scholarly journals Defective STIM-mediated store operated Ca2+ entry in hepatocytes leads to metabolic dysfunction in obesity

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Ana Paula Arruda ◽  
Benedicte Mengel Pers ◽  
Günes Parlakgul ◽  
Ekin Güney ◽  
Ted Goh ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Action ◽  
Glucose Production ◽  
Adaptive Mechanism ◽  
Metabolic Dysfunction ◽  
Obese Mice ◽  
Primary Hepatocytes ◽  
Over Expression ◽  
Impaired Insulin ◽  
Impaired Insulin Action

Defective Ca2+ handling is a key mechanism underlying hepatic endoplasmic reticulum (ER) dysfunction in obesity. ER Ca2+ level is in part monitored by the store-operated Ca2+ entry (SOCE) system, an adaptive mechanism that senses ER luminal Ca2+ concentrations through the STIM proteins and facilitates import of the ion from the extracellular space. Here, we show that hepatocytes from obese mice displayed significantly diminished SOCE as a result of impaired STIM1 translocation, which was associated with aberrant STIM1 O-GlycNAcylation. Primary hepatocytes deficient in STIM1 exhibited elevated cellular stress as well as impaired insulin action, increased glucose production and lipid droplet accumulation. Additionally, mice with acute liver deletion of STIM1 displayed systemic glucose intolerance. Conversely, over-expression of STIM1 in obese mice led to increased SOCE, which was sufficient to improve systemic glucose tolerance. These findings demonstrate that SOCE is an important mechanism for healthy hepatic Ca2+ balance and systemic metabolic control.

Antecedent protein restriction exacerbates development of impaired insulin action after high-fat feeding

1999 ◽  
Vol 276 (1) ◽  
pp. E85-E93 ◽  
Author(s):  
Mark J. Holness ◽  
Mary C. Sugden
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Insulin Action ◽  
Protein Restriction ◽  
Protein Diet ◽  
Glucose Disposal ◽  
High Fat ◽  
Impaired Insulin ◽  
Impaired Insulin Action ◽  
Fat Feeding

The study investigated whether a persistent impairment of insulin secretion resulting from mild protein restriction predisposes to loss of glucoregulatory control and impaired insulin action after the subsequent imposition of the diabetogenic challenge of high-fat feeding. Offspring of dams provided with either control (20% protein) diet (C) or an isocaloric restricted (8%) protein diet (PR) were weaned onto the maintenance diet with which their mothers had been provided. At 20 wk of age, protein restriction enhanced glucose tolerance despite impaired insulin secretion and an augmented and sensitized lipolytic response to norepinephrine in adipocytes. C and PR rats were then transferred to a high-fat diet (HF, 19% protein, 22% lipid, 34% carbohydrate) and sampled after 8 wk. These groups are termed C-HF and PR-HF. Glucose tolerance was impaired in PR-HF, but not C-HF, rats. Insulin-stimulated glucose disposal rates were significantly lower (by 30%; P < 0.01) in the PR-HF group than in the C-HF group, and a specific impairment of antilipolytic response of insulin was unmasked in adipocytes from PR-HF, but not C-HF, rats. The study demonstrates that antecedent protein restriction accelerates and augments the development of impaired glucoregulation and insulin resistance after high-fat feeding.

scholarly journals CaMKIV limits metabolic damage through induction of hepatic autophagy by CREB in obese mice

2020 ◽  
Vol 244 (2) ◽  
pp. 353-367 ◽  
Author(s):  
Jiali Liu ◽  
Yue Li ◽  
Xiaoyan Zhou ◽  
Xi Zhang ◽  
Hao Meng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Inflammatory Response ◽  
Mitochondrial Dysfunction ◽  
High Fat Diet ◽  
Insulin Action ◽  
Hepatic Insulin Resistance ◽  
Obese Mice ◽  
High Fat ◽  
Impaired Insulin

High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance and metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism is not fully understood. In the present study, we aimed to address the direct effects of CaMKIV in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. Our results indicated obese mice receiving CaMKIV showed decreased blood glucose and serum insulin and improved insulin sensitivity as well as increased glucose tolerance compared with vehicle injection. Meanwhile, defective hepatic autophagy activity, impaired insulin signaling, increased inflammatory response and mitochondrial dysfunction in liver tissues which are induced by high-fat diet were also effectively alleviated by injection of CaMKIV. Consistent with these results, the addition of CaMKIV to the culture medium of BNL cl.2 hepatocytes markedly restored palmitate-induced hepatic insulin resistance and autophagic imbalance. These effects were nullified by blockade of cyclic AMP response element-binding protein (CREB), indicating the causative role of CREB in action of CaMKIV. Our findings suggested that CaMKIV restores hepatic autophagic imbalance and improves impaired insulin sensitivity via phosphorylated CREB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.

Impaired Insulin Action in Rats with Non-insulin-dependent Diabetes

Diabetes ◽  
1984 ◽  
Vol 33 (9) ◽  
pp. 901-906 ◽  
Author(s):  
J. Levy ◽  
J. R. Gavin ◽  
A. Fausto ◽  
R. L. Gingerich ◽  
L. V. Avioli
Keyword(s):  
Insulin Action ◽  
Insulin Dependent Diabetes ◽  
Impaired Insulin ◽  
Insulin Dependent ◽  
Impaired Insulin Action

scholarly journals Current views on type 2 diabetes

2009 ◽  
Vol 204 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Yi Lin ◽  
Zhongjie Sun
Keyword(s):  
Type 2 Diabetes ◽  
Animal Models ◽  
Insulin Action ◽  
Large Population ◽  
Specific Aspect ◽  
Multiple Organs ◽  
Impaired Insulin ◽  
Critical Components ◽  
Impaired Insulin Action

Type 2 diabetes mellitus (T2DM) affects a large population worldwide. T2DM is a complex heterogeneous group of metabolic disorders including hyperglycemia and impaired insulin action and/or insulin secretion. T2DM causes dysfunctions in multiple organs or tissues. Current theories of T2DM include a defect in insulin-mediated glucose uptake in muscle, a dysfunction of the pancreatic β-cells, a disruption of secretory function of adipocytes, and an impaired insulin action in liver. The etiology of human T2DM is multifactorial, with genetic background and physical inactivity as two critical components. The pathogenesis of T2DM is not fully understood. Animal models of T2DM have been proved to be useful to study the pathogenesis of, and to find a new therapy for, the disease. Although different animal models share similar characteristics, each mimics a specific aspect of genetic, endocrine, metabolic, and morphologic changes that occur in human T2DM. The purpose of this review is to provide the recent progress and current theories in T2DM and to summarize animal models for studying the pathogenesis of the disease.

059. POOR GROWTH BEFORE BIRTH IMPAIRS INSULIN SECRETION - WHAT WE HAVE LEARNT ABOUT THE MECHANISMS FROM THE PLACENTALLY-RESTRICTED SHEEP

2009 ◽  
Vol 21 (9) ◽  
pp. 14
Author(s):  
K. L. Gatford
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Insulin Action ◽  
Cell Function ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Poor Growth ◽  
Impaired Insulin ◽  
Impaired Insulin Action

Diabetes occurs when insulin secretion fails to increase sufficiently to compensate for developing insulin resistance. This implies that the increased risk of diabetes in adults who were small at birth reflects impaired insulin secretion as well as their well-known insulin resistance. More recently, direct evidence has been obtained that adults and children who were growth-restricted before birth secrete less insulin than they should, given their level of insulin resistance. Our research group is using the placentally-restricted (PR) sheep to investigate the mechanisms underlying impaired insulin action (sensitivity and secretion) induced by poor growth before birth. Like the intra-uterine growth-restricted (IUGR) human, the PR sheep develops impaired insulin action by adulthood, but has enhanced insulin sensitivity in infancy, associated with neonatal catch-up growth1, 2. Impaired insulin action begins to develop in early postnatal life, where although basal insulin action is high due to enhanced insulin sensitivity, maximal glucose-stimulated insulin action is already impaired in males3. Our cellular and molecular studies have identified impaired beta-cell function rather than mass as the likely cause of impaired insulin secretion, and we have reported a novel molecular defect in the calcium channels involved in the insulin secretion pathway in the pancreas of these lambs3. Upregulation of IGF-II and insulin receptor are implicated as key molecular regulators of beta-cell mass in the PR lamb3. By adulthood, both basal and maximal insulin action are profoundly impaired in the male lamb who was growth-restricted at birth2. These studies suggest therapies to prevent diabetes in the individual who grew poorly before birth should target beta-cell function, possibly in addition to further increasing beta-cell mass, to improve insulin secretion capacity, and its ability to increase in response to development of insulin resistance. We are now using the PR sheep to test potential therapies, since the timing of pancreatic development and hence exposure to a growth-restricting environment, is similar to that of the human.

Impaired insulin action but normal insulin receptor activity in diabetic rat liver: effect of vanadate

1990 ◽  
Vol 258 (3) ◽  
pp. E459-E467 ◽  
Author(s):  
O. Blondel ◽  
J. Simon ◽  
B. Chevalier ◽  
B. Portha
Keyword(s):  
Insulin Receptor ◽  
Insulin Action ◽  
Diabetic Rats ◽  
Receptor Kinase ◽  
Peripheral Tissues ◽  
Impaired Insulin ◽  
Insulin Dependent ◽  
Insulin Receptor Kinase ◽  
Impaired Insulin Action

In vivo insulin resistance is a characteristic of the liver and peripheral tissues in 10-wk-old female rats with non-insulin-dependent diabetes induced by streptozotocin given on day 5 after birth. Oral administration of vanadate (0.2 mg/ml) for 20 days in the diabetic rats lowered their plasma glucose levels to normal values without affecting their basal plasma insulin levels. In the basal state as well as after submaximal or maximal hyperinsulinemia (euglycemic clamp studies), peripheral glucose utilization and hepatic glucose production in vivo were normalized in the diabetic rats after the vanadate treatment. In wheat germ agglutinin purified receptors, 125I-labeled porcine insulin binding, basal and insulin-stimulated insulin receptor kinase activities for both the autophosphorylation of the beta-subunit and the phosphorylation of the artificial substrate poly (Glu-Tyr) 4:1, were found identical in diabetic and control rats, treated or not with vanadate. Liver phosphoenolpyruvate carboxykinase activity was significantly enhanced in untreated diabetic rats (P less than 0.01) as compared with control rats and returned to normal values after the 20-day vanadate treatment. Thus, in that model of non-insulin-dependent diabetes, 1) oral vanadate exerts a corrective insulin-like effect on impaired insulin action both at the level of liver and peripheral tissues, 2) impaired insulin action with no alteration of the insulin receptor tyrosine kinase is observed in the liver of untreated rats, and 3) corrective effect of vanadate on liver glucose metabolism is probably distal to the insulin receptor kinase activity.

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