Insulin resistance is accompanied by impairment of amylase-gene expression in the exocrine pancreas of the obese Zucker rat

Trimble, Elisabeth R.; Bruzzone, Roberto; Belin, Dominique

doi:10.1042/bj2370807

Cited by 29 publications

(27 citation statements)

References 41 publications

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“…Regarding the cause-effect relationship, low serum amylase levels were believed to be due to deficient insulin activity [10-13], which is consistent with early findings that insulin and ciglitazone (this drug was never approved for clinical use), a peroxisome proliferator-activated receptor-γ agonist respectively increased and restored the secretion of amylase from pancreases isolated from rats [15,16]. In contrast, the results of our retrospective longitudinal analysis suggest that low serum amylase levels preceded the overt metabolic abnormalities.…”

Section: Discussionsupporting

confidence: 65%

Low serum amylase in association with metabolic syndrome and diabetes: A community-based study

Nakajima

Nemoto

Muneyuki

et al. 2011

Cardiovasc Diabetol

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BackgroundLow serum amylase levels may reflect impaired exocrine-endocrine relationship in the pancreas. However, few clinical studies have addressed this issue. Therefore, in this epidemiological study, we investigated whether low serum amylase was associated with the pathogenesis of impaired insulin action: metabolic syndrome (MetS) and diabetes.Research Design and MethodsSerum amylase, cardiometabolic risk factors, MetS (Adult Treatment Panel III criteria), and diabetes were examined in 2,425 asymptomatic subjects aged 30-80 years who underwent medical checkups recently (April 2009-March 2010) and 5 years ago.ResultsClinical variables, except for age and estimated glomerular filtration rate (eGFR), shifted favorably with increasing serum amylase levels. Plasma glucose levels at 1- and 2-hr during OGTT increased significantly with decreasing serum amylase levels. Multiple logistic analyses showed that, compared with highest quartile of serum amylase, lowest quartile was associated with increased risk for MetS and diabetes after adjustment for confounding factors [odds ratio (95% CI), 2.07 (1.39-3.07) and 2.76 (1.49-5.11), respectively]. In subjects who underwent checkups 5 years ago (n = 571), lower amylase at the previous checkup were associated with larger numbers of metabolic abnormalities at the recent checkup. The fluctuation over time in serum amylase levels in subjects with low serum amylase at the previous checkup was slight and was unaffected by kidney dysfunction.ConclusionsOur results indicate that low serum amylase is associated with increased risk of metabolic abnormalities, MetS and diabetes. These results suggest a pancreatic exocrine-endocrine relationship in certain clinical conditions.

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Section: Discussionsupporting

confidence: 65%

Low serum amylase in association with metabolic syndrome and diabetes: A community-based study

Nakajima

Nemoto

Muneyuki

et al. 2011

Cardiovasc Diabetol

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“…The changes, an increase and a decrease in the synthesis ofanionic trypsinogen and amylase, respectively, are observed in the table both immediately after the pulse and after a 90-min chase period. (7), lipase synthesis is regulated by secretin (13,29), and amylase synthesis is regulated by insulin (30)(31)(32)(33) and glucocorticoids (34). In contrast to the results observed after changes in diets, the findings shown here indicated no change in mRNA levels during 24 hr of caerulein stimulation.…”

Section: Methodscontrasting

confidence: 56%

Translational control of anionic trypsinogen and amylase synthesis in rat pancreas in response to caerulein stimulation.

Steinhilber

Poensgen

Rausch

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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Infusion of rats with optimal doses of caerulein for up to 24 hr resulted in divergent changes in protein synthesis in the exocrine pancreas: a 3-fold increase in synthesis of anionic trypsinogen and a 75% decrease in synthesis of amylase. Lipase synthesis showed no change. Rates of total protein synthesis increased 2-fold, while DNA, RNA, and poly(A)+ mRNA concentrations were unchanged during hormonal stimulation. mRNA concentrations for anionic trypsinogen, lipase, and amylase were determined by dot blot hybridization analysis with cDNA and cRNA probes. Despite 12-fold changes in the ratio of synthesis of anionic trypsinogen to amylase at 24 hr of caerulein stimulation, changes in levels of mRNA encoding these two proteins were not observed. The slight decreases observed in amylase mRNA concentrations were found in both hormone and saline-infused animals. In vitro pulse-chase experiments after 12 hr of saline or caerulein infusion indicated that differential turnover of anionic trypsinogen and amylase did not occur during hormone stimulation. These data demonstrate that the differential regulation observed in protein synthesis that results from a single period of hormone stimulation is mediated by differential regulation of mRNA translation. The high degree of conservation observed in the 5' terminal sequences of both amylase and anionic trypsinogen mRNAs between mouse, rat, and dog suggests that sequence-specific mechanisms and secondary structure may play a role in the translational control of these two mRNAs.Regulation of gene expression has been studied to the greatest extent in prokaryotic organisms where mechanisms that regulate gene transcription predominate (1). In prokaryotes the half-lives of mRNA are measured in minutes (2). In eukaryotes, the half-lives of mRNA, which represent differentiated products of gene transcription (e.g., mRNAs encoding secretory products), are measured in hours to days (2, 3). mRNAs for pancreatic secretory proteins show half-lives of 3-6 hr (3). It is therefore likely that mechanisms that regulate rapid changes in gene expression in eukaryotic tissues (biological response in minutes to hours) occur at the translational level. However, few examples of translational control have been documented in higher animals. Recently, translational control has been demonstrated for insulin biosynthesis in response to changes in glucose concentrations in the blood circulation in the rat (4), for a 70-kDa protein during the response to heat shock in Drosophila (5), and for a group of =20 proteins during the early mitotic response in 3T3 cells (6). In the exocrine pancreas, we have reported that the synthesis of anionic but not cationic trypsinogen is regulated at the level of mRNA translation during caerulein stimulation (7-9). We now report that the divergent changes in synthesis of anionic trypsinogen and amylase during a 24-hr period of caerulein stimulation are regulated through mechanisms of translational control. MATERIALS AND METHODSHormone Infusion. Caerulein, a cholecyst...

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“…In obese rats, the PPAR-␥ agonist ciglitazone corrected hyperinsulinemia and restored glucose homeostasis, but also normalized pancreatic amylase mRNA expression (72,74). Similarly, we report that pioglitazone treatment of nonobese eNOS(Ϫ/Ϫ) mice improves insulin sensitivity (clamp data) and abolishes CCK-evoked hyperinsulinemia, but also completely restores pancreatic exocrine secretion.…”

Section: Discussionmentioning

confidence: 58%

“…Similar to insulinopenic conditions, nondiabetic models of insulin resistance also have reduced pancreatic exocrine function, observed in obese (5,55,(72)(73)(74) and nonobese (12,18,43,58,59,77) models. Adult obese rats (Zucker) (55) and mice (ob/ob) (73) have hyperinsulinemia (55,73), reduced pancreatic amylase activity and mRNA expression (55,73), and reduced pancreatic exocrine secretion evoked in vivo by CCK (5).…”

Section: Discussionmentioning

confidence: 94%

“…Furthermore, because immunohistochemical studies indicate that nNOS localizes to pancreatic nerves and eNOS localizes to the vasculature, we proposed that nNOS tonically inhibits acetylcholine release from pancreatic neurons and that eNOS may act on the pancreatic microvasculature to increase pancreatic microvascular blood flow (PMBF) (15). In addition, decreased pancreatic exocrine secretion in eNOS gene-deleted mice, a nonobese model of insulin resistance (12,18,58,59), may also occur through effects on insulin signaling because pancreatic exocrine secretion decreases with insulin resistance (5,55,(72)(73)(74) and insulinopenia (3,11,13,20,27,33,36,44,50). Finally, eNOS may also have complex biological effects on neural and other nonacinar cell types to maintain pancreatic exocrine secretion (15).…”

mentioning

confidence: 97%

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Pioglitazone reverses insulin resistance and impaired CCK-stimulated pancreatic secretion in eNOS(−/−) mice: therapy for exocrine pancreatic disorders?

Reddy¹,

Hao²,

Lee³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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In mice, eNOS (endothelial nitric oxide synthase) maintains in vivo pancreatic secretory responses to carbachol or cholecystokinin octapeptide (CCK-8), maintains insulin sensitivity, and modulates pancreatic microvascular blood flow (PMBF). eNOS(-/-) mice are insulin resistant, and their exocrine pancreatic secretion is impaired. We hypothesized that the reduced exocrine pancreatic secretion in eNOS(-/-) mice is due to insulin resistance or impaired PMBF. To test this hypothesis, we gave eNOS(-/-) and wild-type (WT) mice pioglitazone (20 or 50 mg.kg(-1).day(-1)), an insulin-sensitizing peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activator, and measured pancreatic protein secretion evoked by CCK-8 (160 pmol.kg(-1).h(-1), a maximal stimulus). We also measured insulin resistance, serum glucose, C-peptide, insulin, pancreatic RNA digestive enzyme expression, and PMBF (microsphere technique). In WT mice, pioglitazone did not increase CCK-8-stimulated protein output over baseline. In eNOS(-/-) mice, however, pioglitazone substantially increased the low CCK-8-stimulated protein output that is characteristic of these mutant mice (P < 0.005). Pioglitazone abolished the CCK-8-evoked hyperinsulinemia (P < 0.005) and increased insulin sensitivity of eNOS(-/-) mice (P < 0.05), the latter based on hyperinsulinemic-euglycemic clamp studies. Pioglitazone had no effect on PMBF or pancreas mRNA expression of insulin or digestive enzymes. We conclude that in hyperinsulinemic eNOS(-/-) mice, a nonobese model of insulin resistance relevant to diabetes mellitus and possibly chronic pancreatitis, reduced pancreatic secretion is caused, at least in part, by insulin resistance. Insulin-sensitizing PPAR-gamma agonists such as pioglitazone may thus simultaneously correct endocrine and exocrine pancreatic disorders.

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Insulin resistance is accompanied by impairment of amylase-gene expression in the exocrine pancreas of the obese Zucker rat

Cited by 29 publications

References 41 publications

Low serum amylase in association with metabolic syndrome and diabetes: A community-based study

Low serum amylase in association with metabolic syndrome and diabetes: A community-based study

Translational control of anionic trypsinogen and amylase synthesis in rat pancreas in response to caerulein stimulation.

Pioglitazone reverses insulin resistance and impaired CCK-stimulated pancreatic secretion in eNOS(−/−) mice: therapy for exocrine pancreatic disorders?

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