scholarly journals Overexpression of FoxO1 in the Hypothalamus and Pancreas Causes Obesity and Glucose Intolerance

Endocrinology ◽  
2012 ◽  
Vol 153 (2) ◽  
pp. 659-671 ◽  
Author(s):  
Hye-Jin Kim ◽  
Masaki Kobayashi ◽  
Tsutomu Sasaki ◽  
Osamu Kikuchi ◽  
Kosuke Amano ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Insulin Secretion ◽  
Glucose Intolerance ◽  
Insulin Signaling ◽  
Uncoupling Protein ◽  
Cell Mass ◽  
Peroxisome Proliferator ◽  
Β Cells ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin

Recent studies have revealed that insulin signaling in pancreatic β-cells and the hypothalamus is critical for maintaining nutrient and energy homeostasis, the failure of which are hallmarks of metabolic syndrome. We previously reported that forkhead transcription factor forkhead box-containing protein of the O subfamily (FoxO)1, a downstream effector of insulin signaling, plays important roles in β-cells and the hypothalamus when we investigated the roles of FoxO1 independently in the pancreas and hypothalamus. However, because metabolic syndrome is caused by the combined disorders in hypothalamus and pancreas, to elucidate the combined implications of FoxO1 in these organs, we generated constitutively active FoxO1 knockin (KI) mice with specific activation in both the hypothalamus and pancreas. The KI mice developed obesity, insulin resistance, glucose intolerance, and hypertriglyceridemia due to increased food intake, decreased energy expenditure, and impaired insulin secretion, which characterize metabolic syndrome. The KI mice also had increased hypothalamic Agouti-related protein and neuropeptide Y levels and decreased uncoupling protein 1 and peroxisome proliferator-activated receptor γ coactivator 1α levels in adipose tissue and skeletal muscle. Impaired insulin secretion was associated with decreased expression of pancreatic and duodenum homeobox 1 (Pdx1), muscyloaponeurotic fibrosarcoma oncogene homolog A (MafA), and neurogenic differentiation 1 (NeuroD) in islets, although β-cell mass was paradoxically increased in KI mice. Based on these results, we propose that uncontrolled FoxO1 activation in the hypothalamus and pancreas accounts for the development of obesity and glucose intolerance, hallmarks of metabolic syndrome.

scholarly journals Glucose Intolerance on Phaeochromocytoma and Paraganglioma—The Current Understanding and Clinical Perspectives

2020 ◽  
Vol 11 ◽  
Author(s):  
Ichiro Abe ◽  
Farhadul Islam ◽  
Alfred King-Yin Lam
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Glucose Intolerance ◽  
Adrenergic Receptors ◽  
Β Cells ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin ◽  
Life Threatening ◽  
The Difference ◽  
Α2 Receptors

Half of the patients with phaeochromocytoma have glucose intolerance which could be life-threatening as well as causing postoperative hypoglycemia. Glucose intolerance is due to impaired insulin secretion and/or increased insulin resistance. Impaired insulin secretion is caused by stimulating adrenergic α2 receptors of pancreatic β-cells and increased insulin resistance is caused by stimulating adrenergic α1 and β3 receptors in adipocytes, α1 and β2 receptors of pancreatic α-cells and skeletal muscle. Furthermore, different affinities to respective adrenergic receptors exist between epinephrine and norepinephrine. Clinical studies revealed patients with phaeochromocytoma had impaired insulin secretion as well as increased insulin resistance. Furthermore, excess of epinephrine could affect glucose intolerance mainly by impaired insulin secretion and excess of norepinephrine could affect glucose intolerance mainly by increased insulin resistance. Glucose intolerance on paraganglioma could be caused by increased insulin resistance mainly considering paraganglioma produces more norepinephrine than epinephrine. To conclude, the difference of actions between excess of epinephrine and norepinephrine could lead to improve understanding and management of glucose intolerance on phaeochromocytoma.

scholarly journals Impaired Insulin Secretion by Diphenyleneiodium Associated with Perturbation of Cytosolic Ca2+ Dynamics in Pancreatic β-Cells

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5391-5400 ◽  
Author(s):  
Hirofumi Imoto ◽  
Nobuhiro Sasaki ◽  
Masanori Iwase ◽  
Udai Nakamura ◽  
Miwako Oku ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Nadph Oxidase ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Mitochondrial Respiratory Chain ◽  
Membrane Depolarization ◽  
Oxidase Inhibitor ◽  
Channel Blockers ◽  
Β Cells ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin

Pancreatic islets express the superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, but its role remains unknown. To address this, we studied the mechanisms of impaired insulin secretion induced by diphenyleneiodium (DPI), an NADPH oxidase inhibitor. We investigated the effects of DPI on glucose- and nonfuel-stimulated insulin secretion, islet glucose metabolism, and intracellular Ca2+ concentration ([Ca2+]i) dynamics in rat islets and β-cell line RINm5F cells. DPI did not affect insulin secretion at 3.3 mm glucose but totally suppressed insulin secretion stimulated by 16.7 mm glucose (percentage of control, 9.2 ± 1.2%; P <0.001). DPI also inhibited insulin release by high K+-induced membrane depolarization (percentage of control, 36.0 ± 5.3%; P <0.01) and protein kinase C activation (percentage of control, 30.2 ± 10.6% in the presence of extracellular Ca2+, P <0.01; percentage of control, 42.0 ± 4.7% in the absence of extracellular Ca2+, P <0.01). However, DPI had no effect on mastoparan-induced insulin secretion at 3.3 and 16.7 mm glucose under Ca2+-free conditions. DPI significantly suppressed islet glucose oxidation and ATP content through its known inhibitory action on complex I in the mitochondrial respiratory chain. On the other hand, DPI altered [Ca2+]i dynamics in response to high glucose and membrane depolarization, and DPI per se dose-dependently increased [Ca2+]i. The DPI-induced [Ca2+]i rise was associated with a transient increase in insulin secretion and was attenuated by removal of extracellular Ca2+, by L-type voltage-dependent Ca2+ channel blockers, by mitochondrial inhibitors, or by addition of 0.1 or 1.0 μm H2O2 exogenously. Our results showed that DPI impairment of insulin secretion involved altered Ca2+ signaling, suggesting that NADPH oxidase may modulate Ca2+ signaling in β-cells.

scholarly journals Peroxisome Proliferator-Activated Receptor α (PPARα) Potentiates, whereas PPARγ Attenuates, Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells

Endocrinology ◽  
2005 ◽  
Vol 146 (8) ◽  
pp. 3266-3276 ◽  
Author(s):  
Kim Ravnskjaer ◽  
Michael Boergesen ◽  
Blanca Rubi ◽  
Jan K. Larsen ◽  
Tina Nielsen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Mitochondrial Membrane ◽  
Uncoupling Protein ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Stimulated Insulin Secretion

Abstract Fatty acids (FAs) are known to be important regulators of insulin secretion from pancreatic β-cells. FA-coenzyme A esters have been shown to directly stimulate the secretion process, whereas long-term exposure of β-cells to FAs compromises glucose-stimulated insulin secretion (GSIS) by mechanisms unknown to date. It has been speculated that some of these long-term effects are mediated by members of the peroxisome proliferator-activated receptor (PPAR) family via an induction of uncoupling protein-2 (UCP2). In this study we show that adenoviral coexpression of PPARα and retinoid X receptor α (RXRα) in INS-1E β-cells synergistically and in a dose- and ligand-dependent manner increases the expression of known PPARα target genes and enhances FA uptake and β-oxidation. In contrast, ectopic expression of PPARγ/RXRα increases FA uptake and deposition as triacylglycerides. Although the expression of PPARα/RXRα leads to the induction of UCP2 mRNA and protein, this is not accompanied by reduced hyperpolarization of the mitochondrial membrane, indicating that under these conditions, increased UCP2 expression is insufficient for dissipation of the mitochondrial proton gradient. Importantly, whereas expression of PPARγ/RXRα attenuates GSIS, the expression of PPARα/RXRα potentiates GSIS in rat islets and INS-1E cells without affecting the mitochondrial membrane potential. These results show a strong subtype specificity of the two PPAR subtypes α and γ on lipid partitioning and insulin secretion when systematically compared in a β-cell context.

scholarly journals β-Cell–Specific Deletion of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) Reductase Causes Overt Diabetes due to Reduction of β-Cell Mass and Impaired Insulin Secretion

Diabetes ◽  
2020 ◽  
Vol 69 (11) ◽  
pp. 2352-2363
Author(s):  
Shoko Takei ◽  
Shuichi Nagashima ◽  
Akihito Takei ◽  
Daisuke Yamamuro ◽  
Tetsuji Wakabayashi ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Coenzyme A ◽  
Cell Mass ◽  
Β Cell ◽  
Impaired Insulin Secretion ◽  
Overt Diabetes ◽  
Impaired Insulin ◽  
Specific Deletion ◽  
Coenzyme A Reductase

scholarly journals Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice

2008 ◽  
Vol 105 (10) ◽  
pp. 3992-3997 ◽  
Author(s):  
N. Gustavsson ◽  
Y. Lao ◽  
A. Maximov ◽  
J.-C. Chuang ◽  
E. Kostromina ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Intolerance ◽  
Mutant Mice ◽  
Null Mutant ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin ◽  
Null Mutant Mice

Glucose Intolerance and Impaired Insulin Secretion by Prostaglandin A1in Fasting Anesthetized Dogs

Endocrinology ◽  
1973 ◽  
Vol 92 (1) ◽  
pp. 31-34 ◽  
Author(s):  
LUIGI SACCA ◽  
FRANCO RENGO ◽  
MASSIMO CHIARIELLO ◽  
MARIO CONDORELLI
Keyword(s):  
Insulin Secretion ◽  
Glucose Intolerance ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin ◽  
Anesthetized Dogs

scholarly journals c-Myc directly induces both impaired insulin secretion and loss of β-cell mass, independently of hyperglycemia in vivo

Islets ◽  
2010 ◽  
Vol 2 (1) ◽  
pp. 37-45 ◽  
Author(s):  
Linda Cheung ◽  
Sevasti Zervou ◽  
Göran Mattsson ◽  
Sylvie Abouna ◽  
Luxian Zhou ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Mass ◽  
Β Cell ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin

scholarly journals Glucose Intolerance and Impaired Insulin Secretion in Pancreas-Specific Signal Transducer and Activator of Transcription-3 Knockout Mice Are Associated with Microvascular Alterations in the Pancreas

Endocrinology ◽  
2010 ◽  
Vol 151 (5) ◽  
pp. 2050-2059 ◽  
Author(s):  
Elena Kostromina ◽  
Natalia Gustavsson ◽  
Xiaorui Wang ◽  
Chun-Yan Lim ◽  
George K. Radda ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Intolerance ◽  
Endocrine Pancreas ◽  
Isolated Islets ◽  
Signal Transducer ◽  
Microvascular Network ◽  
Impaired Insulin Secretion ◽  
Stat3 Signaling ◽  
Impaired Insulin

Maintenance of glucose homeostasis depends on adequate amount and precise pattern of insulin secretion, which is determined by both β-cell secretory processes and well-developed microvascular network within endocrine pancreas. The development of highly organized microvasculature and high degrees of capillary fenestrations in endocrine pancreas is greatly dependent on vascular endothelial growth factor-A (VEGF-A) from islet cells. However, it is unclear how VEGF-A production is regulated in endocrine pancreas. To understand whether signal transducer and activator of transcription (STAT)-3 is involved in VEGF-A regulation and subsequent islet and microvascular network development, we generated a mouse line carrying pancreas-specific deletion of STAT3 (p-KO) and performed physiological analyses both in vivo and using isolated islets, including glucose and insulin tolerance tests, and insulin secretion measurements. We also studied microvascular network and islet development by using immunohistochemical methods. The p-KO mice exhibited glucose intolerance and impaired insulin secretion in vivo but normal insulin secretion in isolated islets. Microvascular density in the pancreas was reduced in p-KO mice, along with decreased expression of VEGF-A, but not other vasotropic factors in islets in the absence of pancreatic STAT3 signaling. Together, our study suggests that pancreatic STAT3 signaling is required for the normal development and maintenance of endocrine pancreas and islet microvascular network, possibly through its regulation of VEGF-A.

scholarly journals Does epigenetic dysregulation of pancreatic islets contribute to impaired insulin secretion and type 2 diabetes?

2015 ◽  
Vol 93 (5) ◽  
pp. 511-521 ◽  
Author(s):  
Tasnim Dayeh ◽  
Charlotte Ling
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Impaired Insulin Secretion ◽  
Expression Of Genes ◽  
Impaired Insulin

β cell dysfunction is central to the development and progression of type 2 diabetes (T2D). T2D develops when β cells are not able to compensate for the increasing demand for insulin caused by insulin resistance. Epigenetic modifications play an important role in establishing and maintaining β cell identity and function in physiological conditions. On the other hand, epigenetic dysregulation can cause a loss of β cell identity, which is characterized by reduced expression of genes that are important for β cell function, ectopic expression of genes that are not supposed to be expressed in β cells, and loss of genetic imprinting. Consequently, this may lead to β cell dysfunction and impaired insulin secretion. Risk factors that can cause epigenetic dysregulation include parental obesity, an adverse intrauterine environment, hyperglycemia, lipotoxicity, aging, physical inactivity, and mitochondrial dysfunction. These risk factors can affect the epigenome at different time points throughout the lifetime of an individual and even before an individual is conceived. The plasticity of the epigenome enables it to change in response to environmental factors such as diet and exercise, and also makes the epigenome a good target for epigenetic drugs that may be used to enhance insulin secretion and potentially treat diabetes.

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