Altered pancreas remodeling following glucose intolerance in pregnancy in mice

Gestational diabetes mellitus increases the risk of dysglycemia postpartum, in part, due to pancreatic β-cell dysfunction. However, no histological evidence exists comparing endocrine pancreas after healthy and glucose-intolerant pregnancies. This study sought to address this knowledge gap, in addition to exploring the contribution of an inflammatory environment to changes in endocrine pancreas after parturition. We used a previously established mouse model of gestational glucose intolerance induced by dietary low protein insult from conception until weaning. Pancreas and adipose samples were collected at 7, 30 and 90 days postpartum for histomorphometric and cytokine analyses, respectively. Glucose tolerance tests were performed prior to euthanasia and blood was collected via cardiac puncture. Pregnant female mice born to dams fed a low protein diet previously shown to develop glucose intolerance at late gestation relative to controls continued to be glucose intolerant until 1 month postpartum. However, glucose tolerance normalized by 3 months postpartum. Glucose intolerance at 7 days postpartum was associated with lower beta- and alpha-cell fractional areas and higher adipose levels of pro-inflammatory cytokine, interleukin-6. By 3 months postpartum, a compensatory increase in the number of small islets and a higher insulin to glucagon ratio likely enabled euglycemia to be attained in the previously glucose-intolerant mice. The results show that impairments in endocrine pancreas compensation in hyperglycemic pregnancy persist after parturition and contribute to prolonged glucose intolerance. These impairments may increase the susceptibility to development of future type 2 diabetes.

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Maternal low-protein diet on the last week of pregnancy contributes to insulin resistance and β-cell dysfunction in the mouse offspring

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00284.2019 ◽

2020 ◽

Vol 319 (4) ◽

pp. R485-R496 ◽

Cited By ~ 1

Author(s):

Emilyn U. Alejandro ◽

Seokwon Jo ◽

Brian Akhaphong ◽

Pau Romaguera Llacer ◽

Maya Gianchandani ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Glucose Intolerance ◽

Protein Diet ◽

Metabolic Dysfunction ◽

Β Cell ◽

Cell Dysfunction ◽

Low Protein

Maternal low-protein diet (LP) throughout gestation affects pancreatic β-cell fraction of the offspring at birth, thus increasing their susceptibility to metabolic dysfunction and type 2 diabetes in adulthood. The present study sought to strictly examine the effects of LP during the last week of gestation (LP12.5) alone as a developmental window for β-cell programming and metabolic dysfunction in adulthood. Islet morphology analysis revealed normal β-cell fraction in LP12.5 newborns. Normal glucose tolerance was observed in 6- to 8-wk-old male and female LP12.5 offspring. However, male LP12.5 offspring displayed glucose intolerance and reduced insulin sensitivity associated with β-cell dysfunction with aging. High-fat diet exposure of metabolically normal 12-wk-old male LP12.5 induced glucose intolerance due to increased body weight, insulin resistance, and insufficient β-cell mass adaptation despite higher insulin secretion. Assessment of epigenetic mechanisms through microRNAs (miRs) by a real-time PCR-based microarray in islets revealed elevation in miRs that regulate insulin secretion (miRs 342, 143), insulin resistance (miR143), and obesity (miR219). In the islets, overexpression of miR143 reduced insulin secretion in response to glucose. In contrast to the model of LP exposure throughout pregnancy, islet protein levels of mTOR and pancreatic and duodenal homeobox 1 were normal in LP12.5 islets. Collectively, these data suggest that LP diet during the last week of pregnancy is critical and sufficient to induce specific and distinct developmental programming effects of tissues that control glucose homeostasis, thus causing permanent changes in specific set of microRNAs that may contribute to the overall vulnerability of the offspring to obesity, insulin resistance, and type 2 diabetes.

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Diminished Sphingolipid Metabolism, a Hallmark of Future Type 2 Diabetes Pathogenesis, Is Linked to Pancreatic β Cell Dysfunction

iScience ◽

10.1016/j.isci.2020.101566 ◽

2020 ◽

Vol 23 (10) ◽

pp. 101566

Author(s):

Saifur R. Khan ◽

Yousef Manialawy ◽

Andreea Obersterescu ◽

Brian J. Cox ◽

Erica P. Gunderson ◽

...

Keyword(s):

Type 2 Diabetes ◽

Sphingolipid Metabolism ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Dysfunction

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Maturation of pancreatic β-cell function in the fetal horse during late gestation

Journal of Endocrinology ◽

10.1677/joe.1.06176 ◽

2005 ◽

Vol 186 (3) ◽

pp. 467-473 ◽

Cited By ~ 23

Author(s):

A L Fowden ◽

D S Gardner ◽

J C Ousey ◽

D A Giussani ◽

A J Forhead

Keyword(s):

Insulin Secretion ◽

Cell Response ◽

Endocrine Pancreas ◽

Cell Function ◽

Late Gestation ◽

Pancreatic Β Cell ◽

Β Cell ◽

Glucose Administration ◽

Β Cell Function ◽

Cortisol Levels

At birth, the endocrine pancreas becomes more directly involved in the control of glycaemia than in utero. However, compared with other tissues, relatively little is known about the maturational changes that occur in the fetal endocrine pancreas in preparation for extrauterine life. This study examined the pancreatic β-cell response to exogenous administration of glucose and arginine in fetal horses with respect to their gestational age and concentration of cortisol, the hormone responsible for prepartum maturation of other fetal tissues. Glucose administration had no effect on fetal insulin secretion between 175 and 230 days of gestation but evoked a rapid insulin response in fetuses closer to term (290–327 days). In late gestation, the β-cell response was more rapid and greater in magnitude in fetuses with basal cortisol levels higher than 15 ng/ml than in those with lower cortisol values at the time of glucose administration. The fetal β-cell response to arginine was unaffected by the rise in fetal plasma cortisol towards term. These findings show that there are maturational changes in pancreatic β-cell function in fetal horses as cortisol levels rise close to term. Primarily, these prepartum maturational changes were in the mechanisms of glucose-stimulated insulin secretion, which would enable the β cells to regulate glycaemia at the higher glucose levels observed postnatally.

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Hyperproinsulinaemia in Acromegaly: Evidence for Abnormal Pancreatic β-Cell Function?

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456329703400605 ◽

1997 ◽

Vol 34 (6) ◽

pp. 627-631 ◽

Cited By ~ 2

Author(s):

R Gama ◽

J D Teale ◽

J Wright ◽

G Ferns ◽

V Marks

Keyword(s):

Glucose Intolerance ◽

Statistical Significance ◽

Growth Hormone Secretion ◽

Oral Glucose ◽

Pancreatic Β Cell ◽

Β Cell ◽

C Peptide ◽

Molar Ratios ◽

Cell Dysfunction ◽

Active Acromegaly

We investigated whether pancreatic β-cell dysfunction has a role in the pathogenesis of glucose intolerance in acromegaly by comparing plasma intact proinsulin, immunoreactive insulin, C-peptide and glucose concentrations during a 75 g oral glucose load in six patients with active acromegaly and eight healthy volunteers. Only acromegalic patients with normal glucose tolerance were studied. Glucose concentrations were similar in acromegalic patients and controls. Acromegalic patients had higher fasting insulin ( P <0·005) and fasting C-peptide ( P <0·005) concentrations than controls. Although fasting proinsulin levels were higher in acromegalic patients than controls, this did not achieve statistical significance. Integrated insulin ( P <0·05), C-peptide ( P <0·05) and proinsulin ( P <0·005) concentrations were greater in acromegalic patients than control subjects. Integrated ( P <0·05) proinsulin: insulin molar ratios were higher in acromegalic patients than controls. Fasting and integrated insulin: C-peptide molar ratios were similar in acromegalic patients and controls. These results indicate that hyperproinsulinaemia contributes to the hyperinsulinaemia which characterizes active acromegaly. The disproportionate hyperproinsulinaemia in acromegaly suggests that prolonged and excessive growth hormone secretion may result in pancreatic β-cell dysfunction which may predispose acromegalic subjects to glucose intolerance.

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Exosome microRNAs in Metabolic Syndrome as Tools for the Early Monitoring of Diabetes and Possible Therapeutic Options

Pharmaceuticals ◽

10.3390/ph14121257 ◽

2021 ◽

Vol 14 (12) ◽

pp. 1257

Author(s):

Erika Cione ◽

Roberto Cannataro ◽

Luca Gallelli ◽

Giovambattista De Sarro ◽

Maria Cristina Caroleo

Keyword(s):

Essential Role ◽

Cell Injury ◽

Cell Types ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Dysfunction ◽

Pathological Conditions ◽

Novel Approach ◽

Almost All

Exosomes are nano-sized extracellular vesicles produced and released by almost all cell types. They play an essential role in cell–cell communications by delivering cellular bioactive compounds such as functional proteins, metabolites, and nucleic acids, including microRNA, to recipient cells. Thus, they are involved in various physio-pathological conditions. Exosome-miRNAs are associated with numerous diseases, including type 2 diabetes, a complex multifactorial metabolic disorder linked to obesity. In addition, exosome-miRNAs are emerging as essential regulators in the progression of diabetes, principally for pancreatic β-cell injury and insulin resistance. Here, we have clustered the recent findings concerning exosome-miRNAs associated with β-cell dysfunction to provide a novel approach for the early diagnosis and therapy of diabetes.

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