Protein calorie restriction has opposite effects on glucose metabolism and insulin gene expression in fetal and adult rat endocrine pancreas

We previously demonstrated that fetuses from undernourished pregnant rats exhibited increased β-cell mass and hyperinsulinemia, whereas keeping food restriction until adult age caused reduced β-cell mass, hypoinsulinemia, and decreased insulin secretion. Because these alterations can be related to insulin availability, we have now investigated early and long-term effects of protein calorie food restriction on insulin mRNA levels as well as the possible mechanisms that could modulate the endogenous insulin mRNA content. We used fetuses at 21.5 days of gestation proceeding from food-restricted rats during the last week of pregnancy and 70-day-old rats undernourished from day 14 of gestation until adult age and with respective controls. Insulin mRNA levels, glucose transporters, and total glycolysis and mitochondrial oxidative fluxes were evaluated. We additionally analyzed undernutrition effects on signals implicated in glucose-mediated insulin gene expression, especially pancreatic duodenal homeobox-1 (PDX-1), stress-activated protein kinase-2 (p38/SAPK2), and phosphatidylinositol 3-kinase. Undernourished fetuses showed increased insulin mRNA, oxidative glucose metabolism, and p38/SAPK2 levels, whereas undernutrition until adult age provoked a decrease in insulin gene expression, oxidative glucose metabolism, and PDX-1 levels. The results indicate that food restriction caused changes in insulin gene expression and content leading to alterations in glucose-stimulated insulin secretion. The molecular events, increased p38/SAPK2 levels in fetuses and decreased PDX-1 levels in adults, seem to be the responsible for the altered insulin mRNA expression. Moreover, because PDX-1 activation appears to be regulated by glucose-derived metabolite(s), the altered glucose oxidation caused by undernutrition could in some manner affect insulin mRNA expression.

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Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells.

Journal of Clinical Investigation ◽

10.1172/jci119105 ◽

1996 ◽

Vol 98 (12) ◽

pp. 2786-2793 ◽

Cited By ~ 147

Author(s):

J B Redmon ◽

L K Olson ◽

M B Armstrong ◽

M J Greene ◽

R P Robertson

Keyword(s):

Gene Expression ◽

Insulin Secretion ◽

Human Insulin ◽

Insulin Gene ◽

Mrna Levels ◽

Human Insulin Gene ◽

Insulin Gene Expression ◽

Insulin Mrna

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Testosterone Effect on Insulin Content, Messenger Ribonucleic Acid Levels, Promoter Activity, and Secretion in the Rat*

Endocrinology ◽

10.1210/endo.142.4.8069 ◽

2001 ◽

Vol 142 (4) ◽

pp. 1442-1447 ◽

Cited By ~ 27

Author(s):

Sumiko Morimoto ◽

Cristina Fernandez-Mejia ◽

Guillermo Romero-Navarro ◽

Nestor Morales-Peza ◽

Vicente DÍaz-Sánchez

Keyword(s):

Gene Expression ◽

Serum Insulin ◽

Serum Testosterone ◽

Insulin Gene ◽

Insulin Concentration ◽

Mrna Levels ◽

Insulin Gene Expression ◽

Insulin Mrna

Abstract Coexistence of hyperinsulinemia and hyperandrogenism in women has been frequently described. Most of the studies addressing this issue have focused on the mechanisms by which insulin produces hyperandrogenism. In the present study, we analyzed the effects of testosterone in vivo and in vitro upon insulin gene expression and release in the rat. Our studies demonstrate that testosterone increases insulin messenger RNA (mRNA) levels in vitro as well as in vivo. In both prepuberal and intact adult rats, serum testosterone concentrations were positively correlated with insulin mRNA levels and insulin concentration in serum. Testosterone deprivation after gonadectomy decreased both insulin gene expression and serum insulin concentration. Insulin mRNA levels were partially restored after 3 days of testosterone administration and serum insulin was 80% and 27% above baseline values at 5 and 7 days posttreatment. Primary cultured pancreatic islets treated with the sexual steroid increased about 80% insulin mRNA, as well as protein, and release. In transfected islets, testosterone increased the activity of the −410 bp rat insulin promoter I by 154%. These data demonstrate that testosterone has a direct effect upon pancreatic islet function by favoring insulin gene expression and release.

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Differential effect of insulin treatment on islet amyloid polypeptide (amylin) and insulin gene expression in streptozotocin-induced diabetes in rats

Journal of Endocrinology ◽

10.1677/joe.0.1520495 ◽

1997 ◽

Vol 152 (3) ◽

pp. 495-501 ◽

Cited By ~ 4

Author(s):

H Mulder ◽

B Ahrén ◽

F Sundler

Keyword(s):

Gene Expression ◽

Insulin Treatment ◽

Islet Cells ◽

Islet Amyloid Polypeptide ◽

Insulin Gene ◽

Mrna Levels ◽

Islet Amyloid ◽

Time Points ◽

Insulin Gene Expression ◽

Insulin Mrna

Islet amyloid polypeptide (IAPP) is a β cell hormone, which forms islet amyloid in non-insulin-dependent diabetes mellitus and may oppose insulin action and release. Therefore, the previously observed relative overexpression of IAPP compared with insulin in streptozotocin-treated rats could be unfavourable if it occurs in diabetes. Using quantitative in situ hybridization, we examined whether insulin treatment affected IAPP and insulin gene expression and their ratio at day 8 and 20 after induction of streptozotocin diabetes (plasma glucose ∼ 30 mm). Total islet IAPP mRNA levels were less reduced than those of insulin at both time points. Differential regulation of the two hormones was further reflected by mean IAPP mRNA levels in the remaining islet cells being unaffected by streptozotocin treatment, whereas those of insulin were reduced. At both time points, insulin treatment decreased total islet levels of IAPP and insulin mRNA even more, IAPP mRNA levels being less reduced. Mean insulin mRNA levels, but not IAPP mRNA levels, in the remaining islet cells were reduced by insulin treatment. Between time points, total islet mRNA levels were higher at day 20, while mean mRNA levels in the remaining islet cells were unchanged, suggesting that regeneration of β cells had occurred. In contrast, insulin gene expression was the same at both time points in insulin-treated rats, suggesting that insulin impaired insulin expression. To summarize, we found that IAPP and insulin were differentially expressed in experimental diabetes and that insulin treatment inhibited insulin, but not IAPP, gene expression. It is therefore unlikely that insulin will protect against amyloid formation and metabolic perturbations which may arise as a consequence of IAPP overexpression. Journal of Endocrinology (1997) 152, 495–501

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Islet amyloid polypeptide and insulin gene expression are regulated in parallel by glucose in vivo in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.271.6.e1008 ◽

1996 ◽

Vol 271 (6) ◽

pp. E1008-E1014 ◽

Cited By ~ 8

Author(s):

H. Mulder ◽

B. Ahren ◽

F. Sundler

Keyword(s):

Gene Expression ◽

Islet Amyloid Polypeptide ◽

Insulin Gene ◽

Dependent Diabetes Mellitus ◽

Amyloid Formation ◽

Mrna Levels ◽

Islet Amyloid ◽

Glucose Levels ◽

Insulin Gene Expression ◽

Insulin Mrna

Islet amyloid polypeptide (IAPP) is a novel amyloid-forming beta-cell hormone with putative roles in glucose metabolism and non-insulin-dependent diabetes mellitus (NIDDM) pathogenesis. To study how IAPP and insulin expression are regulated by glucose, rats were fasted for 48h followed by administration of glucose at repeated 4-h intervals; IAPP and insulin mRNA levels were determined by quantitative in situ hybridization. Fasting markedly reduced IAPP and insulin mRNA levels. Two (6 h) and four (14 h) glucose injections dose dependently increased both mRNA levels; the effects were matched by similar changes in plasma glucose levels. Actinomycin D blocked the glucose-induced increase in IAPP expression. IAPP and insulin mRNA levels were significantly correlated over the range of glucose levels. The parallel regulation of IAPP and insulin gene expression by glucose is consistent with a role for IAPP in glucose homeostasis. Thus, under hyperglycemic conditions such as NIDDM, IAPP gene expression is likely to increase. Hence, IAPP could, by elevated local concentrations, contribute to amyloid formation and/or affect metabolism unfavorably by inhibition of insulin release and action.

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Control of insulin gene expression in pancreatic beta-cells and in an insulin-producing cell line, RIN-5F cells. I. Effects of glucose and cyclic AMP on the transcription of insulin mRNA.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)38764-1 ◽

1985 ◽

Vol 260 (25) ◽

pp. 13585-13589 ◽

Cited By ~ 9

Author(s):

D A Nielsen ◽

M Welsh ◽

M J Casadaban ◽

D F Steiner

Keyword(s):

Gene Expression ◽

Cyclic Amp ◽

Cell Line ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Insulin Gene ◽

Insulin Gene Expression ◽

Insulin Mrna

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VMP1-related autophagy induced by a fructose-rich diet in β-cells: its prevention by incretins

Clinical Science ◽

10.1042/cs20170010 ◽

2017 ◽

Vol 131 (8) ◽

pp. 673-687 ◽

Cited By ~ 5

Author(s):

Bárbara Maiztegui ◽

Verónica Boggio ◽

Carolina L. Román ◽

Luis E. Flores ◽

Héctor Del Zotto ◽

...

Keyword(s):

Caspase 3 ◽

Cell Function ◽

Cell Damage ◽

Cell Mass ◽

Ultrastructural Changes ◽

Mrna Levels ◽

Model Assessment ◽

Β Cells ◽

Β Cell ◽

Insulin Mrna

The aim of the present study was to demonstrate the role of autophagy and incretins in the fructose-induced alteration of β-cell mass and function. Normal Wistar rats were fed (3 weeks) with a commercial diet without (C) or with 10% fructose in drinking water (F) alone or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, β-cell mass, morphology/ultrastructure and apoptosis, vacuole membrane protein 1 (VMP1) expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary to this, islets isolated from normal rats were cultured (3 days) without (C) or with F and F + exendin-4 or chloroquine. Expression of autophagy-related proteins [VMP1 and microtubule-associated protein light chain 3 (LC3)], apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triacylglycerols, thiobarbituric acid-reactive substances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significant reduction in β-cell mass was associated with an increased apoptotic rate and morphological/ultrastructural changes indicative of autophagic activity. All these changes were prevented by either sitagliptin or exendin-4. In cultured islets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNA levels and increased caspase-3 expression. Chloroquine reduced these changes, suggesting the participation of autophagy in this process. Indeed, F induced the increase of both VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured β-cells. Exendin-4 prevented islet-cell damage and autophagy development. VMP1-related autophagy is a reactive process against F-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help in the use of autophagy as a potential target for preventing progression from IGT to type 2 diabetes mellitus.

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Endoplasmic Reticulum Stress-Induced Activation of Activating Transcription Factor 6 Decreases Insulin Gene Expression via Up-Regulation of Orphan Nuclear Receptor Small Heterodimer Partner

Endocrinology ◽

10.1210/en.2008-0015 ◽

2008 ◽

Vol 149 (8) ◽

pp. 3832-3841 ◽

Cited By ~ 71

Author(s):

Hye-Young Seo ◽

Yong Deuk Kim ◽

Kyeong-Min Lee ◽

Ae-Kyung Min ◽

Mi-Kyung Kim ◽

...

Keyword(s):

Gene Expression ◽

Er Stress ◽

Insulin Gene ◽

Orphan Nuclear Receptor ◽

Β Cell ◽

Cell Dysfunction ◽

Small Heterodimer Partner ◽

Insulin Gene Expression ◽

Long Evans ◽

Activating Transcription Factor

The highly developed endoplasmic reticulum (ER) structure of pancreatic β-cells is a key factor in β-cell function. Here we examined whether ER stress-induced activation of activating transcription factor (ATF)-6 impairs insulin gene expression via up-regulation of the orphan nuclear receptor small heterodimer partner (SHP; NR0B2), which has been shown to play a role in β-cell dysfunction. We examined whether ER stress decreases insulin gene expression, and this process is mediated by ATF6. A small interfering RNA that targeted SHP was used to determine whether the effect of ATF6 on insulin gene expression is mediated by SHP. We also measured the expression level of ATF6 in pancreatic islets in Otsuka Long Evans Tokushima Fatty rats, a rodent model of type 2 diabetes. High glucose concentration (30 mmol/liter glucose) increased ER stress in INS-1 cells. ER stress induced by tunicamycin, thapsigargin, or dithiotreitol decreased insulin gene transcription. ATF6 inhibited insulin promoter activity, whereas X-box binding protein-1 and ATF4 did not. Adenovirus-mediated overexpression of active form of ATF6 in INS-1 cells impaired insulin gene expression and secretion. ATF6 also down-regulated pancreatic duodenal homeobox factor-1 and RIPE3b1/MafA gene expression and repressed the cooperative action of pancreatic duodenal homeobox factor-1, RIPE3b1/MafA, and β-cell E box transactivator 2 in stimulating insulin transcription. The ATF6-induced suppression of insulin gene expression was associated with up-regulation of SHP gene expression. Finally, we found that expression of ATF6 was increased in the pancreatic islets of diabetic Otsuka Long Evans Tokushima Fatty rats, compared with their lean, nondiabetic counterparts, Long-Evans Tokushima Otsuka rats. Collectively, this study shows that ER stress-induced activation of ATF6 plays an important role in the development of β-cell dysfunction.

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Impact of scavenging hydrogen peroxide in the endoplasmic reticulum for β cell function

Journal of Molecular Endocrinology ◽

10.1530/jme-15-0132 ◽

2015 ◽

Vol 55 (1) ◽

pp. 21-29 ◽

Cited By ~ 7

Author(s):

S Lortz ◽

S Lenzen ◽

I Mehmeti

Keyword(s):

Gene Expression ◽

Hydrogen Peroxide ◽

Endoplasmic Reticulum ◽

Insulin Secretion ◽

Er Stress ◽

Insulin Gene ◽

Insulin Content ◽

Insulin Biosynthesis ◽

Β Cell ◽

Insulin Gene Expression

Oxidative folding of nascent proteins in the endoplasmic reticulum (ER), catalysed by one or more members of the protein disulfide isomerase family and the sulfhydryl oxidase ER oxidoreductin 1 (ERO1), is accompanied by generation of hydrogen peroxide (H2O2). Because of the high rate of insulin biosynthesis and the low expression of H2O2-inactivating enzymes in pancreatic β cells, it has been proposed that the luminal H2O2concentration might be very high. As the role of this H2O2in ER stress and proinsulin processing is still unsolved, an ER-targeted and luminal-active catalase variant, ER-Catalase N244, was expressed in insulin-secreting INS-1E cells. In these cells, the influence of ER-specific H2O2removal on cytokine-mediated cytotoxicity and ER stress, insulin gene expression, insulin content and secretion was analysed. The expression of ER-Catalase N244 reduced the toxicity of exogenously added H2O2significantly with a threefold increase of the EC50value for H2O2. However, the expression of cytokine-induced ER stress genes and viability after incubation with β cell toxic cytokines (IL1β alone or together with TNFα+IFNγ) was not affected by ER-Catalase N244. In control and ER-Catalase N244 expressing cells, insulin secretion and proinsulin content was identical, while removal of luminal H2O2reduced insulin gene expression and insulin content in ER-Catalase N244 expressing cells. These data show that ER-Catalase N244 reduced H2O2toxicity but did not provide protection against pro-inflammatory cytokine-mediated toxicity and ER stress. Insulin secretion was not affected by decreasing H2O2in the ER in spite of a reduced insulin transcription and processing.

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