Jeoung N.H.,Richard Roudebush Veterans Affairs Medical Center |
Jeoung N.H.,Indiana University |
Jeoung N.H.,Catholic University of Daegu |
Rahimi Y.,Richard Roudebush Veterans Affairs Medical Center |
And 6 more authors.
Biochemical Journal | Year: 2012
The importance of PDHK (pyruvate dehydrogenase kinase) 2 and 4 in regulation of the PDH complex (pyruvate dehydrogenase complex) was assessed in single- and double-knockout mice. PDHK2deficiency caused higher PDHcomplex activity and lower blood glucose levels in the fed, but not the fasted, state. PDHK4 deficiency caused similar effects, but only after fasting. Double deficiency intensified these effects in both the fed and fasted states. PDHK2 deficiency had no effect on glucose tolerance, PDHK4 deficiency produced only a modest effect, but double deficiency caused a marked improvement and also induced lower insulin levels and increased insulin sensitivity. In spite of these beneficial effects, the double-knockout mice were more sensitive than wild-type and single-knockout mice to long-term fasting, succumbing to hypoglycaemia, ketoacidosis and hypothermia. Stable isotope flux analysis indicated that hypoglycaemia was due to a reduced rate of gluconeogenesis and that slightly more glucose was converted into ketone bodies in the double-knockout mice. The findings establish that PDHK2 is more important in the fed state, PDHK4 is more important in the fasted state, and survival during long-term fasting depends upon regulation of the PDH complex by both PDHK2 and PDHK4. © The Authors Journal compilation © 2012 Biochemical Society.
Gattone V.H.,Indiana University |
Bacallao R.L.,Indiana University |
Bacallao R.L.,Richard Roudebush Veterans Affairs Medical Center
American Journal of Physiology - Renal Physiology | Year: 2014
Dichloroacetate (DCA) is a toxicant by-product from the chlorination disinfection process for municipal water. The levels would not affect people with normal renal and liver function. However, people with impaired renal or liver function may have an increased susceptibility to DCA toxicity as those are the organs affected by DCA. People (and rodents) with polycystic kidney disease (PKD) are polyuric, drink more fluids, and have both renal and liver pathology. In PKD, renal tubules and biliary epithelial cells proliferate to form cysts, which can eventually cause renal and/or liver dysfunction. Therefore, PKD may be a predisposing condition with an increased sensitivity to DCA toxicity. PCK rats are an orthologous model of human autosomal recessive PKD and were treated with 75 mg/l DCA in their drinking water. Male and female PCK and male Sprague-Dawley rats were treated from 4 to 8 wk of age, after which the severity of the renal and liver pathology induced by DCA were assessed. Only male PCK rats were adversely affected by DCA treatment, with an increase in the severity of renal cystic disease evinced by an increase in cystic enlargement and proteinuria. In conclusion, the chlorination byproduct DCA may adversely affect those with a preexisting renal disease, especially those who are polydipsic, like those with PKD. © 2014 the American Physiological Society.
Hwang B.,Richard Roudebush Veterans Affairs Medical Center |
Hwang B.,Indiana University |
Hwang B.,Wisconsin Institutes for Medical Research |
Wu P.,Richard Roudebush Veterans Affairs Medical Center |
And 3 more authors.
FEBS Journal | Year: 2012
Although improving glucose metabolism by inhibition of pyruvate dehydrogenase kinase 4 (PDK4) may prove beneficial in the treatment of type 2 diabetes or diet-induced obesity, it may have detrimental effects by inhibiting fatty acid oxidation. Peroxisome proliferator-activated receptor α (PPARα) agonists are often used to treat dyslipidemia in patients, especially in type 2 diabetes. Combinational treatment using a PDK4 inhibitor and PPARα agonists may prove beneficial. However, PPARα agonists may be less effective in the presence of a PDK4 inhibitor because PPARα agonists induce PDK4 expression. In the present study, the effects of clofibric acid, a PPARα agonist, on blood and liver lipids were determined in wild-type and PDK4 knockout mice fed a high-fat diet. As expected, treatment of wild-type mice with clofibric acid resulted in less body weight gain, smaller epididymal fat pads, greater insulin sensitivity, and lower levels of serum and liver triacylglycerol. Surprisingly, rather than decreasing the effectiveness of clofibric acid, PDK4 deficiency enhanced the beneficial effects of clofibric acid on hepatic steatosis, reduced blood glucose levels, and did not prevent the positive effects of clofibric acid on serum triacylglycerols and free fatty acids. The metabolic effects of clofibric acid are therefore independent of the induction of PDK4 expression. The additive beneficial effects on hepatic steatosis may be due to induction of increased capacity for fatty acid oxidation and partial uncoupling of oxidative phosphorylation by clofibric acid, and a reduction in the capacity for fatty acid synthesis as a result of PDK4 deficiency. Here we tested whether the lipid lowering effects of clofibric acid, a PPARα agonist, are affected by PDK4 deficiency. PDK4 deficiency enhanced the beneficial effects of clofibric acid on hepatic steatosis and did not prevent its hypolipidemic effects. Therefore, PDK4 inhibitor and clofibric acid could potentially be used in combination to lower blood glucose and ameliorate hepatic steatosis. © Journal compilation © 2012 FEBS. No claim to original US government works.
Xiong X.,Indiana University |
Wang G.,Indiana University |
Tao R.,Indiana University |
Wu P.,Richard Roudebush Veterans Affairs Medical Center |
And 11 more authors.
Diabetologia | Year: 2016
Aims/hypothesis: Sirtuin 6 (SIRT6) has been implicated in ageing, DNA repair and metabolism; however, its function in pancreatic beta cells is unclear. The aim of this study is to elucidate the role of SIRT6 in pancreatic beta cells. Methods: To investigate the function of SIRT6 in pancreatic beta cells, we performed Sirt6 gene knockdown in MIN6 cells and generated pancreatic- and beta cell-specific Sirt6 knockout mice. Islet morphology and glucose-stimulated insulin secretion (GSIS) were analysed. Glycolysis and oxygen consumption rates in SIRT6-deficient beta cells were measured. Cytosolic calcium was monitored using the Fura-2-AM fluorescent probe (Invitrogen, Grand Island, NY, USA). Mitochondria were analysed by immunoblots and electron microscopy. Results: Sirt6 knockdown in MIN6 beta cells led to a significant decrease in GSIS. Pancreatic beta cell Sirt6 knockout mice showed a ~50% decrease in GSIS. The knockout mouse islets had lower ATP levels compared with the wild-type controls. Mitochondrial oxygen consumption rates were significantly decreased in the SIRT6-deficient beta cells. Cytosolic calcium dynamics in response to glucose or potassium chloride were attenuated in the Sirt6 knockout islets. Numbers of damaged mitochondria were increased and mitochondrial complex levels were decreased in the SIRT6-deficient islets. Conclusions/interpretation: These data suggest that SIRT6 is important for GSIS from pancreatic beta cells and activation of SIRT6 may be useful to improve insulin secretion in diabetes. © 2015, Springer-Verlag Berlin Heidelberg.
Tao R.,Indiana University |
Xiong X.,Indiana University |
Harris R.A.,Indiana University |
Harris R.A.,Richard Roudebush Veterans Affairs Medical Center |
And 2 more authors.
PLoS ONE | Year: 2013
Pyruvate dehydrogenase kinases (PDK1-4) play a critical role in the inhibition of the mitochondrial pyruvate dehydrogenase complex especially when blood glucose levels are low and pyruvate can be conserved for gluconeogenesis. Under diabetic conditions, the Pdk genes, particularly Pdk4, are often induced, and the elevation of the Pdk4 gene expression has been implicated in the increased gluconeogenesis in the liver and the decreased glucose utilization in the peripheral tissues. However, there is no direct evidence yet to show to what extent that the dysregulation of hepatic Pdk genes attributes to hyperglycemia and insulin resistance in vivo. To address this question, we crossed Pdk2 or Pdk4 null mice with a diabetic model that is deficient in hepatic insulin receptor substrates 1 and 2 (Irs1/2). Metabolic analyses reveal that deletion of the Pdk4 gene had better improvement in hyperglycemia and glucose tolerance than knockout of the Pdk2 gene whereas the Pdk2 gene deletion showed better insulin tolerance as compared to the Pdk4 gene inactivation on the Irs1/2 knockout genetic background. To examine the specific hepatic effects of Pdks on diabetes, we also knocked down the Pdk2 or Pdk4 gene using specific shRNAs. The data also indicate that the Pdk4 gene knockdown led to better glucose tolerance than the Pdk2 gene knockdown. In conclusion, our data suggest that hepatic Pdk4 may be critically involved in the pathogenesis of diabetes. © 2013 Tao et al.
Westmoreland G.R.,Wishard Health Services |
Westmoreland G.R.,Indiana University |
Westmoreland G.R.,Regenstrief Institute |
Counsell S.R.,Wishard Health Services |
And 10 more authors.
Journal of the American Geriatrics Society | Year: 2010
Although Web-based instruction offers an advantageous approach to medical education, few studies have addressed the use of Web-based education to teach clinical content at the postgraduate level. Even fewer studies have addressed clinical outcomes after the Web-based instruction, yet postgraduate training requirements now focus on outcomes of training. A randomized trial was conducted to compare knowledge of postgraduate year (PGY) 1 residents after Web-based with that after paper-based instruction and to compare residents' clinical application of their instruction using unannounced standardized patients (SPs) and unannounced activated standardized patients (ASPs). PGY 1 residents were assigned to a month-long ambulatory rotation during which they were randomized as a block to Web- or paper-based instruction covering the same four geriatric syndromes (dementia, depression, falls, and urinary incontinence). Outcome measures were mean change scores for before and after testing and scores from SP and ASP clinical encounter forms (checklist, chart abstraction, and electronic order entry). Residents who completed the Web-based instruction showed significantly greater improvement on the knowledge tests than those who received paper-based instruction. There were no significant differences in the scores from the SP and ASP clinical encounters except that the chart abstraction score was better for Web-based group than the paper-based group for dementia. Web-based instruction is an educational tool that medical residents readily accept and can be used to improve knowledge of core geriatrics content as measured using immediate posttesting. More-intensive educational interventions are needed to improve clinical performance by trainees in the care of older patients. © 2010, The American Geriatrics Society.
PubMed | Richard Roudebush Veterans Affairs Medical Center
Type: Journal Article | Journal: The Biochemical journal | Year: 2012
The importance of PDHK (pyruvate dehydrogenase kinase) 2 and 4 in regulation of the PDH complex (pyruvate dehydrogenase complex) was assessed in single- and double-knockout mice. PDHK2 deficiency caused higher PDH complex activity and lower blood glucose levels in the fed, but not the fasted, state. PDHK4 deficiency caused similar effects, but only after fasting. Double deficiency intensified these effects in both the fed and fasted states. PDHK2 deficiency had no effect on glucose tolerance, PDHK4 deficiency produced only a modest effect, but double deficiency caused a marked improvement and also induced lower insulin levels and increased insulin sensitivity. In spite of these beneficial effects, the double-knockout mice were more sensitive than wild-type and single-knockout mice to long-term fasting, succumbing to hypoglycaemia, ketoacidosis and hypothermia. Stable isotope flux analysis indicated that hypoglycaemia was due to a reduced rate of gluconeogenesis and that slightly more glucose was converted into ketone bodies in the double-knockout mice. The findings establish that PDHK2 is more important in the fed state, PDHK4 is more important in the fasted state, and survival during long-term fasting depends upon regulation of the PDH complex by both PDHK2 and PDHK4.