Hyperamylinemia, hyperinsulinemia, and insulin resistance in genetically obese LA/N-cp rats.

Huang, Huei-Jen Su; Young, Andrew; Koda, Joy E.; Tulp, Orien L; Johnson, M.; Cooper, Garth J. S.

doi:10.1161/01.hyp.19.1_suppl.i101

Cited by 55 publications

(57 citation statements)

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“…Fasting and day-long plasma FFA levels are usually elevated (ϳ600 -800 M) in obese nondiabetic individuals (13,14), and elevated circulating levels of amylin have been detected in obese subjects and obese subjects with impaired glucose tolerance (8,38). Pancreatic amylin mRNA and plasma amylin levels are also elevated in genetically obese, insulin-resistant rats (20) . In addition, FAs have been reported to stimulate the polymerization of amylin in vitro and amyloid fibril formation in cultivated isolated islet of transgenic mice overexpressing human amylin (27).…”

Section: Discussionmentioning

confidence: 99%

Fatty acids induce amylin expression and secretion by pancreatic β-cells

Cai

Wang

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Amylin is the major component of pancreatic amyloid, which is implicated in the development of type 2 diabetes. It is costored with insulin in the secretory granules of pancreatic ␤-cells and cosecreted with insulin following stimulation with glucose. Here, we investigate the effect of fatty acids (FAs) on amylin expression and secretion by ␤-cells and explore the underlying mechanisms. Palmitate and oleate dose-dependently induced amylin mRNA accumulation in murine pancreatic ␤-cell line MIN6 and primary pancreatic islets. the inductive effect of FAs on amylin expression is independent of glucose concentration. FAs upregulated amylin expression at the transcriptional level, and FAs must be metabolized to induce amylin expression. FAs also significantly induced human amylin promoter activation. Pretreatment of MIN6 cells with Ca 2ϩ chelator (EGTA, BAPTA-AM) PKC inhibitor Gö-6976 or protein synthesis inhibitor cycloheximide significantly inhibited FA-induced amylin mRNA expression. Transcription factors cAMP-responsive element-binding protein, pancreatic and duodenal homeobox factor-1, and peroxisome proliferator-activated receptor were not involved in FA-induced amylin expression. Palmitate and oleate both increased amylin and insulin release from MIN6 cells and stimulated amylin expression but had no effect on insulin expression. Mice refed with Intralipid had significantly higher levels of plasma FFA, amylin, and insulin than those refed with saline. These data demonstrate that FAs differently regulate amylin and insulin expression and induce both amylin and insulin release. Ca 2ϩ and PKC signaling pathways and de novo-synthesized protein(s) were involved in FA-induced amylin expression. Induction of amylin production and release by FA may contribute to its biological functions under physiological conditions. pancreas; islet amyloid polypeptide; insulin; gene expression; signal transduction; high-lipid diet AMYLOID DEPOSITION IS A COMMON FEATURE in individuals with type 2 diabetes (30). Amylin, also known as islet amyloid polypeptide, is the most abundant component of pancreatic amyloid (6,49). Amylin is a 37-amino acid peptide of the calcitonin gene family. Amylin has been suggested to be toxic to ␤-cells and to be involved in the development of type 2 diabetes (30, 31). It has been proposed that overexpression of amylin contributes to pancreatic amyloid formation and development of type 2 diabetes, a view supported by transgenic mouse and rat studies involving the overexpression of human amylin in islets of Langerhans (31). Therefore, elucidation of the mechanisms controlling amylin gene expression in pancreatic ␤-cells may contribute to a better understanding of the physiological functions of amylin and prove relevant to the pathogenesis of type 2 diabetes.In pancreatic ␤-cells, amylin is costored with insulin in the secretory granules and cosecreted in a regulated manner following stimulation with glucose and a variety of other secretagogues (5, 22). Glucose stimulates amylin mRNA expression and protein re...

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Section: Discussionmentioning

confidence: 99%

Fatty acids induce amylin expression and secretion by pancreatic β-cells

Cai

Wang

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…22,24 The more rapid glucose disposal in lean than obese animals is consistent with significantly greater insulin resistance and impaired peripheral glucose uptake reported in obese than in lean rats of this strain. 9,11 The effects of chromium may have partially overcome the insulin resistance of the obese animals, and resulted in an attenuation in the glycemic responses observed.…”

Section: Discussionmentioning

confidence: 99%

“…Incorporation of the -cp trait resulted in early onset hypertrophichyperplastic obesity which typically becomes visibly evident by approximately 5 to 6weeks of age in affected offspring. 7 The obese phenotype is associated with hyperphagia, marked hyperlipidemia, hyperinsulinemia, hyperamylinemia, hyperleptinemia, and an impaired glucose tolerance similar to that which may occur in obese humans, [8][9][10][11] and an impaired thermic response to alterations in diet and environment, 7,8,12 Because of the homogeniety conferred by the congenic and SPF-VAF status of this strain, however, characteristics of growth, metabolism, aging, and the metabolic responses to diet and environment of different animals are more similar in this rodent population within phenotypes than might be observed in a less homogenous model or in free-living human subjects. 7 The purpose of the present study was to determine the effects of an inulin-chromium complex, consisting of an indigestible β-linked glycan of fructan units, on glycemic responses of congenic obese rats.…”

Section: Introductionmentioning

confidence: 99%

Effect of a Fructan-Chromium Complex on Glycemic Responses of Congenic Obese La/Ntul/ /-Cp Rats

Brown¹

2016

JNHFE

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Recent studies have shown that the marked adiposity of the obese phenotype of the LA/Ntul/ /-cp rat to be associated with hyperinsulinemia, hyperamylinemia, and impaired glucose tolerance following an oral glucose challenge when compared to glycemic responses of similarly-fed lean littermates, and to be linked to a hypothalamic receptor defect for the obesity hormone, leptin. To determine the effects of an inulin fructan polymer-chromium complex (FCC) derived from dahlia root juice on glycemic responses, groups of congenic lean and obese LA/Ntul//-cp rats were administered an oral glucose tolerance (OGT) alone or in combination with measured amounts of the FCC. Glycemic responses and the glucose area under the curve (AUC) of obese rats were significantly impaired compared to similarly-fed lean littermates. Oral FCC administration resulted in a significant 50% reduction toward normal of the peak glycemic response during OGT in both lean and obese rats, a 75% reduction in the total glucose area of lean rats and a 50% reduction of the total glucose area of obese rats. The greatest segment of the reduced glucose area occurred during the post absorptive phase of the OGT response in both phenotypes. The results of this study are consistent with an acute FCC-mediated improvement in glycemic control in a congenic obese animal model of impaired glucose tolerance, and suggest that the FCC complex may be a useful nutraceutical adjunct in the dietary treatment of obesity and other glucose-intolerant states as they may occur in man and animals.Keywords: fructan, inulin, glucose tolerance, obesity, rat, chromium Journal of Nutritional Health & Food Engineering Research ArticleOpen Access Effect of a fructan-chromium complex on glycemic responses of congenic obese la/ntul//-cp rats 595Copyright: ©2016 Tulp et al. Citation:Tulp OL, Brown T. Effect of a fructan-chromium complex on glycemic responses of congenic obese la/ntul//-cp rats .

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“…Plasma level of amylin or TNF-α is also elevated in genetically obese, insulin-resistant animal models [11,35]. Although we didn't observe inductive effects of TNF-α on amylin expression after prolonged treatment of MIN6 cells with TNF-α for up to 48 h, TNF-α , 100 nmol/l wortmannin) for 1 h followed by 2.87 nmol/l TNF-α (black bars; white bars, control) for additional 6 h.. Luciferase activities were measured, normalised to renilla expression of the pRL-TK plasmid and are shown as fold over the activity of the pGL3-basic construct in control medium.…”

Section: Discussionmentioning

confidence: 99%

“…Elevated circulating levels of amylin have been detected in patients with severe acute pancreatitis [6], pancreas transplantation [7], obesity and insulin resistance [8][9][10]. Pancreatic amylin mRNA and plasma amylin levels are also elevated in genetically obese, insulin-resistant rats [11]. However, the mechanisms underlying amylin expression are not completely understood.…”

Section: Introductionmentioning

confidence: 99%

TNF-α acutely upregulates amylin expression in murine pancreatic beta cells

Cai

Wang

et al. 2010

Diabetologia

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Aims/hypothesis Amylin, a secretory protein mainly produced by pancreatic beta cells, is elevated in the circulation of patients with diseases related to acute and chronic inflammation, including acute pancreatitis, pancreas graft rejection, obesity and insulin resistance. TNF-α is involved in these disorders. We investigated the effect of TNF-α on amylin levels and the underlying mechanisms, using murine pancreatic beta cell line MIN6 and pancreatic islets. Methods Amylin, proinsulin and prohormone convertase 1/3, 2 (Pc1/3, Pc2 [also known as Pcsk1/3 and Pcsk2, respectively]) mRNA levels, and amylin promoter and nuclear factor κB (NF-κB) activation were examined by real-time PCR and luciferase reporter assay, respectively. Amylin protein level and mitogen-activated protein kinase phosphorylation were detected by western blot. Activator protein 1 (AP1) activation was examined by electrophoretic mobility shift assay (EMSA).Results TNF-α acutely induced amylin expression at the transcriptional level and increased proamylin and the intermediate form of amylin in MIN6 cells and islets. However, it had no effect on proinsulin, Pc1/3 and Pc2 expression. Studies with (1) MIN6 cells treated with inhibitors of MEK1/2, c-Jun-N-terminal kinase (JNK) or protein kinase CK PKC ð z Þ, (2) MIN6 cells expressing a c-Jun-dominant negative construct and (3) islets from Fos knockout mice demonstrated that TNF-α induced amylin expression through the PKC z Àextracellular signal-regulated kinase (ERK)/JNK pathways. EMSA showed that PKC z , JNK and ERK1/2 were involved in TNF-α-induced AP1 activation, suggesting that TNF-α induces murine amylin expression through the PKC z ÀERK1=2ÀAP1 and PKC z À JNKÀAP1 pathways. Further studies showed that TNF-α also induced murine amylin expression through the phosphatidylinositol 3 kinase-NF-κB signalling pathway and enhanced human amylin promoter activation through NF-κB and AP1. Conclusions/interpretation TNF-α acutely induces amylin gene expression in beta cells through multiple signalling pathways, possibly contributing to amylin elevation in acute inflammation-related pancreatic disorders.

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Hyperamylinemia, hyperinsulinemia, and insulin resistance in genetically obese LA/N-cp rats.

Cited by 55 publications

References 0 publications

Fatty acids induce amylin expression and secretion by pancreatic β-cells

Fatty acids induce amylin expression and secretion by pancreatic β-cells

Effect of a Fructan-Chromium Complex on Glycemic Responses of Congenic Obese La/Ntul/ /-Cp Rats

TNF-α acutely upregulates amylin expression in murine pancreatic beta cells

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