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PubMed2006

Glucose transporter expression in English sparrows (Passer domesticus).

Patterns of glucose transporter expression have been well-characterized in mammals. However, data for birds is currently restricted to isolated cells, domestic chickens and chicks, and ducklings. Therefore, in the present study, protein and gene expression of various glucose transporters (GLUTs) in English sparrow extensor digitorum communis, gastrocnemius and pectoralis muscles as well as heart, kidney, and brain tissues were examined. The hypothesis is that the expression pattern of avian GLUTs differs from mammals to maintain the high plasma glucose levels of birds and insulin insensitivity. Our studies failed to identify a GLUT4-like insulin responsive transporter in sparrows. GLUT1 gene expression was identified in all tissues examined and shares 88% homology with chicken and 84% homology with human GLUT1. Compared to the rat control, GLUT1 immunostaining of sparrow extensor digitorum communis muscle was weak and appeared to be localized to blood vessels whereas immunostaining of gastrocnemius muscles was comparable to rat muscle controls. Gene expression of GLUT3 was identified in all tissues examined and shares 90% gene sequence homology with chicken embryonic fibroblast and 75% homology with human GLUT3. Protein expression of GLUT3 was not determined as an avian antibody is not available. Moreover, the C-terminus of the mammalian GLUT3 transporter, against which antibodies are typically designed, differs significantly among species. The predominant difference of chicken and sparrow GLUT expression patterns from that of mammals is the lack of an avian GLUT4. The absence of this insulin responsive GLUT in birds may be a contributing factor to the observed high blood glucose levels and insulin insensitivity.

Animals↗
PubMed2006

A novel method to monitor insulin-stimulated GTP-loading of Rab11a in cardiomyocytes.

As a member of the Rab small GTPase family, Rab11a has been shown to be involved in different vesicle trafficking processes. In earlier work we identified Rab11a to be present in GLUT4-containing vesicles after insulin stimulation and showed its involvement in insulin-dependent glucose uptake. However, it remained elusive if Rab11a is directly activated by the insulin signalling cascade and at which step a potential activation occurs. To examine the GTP-loading of Rab11a, we introduced a biotinylated GTP-analog into H9c2-hIR cells, transiently overexpressing HA-tagged Rab11a, and measured its binding to the GTPase after insulin stimulation. We observed that Rab11a is transiently GTP-loaded after insulin stimulation with a 2.3 (+/-0.3) fold activation (n=5), reaching its maximum after 4 min and declining back to basal after additional 2 min. The activation of Rab11a is phosphatidylinositol 3-kinase (PI3-kinase) dependent and downstream of Akt, as shown by in vitro knockdown of this kinase. These data show that Rab11a is directly activated by insulin and represents an element of the GLUT4 trafficking machinery.

Animals↗
PubMed2005

A potential link between muscle peroxisome proliferator- activated receptor-alpha signaling and obesity-related diabetes.

The role of the peroxisome proliferator-activated receptor-alpha (PPARalpha) in the development of insulin-resistant diabetes was evaluated using gain- and loss-of-function approaches. Transgenic mice overexpressing PPARalpha in muscle (MCK-PPARalpha mice) developed glucose intolerance despite being protected from diet-induced obesity. Conversely, PPARalpha null mice were protected from diet-induced insulin resistance in the context of obesity. In skeletal muscle, MCK-PPARalpha mice exhibited increased fatty acid oxidation rates, diminished AMP-activated protein kinase activity, and reduced insulin-stimulated glucose uptake without alterations in the phosphorylation status of key insulin-signaling proteins. These effects on muscle glucose uptake involved transcriptional repression of the GLUT4 gene. Pharmacologic inhibition of fatty acid oxidation or mitochondrial respiratory coupling prevented the effects of PPARalpha on GLUT4 expression and glucose homeostasis. These results identify PPARalpha-driven alterations in muscle fatty acid oxidation and energetics as a potential link between obesity and the development of glucose intolerance and insulin resistance.

Animals↗
PubMed2006

Dioscorea opposita reverses dexamethasone induced insulin resistance.

The effects of Dioscorea opposita (huai shan yao, HSY) on dexamethasone-induced insulin resistance were investigated in vitro and in vivo. D. opposita extract reduced significantly the blood insulin and glucose levels in dexamethasone-induced diabetic rats. In vitro, HSY significantly enhanced insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Moreover, HSY increase the mRNA expression of GLUT4 glucose transporter in 3T3-L1 adipocytes. These data suggest that D. opposita has insulin sensitivity that is associated with the regulation of GLUT4 expression.

Adipocytes↗
PubMed2005

Insulin resistance and clinical aspects of non-alcoholic steatohepatitis (NASH).

Non-alcoholic steatohepatitis (NASH) is one of the most common liver disorders. This is highly prevalent in obese and diabetic subjects. Persons with central obesity are at particular risk. Other clinical predictors are age more than 40-50 years and hyperlipidemias, but none of these factors is invariable for causation of NASH. Other reported associations are, celiac disease, Wilson's Disease and few other metabolic diseases. Drugs, particularly amiodarone, tamoxifen, nucleoside analogues and methotrxate have also been linked to NASH. The disease is evenly distributed in both sexes but advanced disease is more common in women. Ethnic variation exists and African Americans are less affected than Hispanic Americans. Specific clinical features of NASH are infrequent. Patients usually come to clinical attention by elevated liver enzymes found on routine evaluation but on history, about two third of patients will admit to have mild fatigue and about half will report right upper quadrant pain. Rarely, patient may present with a complication of cirrhosis. Physical examination may reveal hepatomegaly and splenomegaly. Research in last few years has stressed that development of steatosis, stetohepatitis, fibrosis with subsequent cirrhosis are most probably the result of insulin resistance. Therefore, clinical features may reflect existence of insulin resistance. Obesity, particularly central obesity is most important of these. Patients may have sleep apnea syndrome. Hypertension and manifestations of diabetes mellitus like polyuria, polydypsia, and neurological deficits may occur. Patients may have varying combination of obesity, diabetes, hyperlipidemia, hypertension and impaired fibrinolysis (syndrome X). Children with insulin resistance may show acanthosis nigricance. Patients with polycystic ovary syndrome, which consists of insulin resistance, diabetes, obesity, hirsutism, oligo or polymenorrha and hyperlipidemia may have NASH. Other rare manifestations of insulin resistance, which can be seen in patients of NASH are lipomatosis, lipoatrophy/lipodystrophy and panniculitis. Most other rare conditions known to cause NASH like peroxisomal diseases, mitochondialpathies, Weber-Christian disease, Mauriac syndrome, Madelung's lipomatosis and abetaliopprotenemia also have insulin resistance. This is believed that primary defect underlying insulin resistance is impairment in postreceptor pathways (through tyrosine kinase activity) of insulin action. Primary defect in insulin receptors appear uncommon. This results in down regulation of insulin receptor substance 1 (IRS-1) signaling by excess free fatty acids. In muscle, activated IRS-1 promotes translocation of glucose transporter protein 4 (GLUT4) to cell membrane. As a result, monocyte glucose uptake by GLUT4 increases glucose disposal from blood and reduced need for insulin. PKC-0 is a likely candidate as serine kinase in muscle regulated by fatty acids that can impair the activation of IRS-1. Insulin resistance is usually evaluated by fasting insulin levels, Quantitative Insulin Check Index (QUICKI) and Homeostasis Model Assessment of Insulin Resistance (HOMA), C-peptid/insulin ratio oral glucose tolerance test and hyper insulinemic euglycemic clamp. The clamp technique is considered the gold standard.

Journal Article↗
PubMed2006

Myocardial glucose transport and utilization in patients with type 2 diabetes mellitus, left ventricular dysfunction, and coronary artery disease.

OBJECTIVES: This research was designed to assess the effect of type 2 diabetes mellitus (T2DM) on myocardial glucose utilization in patients with heart failure secondary to coronary artery disease. BACKGROUND: Patients with T2DM and coronary artery disease have an increased morbidity and mortality compared with patients with coronary artery disease without diabetes that may relate to a reduction in the ability of the myocardium to utilize glucose. METHODS: Myocardial blood flow and glucose utilization were assessed during a hyperinsulinemic clamp by 18F-flurodeoxyglucose and positron emission tomography in 54 patients (19 with T2DM) with multivessel coronary artery disease and heart failure. In a subgroup of 18 patients, myocardial biopsies were obtained during coronary bypass surgery to assess glucose transporter (GLUT4) distribution and protein concentration, and compared with myocardium from transplant donor hearts. RESULTS: Myocardial blood flow was similar in patients without diabetes and those with T2DM. Myocardial glucose utilization was lower in patients with T2DM (0.34 +/- 0.16 vs. 0.47 +/- 0.24 micromol x min(-1) x g(-1), p = 0.0002) despite comparable plasma insulin concentrations and a higher blood glucose concentration. Extraction of glucose by the myocardium was reduced in patients with T2DM (7.1 +/- 3.1% vs. 13.5 +/- 5.2%, p < 0.01). Myocardial GLUT4 protein was similar in patients with and without T2DM (p = 0.75). CONCLUSIONS: Patients with coronary artery disease and heart failure exhibit myocardial insulin resistance, and this is greater in those with T2DM. This may limit the ability of the myocardium in patients with T2DM to withstand ischemia and may contribute to the increased cardiovascular morbidity and mortality in such patients.

Aged↗
PubMed2006

Impaired insulin action despite upregulation of proximal insulin signaling: novel insights into skeletal muscle insulin resistance in liver cirrhosis.

BACKGROUND/AIMS: Disturbance in glucose metabolism is a common feature in liver diseases and this is associated with skeletal muscle insulin resistance. However, the underlying molecular mechanisms are unclear. To characterize skeletal muscle insulin resistance associated with liver disease, we examined muscles from animals after an acute, 5 weeks perturbation of the common bile duct. Clinical findings, elevated plasma levels of liver enzymes and histological examinations confirmed cirrhosis. METHODS/RESULTS: : Cirrhotic animals were insulin resistant and this was associated with reduced glucose transport into muscles. Interestingly, activity in the proximal part of the insulin signaling cascade was not decreased, as evinced by increased activity of key enzymes in the signal to glucose transport. Expression of the glucose transporter, GLUT4, was normal. So together these results indicate that signaling downstream of PKB/Akt and/or the translocation of GLUT4 is impaired in skeletal muscle from cirrhotic animals. CONCLUSIONS: In conclusion, in an animal model of liver cirrhosis whole body insulin resistance is associated with insulin resistance in skeletal muscles. Unlike other common forms of insulin resistance, muscles from cirrhotic animals have increased activity in the proximal insulin signaling cascade. This emphasizes the fact that skeletal muscle insulin resistance associated with liver cirrhosis is a unique entity.

Animals↗
PubMed2005

Effects of different antipsychotics and the antidepressant mirtazapine on glucose transporter mRNA levels in human blood cells.

A relationship between cell metabolism and the expression of glucose transporters (GLUT) has been reported. On the other side, treatment with some antipsychotics has been associated with an increased incidence of hyperglycemia and new-onset type 2 diabetes. We here examined the effects of different concentrations of the conventional antipsychotic haloperidol (400 and 800 microg/ml), of the atypical antipsychotics clozapine (100 and 200 microg/ml) and olanzapine (100 and 200 microg/ml) as well as of the antidepressant mirtazapine (10(-7) mol) on the mRNA levels of GLUT1-5 in the human leukemic blood cell line U937 after incubation for 48 h. After experimental treatment, significant increases were detected by ANOVA and appropriate post-hoc tests for mirtazapine in GLUT4 mRNA levels as well as for haloperidol 400 and 800 microg/ml, olanzapine 200 microg/ml, and mirtazapine in GLUT5 mRNA levels. ANOVAs revealed no statistically significant changes in GLUT1-3 and beta-actin mRNA levels. These findings suggest that direct effects of psychotropic drugs on cellular GLUT4 and GLUT5 may be involved in the metabolic dysfunctions occurring during psychopharmacological treatment.

Actins↗
PubMed2004

Chronic leptin treatment enhances insulin-stimulated glucose disposal in skeletal muscle of high-fat fed rodents.

The aim of this investigation was to evaluate if chronic leptin administration corrects high fat diet-induced skeletal muscle insulin resistance, in part, by enhancing rates of glucose disposal and if the improvements are accounted for by alterations in components of the insulin-signaling cascade. Sprague-Dawley rats consumed normal (CON) or high fat diets for three months. After the dietary lead in, the high fat diet group was further subdivided into high fat (HF) and high fat, leptin treated (HF-LEP) animals. HF-LEP animals were injected twice daily with leptin (5 mg/100 g body weight) for 10 days, while the CON and HF animals were injected with vehicle. Following the treatment periods, all animals were prepared for and subjected to hind limb perfusion. The high fat diet decreased rates of insulin-stimulated skeletal muscle glucose uptake and glycogen synthesis in the red gastrocnemius (RG), but did not affect glycogen synthase activity, rates of glucose oxidation or nonoxidative disposal of glucose. Of interest, IRS-1-associated PI3-K activity and total GLUT4 protein concentration were reduced in the RG of the high fat-fed animals. Leptin treatment increased rates of insulin-stimulated glucose uptake and glucose oxidation, and normalized rates of glycogen synthesis. Leptin appeared to mediate these effects by normalizing insulin-stimulated PI3-K activation and GLUT4 protein concentration in the RG. Collectively, these data suggest that chronic leptin treatment reverses the effects of a high fat diet thereby allowing the insulin signaling cascade and glucose transport effector system to be fully activated which in turn affects the amount of glucose that is transported across the plasma membrane and made available for glycogen synthesis.

Animals↗
PubMed2004

The insulin sensitizing effect of homoisoflavone-enriched fraction in Liriope platyphylla Wang et Tang via PI3-kinase pathway.

In the present study, we screened candidates for enhancing insulin action, using glucose uptake as an indicator, from Liriope platyphylla Wang et Tang (LPWT) extract, Liliaceae, in 3T3-L1 adipocytes. The mechanism of insulin sensitizing action in the fractions was also investigated. LPWT extract with 70% MeOH was sequentially separated with Diaion HP-20 and silica gel column chromatography. The 9:1 fraction from silica gel column chromatography increased glucose uptake with 1 ng/mL up to glucose uptake with 50 ng/mL insulin. The 9:1 fraction, determined as homoisoflavone-enriched fraction, worked as an insulin sensitizer. It increased insulin stimulated glucose uptake in 3T3-L1 adipocytes, insulin responsive cells, through increased glucose transporter 4 (GLUT4) contents in the plasma membrane. GLUT4 translocation was increased through insulin receptor substrate 1 (IRS1)-PI3 kinase-Akt signaling mechanism. Thus, homoisoflavone-enriched fraction in LPWT extract played an important role as an insulin sensitizer in adipocytes.

3T3-L1 Cells↗
PubMed2005

Pharmacological inhibition of p38 MAP kinase results in improved glucose uptake in insulin-resistant 3T3-L1 adipocytes.

Inhibition of p38, a member of the mitogen-activated protein kinase family, has been shown to prevent the loss of GLUT4 protein expression in insulin-resistant adipocytes without improving insulin receptor substrate 1 (IRS-1) protein levels and presumably insulin signaling. Thus, it was unclear whether p38 inhibitors would have a beneficial effect upon insulin-stimulated glucose uptake. We evaluated the effects of p38 inhibition during the development of insulin resistance upon glucose uptake and components of the insulin signaling pathway to determine the therapeutic value of p38 inhibitors. Treatment with the specific p38 inhibitor, A304000, during the development of insulin resistance increased basal glucose uptake as well as glucose uptake in response to a subsequent insulin stimulation. p38 inhibition increased GLUT1 protein levels and prevented the loss of GLUT4. However, p38 inhibition did not prevent the loss of IRS-1 protein levels or insulin signaling to PKB in insulin-resistant cells. Rapamycin, an inhibitor or mTOR, could partially improve insulin-stimulated glucose uptake through maintaining IRS-1 protein levels. Combined treatment with both A304000 and rapamycin had an additive effect upon glucose uptake. These data indicate that p38 inhibition can enhance glucose uptake through regulating the expression of GLUT1 and 4, but did not prevent the development of insulin resistance.

3T3-L1 Cells↗
PubMed2006

Chromium picolinate positively influences the glucose transporter system via affecting cholesterol homeostasis in adipocytes cultured under hyperglycemic diabetic conditions.

Since trivalent chromium (Cr(3+)) enhances glucose metabolism, interest in the use of Cr(3+)as a therapy for type 2 diabetes has grown in the mainstream medical community. Moreover, accumulating evidence suggests that Cr(3+) may also benefit cardiovascular disease (CVD) and atypical depression. We have found that cholesterol, a lipid implicated in both CVD and neurodegenerative disorders, also influences cellular glucose uptake. A recent study in our laboratory shows that exposure of 3T3-L1 adipocytes to chromium picolinate (CrPic, 10 nM) induces a loss of plasma membrane cholesterol. Concomitantly, accumulation of intracellularly sequestered glucose transporter GLUT4 at the plasma membrane was dependent on the CrPic-induced cholesterol loss. Since CrPic supplementation has the greatest benefit on glucose metabolism in hyperglycemic insulin-resistant individuals, we asked here if the CrPic effect on cells was glucose-dependent. We found that GLUT4 redistribution in cells treated with CrPic occurs only in cells cultured under high glucose (25 mM) conditions that resemble the diabetic-state, and not in cells cultured under non-diabetic (5.5 mM glucose) conditions. Examination of the effect of CrPic on proteins involved in cholesterol homeostasis revealed that the activity of sterol regulatory element-binding protein (SREBP), a membrane-bound transcription factor ultimately responsible for controlling cellular cholesterol balance, was upregulated by CrPic. In addition, ABCA1, a major player in mediating cholesterol efflux was decreased, consistent with SREBP transcriptional repression of the ABCA1 gene. Although the exact mechanism of Cr(3+)-induced cholesterol loss remains to be determined, these cellular responses highlight a novel and significant effect of chromium on cholesterol homeostasis. Furthermore, these findings provide an important clue to our understanding of how chromium supplementation might benefit hypercholesterolemia-associated disorders.

3T3-L1 Cells↗
PubMed2005

Evidence that Akt mediates platelet-derived growth factor-dependent increases in activity and surface expression of the neuronal glutamate transporter, EAAC1.

Previously we have shown that platelet-derived growth factor (PDGF) rapidly increases the activity of the neuronal glutamate transporter, EAAC1. This increase in activity is associated with a rapid (within minutes) redistribution of transporter from a subcellular compartment to the plasma membrane and is blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K). Similar effects of PI3K inhibitors have been observed for insulin-dependent up-regulation of the GLUT4 subtype of glucose transporter. Although GLUT4 regulation also depends on the serine-threonine kinase (Akt/protein kinase B), a downstream target of PI3K, the downstream effectors responsible of PDGF-dependent regulation of EAAC1 have not been identified. In the present study, PDGF increased the level of Akt phosphorylation (Ser 473) in C6 glioma cells, a cell line that has been used to study regulated trafficking of endogenous EAAC1. Two inhibitors of PI3K blocked this effect. In transient transfection studies, a dominant negative mutant of Akt-1 blocked PDGF-induced redistribution of epitope-tagged EAAC1 (myc-EAAC1). Conversely, constitutively active Akt-1 (CA Akt-1) increased the cell surface expression of myc-EAAC1. A lentiviral vector engineered to express CA Akt-1 increased Akt activation, cell surface expression of endogenous EAAC1, and Na(+)-dependent glutamate transport activity. Together, these studies suggest that Akt is required for PDGF-induced regulation of EAAC1.

Animals↗
PubMed2005

At therapeutic concentrations, olanzapine does not affect basal or insulin-stimulated glucose transport in 3T3-L1 adipocytes.

The newer, atypical antipsychotic drugs have improved the treatment of schizophrenia and are widely used. A disadvantage is that they increase food intake, promote weight gain and may facilitate development of diabetes. The mechanism of the latter effect is controversial. A possible interaction of these drugs with glucose transporters has been proposed: peripheral insulin resistance may develop if these drugs inhibited glucose transport in cells which express the insulin responsive glucose transporter, GLUT4, i.e., muscle and adipocytes. To test this hypothesis, we incubated 3T3-L1 adipocytes, which express GLUT1 and GLUT4, with the atypical antipsychotic drug olanzapine for 1 or 20 h and then measured basal and insulin-stimulated glucose transport. The doses of olanzapine tested (70 nM and 350 nM) encompass and exceed maximal steady-state concentrations of the drug in plasma of patients maintained on maximal recommended doses (20 mg QD) of olanzapine. A maximally stimulating insulin concentration (100 nM) accelerated glucose transport 10- to 15-fold in 3T3-L1 adipocytes, and the half-maximally stimulating insulin dose was 0.4 nM. Olanzapine (70 or 350 nM) did not affect basal or insulin-stimulated glucose transport following 1 or 20 h drug treatment at any insulin concentration tested. The data do not support the hypothesis that olanzapine at therapeutically relevant concentrations may cause peripheral insulin resistance by direct interaction with the insulin responsive glucose transport system.

3T3 Cells↗
PubMed2006

Overfeeding during lactation modulates insulin and leptin signaling cascade in rats' hearts.

Insulin has been described as a potential mediator of intrinsic responses to the nutritional state in the heart due to its effects on cardiac metabolism, mainly on glucose transport. It has been demonstrated that leptin can act through some components of the insulin-signaling cascade. We investigated the association between overfeeding during lactation and alterations of insulin and leptin signaling in the heart. In summary, we analyzed a feasible cross-talk between insulin and leptin through the study of some key proteins of their cascades in the heart. In order to study the effect of overfeeding on these cascades, Wistar rats were overfed through litter size reduction to only three pups. At 10 and 21 days of life, key proteins such as insulin receptor, leptin receptor, PI3-kinase, JAK2, STAT3, and GLUT4 were measured by Western blotting. Furthermore, the pups' weight and the plasma levels of insulin, leptin and glucose were determined. Overfed animals were overweight, had high insulin and leptin plasma levels, and displayed an activation of insulin and leptin cascade, leading to an increased translocation of GLUT4. We suggest that overfeeding during lactation probably alters cardiac metabolism, through the activation of a modulated cross-talk between leptin and insulin cascades.

Animals↗
PubMed2004

Inhibition of insulin-dependent glucose uptake by trivalent arsenicals: possible mechanism of arsenic-induced diabetes.

Chronic exposures to inorganic arsenic (iAs) have been associated with increased incidence of noninsulin (type-2)-dependent diabetes mellitus. Although mechanisms by which iAs induces diabetes have not been identified, the clinical symptoms of the disease indicate that iAs or its metabolites interfere with insulin-stimulated signal transduction pathway or with critical steps in glucose metabolism. We have examined effects of iAs and methylated arsenicals that contain trivalent or pentavalent arsenic on glucose uptake by 3T3-L1 adipocytes. Treatment with inorganic and methylated pentavalent arsenicals (up to 1 mM) had little or no effect on either basal or insulin-stimulated glucose uptake. In contrast, trivalent arsenicals, arsenite (iAs(III)), methylarsine oxide (MAs(III)O), and iododimethylarsine (DMAs(III)O) inhibited insulin-stimulated glucose uptake in a concentration-dependent manner. Subtoxic concentrations of iAs(III) (20 microM), MAs(III)O (1 microM), or DMAs(III)I (2 microM) decreased insulin-stimulated glucose uptake by 35-45%. Basal glucose uptake was significantly inhibited only by cytotoxic concentrations of iAs(III) or MAs(III)O. Examination of the components of the insulin-stimulated signal transduction pathway showed that all trivalent arsenicals suppressed expression and possibly phosphorylation of protein kinase B (PKB/Akt). The concentration of an insulin-responsive glucose transporter (GLUT4) was significantly lower in the membrane region of 3T3-L1 adipocytes treated with trivalent arsenicals as compared with untreated cells. These results suggest that trivalent arsenicals inhibit insulin-stimulated glucose uptake by interfering with the PKB/Akt-dependent mobilization of GLUT4 transporters in adipocytes. This mechanism may be, in part, responsible for the development of type-2 diabetes in individuals chronically exposed to iAs.

Animals↗
PubMed1993

Sequential evaluation of islet cell responses to glucose in the transplanted pancreas in humans.

We evaluated the hormonal and metabolic responses of denervated pancreas allografts in nine volunteers 3 to 12 months after the transplant (initial) and again 1 year later (follow-up). Eight of the patients received simultaneous pancreas-kidney transplants. The glucose clamp technique was used to create a square wave of hyperglycemia 5.5 mmol/L above the basal glucose level for 2 hours. A biphasic insulin response was evident in each subject, both initially and at follow-up. The initial plasma insulin response was fourfold higher in patients with pancreas-kidney transplants than in normal volunteers. However, the plasma insulin response of the patients with pancreas-kidney transplants at the follow-up study was more similar to that of the normal controls. The plasma glucagon levels were elevated in follow-up clamp studies. Hepatic glucose production and glucose disposal were similar in both studies. At the follow-up examination only, GLUT4, the major insulin-sensitive glucose transporter, was measured in muscle homogenates by immunoblotting. GLUT4 levels in the patients with pancreas-kidney transplants were only 55% as abundant as in normal volunteers. This may be due, in part, to immunosuppressive therapy or to persistent, albeit reduced, levels of hyperinsulinemia even 2 years after transplantation. We concluded that, despite systemic drainage of the pancreas and immunosuppressive therapy, pancreatic insulin secretion, peripheral insulin levels, and muscle insulin responsiveness are restored toward normal levels approximately 2 years after the transplant.

Adult↗
PubMed2002

ATP stimulates glucose transport through activation of P2 purinergic receptors in C(2)C(12) skeletal muscle cells.

Extracellular ATP acts as a signal that regulates a variety of cellular processes via binding to P2 purinergic receptors (P2 receptors). We herein investigated the effects and signaling pathways of ATP on glucose uptake in C(2)C(12) skeletal muscle cells. ATP as well as P2 receptor agonists (ATP-gamma S) stimulated the rate of glucose uptake, while P2 receptor antagonists (suramin) inhibited the stimulatory effect of ATP, indicating that P2 receptors are involved. This ATP-stimulated glucose transport was blocked by specific inhibitors of Gi protein (pertusiss toxin), phospholipase C (U73122), protein kinase C (GF109203X), and phosphatidylinositol (PI) 3-kinase (LY294002). ATP stimulated PI 3-kinase activity and P2 receptor antagonists blocked this activation. In C(2)C(12) myotubes expressing glucose transporter GLUT4, ATP increased basal and insulin-stimulated glucose transport. Finally, ATP facilitated translocation of GLUT1 and GLUT4 into plasma membrane. These results together suggest that cells respond to extracellular ATP to increase glucose transport through P2 receptors.

3T3 Cells↗