MEK/ERK Signaling in β Cells Bifunctionally Regulates β-cell Mass and Glucose-stimulated Insulin-secretion Response to Maintain Glucose Homeostasis.

Diabetes ◽  
2021 ◽  
pp. db201295
Author(s):  
Yoshiko Matsumoto Ikushima ◽  
Motoharu Awazawa ◽  
Naoki Kobayashi ◽  
Sho Osonoi ◽  
Seiichi Takemiya ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Cell Mass ◽  
Erk Signaling ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion

scholarly journals MEK/ERK Signaling in β Cells Bifunctionally Regulates β-cell Mass and Glucose-stimulated Insulin-secretion Response to Maintain Glucose Homeostasis

2021 ◽  
Author(s):  
Yoshiko Matsumoto Ikushima ◽  
Motoharu Awazawa ◽  
Naoki Kobayashi ◽  
Sho Osonoi ◽  
Seiichi Takemiya ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Cell Mass ◽  
Erk Signaling ◽  
Insulin Production ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulin Exocytosis

In diabetic pathology, insufficiency in β-cell mass unable to meet peripheral insulin demand and functional defects of individual β cells to produce insulin are often concurrently observed, collectively causing hyperglycemia. Here we show that the phosphorylation of ERK1/2 is significantly decreased in the islets of <i>db/db</i> mice as well as in those of a cohort of subjects with type 2 diabetes. In mice with abrogation of ERK signaling in pancreatic β cells through deletion of <i>Mek1</i> and <i>Mek2</i>, glucose intolerance aggravates under high-fat diet-fed conditions due to insufficient insulin production with lower β-cell proliferation and reduced β-cell mass, while in individual β cells dampening of the number of insulin exocytosis events is observed, with the molecules involved in insulin exocytosis being less phosphorylated. These data reveal bifunctional roles for MEK/ERK signaling in β cells for glucose homeostasis, i.e., in regulating β-cell mass as well as in controlling insulin exocytosis in individual β cells, thus providing not only a novel perspective for the understanding of diabetes pathophysiology but also a potential clue for new drug development for diabetes treatment.

scholarly journals MEK/ERK Signaling in β Cells Bifunctionally Regulates β-cell Mass and Glucose-stimulated Insulin-secretion Response to Maintain Glucose Homeostasis

2021 ◽  
Author(s):  
Yoshiko Matsumoto Ikushima ◽  
Motoharu Awazawa ◽  
Naoki Kobayashi ◽  
Sho Osonoi ◽  
Seiichi Takemiya ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Cell Mass ◽  
Erk Signaling ◽  
Insulin Production ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulin Exocytosis

In diabetic pathology, insufficiency in β-cell mass unable to meet peripheral insulin demand and functional defects of individual β cells to produce insulin are often concurrently observed, collectively causing hyperglycemia. Here we show that the phosphorylation of ERK1/2 is significantly decreased in the islets of <i>db/db</i> mice as well as in those of a cohort of subjects with type 2 diabetes. In mice with abrogation of ERK signaling in pancreatic β cells through deletion of <i>Mek1</i> and <i>Mek2</i>, glucose intolerance aggravates under high-fat diet-fed conditions due to insufficient insulin production with lower β-cell proliferation and reduced β-cell mass, while in individual β cells dampening of the number of insulin exocytosis events is observed, with the molecules involved in insulin exocytosis being less phosphorylated. These data reveal bifunctional roles for MEK/ERK signaling in β cells for glucose homeostasis, i.e., in regulating β-cell mass as well as in controlling insulin exocytosis in individual β cells, thus providing not only a novel perspective for the understanding of diabetes pathophysiology but also a potential clue for new drug development for diabetes treatment.

scholarly journals MEK/ERK Signaling in β Cells Bifunctionally Regulates β-cell Mass and Glucose-stimulated Insulin-secretion Response to Maintain Glucose Homeostasis

2021 ◽  
Author(s):  
Yoshiko Matsumoto Ikushima ◽  
Motoharu Awazawa ◽  
Naoki Kobayashi ◽  
Sho Osonoi ◽  
Seiichi Takemiya ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Cell Mass ◽  
Erk Signaling ◽  
Insulin Production ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulin Exocytosis

In diabetic pathology, insufficiency in β-cell mass unable to meet peripheral insulin demand and functional defects of individual β cells to produce insulin are often concurrently observed, collectively causing hyperglycemia. Here we show that the phosphorylation of ERK1/2 is significantly decreased in the islets of <i>db/db</i> mice as well as in those of a cohort of subjects with type 2 diabetes. In mice with abrogation of ERK signaling in pancreatic β cells through deletion of <i>Mek1</i> and <i>Mek2</i>, glucose intolerance aggravates under high-fat diet-fed conditions due to insufficient insulin production with lower β-cell proliferation and reduced β-cell mass, while in individual β cells dampening of the number of insulin exocytosis events is observed, with the molecules involved in insulin exocytosis being less phosphorylated. These data reveal bifunctional roles for MEK/ERK signaling in β cells for glucose homeostasis, i.e., in regulating β-cell mass as well as in controlling insulin exocytosis in individual β cells, thus providing not only a novel perspective for the understanding of diabetes pathophysiology but also a potential clue for new drug development for diabetes treatment.

scholarly journals Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Brenda Strutt ◽  
Sandra Szlapinski ◽  
Thineesha Gnaneswaran ◽  
Sarah Donegan ◽  
Jessica Hill ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glucose Transporter ◽  
Cell Mass ◽  
Elevated Serum ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Transporter 2 ◽  
Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

scholarly journals ROCK1 regulates insulin secretion from β-cells

2021 ◽  
Author(s):  
Byung-Jun Sung ◽  
Sung-Bin Lim ◽  
Jae Hyeon Kim ◽  
Won-Mo Yang ◽  
Rohit N Kulkarni ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pyruvate Kinase ◽  
Glucose Homeostasis ◽  
Isolated Islets ◽  
Whole Body ◽  
Proximity Ligation Assay ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Glucose Stimulated Insulin Secretion

Objective: The endocrine pancreatic β-cells play a pivotal role in the maintenance of whole-body glucose homeostasis and its dysregulation is a consistent feature in all forms of diabetes. However, knowledge of intracellular regulators that modulate b-cell function remains incomplete. We investigated the physiological role of ROCK1 in the regulation of insulin secretion and glucose homeostasis. Methods: Mice lacking ROCK1 in pancreatic β-cells (RIP-Cre; ROCK1loxP/loxP, β-ROCK1-/-) were studied. Glucose and insulin tolerance tests as well as glucose-stimulated insulin secretion (GSIS) were measured. Insulin secretion response to a direct glucose or pyruvate or pyruvate kinase (PK) activator stimulation in isolated islets from β-ROCK1-/- mice or β-cell lines with knockdown of ROCK1 were also evaluated. Proximity ligation assay was performed to determine the physical interactions between PK and ROCK1. Results: Mice with a deficiency of ROCK1 in pancreatic β-cells exhibited significantly increased blood glucose levels and reduced serum insulin without changes in body weight. Interestingly, β-ROCK1-/- mice displayed progressive impairment of glucose tolerance while maintaining insulin sensitivity mostly due to impaired GSIS. Consistently, GSIS was markedly decreased in ROCK1-deficient islets and ROCK1 knockdown INS-1 cells. Concurrently, ROCK1 blockade led to a significant decrease in intracellular calcium levels, ATP levels, and oxygen consumption rates in isolated islets and INS-1 cells. Treatment of ROCK1-deficient islets or ROCK1 knockdown β-cells either with pyruvate or a PK activator rescued the impaired GSIS. Mechanistically, we observed that ROCK1 binding to PK is greatly enhanced by glucose stimulation in β-cells. Conclusions: Our findings demonstrate that β-cell ROCK1 is essential for glucose-stimulated insulin secretion and maintenance of glucose homeostasis and that ROCK1 acts as an upstream regulator of glycolytic pyruvate kinase signaling.

scholarly journals Loss of Liver Kinase B1 (LKB1) in Beta Cells Enhances Glucose-stimulated Insulin Secretion Despite Profound Mitochondrial Defects

2015 ◽  
Vol 290 (34) ◽  
pp. 20934-20946 ◽  
Author(s):  
Avital Swisa ◽  
Zvi Granot ◽  
Natalia Tamarina ◽  
Sophie Sayers ◽  
Nabeel Bardeesy ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Polarity ◽  
Cell Biology ◽  
Calcium Influx ◽  
Cell Mass ◽  
Negative Regulator ◽  
Β Cells ◽  
Β Cell ◽  
Liver Kinase B1 ◽  
Glucose Stimulated Insulin Secretion

The tumor suppressor liver kinase B1 (LKB1) is an important regulator of pancreatic β cell biology. LKB1-dependent phosphorylation of distinct AMPK (adenosine monophosphate-activated protein kinase) family members determines proper β cell polarity and restricts β cell size, total β cell mass, and glucose-stimulated insulin secretion (GSIS). However, the full spectrum of LKB1 effects and the mechanisms involved in the secretory phenotype remain incompletely understood. We report here that in the absence of LKB1 in β cells, GSIS is dramatically and persistently improved. The enhancement is seen both in vivo and in vitro and cannot be explained by altered cell polarity, increased β cell number, or increased insulin content. Increased secretion does require membrane depolarization and calcium influx but appears to rely mostly on a distal step in the secretion pathway. Surprisingly, enhanced GSIS is seen despite profound defects in mitochondrial structure and function in LKB1-deficient β cells, expected to greatly diminish insulin secretion via the classic triggering pathway. Thus LKB1 is essential for mitochondrial homeostasis in β cells and in parallel is a powerful negative regulator of insulin secretion. This study shows that β cells can be manipulated to enhance GSIS to supra-normal levels even in the face of defective mitochondria and without deterioration over months.

scholarly journals Regulation of Insulin Secretion and β-Cell Mass by Activating Signal Cointegrator 2

2006 ◽  
Vol 26 (12) ◽  
pp. 4553-4563 ◽  
Author(s):  
Seon-Yong Yeom ◽  
Geun Hyang Kim ◽  
Chan Hee Kim ◽  
Heun Don Jung ◽  
So-Yeon Kim ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Endocrine Cells ◽  
Potential Role ◽  
Cell Mass ◽  
Dominant Negative ◽  
Transcriptional Coactivator ◽  
Β Cells ◽  
Β Cell ◽  
Islet Mass

ABSTRACT Activating signal cointegrator 2 (ASC-2) is a transcriptional coactivator of many nuclear receptors (NRs) and other transcription factors and contains two NR-interacting LXXLL motifs (NR boxes). In the pancreas, ASC-2 is expressed only in the endocrine cells of the islets of Langerhans, but not in the exocrine cells. Thus, we examined the potential role of ASC-2 in insulin secretion from pancreatic β-cells. Overexpressed ASC-2 increased glucose-elicited insulin secretion, whereas insulin secretion was decreased in islets from ASC-2+/− mice. DN1 and DN2 are two dominant-negative fragments of ASC-2 that contain NR boxes 1 and 2, respectively, and block the interactions of cognate NRs with the endogenous ASC-2. Primary rat islets ectopically expressing DN1 or DN2 exhibited decreased insulin secretion. Furthermore, relative to the wild type, ASC-2+/− mice showed reduced islet mass and number, which correlated with increased apoptosis and decreased proliferation of ASC-2+/− islets. These results suggest that ASC-2 regulates insulin secretion and β-cell survival and that the regulatory role of ASC-2 in insulin secretion appears to involve, at least in part, its interaction with NRs via its two NR boxes.

scholarly journals Insulin secretion in health and disease: nutrients dictate the pace

2015 ◽  
Vol 75 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Romano Regazzi ◽  
Adriana Rodriguez-Trejo ◽  
Cécile Jacovetti
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Cell Mass ◽  
Insulin Biosynthesis ◽  
Β Cells ◽  
Β Cell ◽  
Altered Expression ◽  
Cell Dysfunction ◽  
Dietary Nutrients ◽  
Underlying Mechanisms

Insulin is a key hormone controlling metabolic homeostasis. Loss or dysfunction of pancreatic β-cells lead to the release of insufficient insulin to cover the organism needs, promoting diabetes development. Since dietary nutrients influence the activity of β-cells, their inadequate intake, absorption and/or utilisation can be detrimental. This review will highlight the physiological and pathological effects of nutrients on insulin secretion and discuss the underlying mechanisms. Glucose uptake and metabolism in β-cells trigger insulin secretion. This effect of glucose is potentiated by amino acids and fatty acids, as well as by entero-endocrine hormones and neuropeptides released by the digestive tract in response to nutrients. Glucose controls also basal and compensatory β-cell proliferation and, along with fatty acids, regulates insulin biosynthesis. If in the short-term nutrients promote β-cell activities, chronic exposure to nutrients can be detrimental to β-cells and causes reduced insulin transcription, increased basal secretion and impaired insulin release in response to stimulatory glucose concentrations, with a consequent increase in diabetes risk. Likewise, suboptimal early-life nutrition (e.g. parental high-fat or low-protein diet) causes altered β-cell mass and function in adulthood. The mechanisms mediating nutrient-induced β-cell dysfunction include transcriptional, post-transcriptional and translational modifications of genes involved in insulin biosynthesis and secretion, carbohydrate and lipid metabolism, cell differentiation, proliferation and survival. Altered expression of these genes is partly caused by changes in non-coding RNA transcripts induced by unbalanced nutrient uptake. A better understanding of the mechanisms leading to β-cell dysfunction will be critical to improve treatment and find a cure for diabetes.

scholarly journals β-Cell adaptation in 60% pancreatectomy rats that preserves normoinsulinemia and normoglycemia

2000 ◽  
Vol 279 (1) ◽  
pp. E68-E73 ◽  
Author(s):  
Ye Qi Liu ◽  
Peter W. Nevin ◽  
Jack L. Leahy
Keyword(s):  
Insulin Secretion ◽  
Regulatory Element ◽  
Cell Mass ◽  
Maximal Velocity ◽  
Β Cells ◽  
Β Cell ◽  
Biochemical Basis ◽  
Adaptive Mechanisms ◽  
Sense And Respond ◽  
Glucose Responsiveness

Islet β-cells are the regulatory element of the glucose homeostasis system. When functioning normally, they precisely counterbalance changes in insulin sensitivity or β-cell mass to preserve normoglycemia. This understanding seems counter to the dogma that β-cells are regulated by glycemia. We studied 60% pancreatectomy rats (Px) 4 wk postsurgery to elucidate the β-cell adaptive mechanisms. Nonfasting glycemia and insulinemia were identical in Px and sham-operated controls. There was partial regeneration of the excised β-cells in the Px rats, but it was limited in scope, with the pancreas β-cell mass reaching 55% of the shams (40% increase from the time of surgery). More consequential was a heightened glucose responsiveness of Px islets so that glucose utilization and insulin secretion per milligram of islet protein were both 80% augmented at normal levels of glycemia. Investigation of the biochemical basis showed a doubled glucokinase maximal velocity in Px islets, with no change in the glucokinase protein concentration after adjustment for the different β-cell mass in Px and sham islets. Hexokinase activity measured in islet extracts was also minimally increased, but the glucose 6-phosphate concentration and basal glucose usage of Px islets were not different from those in islets from sham-operated rats. The dominant β-cell adaptive response in the 60% Px rats was an increased catalytic activity of glucokinase. The remaining β-cells thus sense, and respond to, perceived hyperglycemia despite glycemia actually being normal. β-Cell mass and insulin secretion are both augmented so that whole pancreas insulin output, and consequently glycemia, are maintained at normal levels.

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