scholarly journals Maternal insulin resistance and transient hyperglycemia impact the metabolic and endocrine phenotypes of offspring

2014 ◽  
Vol 307 (10) ◽  
pp. E906-E918 ◽  
Author(s):  
Sevim Kahraman ◽  
Ercument Dirice ◽  
Dario F. De Jesus ◽  
Jiang Hu ◽  
Rohit N. Kulkarni
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
Blood Glucose ◽  
Endocrine Pancreas ◽  
Cell Mass ◽  
Postnatal Life ◽  
Pancreas Development ◽  
Β Cell ◽  
Early Postnatal Life ◽  
The Impact

Studies in both humans and rodents suggest that maternal diabetes leads to a higher risk of the fetus developing impaired glucose tolerance and obesity during adulthood. However, the impact of hyperinsulinemia in the mother on glucose homeostasis in the offspring has not been fully explored. We aimed to determine the consequences of maternal insulin resistance on offspring metabolism and endocrine pancreas development using the LIRKO mouse model, which exhibits sustained hyperinsulinemia and transient increase in blood glucose concentrations during pregnancy. We examined control offspring born to either LIRKO or control mothers on embryonic days 13.5, 15.5, and 17.5 and postpartum days 0, 4, and 10. Control offspring born to LIRKO mothers displayed low birth weights and subsequently rapidly gained weight, and their blood glucose and plasma insulin concentrations were higher than offspring born to control mothers in early postnatal life. In addition, concentrations of plasma leptin, glucagon, and active GLP-1 were higher in control pups from LIRKO mothers. Analyses of the endocrine pancreas revealed significantly reduced β-cell area in control offspring of LIRKO mothers shortly after birth. β-Cell proliferation and total islet number were also lower in control offspring of LIRKO mothers during early postnatal days. Together, these data indicate that maternal hyperinsulinemia and the transient hyperglycemia impair endocrine pancreas development in the control offspring and induce multiple metabolic alterations in early postnatal life. The relatively smaller β-cell mass/area and β-cell proliferation in these control offspring suggest cell-autonomous epigenetic mechanisms in the regulation of islet growth and development.

scholarly journals Maternal undernutrition increases pancreatic IGF-2 and partially suppresses the physiological wave of β-cell apoptosis during the neonatal period

2009 ◽  
Vol 44 (1) ◽  
pp. 25-36 ◽  
Author(s):  
Laura de Miguel-Santos ◽  
Elisa Fernández-Millán ◽  
María Ángeles Martín ◽  
Fernando Escrivá ◽  
Carmen Álvarez
Keyword(s):  
Cell Growth ◽  
Cell Apoptosis ◽  
Endocrine Pancreas ◽  
Glycogen Synthase ◽  
Cell Mass ◽  
Main Role ◽  
Β Cell ◽  
Adult Age ◽  
Maternal Undernutrition ◽  
The Impact

Replication, neogenesis, and apoptosis play a main role in neonatal endocrine pancreas remodeling. IGFs are major contributors to β-cell growth and function and are highly sensitive to nutritional status. We previously showed that maternal malnutrition caused an increase in β-cell mass in fetuses related to the stimulation of β-cell proliferation due to increased pancreatic IGF-1. At 4 days of life, the β-cell mass was decreased in undernourished neonates and persisted until adult age. To clarify whether undernutrition disrupts islet remodeling, we quantified β-cell mass, neogenesis, replication, and apoptosis on days 4, 14, and 23. To determine the impact of food restriction on IGF ontogeny and the consequences for β-cell growth, we measured IGF-1/-2 protein content in pancreas and liver and pancreatic IGF-1 receptor (IGF-1R)-signaling pathway at the same days. Our results indicate that undernutrition alters the timing and intensity of neonatal β-cell ontogeny. However, although malnutrition causes β-cell deficiency in neonates, an active process of β-cell neogenesis and a lower incidence of β-cell apoptosis maintain the regenerative capacity of the endocrine pancreas. Interestingly, our data provide evidence that local production of IGFs seems to be instrumental in these processes. In particular, increased pancreatic IGF-2 in undernourished rats may contribute to the partial suppression of the developmental wave of β-cell apoptosis probably through the inhibition of glycogen synthase kinase-3. In addition, decreased pancreatic levels of IGFBP-1/-2/-3 in undernourished neonates could enhance IGF availability for interacting with IGF-1R/IR.

scholarly journals Effects of the Antitumor Drug OSI-906, a Dual Inhibitor of IGF-1 Receptor and Insulin Receptor, on the Glycemic Control, β-Cell Functions, and β-Cell Proliferation in Male Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (6) ◽  
pp. 2102-2111 ◽  
Author(s):  
Jun Shirakawa ◽  
Tomoko Okuyama ◽  
Eiko Yoshida ◽  
Mari Shimizu ◽  
Yuka Horigome ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glycemic Control ◽  
Insulin Receptor ◽  
Cell Mass ◽  
Male Mice ◽  
Β Cell ◽  
Dual Inhibitor ◽  
Cell Functions

The IGF-1 receptor has become a therapeutic target for the treatment of cancer. The efficacy of OSI-906 (linstinib), a dual inhibitor of IGF-1 receptor and insulin receptor, for solid cancers has been examined in clinical trials. The effects of OSI-906, however, on the blood glucose levels and pancreatic β-cell functions have not yet been reported. We investigated the impact of OSI-906 on glycemic control, insulin secretion, β-cell mass, and β-cell proliferation in male mice. Oral administration of OSI-906 worsened glucose tolerance in a dose-dependent manner in the wild-type mice. OSI-906 at a dose equivalent to the clinical daily dose (7.5 mg/kg) transiently evoked glucose intolerance and hyperinsulinemia. Insulin receptor substrate (IRS)-2-deficient mice and mice with diet-induced obesity, both models of peripheral insulin resistance, exhibited more severe glucose intolerance after OSI-906 administration than glucokinase-haploinsufficient mice, a model of impaired insulin secretion. Phloridzin improved the hyperglycemia induced by OSI-906 in mice. In vitro, OSI-906 showed no effect on insulin secretion from isolated islets. After daily administration of OSI-906 for a week to mice, the β-cell mass and β-cell proliferation rate were significantly increased. The insulin signals in the β-cells were apparently unaffected in those mice. Taken together, the results suggest that OSI-906 could exacerbate diabetes, especially in patients with insulin resistance. On the other hand, the results suggest that the β-cell mass may expand in response to chemotherapy with this drug.

scholarly journals Glucagon receptor inhibition normalizes blood glucose in severe insulin-resistant mice

2017 ◽  
Vol 114 (10) ◽  
pp. 2753-2758 ◽  
Author(s):  
Haruka Okamoto ◽  
Katie Cavino ◽  
Erqian Na ◽  
Elizabeth Krumm ◽  
Sun Y. Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Insulin Receptor ◽  
Therapeutic Option ◽  
Cell Mass ◽  
Β Cell ◽  
Glucagon Receptor ◽  
Severe Insulin Resistance ◽  
Insulin Resistant ◽  
Extreme Insulin Resistance

Inactivating mutations in the insulin receptor results in extreme insulin resistance. The resulting hyperglycemia is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes. We used the insulin receptor antagonist S961 to induce severe insulin resistance, hyperglycemia, and ketonemia in mice. Using this model, we show that glucagon receptor (GCGR) inhibition with a monoclonal antibody normalized blood glucose and β-hydroxybutyrate levels. Insulin receptor antagonism increased pancreatic β-cell mass threefold. Normalization of blood glucose levels with GCGR-blocking antibody unexpectedly doubled β-cell mass relative to that observed with S961 alone and 5.8-fold over control. GCGR antibody blockage expanded α-cell mass 5.7-fold, and S961 had no additional effects. Collectively, these data show that GCGR antibody inhibition represents a potential therapeutic option for treatment of patients with extreme insulin-resistance syndromes.

scholarly journals Effects of metformin on compensatory pancreatic β-cell hyperplasia in mice fed a high-fat diet

2017 ◽  
Vol 313 (3) ◽  
pp. E367-E380 ◽  
Author(s):  
Kazuki Tajima ◽  
Jun Shirakawa ◽  
Tomoko Okuyama ◽  
Mayu Kyohara ◽  
Shunsuke Yamazaki ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
High Fat Diet ◽  
Cell Mass ◽  
Mammalian Target Of Rapamycin ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Hyperplasia

Metformin has been widely used for the treatment of type 2 diabetes. However, the effect of metformin on pancreatic β-cells remains controversial. In this study, we investigated the impacts of treatment with metformin on pancreatic β-cells in a mouse model fed a high-fat diet (HFD), which triggers adaptive β-cell replication. An 8-wk treatment with metformin improved insulin resistance and suppressed the compensatory β-cell hyperplasia induced by HFD-feeding. In contrast, the increment in β-cell mass arising from 60 wk of HFD feeding was similar in mice treated with and those treated without metformin. Interestingly, metformin suppressed β-cell proliferation induced by 1 wk of HFD feeding without any changes in insulin resistance. Metformin directly suppressed glucose-induced β-cell proliferation in islets and INS-1 cells in accordance with a reduction in mammalian target of rapamycin phosphorylation. Taken together, metformin suppressed HFD-induced β-cell proliferation independent of the improvement of insulin resistance, partly via direct actions.

scholarly journals High-fat diet-induced β-cell proliferation occurs prior to insulin resistance in C57Bl/6J male mice

2015 ◽  
Vol 308 (7) ◽  
pp. E573-E582 ◽  
Author(s):  
Rockann E. Mosser ◽  
Matthew F. Maulis ◽  
Valentine S. Moullé ◽  
Jennifer C. Dunn ◽  
Bethany A. Carboneau ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
High Fat Diet ◽  
Cell Mass ◽  
Chow Diet ◽  
High Fat ◽  
Β Cell ◽  
Peripheral Insulin Resistance ◽  
Insulin Tolerance

Both short- (1 wk) and long-term (2–12 mo) high-fat diet (HFD) studies reveal enhanced β-cell mass due to increased β-cell proliferation. β-Cell proliferation following HFD has been postulated to occur in response to insulin resistance; however, whether HFD can induce β-cell proliferation independent of insulin resistance has been controversial. To examine the kinetics of HFD-induced β-cell proliferation and its correlation with insulin resistance, we placed 8-wk-old male C57Bl/6J mice on HFD for different lengths of time and assayed the following: glucose tolerance, insulin secretion in response to glucose, insulin tolerance, β-cell mass, and β-cell proliferation. We found that β-cell proliferation was significantly increased after only 3 days of HFD feeding, weeks before an increase in β-cell mass or peripheral insulin resistance was detected. These results were confirmed by hyperinsulinemic euglycemic clamps and measurements of α-hydroxybutyrate, a plasma biomarker of insulin resistance in humans. An increase in expression of key islet-proliferative genes was found in isolated islets from 1-wk HFD-fed mice compared with chow diet (CD)-fed mice. These data indicate that short-term HFD feeding enhances β-cell proliferation before insulin resistance becomes apparent.

scholarly journals TCTP Is Essential for β-Cell Proliferation and Mass Expansion During Development and β-Cell Adaptation in Response to Insulin Resistance

Endocrinology ◽  
2014 ◽  
Vol 155 (2) ◽  
pp. 392-404 ◽  
Author(s):  
Ming-Jen Tsai ◽  
Hsin-Fang Yang-Yen ◽  
Ming-Ko Chiang ◽  
Mei-Jen Wang ◽  
Shiou-Shian Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
Cell Mass ◽  
Perinatal Period ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Adaptation ◽  
Insulin Resistant ◽  
Mass Expansion

The perinatal period is critical for β-cell mass establishment, which is characterized by a transient burst in proliferation to increase β-cell mass in response to the need for glucose homeostasis throughout life. In adulthood, the ability of β-cells to grow, proliferate, and expand their mass is also characteristic of pathological states of insulin resistance. Translationally controlled tumor-associated protein (TCTP), an evolutionarily highly conserved protein that is implicated in cell growth and proliferation, has been identified as a novel glucose-regulated survival-supporting protein in pancreatic β-cells. In this study, the enhanced β-cell proliferation detected both during the perinatal developmental period and in insulin-resistant states in high-fat diet-fed mice was found to parallel the expression of TCTP in pancreatic β-cells. Specific knockout of TCTP in β-cells led to increased expression of total and nuclear Forkhead box protein O1 and tumor suppressor protein 53, and decreased expression of p70S6 kinase phosphorylation and cyclin D2 and cyclin-dependent kinase 2. This resulted in decreased β-cell proliferation and growth, reduced β-cell mass, and insulin secretion. Together, these effects led to hyperglycemia. These observations suggest that TCTP is essential for β-cell mass expansion during development and β-cell adaptation in response to insulin resistance.

High doses of dexamethasone induce increased β-cell proliferation in pancreatic rat islets

2009 ◽  
Vol 296 (4) ◽  
pp. E681-E689 ◽  
Author(s):  
Alex Rafacho ◽  
Tânia M. Cestari ◽  
Sebastião R. Taboga ◽  
Antonio C. Boschero ◽  
José R. Bosqueiro
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
Cell Mass ◽  
Fold Increase ◽  
Insulin Requirement ◽  
Β Cell ◽  
Cell Hyperplasia ◽  
Glucose Levels ◽  
Cell Alterations ◽  
High Doses

Activation of insulin signaling and cell cycle intermediates is required for adult β-cell proliferation. Here, we report a model to study β-cell proliferation in living rats by administering three different doses of dexamethasone (0.1, 0.5, and 1.0 mg/kg ip, DEX 0.1, DEX 0.5, and DEX 1.0, respectively) for 5 days. Insulin sensitivity, insulin secretion, and histomorphometric data were investigated. Western blotting was used to analyze the levels of proteins related to the control of β-cell growth. DEX 1.0 rats, which present moderate hyperglycemia and marked hyperinsulinemia, exhibited a 5.1-fold increase in β-cell proliferation and an increase (17%) in β-cell size, with significant increase in β-cell mass, compared with control rats. The hyperinsulinemic but euglycemic DEX 0.5 rats also showed a significant 3.6-fold increase in β-cell proliferation. However, DEX 0.1 rats, which exhibited the lowest degree of insulin resistance, compensate for insulin demand by improving only islet function. Activation of the insulin receptor substrate 2/phosphatidylinositol 3-kinase/serine-threonine kinase/ribosomal protein S6 kinase pathway, as well as protein retinoblastoma in islets from DEX 1.0 and DEX 0.5, but not in DEX 0.1, rats was also observed. Therefore, increasing doses of dexamethasone induce three different degrees of insulin requirement in living rats, serving as a model to investigate compensatory β-cell alterations. Augmented β-cell mass involves β-cell hyperplasia and, to a lower extent, β-cell hypertrophy. We suggest that alterations in circulating insulin and, to a lesser extent, glucose levels could be the major stimuli for β-cell proliferation in the dexamethasone-induced insulin resistance.

The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases β-cell mass in diabetic mice

2002 ◽  
Vol 283 (4) ◽  
pp. E745-E752 ◽  
Author(s):  
Bidda Rolin ◽  
Marianne O. Larsen ◽  
Carsten F. Gotfredsen ◽  
Carolyn F. Deacon ◽  
Richard D. Carr ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Body Weight ◽  
Blood Glucose ◽  
Food Intake ◽  
Cell Mass ◽  
Proliferation Rate ◽  
Β Cell ◽  
Duration Of Action ◽  
Cell Proliferation Rate ◽  
Long Acting

NN2211 is a long-acting, metabolically stable glucagon-like peptide-1 (GLP-1) derivative designed for once daily administration in humans. NN2211 dose dependently reduced the glycemic levels in ob/ob mice, with antihyperglycemic activity still evident 24 h postdose. Apart from an initial reduction in food intake, there were no significant differences between NN2211 and vehicle treatment, and body weight was not affected. Histological examination revealed that β-cell proliferation and mass were not increased significantly in ob/ob mice with NN2211, although there was a strong tendency for increased proliferation. In db/db mice, exendin-4 and NN2211 decreased blood glucose compared with vehicle, but NN2211 had a longer duration of action. Food intake was lowered only on day 1 with both compounds, and body weight was unaffected. β-Cell proliferation rate and mass were significantly increased with NN2211, but with exendin-4, only the β-cell proliferation rate was significantly increased. In conclusion, NN2211 reduced blood glucose after acute and chronic treatment in ob/ob and db/db mice and was associated with increased β-cell mass and proliferation in db/db mice. NN2211 is currently in phase 2 clinical development.

scholarly journals Intergenerational Effect of an Adverse Intrauterine Environment on Perturbation of Glucose Metabolism

Twin Research ◽  
2001 ◽  
Vol 4 (5) ◽  
pp. 406-411 ◽  
Author(s):  
Brigitte Reusens ◽  
Claude Remacle
Keyword(s):  
Insulin Resistance ◽  
Animal Studies ◽  
Endocrine Pancreas ◽  
Cell Mass ◽  
Maternal Diabetes ◽  
Amino Acid Profile ◽  
Next Generation ◽  
Intergenerational Effect ◽  
Nutritional Environment ◽  
The Impact

AbstractHuman epidemiological and animal studies have revealed the late consequences of malnutrition during gestation and early life on the health of the offspring. These studies have highlighted the inverse relationship between birth weight and the incidence of insulin resistance and type 2 diabetes later in life. The aim of this paper is to review the different means of achieving foetal malnutrition and its consequences even for a next generation, in animal models and to identify key area for further research. We address the impact of two models of maternal malnutrition (protein restriction and caloric restriction) as well as the impact of maternal diabetes, the three maternal conditions leading to perturbed foetal nutritional environment. Particular emphasis is given to the endocrine pancreas and the insulin sensitive tissues. More specifically, alterations of the foetal nutritional environment perturb the development of the endocrine pancreas and target the ß cell mass at birth. Some adaptations later in life may take place but stress situations such as pregnancy and ageing precipitate the animals to glucose intolerance and insulin resistance. Even the next generation features alterations in the development of the endocrine pancreas. Some mechanisms by which the foetal ß cell mass is altered are approached in this review and specific attention is paid to the amino acid profile. The preventive role of taurine is discussed.

scholarly journals Endocrine Pancreas Development and Dysfunction Through the Lens of Single-Cell RNA-Sequencing

2021 ◽  
Vol 9 ◽  
Author(s):  
Wojciech J. Szlachcic ◽  
Natalia Ziojla ◽  
Dorota K. Kizewska ◽  
Marcelina Kempa ◽  
Malgorzata Borowiak
Keyword(s):  
Blood Glucose ◽  
Single Cell ◽  
Rna Sequencing ◽  
Endocrine Pancreas ◽  
Pancreas Development ◽  
Β Cells ◽  
Β Cell ◽  
Regulatory Pathways ◽  
Endocrine Differentiation ◽  
Single Cell Rna Sequencing

A chronic inability to maintain blood glucose homeostasis leads to diabetes, which can damage multiple organs. The pancreatic islets regulate blood glucose levels through the coordinated action of islet cell-secreted hormones, with the insulin released by β-cells playing a crucial role in this process. Diabetes is caused by insufficient insulin secretion due to β-cell loss, or a pancreatic dysfunction. The restoration of a functional β-cell mass might, therefore, offer a cure. To this end, major efforts are underway to generate human β-cells de novo, in vitro, or in vivo. The efficient generation of functional β-cells requires a comprehensive knowledge of pancreas development, including the mechanisms driving cell fate decisions or endocrine cell maturation. Rapid progress in single-cell RNA sequencing (scRNA-Seq) technologies has brought a new dimension to pancreas development research. These methods can capture the transcriptomes of thousands of individual cells, including rare cell types, subtypes, and transient states. With such massive datasets, it is possible to infer the developmental trajectories of cell transitions and gene regulatory pathways. Here, we summarize recent advances in our understanding of endocrine pancreas development and function from scRNA-Seq studies on developing and adult pancreas and human endocrine differentiation models. We also discuss recent scRNA-Seq findings for the pathological pancreas in diabetes, and their implications for better treatment.

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