Browsing by Subject "insulin"

Now showing 1 - 10 of 15
  • Thumbnail Image
    Item
    An Analysis of Pancreatic Cancer
    (Office of the Vice Chancellor for Research, 2015-04-17) Wagle, Pragat
    The pancreas is extremely important in various enzymatic activities, such as the production of numerous enzymes such as insulin. Pancreatic Cancer is an extremely deadly disease, which 40,000 people of the 46,000 diagnosed each year fail to survive. It is the 12th most common type of cancer and the 4th leading cause of cancer related deaths. There are 4 stages to Pancreatic ranging from stage 1 to stage 4, where the cancer has spread to a distant organ. Pancreatic cancer is an extremely difficult to diagnose as early symptoms aren’t suggestive as many other illnesses have similar signs and symptoms. Diagnosis can be done through the use of physical examinations, ct scan, ultrasound, endoscopic ultrasound, PET scan, and most effectively a needle biopsy. Currently in development are numerous different therapies. A collective effort is being put forth to further improve current established methods to combat Pancreatic Cancer. A current four-drug chemotherapy, that had results published in May 2011 has shown a 4-month improvement using a regimen called Folfirinox. Compared to treatment with gemcitabine, which is the current therapy mainly utilized, Folfirinox showed improvement on 16 percent more patients in a phase 3 trial. Another trial with a combination of Nab-Paclitaxel and Gemcitabine was conducted against just gemcitabine. Patients with the combination showed a 1.8 months higher average survival rate than without, and showed a significantly higher survival rate through two years of 13% and 5% respectively. Overall these therapies must be reformed to be compatible with a bigger patient population. Subsequently the side effects of the treatments also need to be improved as the side effects include high risk of neutropenia. Both these treatments demonstrate a more efficient therapy and have been implemented into practice but still require improvement.
  • Thumbnail Image
    Item
    Combination GLP-1 and Insulin Treatment Fails to Alter Myocardial Fuel Selection Versus Insulin Alone in Type 2 Diabetes
    (Oxford, 2018-07) Mather, Kieren J.; Considine, Robert V.; Hamilton, LaTonya; Patel, Niral A.; Mathias, Carla; Territo, Wendy; Goodwill, Adam; Tune, Johnathan D.; Green, Mark A.; Hutchins, Gary D.; Medicine, School of Medicine
    Context Glucagon-like peptide-1 (GLP-1) and the clinically available GLP-1 agonists have been shown to exert effects on the heart. It is unclear whether these effects occur at clinically used doses in vivo in humans, possibly contributing to CVD risk reduction. Objective To determine whether liraglutide at clinical dosing augments myocardial glucose uptake alone or in combination with insulin compared to insulin alone in metformin-treated Type 2 diabetes mellitus. Design Comparison of myocardial fuel utilization after 3 months of treatment with insulin detemir, liraglutide, or combination detemir+liraglutide. Setting Academic hospital Participants Type 2 diabetes treated with metformin plus oral agents or basal insulin. Interventions Insulin detemir, liraglutide, or combination added to background metformin Main Outcome Measures Myocardial blood flow, fuel selection and rates of fuel utilization evaluated using positron emission tomography, powered to demonstrate large effects. Results We observed greater myocardial blood flow in the insulin-treated groups (median[25th, 75th percentile]: detemir 0.64[0.50, 0.69], liraglutide 0.52[0.46, 0.58] and detemir+liraglutide 0.75[0.55, 0.77] mL/g/min, p=0.035 comparing 3 groups and p=0.01 comparing detemir groups to liraglutide alone). There were no evident differences between groups in myocardial glucose uptake (detemir 0.040[0.013, 0.049], liraglutide 0.055[0.019, 0.105], detemir+liraglutide 0.037[0.009, 0.046] µmol/g/min, p=0.68 comparing 3 groups). Similarly there were no treatment group differences in measures of myocardial fatty acid uptake or handling, and no differences in total oxidation rate. Conclusions These observations argue against large effects of GLP-1 agonists on myocardial fuel metabolism as mediators of beneficial treatment effects on myocardial function and ischemia protection.
  • Thumbnail Image
    Item
    Cyclin D2 is sufficient to drive β cell self-renewal and regeneration
    (Taylor & Francis, 2017-11-03) Tschen, Shuen-ing; Zeng, Chun; Field, Loren; Dhawan, Sangeeta; Bhushan, Anil; Georgia, Senta; Medicine, School of Medicine
    Diabetes results from an inadequate mass of functional β cells, due to either β cell loss caused by autoimmune destruction (type I diabetes) or β cell failure in response to insulin resistance (type II diabetes). Elucidating the mechanisms that regulate β cell mass may be key to developing new techniques that foster β cell regeneration as a cellular therapy to treat diabetes. While previous studies concluded that cyclin D2 is required for postnatal β cell self-renewal in mice, it is not clear if cyclin D2 is sufficient to drive β cell self-renewal. Using transgenic mice that overexpress cyclin D2 specifically in β cells, we show that cyclin D2 overexpression increases β cell self-renewal post-weaning and results in increased β cell mass. β cells that overexpress cyclin D2 are responsive to glucose stimulation, suggesting they are functionally mature. β cells that overexpress cyclin D2 demonstrate an enhanced regenerative capacity after injury induced by streptozotocin toxicity. To understand if cyclin D2 overexpression is sufficient to drive β cell self-renewal, we generated a novel mouse model where cyclin D2 is only expressed in β cells of cyclin D2−/− mice. Transgenic overexpression of cyclin D2 in cyclin D2−/− β cells was sufficient to restore β cell mass, maintain normoglycaemia, and improve regenerative capacity when compared with cyclin D2−/− littermates. Taken together, our results indicate that cyclin D2 is sufficient to regulate β cell self-renewal and that manipulation of its expression could be used to enhance β cell regeneration.
  • Thumbnail Image
    Item
    Evidence for a regulatory role of Cullin-RING E3 ubiquitin ligase 7 in insulin signalling
    (Elsevier B.V., 2014-02) Scheufele, Florian; Wolf, Benjamin; Kruse, Michael; Hartmann, Thomas; Lempart, Justine; Mühlich, Susanne; Pfeiffer, Andreas F. H.; Field, Loren J.; Charron, Maureen J.; Pan, Zhen-Qiang; Engelhardt, Stefan; Sarikas, Antonio; Department of Medicine, IU School of Medicine
    Dysfunctional regulation of signalling pathways downstream of the insulin receptor plays a pivotal role in the pathogenesis of insulin resistance and type 2 diabetes. In this study we report both in vitro and in vivo experimental evidence for a role of Cullin-RING E3 ubiquitin ligase 7 (CRL7) in the regulation of insulin signalling and glucose homeostasis. We show that Cul7−/− mouse embryonic fibroblasts displayed enhanced AKT and Erk MAP kinase phosphorylation upon insulin stimulation. Depletion of CUL7 by RNA interference in C2C12 myotubes led to increased activation of insulin signalling pathways and cellular glucose uptake, as well as a reduced capacity of these cells to execute insulin-induced degradation of insulin receptor substrate 1 (IRS1). In vivo, heterozygosity of either Cul7 or Fbxw8, both key components of CRL7, resulted in elevated PI3 kinase / AKT activation in skeletal muscle tissue upon insulin stimulation when compared to wild-type controls. Finally, Cul7+/− or Fbxw8+/− mice exhibited enhanced insulin sensitivity and plasma glucose clearance. Collectively, our findings point to a yet unrecognized role of CRL7 in insulin-mediated control of glucose homeostasis by restraining PI3 kinase / AKT activities in skeletal muscle cells.
  • Thumbnail Image
    Item
    Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western‐style high‐fat diet
    (Wiley, 2017-08-15) Ambery, Ashley G.; Tackett, Lixuan; Penque, Brent A.; Brozinick, Joseph T.; Elmendorf, Jeffrey S.; Cellular and Integrative Physiology, School of Medicine
    Insulin action and glucose disposal are enhanced by exercise, yet the mechanisms involved remain imperfectly understood. While the causes of skeletal muscle insulin resistance also remain poorly understood, new evidence suggest excess plasma membrane (PM) cholesterol may contribute by damaging the cortical filamentous actin (F‐actin) structure essential for GLUT4 glucose transporter redistribution to the PM upon insulin stimulation. Here, we investigated whether PM cholesterol toxicity was mitigated by exercise. Male C57BL/6J mice were placed on low‐fat (LF, 10% kCal) or high‐fat (HF, 45% kCal) diets for a total of 8 weeks. During the last 3 weeks of this LF/HF diet intervention, all mice were familiarized with a treadmill for 1 week and then either sham‐exercised (0 m/min, 10% grade, 50 min) or exercised (13.5 m/min, 10% grade, 50 min) daily for 2 weeks. HF‐feeding induced a significant gain in body mass by 3 weeks. Sham or chronic exercise did not affect food consumption, water intake, or body mass gain. Prior to sham and chronic exercise, “pre‐intervention” glucose tolerance tests were performed on all animals and demonstrated that HF‐fed mice were glucose intolerant. While sham exercise did not affect glucose tolerance in the LF or HF mice, exercised mice showed an improvement in glucose tolerance. Muscle from sham‐exercised HF‐fed mice showed a significant increase in PM cholesterol, loss of cortical F‐actin, and decrease in insulin‐stimulated glucose transport compared to sham‐exercised LF‐fed mice. These HF‐fed skeletal muscle membrane/cytoskeletal abnormalities and insulin resistance were improved in exercised mice. These data reveal a new therapeutic aspect of exercise being regulation of skeletal muscle PM cholesterol homeostasis. Further studies on this mechanism of insulin resistance and the benefits of exercise on its prevention are needed.
  • Thumbnail Image
    Item
    Hexosamines Provoke Membrane Cholesterol Accrual, Filamentous Actin Loss, and GLUT4 Dysregulation in Adipocytes through Transcriptional Activation of Specificity Protein 1
    (Poster session presented at IUPUI Research Day 2012, Indianapolis, Indiana., 2012-04-13) Penque, Brent A.; Elmendorf, Jeffrey S.
    The hexosamine biosynthesis pathway (HBP) serves as a sensor of excess nutrient bioavailability and has been implicated in the pathogenesis of type 2 diabetes. Previous study observed that hyperinsulinemic culturing conditions akin to those seen clinically activate the HBP provoking gains in plasma membrane (PM) cholesterol content in L6 myotubes and 3T3-L1 adipocytes. This, in turn, compromised the cortical filamentous actin (F-actin) structure necessary for the proper incorporation of the insulin sensitive glucose transporter GLUT4 into the membrane. The mechanism(s), however, by which HBP activation provokes PM cholesterol accrual, remains unclear. Here, the hypothesis that HBP engages a cholesterolgenic transcriptional response resulting in PM cholesterol accrual/toxicity was tested. In 3T3-L1 adipocytes, pathophysiologically relevant doses of hyperinsulinemia (0.25, 0.5, and 5 nM) resulted in a dose-dependent gain in PM cholesterol as well as mRNA and protein levels of HMG-CoA reductase (HMGR), the rate limiting enzyme in cholesterol synthesis. Immunoprecipitation experiments demonstrated that hyperinsulinemia induced elevations in O-linked N-acetylglucosamine post-translational modification of the cholesterolgenic transcription factor specificity protein 1 (Sp1). This modification was prevented in cells in which the HBP was inhibited. Chromatin immunoprecipitation demonstrated that hyperinsulinemia induced a ~4 fold increase in the affinity of Sp1 to the promoter region of HMGR, which was lost with HBP inhibition. Luciferase assays confirmed that this altered binding resulted in a ~50% increase in promoter activity of this cholesterolgenic gene. Hyperinsulinemia also augmented Sp1 binding to the promoter of the sterol response element binding protein gene, resulting in increased total and nuclear content of this factor. To further delineate the role of Sp1 in this process, a specific inhibitor, mithramycin (MTR), of Sp1 binding to DNA was employed. This inhibitor prevented against hyperinsulinemia-induced gains in HMGR and PM cholesterol as well as F-actin loss. Importantly, this treatment corrected the impaired insulin-stimulated GLUT4 translocation and glucose transport induced by hyperinsulinemia. These data suggest hyperinsulinemia-induced HBP activity provokes cholesterol synthesis and PM cholesterol accrual/F-actin loss that compromises GLUT4/glucose transport regulation by insulin.
  • Thumbnail Image
    Item
    Ludwigia octovalvis extract improves glycemic control and memory performance in diabetic mice
    (Elsevier, 2017-07) Lin, Wei-Sheng; Lo, Jung-Hsin; Yang, Jo-Hsuan; Wang, Hao-Wei; Fan, Shou-Zen; Yen, Jui-Hung; Wang, Pei-Yu; Department of Microbiology and Immunology, IU School of Medicine
    Ethnopharmacological relevance Ludwigia octovalvis (Jacq.) P.H. Raven (Onagraceae) extracts have historically been consumed as a healthful drink for treating various conditions, including edema, nephritis, hypotension and diabetes. Aim of the study We have previously shown that Ludwigia octovalvis extract (LOE) can significantly extend lifespan and improve age-related memory deficits in Drosophila melanogaster through activating AMP-activated protein kinase (AMPK). Since AMPK has become a critical target for treating diabetes, we herein investigate the anti-hyperglycemic potential of LOE. Materials and methods Differentiated C2C12 muscle cells, HepG2 hepatocellular cells, streptozotocin (STZ)-induced diabetic mice and high fat diet (HFD)-induced diabetic mice were used to investigate the anti-hyperglycemic potential of LOE. The open field test and novel object recognition test were used to evaluate spontaneous motor activity and memory performance of HFD-induced diabetic mice. Results In differentiated C2C12 muscle cells and HepG2 hepatocellular cells, treatments with LOE and its active component (β-sitosterol) induced significant AMPK phosphorylation. LOE also enhanced uptake of a fluorescent glucose derivative (2-NBDG) and inhibited glucose production in these cells. The beneficial effects of LOE were completely abolished when an AMPK inhibitor, dorsomorphin, was added to the culture system, suggesting that LOE requires AMPK activation for its action in vitro. In streptozotocin (STZ)-induced diabetic mice, we found that both LOE and β-sitosterol induced an anti-hyperglycemic effect comparable to that of metformin, a drug that is commonly prescribed to treat diabetes. Moreover, LOE also improved glycemic control and memory performance of mice fed a HFD. Conclusions These results indicate that LOE is a potent anti-diabetic intervention that may have potential for future clinical applications.
  • Thumbnail Image
    Item
    Magnesium intake and mortality due to liver diseases: Results from the Third National Health and Nutrition Examination Survey Cohort
    (Nature Publishing group, 2017-12-20) Wu, Lijun; Zhu, Xiangzhu; Fan, Lei; Kabagambe, Edmond K.; Song, Yiqing; Tao, Menghua; Zhong, Xiaosong; Hou, Lifang; Shrubsole, Martha J.; Liu, Jie; Dai, Qi; Epidemiology, School of Public Health
    People with fatty liver disease are at high risk of magnesium deficiency. Meanwhile, low magnesium status is linked to both chronic inflammation and insulin resistance. However, no study has investigated the association between intake of magnesium and risk of mortality due to liver diseases. We evaluated the association between total magnesium intake and mortality due to liver diseases in the Third National Health and Nutrition Examination Study (NHANES III) cohort, which included 13,504 participants who completed liver ultrasound examination for hepatic steatosis. Overall magnesium intake was associated with a reduced risk of mortality due to liver disease at borderline significance (P = 0.05). In fully-adjusted analyses, every 100 mg increase in intake of magnesium was associated with a 49% reduction in the risk for mortality due to liver diseases. Although interactions between magnesium intake and alcohol use and hepatic steatosis at baseline were not significant (P > 0.05), inverse associations between magnesium intake and liver disease mortality were stronger among alcohol drinkers and those with hepatic steatosis. Our findings suggest higher intakes of magnesium may be associated with a reduced risk of mortality due to liver disease particularly among alcohol drinkers and those with hepatic steatosis. Further studies are warranted to confirm the findings.
  • Thumbnail Image
    Item
    miR-146a-5p mediates inflammation-induced β cell mitochondrial dysfunction and apoptosis
    (bioRxiv, 2024-03-19) Krishnan, Preethi; Branco, Renato Chaves Souto; Weaver, Staci A.; Chang, Garrick; Lee, Chih-Chun; Syed, Farooq; Evans-Molina, Carmella; Medicine, School of Medicine
    We previously showed that miR-146a-5p is upregulated in pancreatic islets treated with pro-inflammatory cytokines. Others have reported that miR-146a-5p overexpression is associated with β cell apoptosis and impaired insulin secretion. However, the molecular mechanisms mediating these effects remain elusive. To investigate the role of miR-146a-5p in β cell function, we developed stable MIN6 cell lines to either overexpress or inhibit the expression of miR-146a-5p. Monoclonal cell populations were treated with pro-inflammatory cytokines (IL-1β, IFNγ, and TNFα) to model T1D in vitro. We found that overexpression of miR-146a-5p increased cell death under conditions of inflammatory stress, whereas inhibition of miR-146a-5p reversed these effects. Additionally, inhibition of miR-146a-5p increased mitochondrial DNA copy number, respiration rate, and ATP production. Further, RNA sequencing data showed enrichment of pathways related to insulin secretion, apoptosis, and mitochondrial function when the expression levels of miR-146a-5p were altered. Finally, a temporal increase in miR-146a-5p expression levels and a decrease in mitochondria function markers was observed in islets derived from NOD mice. Collectively, these data suggest that miR-146a-5p may promote β cell dysfunction and death during inflammatory stress by suppressing mitochondrial function.
  • Thumbnail Image
    Item
    A Nutrient Network Regulating Cellular Cholesterol and Glucose Metabolism
    (2014) Pattar, Guruprasad R.; Elmendorf, Jeffrey S.; Considine, Robert V.; Deeg, Mark A.; Herring, B. Paul; Kempson, Stephen A.
    Insulin resistance, a hallmark of type 2 diabetes (T2D), is associated with accompanying derangements such as hyperinsulinemia that promote the progression of insulin resistance, yet a mechanism(s) is imperfectly understood. Data have demonstrated that hyperinsulinemia promotes insulin resistance as evidenced by diminished ability of insulin to mobilize glucose transporter GLUT4 to the plasma membrane (PM). We found that loss of PM phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated filamentous actin (F-actin) structure contributes to hyperinsulinemia-induced insulin resistance. We tested if increased glucose flux through hexosamine biosynthesis pathway (HBP) causes dysregulation of PM components necessary for GLUT4 translocation. Increased HBP activity was detected in 3T3-L1 adipocytes cultured in hyperinsulinemia (5 nM Ins; 12 h) and also 2 mM glucosamine (GlcN), a distal HBP activator, inducing losses of PM PIP2 and F-actin. In accordance with HBP flux directly weakening PIP2/F-actin structure, inhibition of the rate-limiting HBP enzyme (glutamine:fructose-6-phosphate amidotransferase) restored F-actin and insulin responsiveness. Furthermore, less invasive challenges with glucose led to PIP2/F-actin dysregulation. New findings support a negative correlation between PM cholesterol accrual, PIP2/F-actin structure and GLUT4 regulation. These data stemmed from parallel study aimed at understanding the antidiabetic mechanism of the nutrient chromium (Cr3+). We found that chromium picolinate (CrPic) enhanced insulin-stimulated GLUT4 trafficking via reduction in PM cholesterol. In line with glucose/cholesterol toxicity findings, we demonstrated that therapeutic effects of CrPic occurred solely in adipocytes with increased HBP activity and a concomitant elevation in PM cholesterol. Mechanistically, data are consistent with a role of AMP-activated protein kinase (AMPK) in CrPic action. These data show that CrPic increases AMPK activity and perhaps suppresses cholesterol synthesis via distal phosphorylation and inactivation of 3-hydroxy-3-methylglutaryl CoA reductase (HMGR), a rate-limiting enzyme in cholesterol synthesis. Continued study of the consequence of increased HBP activity revealed alterations in cholesterogenic transcription factors – Sp1, SREBP-1, and NFY – with Sp1 showing a significant increase in O-linked glycosylation. Consistent with Sp1 modification eliciting maximal transcriptional activation of SREBP-1, Hmgr mRNA was significantly enhanced. In conclusion, these data are consistent with a central role of PM cholesterol in glucose transport and suggest perturbations in this lipid have a contributory role in developing insulin resistance.