scholarly journals ACE2 deficiency reduces β-cell mass and impairs β-cell proliferation in obese C57BL/6 mice

2015 ◽  
Vol 309 (7) ◽  
pp. E621-E631 ◽  
Author(s):  
Robin Shoemaker ◽  
Frederique Yiannikouris ◽  
Sean Thatcher ◽  
Lisa Cassis
Keyword(s):  
Cell Proliferation ◽  
Cell Function ◽  
Critical Role ◽  
Cell Mass ◽  
Renin Angiotensin System ◽  
Β Cell ◽  
Β Cell Function ◽  
Islet Dysfunction ◽  
Glucose Stimulated Insulin Secretion

Drugs that inhibit the renin-angiotensin system (RAS) decrease the onset of type 2 diabetes (T2D). Pancreatic islets express RAS components, including angiotensin-converting enzyme 2 (ACE2), which cleaves angiotensin II (Ang II) to angiotensin-(1–7) [Ang-(1–7)]. Overexpression of ACE2 in pancreas of diabetic mice improved glucose homeostasis. The purpose of this study was to determine if deficiency of endogenous ACE2 contributes to islet dysfunction and T2D. We hypothesized that ACE2 deficiency potentiates the decline in β-cell function and augments the development of diet-induced T2D. Male Ace2 +/y or Ace2 −/y mice were fed a low-fat (LF) or high-fat (HF) diet for 1 or 4 mo. A subset of 1-mo HF-fed mice were infused with Sal (Sal), losartan (Los), or Ang-(1–7). At 4 mo, while both genotypes of HF-fed mice developed a similar level of insulin resistance, adaptive hyperinsulinemia was reduced in Ace2 −/y vs. Ace2 +/y mice. Similarly, in vivo glucose-stimulated insulin secretion (GSIS) was reduced in 1-mo HF-fed Ace2 −/y compared with Ace2 +/y mice, resulting in augmented hyperglycemia. The average islet area was significantly smaller in both LF- and HF-fed Ace2 −/y vs. Ace2 +/y mice. Additionally, β-cell mass and proliferation were reduced significantly in HF-fed Ace2 −/y vs. Ace2 +/y mice. Neither infusion of Los nor Ang-(1–7) was able to correct impaired in vivo GSIS of HF-fed ACE2-deficient mice. These results demonstrate a critical role for endogenous ACE2 in the adaptive β-cell hyperinsulinemic response to HF feeding through regulation of β-cell proliferation and growth.

scholarly journals NKX6.1 transcription factor: a crucial regulator of pancreatic β cell development, identity, and proliferation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Idil I. Aigha ◽  
Essam M. Abdelalim
Keyword(s):  
Transcription Factor ◽  
Cell Function ◽  
Disease Modeling ◽  
Critical Role ◽  
Cell Mass ◽  
Cell Development ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

Abstract Understanding the biology underlying the mechanisms and pathways regulating pancreatic β cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin-producing β cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive to β cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1+/NKX6.1+), warrants their future commitment to monohormonal β cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1+/NKX6.1−) results in an undesirable generation of non-functional polyhormonal β cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a means to increase β cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

scholarly journals Spontaneous restoration of functional β-cell mass in obese SM/J mice

2020 ◽  
Author(s):  
Mario A Miranda ◽  
Caryn Carson ◽  
Celine L St Pierre ◽  
Juan F Macias-Velasco ◽  
Jing W Hughes ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Mitotic Index ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Physiological Mechanisms ◽  
Β Cell Function ◽  
Basal Insulin Secretion ◽  
Glucose Stimulated Insulin Secretion ◽  
Mass Expansion

AbstractMaintenance of functional β-cell mass is critical to preventing diabetes, but the physiological mechanisms that cause β-cell populations to thrive or fail in the context of obesity are unknown. High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and β-cell function during SM/J’s diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase β-cell mass but not α-cell mass. Obese SM/J mice do not show elevated β-cell mitotic index, but rather elevated α-cell mitotic index. Functional assessment of isolated islets reveals that obese SM/J mice increase glucose stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin content. These results establish that β-cell mass expansion and improved β-cell function underlie the resolution of hyperglycemia, indicating that obese SM/J mice are a valuable tool for exploring how functional β-cell mass can be recovered in the context of obesity.

scholarly journals TRPM7 is a critical regulator of pancreatic endocrine development and high-fat diet-induced β-cell proliferation

Development ◽  
2021 ◽  
Author(s):  
Molly K. Altman ◽  
Charles M. Schaub ◽  
Matthew T. Dickerson ◽  
Karolina E. Zaborska ◽  
Prasanna K. Dadi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Transient Receptor Potential ◽  
Cell Function ◽  
Cell Mass ◽  
Transient Receptor Potential Channels ◽  
High Fat ◽  
Β Cell ◽  
Β Cell Function

The melastatin subfamily of the transient receptor potential channels (TRPM) are regulators of pancreatic β-cell function. TRPM7 is the most abundant islet TRPM channel; however, the role of TRPM7 in β-cell function has not been determined. Here, we utilized various spatiotemporal transgenic mouse models to investigate how TRPM7 knockout influences pancreatic endocrine development, proliferation, and function. Ablation of TRPM7 within pancreatic progenitors reduced pancreatic size, α-cell and β-cell mass. This resulted in modestly impaired glucose tolerance. However, TRPM7 ablation following endocrine specification or in adult mice did not impact endocrine expansion or glucose tolerance. As TRPM7 regulates cell proliferation, we assessed how TRPM7 influences β-cell hyperplasia under insulin resistant conditions. β-cell proliferation induced by high-fat diet was significantly decreased in TRPM7-deficient β-cells. The endocrine roles of TRPM7 may be influenced by cation flux through the channel, and indeed we find that TRPM7 ablation alters β-cell Mg2+ and reduces the magnitude of elevation in β-cell Mg2+ during proliferation. Together, these findings reveal that TRPM7 controls pancreatic development and β-cell proliferation, which is likely due to regulation of Mg2+ homeostasis.

scholarly journals Elevation of transcription factor Islet-1 levels in vivo increases β-cell function but not β-cell mass

Islets ◽  
2012 ◽  
Vol 4 (3) ◽  
pp. 199-206 ◽  
Author(s):  
Jingxuan Liu ◽  
Erik R. Walp ◽  
Catherine Lee May
Keyword(s):  
Transcription Factor ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Β Cell Function ◽  
Islet 1

Exercise improves glucose homeostasis that has been impaired by a high-fat diet by potentiating pancreatic β-cell function and mass through IRS2 in diabetic rats

2007 ◽  
Vol 103 (5) ◽  
pp. 1764-1771 ◽  
Author(s):  
Sunmin Park ◽  
Sang Mee Hong ◽  
Ji Eun Lee ◽  
So Ra Sung
Keyword(s):  
Cell Proliferation ◽  
High Fat Diet ◽  
Cell Function ◽  
Cell Mass ◽  
Diabetic Rats ◽  
Pancreatic Β Cell ◽  
High Fat ◽  
Β Cell ◽  
Igf I ◽  
Β Cell Function

In this study, we investigated the effects of a high-fat diet and exercise on pancreatic β-cell function and mass and its molecular mechanism in 90% pancreatectomized male rats. The pancreatectomized diabetic rats were given control diets (20% energy) or a high-fat (HF) diet (45% energy) for 12 wk. Half of each group was given regular exercise on an uphill treadmill at 20 m/min for 30 min 5 days/wk. HF diet lowered first-phase insulin secretion with glucose loading, whereas exercise training reversed this decrease. However, second-phase insulin secretion did not differ among the groups. Exercise increased pancreatic β-cell mass. This resulted from stimulated β-cell proliferation and reduced apoptosis, which is associated with potentiated insulin or IGF-I signaling through insulin receptor substrate-2 (IRS2) induction. Although the HF diet resulted in decreased proliferation and accelerated apoptosis by weakened insulin and IGF-I signaling from reduction of IRS2 protein, β-cell mass was maintained in HF rats just as much as in control rats via increased individual β-cell size and neogenesis from precursor cells. Consistent with the results of β-cell proliferation, pancreas duodenal homeobox-1 expression increased in the islets of rats in the exercise groups, and it was reduced the most in rats fed the HF diet. In conclusion, exercise combined with a moderate fat diet is a good way to maximize β-cell function and mass through IRS2 induction to alleviate the diabetic condition. This study suggests that dietary fat contents and exercise modulate β-cell function and mass to overcome insulin resistance in two different pathways.

scholarly journals Over-expression of AMP-activated protein kinase impairs pancreatic β-cell function in vivo

2005 ◽  
Vol 187 (2) ◽  
pp. 225-235 ◽  
Author(s):  
S K Richards ◽  
L E Parton ◽  
I Leclerc ◽  
G A Rutter ◽  
R M Smith
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Islet Transplantation ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Over Expression ◽  
Β Cell Function ◽  
Amp Activated Protein Kinase

Treatment of type 1 diabetes by islet transplantation is currently limited by loss of functional β-cell mass after transplantation. We investigated here whether adenovirus-mediated changes in AMP-activated protein kinase (AMPK) activity, previously shown to affect insulin secretion in vitro, might affect islet graft function in vivo. In isolated mouse and rat islets, insulin secretion stimulated by 17 (vs 3) mmol/l glucose was inhibited by 36.5% (P<0.01) and 43% (P<0.02) respectively after over-expression of constitutively-active AMPK- (AMPK CA) versus null (eGFP-expressing) viruses, and glucose oxidation was decreased by 38% (P<0.05) and 26.6% (P<0.05) respectively. Increases in apoptotic index (terminal deoxynucleotide transferase-mediated deoxyuridine trisphosphate biotin nick end-labelling) (TUNEL)) were also observed in AMPK CA- (22.8 ± 3.6% TUNEL-positive cells, P<0.001), but not AMPK DN- (2.72 ± 3.9%, positive cells, P=0.05) infected islets, versus null adenovirus-treated islets (0.68 ± 0.36% positive cells). Correspondingly, transplantation of islets expressing AMPK CA into streptozotocin-diabetic C57 BL/6 mice improved glycaemic control less effectively than transplantation with either null (P<0.02) or AMPK-DN-infected (P<0.01) islets. We conclude that activation of AMPK inhibits β-cell function in vivo and may represent a target for therapeutic intervention during islet transplantation.

scholarly journals Conventional and Unconventional Mechanisms by which Exocytosis Proteins Oversee β-cell Function and Protection

2021 ◽  
Vol 22 (4) ◽  
pp. 1833
Author(s):  
Diti Chatterjee Bhowmick ◽  
Miwon Ahn ◽  
Eunjin Oh ◽  
Rajakrishnan Veluthakal ◽  
Debbie C. Thurmond
Keyword(s):  
Cell Function ◽  
Secretory Granules ◽  
Clinical Care ◽  
Cell Mass ◽  
The United States ◽  
Whole Body ◽  
Β Cell ◽  
Protein Receptors ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

Type 2 diabetes (T2D) is one of the prominent causes of morbidity and mortality in the United States and beyond, reaching global pandemic proportions. One hallmark of T2D is dysfunctional glucose-stimulated insulin secretion from the pancreatic β-cell. Insulin is secreted via the recruitment of insulin secretory granules to the plasma membrane, where the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and SNARE regulators work together to dock the secretory granules and release insulin into the circulation. SNARE proteins and their regulators include the Syntaxins, SNAPs, Sec1/Munc18, VAMPs, and double C2-domain proteins. Recent studies using genomics, proteomics, and biochemical approaches have linked deficiencies of exocytosis proteins with the onset and progression of T2D. Promising results are also emerging wherein restoration or enhancement of certain exocytosis proteins to β-cells improves whole-body glucose homeostasis, enhances β-cell function, and surprisingly, protection of β-cell mass. Intriguingly, overexpression and knockout studies have revealed novel functions of certain exocytosis proteins, like Syntaxin 4, suggesting that exocytosis proteins can impact a variety of pathways, including inflammatory signaling and aging. In this review, we present the conventional and unconventional functions of β-cell exocytosis proteins in normal physiology and T2D and describe how these insights might improve clinical care for T2D.

scholarly journals The circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis during obesity

2022 ◽  
Author(s):  
Yue Liu ◽  
Yue Yang ◽  
Chenying Xu ◽  
Jianxing Liu ◽  
Jiale Chen ◽  
...  
Keyword(s):  
Cell Function ◽  
Critical Role ◽  
Cell Mass ◽  
Physiological Role ◽  
Circular Rna ◽  
Obese Mouse ◽  
Β Cell ◽  
Insulin Synthesis ◽  
Cell Dysfunction ◽  
Β Cell Function

Abstract The molecular link between obesity and β-cell decompensation that causes diabetes remains incompletely understood. Here we found that circGlis3, a circular RNA derived from Glis3, plays a critical role in islet β-cell compensation. circGlis3 was increased in islets of obese mouse models and moderately diabetic individuals with compensated β-cell function by Quaking (QKI)-mediated splicing. Overexpression of circGlis3 functions to restrain islet β-cell dysfunction and maintain β-cell mass in high-fat diet (HFD) fed mice and Leprdb/db mice. The cellular levels of circGlis3 modulate both insulin synthesis and secretion and lipotoxicity-induced apoptosis, resulting in profound changes in β-cell compensation. In an obesity model, circGlis3 promotes the synthesis and secretion of insulin by upregulating NeuroD1 and Creb1 through sponging miR-124-3p. In addition, we identified SCOTIN and fused in sarcoma (FUS) as interacting proteins using quantitative mass spectrometry. We demonstrated that the binding of SCOTIN to circGlis3 regulated the apoptosis of β-cell. And more, FUS binding to circGlis3 could decrease free circGlis3 in cytoplasm and block mechanism of circGlis3 via abnormal stable formation of stress granules (SGs) in hyperactive response to chronic stresses in obesity that is thought to contribute to the β-cell decompensation. These findings highlight a physiological role for circRNAs in compensation and indicate that modulation of circGlis3 expression may represent a potential strategy to protect against islet β-cell dysfunction and apoptosis during obesity.

scholarly journals Glucocorticoid-Induced Suppression of β-Cell Proliferation Is Mediated by Mig6

Endocrinology ◽  
2013 ◽  
Vol 154 (3) ◽  
pp. 1039-1046 ◽  
Author(s):  
E. Scott Colvin ◽  
Hong-Yun Ma ◽  
Yi-Chun Chen ◽  
Angelina M. Hernandez ◽  
Patrick T. Fueger
Keyword(s):  
Cell Proliferation ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Function ◽  
Cell Mass ◽  
Growth Factor Receptor ◽  
Β Cell ◽  
Β Cell Function ◽  
Epidermal Growth

Abstract Glucocorticoids can cause steroid-induced diabetes or accelerate the progression to diabetes by creating systemic insulin resistance and decreasing functional β-cell mass, which is influenced by changes in β-cell function, growth, and death. The synthetic glucocorticoid agonist dexamethasone (Dex) is deleterious to functional β-cell mass by decreasing β-cell function, survival, and proliferation. However, the mechanism by which Dex decreases β-cell proliferation is unknown. Interestingly, Dex induces the transcription of an antiproliferative factor and negative regulator of epidermal growth factor receptor signaling, Mig6 (also known as gene 33, RALT, and Errfi1). We, therefore, hypothesized that Dex impairs β-cell proliferation by increasing the expression of Mig6 and thereby decreasing downstream signaling of epidermal growth factor receptor. We found that Dex induced Mig6 and decreased [3H]thymidine incorporation, an index of cellular replication, in mouse, rat, and human islets. Using adenovirally delivered small interfering RNA targeted to Mig6 in rat islets, we were able to limit the induction of Mig6 upon exposure to Dex, compared with islets treated with a control virus, and completely rescued the Dex-mediated impairment in replication. We demonstrated that both Dex and overexpression of Mig6 attenuated the phosphorylation of ERK1/2 and blocked the G1/S transition of the cell cycle. In conclusion, Mig6 functions as a molecular brake for β-cell proliferation during glucocorticoid treatment in β-cells, and thus, Mig6 may be a novel target for preventing glucocorticoid-induced impairments in functional β-cell mass.

Elevated Circulating LINC-P21 Serves as a Diagnostic Biomarker of Type 2 Diabetes Mellitus and Regulates Pancreatic β-cell Function by Sponging miR-766-3p to Upregulate NR3C2

2020 ◽  
Author(s):  
Zhibin Cao ◽  
Fuwang Yao ◽  
Yuqin Lang ◽  
Xueqiang Feng
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Cell Proliferation ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Cell Function ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

Abstract Objective The purpose of this study was to evaluate the clinical value and biological function of long non-coding RNA (lncRNA) LINC-P21 in type 2 diabetes mellitus (T2DM), and explore the underlying mechanisms. Methods The expression of LINC-P21 was estimated using quantitative real-time PCR. The functional role of LINC-P21 was explored by gain- and loss-of-function experiments. INS-1 cell proliferation was analyzed using a cell counting kit-8 (CCK-8)assay, and the glucose-stimulated insulin secretion was measured using an ELISA kit. The miRNAs that might be sponged by LINC-P21 were analyzed, and the subsequent target genes were predicted and assessed in INS-1 cells. Results Serum expression of LINC-P21 was elevated in T2DM patients, which was correlated with fasting blood glucose levels and disease diagnosis. The glucose-stimulated insulin secretion and the proliferation of INS-1 cells were enhanced by LINC-P21 knockdown, but the overexpression of LINC-P21 led to opposite effects. miR-766-3p could be directly inhibited by LINC-P21 in INS-1 cells and reverse the effects of LINC-P21 on β-cell function. Additionally, NR3C2 was determined as a target of miR-766-3p, which could be positively regulated by LINC-P21 and had same effects with LINC-P21 on INS-1 cell proliferation and insulin secretion. Conclusion All the data demonstrated that serum elevated LINC-P21 and decreased miR-766-3p serve as candidate diagnostic biomarkers in T2DM patients. LINC-P21 acts as a potential regulator in insulin secretion and proliferation of pancreatic β-cells through targeting miR-766-3p to upregulate NR3C2.

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