76 and 90% in the depleted cells, respectively. The plasma membrane (PM) GLUT4 in the basal state was decreased, and the insulin-stimulated GLUT4 translocation to the PM was drastically reduced by mtDNA depletion. Moreover, insulin-stimulated phosphorylation of IRS-1 and Akt2/protein kinase B were drastically reduced in the depleted cells. Those changes returned to control levels after mtDNA repletion. Taken together, our data suggest that PM GLUT4 content and insulin signal pathway intermediates are modulated by the alteration of cellular mtDNA content, and the reductions in the expression of IRS-1 and insulin-stimulated phosphorylation of IRS-1 and Akt2/protein kinase B are associated with insulin resistance in the mtDNA-depleted L6 GLUT4myc myocytes.
 ...
PMID:Depletion of mitochondrial DNA causes impaired glucose utilization and insulin resistance in L6 GLUT4myc myocytes. 1576 7

Insulin resistance is a hallmark of Type II diabetes. It is well documented that insulin sensitizers such as peroxisome-proliferator-activated receptor gamma agonists and aspirin improve insulin action in vivo. The detailed mechanisms by which the insulin sensitizers promote insulin signalling, however, are not completely understood and remain somewhat controversial. In the present review, we summarize our studies attempting to explore the molecular mechanisms underlying the effects of insulin sensitizers in cells and in animal models of insulin resistance. In 3T3-L1 adipocytes and/or in HEK-293 cells stably expressing recombinant IRS1 protein (insulin receptor substrate protein 1), the peroxisome-proliferator-activated receptor gamma agonist rosiglitazone and aspirin promote insulin signalling by decreasing inhibitory IRS1 serine phosphorylation. Increased IRS1 Ser-307 phosphorylation and concomitant decreased insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation and Akt threonine phosphorylation were observed in adipose tissues of Zucker obese rats compared with lean control rats. Treatment with rosiglitazone for 24 and 48 h increased insulin signalling and decreased IRS1 Ser-307 phosphorylation concomitantly. Treatment of the Zucker obese rats with rosiglitazone for 24 h also reversed the high circulating levels of free fatty acids, which have been shown to correlate with increased IRS1 serine phosphorylation. Taken together, the results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal may be physiologically relevant to insulin sensitization in vivo.
 ...
PMID:Modulation of insulin signalling by insulin sensitizers. 1578 6

Insulin and IGF-I activate antiapoptotic pathways via insulin receptor substrate (IRS) proteins in most mammalian cells, including beta-cells. IRS-1 knockout (IRS-1KO) mice show growth retardation, hyperinsulinemia, and hyperplastic but dysfunctional islets without developing overt diabetes, whereas IRS-2KOs develop insulin resistance and islet hypoplasia leading to diabetes. Because both models display insulin resistance, it is difficult to differentiate islet response to insulin resistance from islet defects due to loss of proteins in the islets themselves. We used a transplantation approach, as a means of separating host insulin resistance from islet function, to examine alterations in proteins in insulin/IGF-I signaling pathways that may contribute to beta-cell proliferation and/or apoptosis in IRS-1KO islets. Islets isolated from wild-type (WT) or IRS-1KO mice were transplanted into WT or insulin-resistant IRS-1KO males under the kidney capsule. The beta-cell mitotic rate in transplanted islets in IRS-1KO recipients was increased 1.5-fold compared with WT recipients and was similar to that in endogenous pancreases of IRS-1KOs, whereas beta-cell apoptosis was reduced by approximately 80% in IRS-1KO grafts in IRS-1KO recipients compared with WT recipients. Immunohistochemistry showed a substantial increase in IRS-2 expression in IRS-1KO islets transplanted into IRS-1KO mice as well as in endogenous islets from IRS-1KOs. Furthermore, enhanced cytosolic forkhead transcription factor (FoxO1) staining in IRS-1KO grafts suggests intact Akt/PKB activity. Together, these data indicate that, even in the absence of insulin resistance, beta-cells deficient in IRS-1 exhibit a compensatory increase in IRS-2, which is associated with islet growth and is characterized by both proliferative and antiapoptotic effects that likely occur via an insulin/IGF-I/IRS-2 pathway.
 ...
PMID:Alterations in growth and apoptosis of insulin receptor substrate-1-deficient beta-cells. 1582 66

Chronic inflammation has been postulated to play an important role in the pathogenesis of insulin resistance. Inducible nitric oxide synthase (iNOS) has been implicated in many human diseases associated with inflammation. iNOS deficiency was shown to prevent high-fat diet-induced insulin resistance in skeletal muscle but not in the liver. A role for iNOS in fasting hyperglycemia and hepatic insulin resistance, however, remains to be investigated in obesity-related diabetes. To address this issue, we examined the effects of a specific inhibitor for iNOS, L-NIL, in obese diabetic (ob/ob) mice. iNOS expression was increased in the liver of ob/ob mice compared with wild-type mice. Treatment with iNOS inhibitor reversed fasting hyperglycemia with concomitant amelioration of hyperinsulinemia and improved insulin sensitivity in ob/ob mice. iNOS inhibitor also increased the protein expression of insulin receptor substrate (IRS)-1 and -2 1.5- and 2-fold, respectively, and enhanced IRS-1- and IRS-2-mediated insulin signaling in the liver of ob/ob mice. Exposure to NO donor and ectopically expressed iNOS decreased the protein expression of IRS-1 and -2 in cultured hepatocytes. These results suggest that iNOS plays a role in fasting hyperglycemia and contributes to hepatic insulin resistance in ob/ob mice.
Diabetes 2005 May
PMID:A role for iNOS in fasting hyperglycemia and impaired insulin signaling in the liver of obese diabetic mice. 1585 18

Currently, we observe an epidemic expansion of diabetes mellitus. In subjects with Type 2 diabetes the resistance of fat, muscle and liver to insulin is the central pathophysiological event in the development of this disease. Genetic and environmental factors play a major role in this process, although the precise pathogenesis of insulin resistance and Type 2 diabetes is still largely unknown. However, recent studies have contributed to a deeper understanding of the molecular mechanisms underlying this process. In this review we therefore summarize the current developments in understanding the pathophysiological process of insulin resistance and Type 2 diabetes. Among the many molecules involved in the intracellular processing of the signal provided by insulin, insulin receptor substrate (IRS)-2, the protein kinase B (PKB)-beta isoform and the forkhead transcription factor Foxo1a (FKHR) are of particular interest in this context as recent data have provided strong evidence that dysfunction of these proteins results in insulin resistance in-vivo. Furthermore, we have now increasing evidence that the adipose tissue not only produces free fatty acids that contribute to insulin resistance, but also acts as a relevant endocrine organ producing mediators (adipokines) that can modulate insulin signalling. The identification of the molecular pathophysiological mechanisms of insulin resistance and Type 2 diabetes is essential for the development of novel and more effective therapies to better treat our patients with insulin resistance and Type 2 diabetes.
 ...
PMID:Molecular mechanisms of insulin resistance. 1591 Jun 15

The dose-response relationship between elevated plasma free fatty acid (FFA) levels and impaired insulin-mediated glucose disposal and insulin signaling was examined in 21 lean, healthy, normal glucose-tolerant subjects. Following a 4-h saline or Liposyn infusion at 30 (n = 9), 60 (n = 6), and 90 (n = 6) ml/h, subjects received a 2-h euglycemic insulin (40 mU . m(-2) . min(-1)) clamp. Basal plasma FFA concentration ( approximately 440 micromol/l) was increased to 695, 1,251, and 1,688 micromol/l after 4 h of Liposyn infusion and resulted in a dose-dependent reduction in insulin-stimulated glucose disposal (R(d)) by 22, 30, and 34%, respectively (all P < 0.05 vs. saline control). At the lowest lipid infusion rate (30 ml/h), insulin receptor and insulin receptor substrate (IRS)-1 tyrosine phosphorylation, phosphatidylinositol (PI) 3-kinase activity associated with IRS-1, and Akt serine phosphorylation were all significantly impaired (P < 0.05-0.01). The highest lipid infusion rate (90 ml/h) caused a further significant reduction in all insulin signaling events compared with the low-dose lipid infusion (P < 0.05-0.01) whereas the 60-ml/h lipid infusion caused an intermediate reduction in insulin signaling. However, about two-thirds of the maximal inhibition of insulin-stimulated glucose disposal already occurred at the rather modest increase in plasma FFA induced by the low-dose (30-ml/h) lipid infusion. Insulin-stimulated glucose disposal was inversely correlated with both the plasma FFA concentration after 4 h of lipid infusion (r = -0.50, P = 0.001) and the plasma FFA level during the last 30 min of the insulin clamp (r = -0.54, P < 0.001). PI 3-kinase activity associated with IRS-1 correlated with insulin-stimulated glucose disposal (r = 0.45, P < 0.01) and inversely with both the plasma FFA concentration after 4 h of lipid infusion (r = -0.39, P = 0.01) and during the last 30 min of the insulin clamp (r = -0.43, P < 0.01). In summary, in skeletal muscle of lean, healthy subjects, a progressive increase in plasma FFA causes a dose-dependent inhibition of insulin-stimulated glucose disposal and insulin signaling. The inhibitory effect of plasma FFA was already significant following a rather modest increase in plasma FFA and develops at concentrations that are well within the physiological range (i.e., at plasma FFA levels observed in obesity and type 2 diabetes).
Diabetes 2005 Jun
PMID:Dose-response effect of elevated plasma free fatty acid on insulin signaling. 1591 84

Hyperglycemic impairment of nitric oxide (NO) production by endothelial cells is implicated in the effect of diabetes to increase cardiovascular disease risk, but the molecular basis for this effect is unknown. In skeletal muscle, diabetes induces activation of inhibitor kappaB kinase (IKKbeta), a key cellular mediator of the response to inflammatory stimuli, and this impairs insulin signal transduction via the insulin receptor substrate-phosphatidylinositol 3-OH kinase (IRS-1/PI3-kinase) pathway. Since activation of endothelial nitric oxide synthase (eNOS) is dependent on IRS-1/PI3-kinase signaling, we hypothesized that activation of IKKbeta may contribute to the effect of glucose to impair NO production. Here, we show that exposure of bovine aortic endothelial cells to high glucose (25 mM) for 24 h impaired insulin-mediated tyrosine phosphorylation of IRS-1, serine phosphorylation of Akt, activation of eNOS, and production of NO. High glucose treatment also activated IKKbeta, and pretreatment with aspirin, a pharmacological inhibitor of IKKbeta, prevented both glucose-induced IKKbeta activation and the effect of high glucose to impair insulin-mediated NO production. These adverse responses to glucose were also blocked by selective inhibition of IKKbeta signaling via overexpression of a kinase-inactive form of the enzyme. Conversely, overexpression of wild-type IKKbeta recapitulated the deleterious effect of high glucose on insulin-mediated activation of eNOS. These data demonstrate that activation of IKKbeta plays a critical and novel role to mediate the deleterious effects of high glucose on endothelial cell function.
 ...
PMID:Activation of IKKbeta by glucose is necessary and sufficient to impair insulin signaling and nitric oxide production in endothelial cells. 1597 11


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