PPARα activation and increased dietary lipid oppose thyroid hormone signaling and rescue impaired glucose-stimulated insulin secretion in hyperthyroidism

2008 ◽  
Vol 295 (6) ◽  
pp. E1380-E1389 ◽  
Author(s):  
Mark J. Holness ◽  
Gemma K. Greenwood ◽  
Nicholas D. Smith ◽  
Mary C. Sugden
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Thyroid Hormone ◽  
Dietary Lipid ◽  
High Fat ◽  
Carbohydrate Diet ◽  
Low Carbohydrate Diet ◽  
Glucose Stimulated Insulin Secretion ◽  
Glucose Responsiveness ◽  
The Impact

The aim of the study was to investigate the impact of hyperthyroidism on the characteristics of the islet insulin secretory response to glucose, particularly the consequences of competition between thyroid hormone and peroxisome proliferator-activated receptor (PPAR)α in the regulation of islet adaptations to starvation and dietary lipid-induced insulin resistance. Rats maintained on standard (low-fat/high-carbohydrate) diet or high-fat/low-carbohydrate diet were rendered hyperthyroid (HT) by triiodothyronine (T3) administration (1 mg·kg body wt−1·day−1 sc, 3 days). The PPARα agonist WY14643 (50 mg/kg body wt ip) was administered 24 h before sampling. Glucose-stimulated insulin secretion (GSIS) was assessed during hyperglycemic clamps or after acute glucose bolus injection in vivo and with step-up and step-down islet perifusions. Hyperthyroidism decreased the glucose responsiveness of GSIS, precluding sufficient enhancement of insulin secretion for the degree of insulin resistance, in rats fed either standard diet or high-fat diet. Hyperthyroidism partially opposed the starvation-induced increase in the glucose threshold for GSIS and decrease in glucose responsiveness. WY14643 administration restored glucose tolerance by enhancing GSIS in fed HT rats and relieved the impact of hyperthyroidism to partially oppose islet starvation adaptations. Competition between thyroid hormone receptor (TR) and PPARα influences the characteristics of GSIS, such that hyperthyroidism impairs GSIS while PPARα activation (and increased dietary lipid) opposes TR signaling and restores GSIS in the fed hyperthyroid state. Increased islet PPARα signaling and decreased TR signaling during starvation facilitates appropriate modification of islet function.

scholarly journals Hyperinsulinemia and Insulin Resistance in Dopamine β-Hydroxylase Deficiency

2016 ◽  
Vol 102 (1) ◽  
pp. 10-14 ◽  
Author(s):  
Amy C. Arnold ◽  
Emily M. Garland ◽  
Jorge E. Celedonio ◽  
Satish R. Raj ◽  
Naji N. Abumrad ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Genetic Testing ◽  
Orthostatic Hypotension ◽  
Glucose Homeostasis ◽  
Hyperglycemic Clamp ◽  
Deficient Patient ◽  
Treatment Naïve ◽  
Glucose Stimulated Insulin Secretion ◽  
The Impact

Abstract Context: Dopamine β-hydroxylase (DBH) deficiency is a rare genetic disorder characterized by failure to convert dopamine to norepinephrine. DBH-deficient patients lack sympathetic adrenergic function and are therefore predisposed to orthostatic hypotension. DBH-deficient mice exhibit hyperinsulinemia, lower plasma glucose levels, and insulin resistance due to loss of tonic sympathetic inhibition of insulin secretion. The impact of DBH deficiency on glucose homeostasis in humans is unknown. Case Description: We describe the metabolic profile of an adolescent female DBH-deficient patient. The patient underwent genetic testing, cardiovascular autonomic function testing, and evaluation of insulin secretion and sensitivity with hyperglycemic clamp under treatment-naive conditions. All procedures were repeated after 1 year of treatment with the norepinephrine prodrug droxidopa (300 mg, 3 times a day). Genetic testing showed a homozygous mutation in the DBH gene (rs74853476). Under treatment-naive conditions, she had undetectable plasma epinephrine and norepinephrine levels, resulting in sympathetic noradrenergic failure and orthostatic hypotension (−32 mm Hg supine to seated). She had high adiposity (41%) and fasting plasma insulin levels (25 μU/mL), with normal glucose (91 mg/dL). Hyperglycemic clamp revealed increased glucose-stimulated insulin secretion and insulin resistance. Droxidopa restored plasma norepinephrine and improved orthostatic tolerance, with modest effects on glucose homeostasis. Conclusions: We provide evidence for impairment in cardiovascular autonomic regulation, hyperinsulinemia, enhanced glucose-stimulated insulin secretion, and insulin resistance in a DBH-deficient patient. These metabolic derangements were not corrected by chronic droxidopa treatment. These findings provide insight into the pathophysiology and treatment of DBH deficiency and into the importance of catecholaminergic mechanisms to resting metabolism.

scholarly journals IP6-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hong Lin ◽  
Yuan Yan ◽  
Yifan Luo ◽  
Wing Yan So ◽  
Xiayun Wei ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
High Fat Diet ◽  
E3 Ligase ◽  
Human Islets ◽  
Cop9 Signalosome ◽  
Congenital Hyperinsulinism ◽  
High Fat ◽  
Transcriptional Suppressor

AbstractCOP1 and COP9 signalosome (CSN) are the substrate receptor and deneddylase of CRL4 E3 ligase, respectively. How they functionally interact remains unclear. Here, we uncover COP1–CSN antagonism during glucose-induced insulin secretion. Heterozygous Csn2WT/K70E mice with partially disrupted binding of IP6, a CSN cofactor, display congenital hyperinsulinism and insulin resistance. This is due to increased Cul4 neddylation, CRL4COP1 E3 assembly, and ubiquitylation of ETV5, an obesity-associated transcriptional suppressor of insulin secretion. Hyperglycemia reciprocally regulates CRL4-CSN versus CRL4COP1 assembly to promote ETV5 degradation. Excessive ETV5 degradation is a hallmark of Csn2WT/K70E, high-fat diet-treated, and ob/ob mice. The CRL neddylation inhibitor Pevonedistat/MLN4924 stabilizes ETV5 and remediates the hyperinsulinemia and obesity/diabetes phenotypes of these mice. These observations were extended to human islets and EndoC-βH1 cells. Thus, a CRL4COP1-ETV5 proteolytic checkpoint licensing GSIS is safeguarded by IP6-assisted CSN-COP1 competition. Deregulation of the IP6-CSN-CRL4COP1-ETV5 axis underlies hyperinsulinemia and can be intervened to reduce obesity and diabetic risk.

Human GLUT-2 overexpression does not affect glucose-stimulated insulin secretion in MIN6 cells

1995 ◽  
Vol 269 (5) ◽  
pp. E897-E902
Author(s):  
H. Ishihara ◽  
T. Asano ◽  
K. Tsukuda ◽  
H. Katagiri ◽  
K. Inukai ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Glucose Utilization ◽  
Glucose Sensing ◽  
Min6 Cells ◽  
Over Expression ◽  
Twofold Increase ◽  
Glucose Stimulated Insulin Secretion ◽  
Glucose Responsiveness

Accumulated evidence suggests that GLUT-2, in addition to its role in glucose transport, may also have other functions in glucose-stimulated insulin secretion. As a first step in addressing this possibility, we have engineered MIN6 cells overexpressing human GLUT-2 by transfection with human GLUT-2 cDNA. Stable transformants harboring human GLUT-2 cDNA exhibited an approximately twofold increase in 3-O-methyl-D-glucose uptake at 0.5 and 15 mM. Glucokinase activity or glucose utilization measured by conversion of [5-3H]glucose to [3H]H2O was not, however, altered in the MIN6 cells overexpressing human GLUT-2. Furthermore, glucose-stimulated insulin secretion was not affected by over-expression of human GLUT-2. An abundance of GLUT-2, therefore, does not correlate with the glucose responsiveness of cells in which glycolysis is regulated at the glucose phosphorylating step. These data suggest that GLUT-2 by itself does not have significant functions other than its role in glucose transport in glucose sensing by MIN6 cells.

scholarly journals Response of Insulin Secretion to Small Amount of Meal on Low Carbohydrate Diet (LCD)

2020 ◽  
Author(s):  
Mayumi Hashimoto ◽  
Koji Ebe ◽  
Hiroshi Bando ◽  
Masahiro Bando ◽  
Tetsuo Muneta
Keyword(s):  
Insulin Secretion ◽  
Carbohydrate Diet ◽  
Low Carbohydrate Diet ◽  
Low Carbohydrate

scholarly journals Acute (24 h) activation of peroxisome proliferator-activated receptor-alpha (PPARalpha) reverses high-fat feeding-induced insulin hypersecretion in vivo and in perifused pancreatic islets

2003 ◽  
Vol 177 (2) ◽  
pp. 197-205 ◽  
Author(s):  
MJ Holness ◽  
ND Smith ◽  
GK Greenwood ◽  
MC Sugden
Keyword(s):  
Insulin Secretion ◽  
Ex Vivo ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Intravenous Glucose ◽  
Perifused Islets ◽  
Glucose Stimulated Insulin Secretion ◽  
Fat Feeding

Abnormal depletion or accumulation of islet lipid may be important for the development of pancreatic beta cell failure. Long-term lipid sensing by beta cells may be co-ordinated via peroxisome proliferator-activated receptors (PPARs). We investigated whether PPARalpha activation in vivo for 24 h affects basal and glucose-stimulated insulin secretion in vivo after intravenous glucose administration and ex vivo in isolated perifused islets. Insulin secretion after intravenous glucose challenge was greatly increased by high-fat feeding (4 weeks) but glucose tolerance was minimally perturbed, demonstrating insulin hypersecretion compensated for insulin resistance. The effect of high-fat feeding to enhance glucose-stimulated insulin secretion was retained in perifused islets demonstrating a stable, long-term effect of high-fat feeding to potentiate islet glucose stimulus-secretion coupling. Treatment of high-fat-fed rats with WY14,643 for 24 h reversed insulin hypersecretion in vivo without impairing glucose tolerance, suggesting improved insulin action, and ex vivo in perfused islets. PPARalpha activation only affected hypersecretion of insulin since glucose-stimulated insulin secretion was unaffected by WY14,643 treatment in vivo in control rats or in perifused islets from control rats. Our data demonstrate that activation of PPARalpha for 24 h can oppose insulin hypersecretion elicited by high-fat feeding via stable long-term effects exerted on islet function. PPARalpha could, therefore, participate in ameliorating abnormal glucose homeostasis and hyperinsulinaemia in dietary insulin resistance via modulation of islet function, extending the established requirement for PPARalpha for normal islet lipid homeostasis.

scholarly journals Ketogenic Diet-Induced Severe Ketoacidosis in a Lactating Woman: A Case Report and Review of the Literature

2019 ◽  
Vol 2019 ◽  
pp. 1-4
Author(s):  
Benedicta Nneoma Nnodum ◽  
Eziafa Oduah ◽  
David Albert ◽  
Mark Pettus
Keyword(s):  
Ketogenic Diet ◽  
Case Reports ◽  
High Fat ◽  
Carbohydrate Diet ◽  
Low Carbohydrate Diet ◽  
Lactating Mothers ◽  
Low Carbohydrate ◽  
Life Threatening ◽  
Clinically Significant ◽  
Prompt Diagnosis

The ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet that leads to nutritional ketosis and weight loss. It is known to induce ketosis but is not an established cause of clinically significant ketoacidosis. Lactation ketoacidosis is well established in bovine literature but remains a rare phenomenon in humans. Here we present a life-threatening case of severe ketoacidosis in a nondiabetic lactating mother on a strict ketogenic diet. We review the available case reports of lactation ketoacidosis in humans and the mechanisms thereof. Although ketogenic diet has been shown to be safe in nonpregnant individuals, the safety of this diet in lactating mothers is not known. Health professionals and mothers should be made aware of the potential risk associated with a strict ketogenic diet when combined with lactation. Prompt diagnosis and immediate treatment cannot be overemphasized. To our knowledge, this is the first reported case of life-threatening lactation ketoacidosis associated with ketogenic diet while consuming an adequate number of calories per day.

scholarly journals PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling

2018 ◽  
Vol 115 (38) ◽  
pp. E8996-E9005 ◽  
Author(s):  
Brandon M. Gassaway ◽  
Max C. Petersen ◽  
Yulia V. Surovtseva ◽  
Karl W. Barber ◽  
Joshua B. Sheetz ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Phosphorylation ◽  
Cross Talk ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Large Scale ◽  
Kinase Assay ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
The Impact

Insulin resistance drives the development of type 2 diabetes (T2D). In liver, diacylglycerol (DAG) is a key mediator of lipid-induced insulin resistance. DAG activates protein kinase C ε (PKCε), which phosphorylates and inhibits the insulin receptor. In rats, a 3-day high-fat diet produces hepatic insulin resistance through this mechanism, and knockdown of hepatic PKCε protects against high-fat diet-induced hepatic insulin resistance. Here, we employed a systems-level approach to uncover additional signaling pathways involved in high-fat diet-induced hepatic insulin resistance. We used quantitative phosphoproteomics to map global in vivo changes in hepatic protein phosphorylation in chow-fed, high-fat–fed, and high-fat–fed with PKCε knockdown rats to distinguish the impact of lipid- and PKCε-induced protein phosphorylation. This was followed by a functional siRNA-based screen to determine which dynamically regulated phosphoproteins may be involved in canonical insulin signaling. Direct PKCε substrates were identified by motif analysis of phosphoproteomics data and validated using a large-scale in vitro kinase assay. These substrates included the p70S6K substrates RPS6 and IRS1, which suggested cross talk between PKCε and p70S6K in high-fat diet-induced hepatic insulin resistance. These results identify an expanded set of proteins through which PKCε may drive high-fat diet-induced hepatic insulin resistance that may direct new therapeutic approaches for T2D.

Adjusting Glucose-Stimulated Insulin Secretion For Adipose Insulin Resistance

2014 ◽  
Vol 46 ◽  
pp. 158
Author(s):  
Steven K. Malin ◽  
Sangeeta R. Kashyap ◽  
Jeff Hammel ◽  
Yoshi Miyazaki ◽  
John P. Kirwan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Glucose Stimulated Insulin Secretion

scholarly journals Long-Term Ketogenic Diet Induces Metabolic Acidosis, Anemia, and Oxidative Stress in Healthy Wistar Rats

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Aryadi Arsyad ◽  
Irfan Idris ◽  
Andi A. Rasyid ◽  
Rezky A. Usman ◽  
Kiki R. Faradillah ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Metabolic Acidosis ◽  
Ketogenic Diet ◽  
Wistar Rats ◽  
Blood Gas ◽  
High Fat ◽  
Carbohydrate Diet ◽  
Low Carbohydrate Diet ◽  
Low Carbohydrate

Background. Ketogenic diet has been used as supportive therapy in a range of conditions including epilepsy, diabetes mellitus, and cancer. Objective. This study aimed to investigate the effects of long-term consumption of ketogenic diet on blood gas, hematological profiles, organ functions, and superoxide dismutase level in a rat model. Materials and Methods. Fifteen male Wistar rats were divided into control (n = 8) and ketogenic (n = 7) groups. Controls received standard diet contained 52.20% of carbohydrates, 7.00% fat, and 15.25% protein; meanwhile, the ketogenic group received a high-fat-low-carbohydrate diet which contained 5.66% of carbohydrate, 86.19% fat, and 8.15% protein. All rats were caged individually and received 30g of either standard or high-fat-low-carbohydrate pellets. The experiment was carried out for 60 days before the blood samples were taken and analyzed to obtain blood gas, cell counts, organ biomarkers, and plasma antioxidant superoxide dismutase (SOD) levels. Results. The rats subjected to ketogenic diet experienced a marked decrease in body weight, blood sugar, and increased blood ketones (p<0.05). The average blood pH was 7.36 ± 0.02 and base excess was −5.57 ± 2.39 mOsm/L, which were significantly lower than controls (p<0.05). Hematological analysis showed significantly lower erythrocyte, hemoglobin, and hematocrit levels. No significant changes were found in alanine aminotransferase, aspartate aminotransferase, urea, and creatinine levels, indicating normal liver and kidney functions. Nevertheless, plasma SOD level significantly reduced with ketogenic diet. Conclusion. Long-term ketogenic diet induces metabolic acidosis, anemia, and reduced antioxidant enzyme level in rats following 60 days of consuming high-fat-low-carbohydrate diet.

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