Pancreatic Beta Cell Proliferation Research Articles

High expression of CNOT6L contributes to the negative development of type 2 diabetes.

Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by reduced responsiveness of body cells to insulin, leading to elevated blood sugar levels. CNOT6L is involved in glucose metabolism, insulin secretion regulation, pancreatic beta-cell proliferation, and apoptosis. These functions may be closely related to the pathogenesis of T2D. However, the exact molecular mechanisms linking CNOT6L to T2D remain unclear. Therefore, this study aims to elucidate the role of CNOT6L in T2D. The T2D datasets GSE163980 and GSE26168 profiles were downloaded from the Gene Expression Omnibusdatabase generated by GPL20115 and GPL6883.The R package limma was used to screen differentially expressed genes (DEGs). A weighted gene co-expression network analysis was performed. Construction and analysis of the protein-protein interaction (PPI) network, functional enrichment analysis, gene set enrichment analysis, and comparative toxicogenomics database (CTD) analysis were performed. Target Scan was used to screen miRNAs that regulate central DEGs. The results were verified by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), western blotting (WB), and blood glucose measurements in mice. A total of 1951 DEGs were identified. GO and KEGG enrichment analysis revealed that differentially expressed genes were mainly enriched in the insulin signaling pathway, ECM-receptor interaction, and PPAR signaling pathway. Metascape analysis indicated enrichment primarily in the cAMP signaling pathway and enzyme-linked receptor protein signaling pathway. WGCNA analysis yielded 50 intersecting genes. PPI network construction and algorithm identification identified two core genes (CNOT6L and GRIN2B), among which CNOT6L gene was associated with multiple miRNAs. CTD analysis revealed associations of core genes with type 2 diabetes, diabetic complications, dyslipidemia, hyperglycemia, and inflammation. WB and RT-qPCR results showed that in different pathways, CNOT6L protein and mRNA levels were upregulated in type 2 diabetes. CNOT6L is highly expressed in type 2 diabetes mellitus, and can cause diabetes complications, inflammation and other physiological processes by regulating miRNA, PPAR and other related signaling pathways, with poor prognosis. CNOT6L can be used as a potential therapeutic target for type 2 diabetes.

Dual PPAR-a/g enhances beta cell identity, preserving islet structure in HF-fed mice.

The pancreas suffers from lipotoxicity, which threatens the survival of pancreatic islets. Dual PPAR-alpha(a)/gamma(g) agonism is a promising method for treating type 2 diabetes. This study evaluated the effects of single PPAR-a and PPAR-g or their combined activation on pancreatic islet remodeling, beta-cell proliferation, identity, and maintenance in an experimental obesity model. Fifty three-month-old mice, randomly divided to receive the control (C) or high-fat (HF) diet for ten weeks, were then redivided for a four-week treatment: C, HF, HF-a (received the PPAR-a agonist), HF-g (PPAR-g agonist pioglitazone), and HF-d (PPAR-a/g agonists). The HF group was overweight, had oral glucose intolerance, showed a proinflammatory adipokine profile, exhibited increased alpha and beta cell masses, and islet gene expression compatible with compromised beta cell proliferation and favored dedifferentiation. All treatments reduced body weight, mitigated oral glucose intolerance, and produced an anti-inflammatory adipokine profile, which rescued islet cytoarchitecture, and beta cell function. Principal component analysis (PCA) revealed a shift in the antiapoptotic gene Bcl2 and beta cell proliferation genes (Pax4 and Neurog3) in HF-a. Conversely, HF-g and HF-d benefited from the upregulation of genes related to beta cell function (Fgf21, Glut2, and Glp1r), identity, and maintenance (Pdx1, Neurod1, Mafa, and Nkx6.1). The HF mice were glucose intolerant, showing islet hypertrophy and low beta cell identity-related genes. In contrast, PPAR activation rescued islet structure, and PCA showed that the PPAR-a/g combination was the most effective treatment because it favored beta cell function, identity, and maintenance-related genes, halting the T2DM spectrum in diet-induced obese mice.

Evaluation of serum levels of sestrin 2 and betatrophin in type 2 diabetic patients with diabetic nephropathy

BackgroundDiabetic kidney disease (DKD) is one of the most serious microvascular complications of diabetes mellitus (DM) and the leading cause of chronic kidney disease (CKD) worldwide. Since obesity and type 2 DM (T2DM) are considered as inflammatory conditions, thus reducing their accompanied systemic inflammation may lessen their complications. Sestrin 2 belongs to a group of stress induced proteins which are produced in response to oxidative stress, inflammation and DNA damage. Betatrophin; a hormone that stimulates the growth, proliferation and mass expansion of pancreatic beta-cells and improves glucose tolerance. The objective of the study was to evaluate levels of serum Sestrin 2 and betatrophin in patients with different stages of diabetic nephropathy (DN)) and compare results with healthy control.MethodsThis cross sectional study was carried out on 60 patients above 18 years old, recruited from Tanta University hospitals out patients clinics and 20 apparently healthy individuals of matched sex and age as a control group. Participants were divided into two groups: group I: 20 normal subjects as control group and group II: 60 patients with type 2 DM,. further subdivided in to three equal groups: group 1IIA(20 patients) with normo-albuminuria (ACR < 30 mg/g), group IIB (20 patients) with micro albuminuria (ACR = 30 to 300 mg/g) and group IIC (20 patients) with macro albuminuria (ACR > 300 mg/g). They were subjected to detailed history taking, careful clinical examination and laboratory investigations including blood urea, serum creatinine, estimated glomerular filtration rate (eGFR), urinary albumin creatinine ratio, and specific laboratory tests for Sestrin 2 and Betatrophin by using ELISA technique.ResultsSerum Sestrin 2 significantly decreased, while serum betatrophin level significantly increased in macroalbuminuric group compared to control and other 2 diabetic groups (P value < 0.05). The cut off value of serum sestrin 2 was 0.98 ng/ml with sensitivity 99%, specificity 66% while the cut off value of serum betatrophin was > 98.25 ng/ml with sensitivity 98%, specificity 82%. Serum betatrophin positively correlated with age, fasting, 2 h postprandial, BMI, triglyceride, total cholesterol, serum creatinine, blood urea, UACR, and negatively correlated with eGFR and serum albumin. Serum Sestrin 2 positively correlated with serum albumin. BMI, serum urea, UACR and serum albumin. Serum betatrophin are found to be risk factors or predictors for diabetic nephropathy.ConclusionsPatients with DN, particularly the macroalbuminuria group, had a significant increase in betatrophin levels and a significant decrease in serum Sestrin 2 level. The function of Sestrin 2 is compromised in DN, and restoring it can reverse a series of molecular alterations with subsequent improvement of the renal functions, albuminuria and structural damage.

Soluble T-cadherin secretion from endothelial cells is regulated via insulin/PI3K/Akt signalling

Aim and objectiveOur recent report showed that soluble T-cadherin promotes pancreatic beta-cell proliferation. However, how and where the secretion of soluble T-cadherin is regulated remain unclear. Methods and resultsSoluble T-cadherin levels significantly increased in leptin receptor-deficient db/db mice with hypoinsulinaemia or in wild-type mice treated with insulin receptor blockade by S961. Similar results were observed in human subjects; Diabetic ketoacidosis patients at the time of hospitalization had increased plasma soluble T-cadherin levels, which decreased after insulin infusion therapy. Patients with recurrent ovarian cancer who were administered a phosphatidylinositol-3 kinase (PI3K)-alpha inhibitor (a new anticancer drug) had increased plasma soluble T-cadherin and plasma C-peptide levels. Endothelial cell-specific T-cadherin knockout mice, but not skeletal muscle- or cardiac muscle-specific T-cadherin knockout mice, showed a 26 % reduction in plasma soluble T-cadherin levels and a significant increase in blood glucose levels in streptozocin-induced diabetes. The secretion of soluble T-cadherin from human endothelial cells was approximately 20 % decreased by insulin and this decrease was canceled by blockade of insulin receptor/Akt signalling, not Erk signalling. ConclusionWe conclude that insulin regulates soluble T-cadherin levels and soluble T-cadherin secretion from endothelial cells is positively regulated by insulin/insulin receptor/Akt signalling.

Pharmacodynamic Interaction of Areca catechu with Gliclazide in Wistar Rats

Background and Purpose In alloxan-induced diabetic rats, this study sought to evaluate the hypoglycemic potential of the hydroalcoholic seed extract of Areca catechu, also referred to as areca nut, both as a stand-alone treatment and in combination with the diabetic drug gliclazide. Materials and Methods The hot percolation method was used to produce the hydroalcoholic seed extract of A. catechu. Rats were given alloxan monohydrate and developed type II diabetes. The hydroalcoholic seed extract of A. catechu (1000 mg/kg p.o.) alone or in different combinations of gliclazide (25 mg/kg p.o.) and A. catechu extract (250, 500, and 1000 mg/kg p.o.) were administered to the six diabetic rats. Body weights and blood glucose levels were measured on days 7, 14, 21, and 28 of the treatment. On the 28th day, the kidney, liver, and pancreas underwent histological investigations in addition to an oral glucose tolerance test (OGTT). Results Blood glucose levels were significantly lowered upon administration of A. catechu’s hydroalcoholic seed extract, both alone and in conjunction with gliclazide. Comparing the diabetic control group to the A. catechu extract-treated group, histopathological examinations showed that high amounts of the extract, either by itself or in conjunction with gliclazide, caused the active proliferation of pancreatic beta cells, protecting against damage to the liver and kidneys. Conclusion The hydroalcoholic seed extract of A. catechu showed promise as a monotherapy for controlling blood glucose levels, and as a co-administer for gliclazide, it showed signs of hypoglycemia. These results indicate A. catechu’s possible therapeutic benefit as an adjuvant diabetic treatment. To investigate the underlying mechanisms of action and evaluate its safety and effectiveness in clinical settings, more study is necessary.

Genetic Association of Transcription Factor 7-Like-2 rs7903146 Polymorphism With Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) mainly results from the inability of muscle, fat, and liver cells to uptake glucose due to insulin resistance or deficiency of insulin production by thepancreas. Predisposition to T2DM may be due to environmental, hereditary, or both factors. Although there are many genes involved in causing T2DM, transcription factor 7-like-2 gene (TCF7L2) rs7903146 (C/T) single nucleotide polymorphism (SNP) found in genome-wide association studies (GWAS) is susceptible to T2DM. TCF7L2 is involved in pancreatic beta cell proliferation and differentiation via the Wnt signaling mechanism. To find the genetic association of TCF7L2 rs7903146 (C/T) gene polymorphism in patients with T2DM. A case-control study was conducted on 194 T2DM patients recruited from the endocrinology department at Indira Gandhi Institute of Medical Sciences, Patna, and 180 non-diabetic healthy controls that were age and sex-matched with the patients. All clinical examination and biochemical investigations like glycosylated hemoglobin (HbA1c), total cholesterol, triglycerides, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol; and determination of TCF7L2 gene polymorphism by allele-specific polymerase chain reaction (AS-PCR) were carried out for each subject. The T allele of the rs7903146 (C/T) SNP was associated with a two-fold higher risk of T2DM and the heterozygous genotype (CT) with a 1.96 times higher risk. There is a high association of this SNP with the development of T2DM in the eastern Indian population. Serial monitoring of HbA1c should be done in an individual having this type of polymorphism for early detection of T2DM to prevent future complications.

Serum and salivary adiponectin levels as predictive markers for diabetes mellitus in children with a family history of diabetes.

Diabetes mellitus (DM) is a chronic, metabolic condition marked by defects in insulin production, action, or both. Environmental and genetic factors can contribute to the onset of diabetes mellitus. Adiponectin, a hormone affecting pancreatic beta cell proliferation, has emerged as a potential indicator of diabetes risk. This cross-sectional study aimed to evaluate serum and salivary adiponectin levels as predictors of diabetes mellitus in children with/without a family history of diabetes mellitus. The study was conducted at Al-Zahra Hospital in Najaf city and included 125 children aged 5 to 16. Data on demographics, including name, age, and gender, were collected, and body mass index (BMI) was assessed. Serum and salivary adiponectin levels were measured and analyzed in relation to family history and BMI. Children with a family history of DM had high serum adiponectin (ADP) levels. Serum adiponectin levels were significantly higher in children with first-degree relatives having a history of diabetes mellitus, except for cases involving mothers and other relatives with diabetes mellitus history (p<0.05). Furthermore, serum adiponectin levels were higher in obese children. Salivary adiponectin levels were significantly elevated in children with a maternal family history of diabetes (p=0.01), while no significant correlation was found with BMI. A significant negative correlation (r=-0.180, p=0.05) between salivary and serum adiponectin concentrations was observed. Compared to children with a normal, healthy weight, children with obesity had decreased salivary adiponectin levels and increased serum adiponectin levels.

BIBLIOMETRIC ANALYSIS: THE USE OF STREPTOZOTOCIN (STZ) IN DIABETIC ANIMAL MODEL

Bibliometric analysis is a relatively new tool in healthcare and therefore does not yet make full use of its potential. This statistical tool analyses scientific publications which further describe trends in academic literature and research in various fields. This study focused on the development of diabetes research using animal models induced by streptozotocin (STZ), a diabetogenic molecule that triggers DNA damage in pancreatic beta cells and causes extreme oxidative stress. 1090 related articles published between 2017-2022 were obtained from the Scopus-Elsevier database using specific keywords “streptozotocin or STZ, animal models, diabetes, intraperitoneal”. Statistical analysis showed 1.67% Annual Growth Rate of publication with 10.66 citation rate per document. Co-occurrence analysis also successfully visualized the main topics related to the mechanism of action of streptozotocin such as oxidative stress, inflammation, rats, diabetic nephropathy, diabetic cardiomyopathy, hyperglycemia, antioxidants, and insulin. An important finding in this study indicated the diabetes research development was not in line with the main problem using animal models that remain unsolved, especially in diabetes research related to pancreatic beta cell proliferation. The result also provided valuable insights of research trends that involved diabetic animal models. The latest research datas are significantly important since it can be used for future research development. Further, more comprehensive information could be achieved by using other databases such as Web of Science (WOS) and Dimension in bibliometric analysis.

17:45-17:55 Blood sEVs from healthy and GDM patients modulate 1.1B4 pancreatic beta cell proliferation and metabolism

17:45-17:55 Blood sEVs from healthy and GDM patients modulate 1.1B4 pancreatic beta cell proliferation and metabolism

1732-P: Correlation of Cyclin D2 with Cell Proliferation in Human Pancreatic Beta Cells and Possible Regulation by CCND2-AS1

Though Cyclin D2 (CCND2) has been considered to be essential for rodent beta cell proliferation, its expression in human beta cells is controversial. We reported CCND2 protein was abundantly expressed also in human perinatal beta cells at ADA 2019. This exclusive expression of CCND2 in the perinatal period would implicate a relationship with beta cell proliferation which is by far rare in human adults, while its regulation mechanism is unclear. GWAS studies identified rs76895963 in CCND2 locus as a genotype that reduced the susceptibility for type 2 diabetes by 50%. The SNP is also located in the sequence of CCND2-AS1, an anti-sense RNA. In this study, we explored the relationship between CCND2 and beta cell proliferation in humans, figuring out any possible regulations associated with CCND2-AS1. We obtained 49 pancreas samples from autopsies. Subjects were divided into 6 groups by age; fetus (F: gestational age 24 to 40 weeks), newborn (N: 0 days to1 month), infant (I: 2 to 12 months), toddler (T: 3 months to 4 years), child (C: 5 to 12 years), and adolescent (A: 13 to 19 years). Formalin-fixed paraffin-embedded sections were used for immunostaining and in situ hybridization analysis. Beta cell proliferation labeled with Ki67 was most abundant in N and rapidly decreased after T. Nuclear CCND2 expression was the highest in F followed by I and was almost not detected in C and A, showing a positive correlation with Ki67 though their peaks were different (p&amp;lt;0.01). CCND2 mRNA was abundant in F and N but was also detectable in C and A. The correlation between CCND2 mRNA and protein was linear (p=0.0513). On the other hand, the expression of CCND2-AS1 was significantly correlated with CCND2 protein and Ki67 (p&amp;lt;0.01 and &amp;lt;0.05). Antisense RNAs are reported to show a variety of post-transcriptional regulations on their corresponding mRNA and protein. Our results suggest that CCND2-AS1 may positively regulate CCND2 expression and be a provisional therapeutic target for beta cell proliferation. Disclosure S.Osonoi: None. T.Sasaki: None. Y.Takeuchi: None. H.Mizukami: None.

MiRNA Theranostic Nanoparticles Promote Pancreatic Beta Cell Proliferation in Type 1 Diabetes Model.

Type 1 diabetes (T1D) is a chronic autoimmune disorder which affects the insulin-producing beta cells in the pancreas. A variety of strategies, namely, insulin replacement therapy, engineered vaccines, immunomodulators, etc., have been explored to correct this condition. Recent studies have attributed the development of T1D to the anomalous expression of microRNAs in the pancreatic islets. Here, we describe the protocol for the development of a theranostic approach to modify the expression of aberrant miRNAs. The MRI-based nanodrug consists of superparamagnetic iron oxide nanoparticles conjugated to microRNA-targeting oligonucleotides that can promote proliferation of pancreatic beta cells in a mouse model of T1D. This theranostic approach can successfully serve as a potential therapeutic approach for the targeted treatment of T1D with minimal side effects.

Gli-similar 3 (GLIS3) rs7020763 (C&gt;G) polymorphism in patients with type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a heterogeneous group of metabolic disorders characterized by the incapability of pancreatic beta cells to increase insulin secretion to compensate for insulin resistance in the peripheral tissues. T2DM is a multi-factorial disease including several environmental factors with the presence of genetic predisposition. The transcription factor GLI-Similar 3 (GLIS3) has an important role in the development, survival and proliferation of pancreatic beta-cells and insulin gene expression regulation. Accordingly, genome-wide association studies have shown that GLIS3 gene polymorphism may confer risk to type 2 diabetes mellitus T2DM. The present study intended to investigate the association between GLIS3 rs7020673 gene polymorphism and type 2 diabetes mellitus and its impact on glycemic control among Egyptian population. This study was conducted on 100 Egyptian patients diagnosed asT2DM patients and 100 age- and sex-matched non-diabetic normal controls. All subjects underwent full history taking, thorough clinical examination, routine laboratory investigations including fasting blood glucose (FBG), fasting insulin and hemoglobin A1c (HbA1c). Detection of rs7020673 polymorphism of GLIS3 gene was done by real-time polymerase chain reaction (PCR) and verified by sanger sequencing. Genotype and allele frequencies of rs7020673 did not differ between case and control groups. Regarding the heterozygous mutant genotype (GC), it was statistically less frequently distributed in diabetic patients (53%) versus controls (67%). Therefore, it can be considered as a negative risk factor for T2DM (OR: 0.5098, 95% CI (0.2827-0.9193), (P&lt; 0.05). In conclusion, our study indicated that the GC mutant genotype may be proposed as a negative risk factor for T2DM in Egyptian population.

E2F1 transcription factor mediates a link between fat and islets to promote β cell proliferation in response to acute insulin resistance.

SUMMARYPrevention or amelioration of declining β cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by β cells to robustly replicate in response to acute insulin resistance induced by S961, a pharmacological insulin receptor antagonist. Interestingly, pathways that include CENP-A and the transcription factor E2F1 that are independent of insulin signaling and its substrates appeared to mediate S961-induced β cell multiplication. Consistently, pharmacological inhibition of E2F1 blocks β-cell proliferation in S961-injected mice. Serum from S961-treated mice recapitulates replication of β cells in mouse and human islets in an E2F1-dependent manner. Co-culture of islets with adipocytes isolated from S961-treated mice enables β cells to duplicate, while E2F1 inhibition limits their growth even in the presence of adipocytes. These data suggest insulin resistance-induced proliferative signals from adipocytes activate E2F1, a potential therapeutic target, to promote β cell compensation.

Apolipoprotein C3 and circulating mediators of preadipocyte proliferation in states of lipodystrophy

Adipogenesis is a complex process controlled by intrinsic and extrinsic factors that regulate preadipocyte proliferation, adipogenic capacity and maturation of metabolic function. Here we show that insulin and IGF-1 receptors are essential for mature adipocyte survival and that deletion of both IR and IGF1R specifically in fat using a tamoxifen inducible-AdipoQ-Cre (Ai-DKO) leads to rapid and severe loss of adipocytes in all depots, associated with a metabolic syndrome characterized by hypertriglyceridemia, hyperglycemia, hyperinsulinemia, fatty liver, and pancreatic beta cell proliferation. In this model, this pathological phenotype reverses over a few weeks, in large part, due to preadipocyte proliferation and adipose tissue regeneration. Incubation of preadipocytes with serum from the Ai-DKO mice in vitro stimulates cell proliferation, and this effect can be mimicked by conditioned media from liver slices of Ai-DKO mice, but not by media of cultured Ai-DKO adipocytes, indicating a hepatic origin of the growth factor. Proteomic analysis of serum reveals apolipoprotein C3 (APOC3), a protein secreted by liver, as one of the most upregulated proteins in the Ai-DKO mice. In vitro, purified and delipidated APOC3 stimulates preadipocyte proliferation, however, knockdown of hepatic APOC3 in vivo in Ai-DKO mice is not sufficient to block adipose regeneration. Thus, lipodystrophy is associated with presence of increased preadipocyte-stimulating growth factors in serum. Our study indicates that APOC3 is one contributing factor to preadipocyte proliferation, however, other still-unidentified circulating growth factors are also likely present in Ai-DKO mice. Identification of these factors may provide a new approach to regulation of adipose mass in health and disease.

Phosphatases are predicted to govern prolactin-mediated JAK-STAT signaling in pancreatic beta cells.

Patients with diabetes are unable to produce a sufficient amount of insulin to properly regulate their blood glucose levels. One potential method of treating diabetes is to increase the number of insulin-secreting beta cells in the pancreas to enhance insulin secretion. It is known that during pregnancy, pancreatic beta cells proliferate in response to the pregnancy hormone, prolactin (PRL). Leveraging this proliferative response to PRL may be a strategy to restore endogenous insulin production for patients with diabetes. To investigate this potential treatment, we previously developed a computational model to represent the PRL-mediated JAK-STAT signaling pathway in pancreatic beta cells. Here, we applied the model to identify the importance of particular signaling proteins in shaping the response of a population of beta cells. We simulated a population of 10 000 heterogeneous cells with varying initial protein concentrations responding to PRL stimulation. We used partial least squares regression to analyze the significance and role of each of the varied protein concentrations in producing the response of the cell. Our regression models predict that the concentrations of the cytosolic and nuclear phosphatases strongly influence the response of the cell. The model also predicts that increasing PRL receptor strengthens negative feedback mediated by the inhibitor suppressor of cytokine signaling. These findings reveal biological targets that can potentially be used to modulate the proliferation of pancreatic beta cells to enhance insulin secretion and beta cell regeneration in the context of diabetes.

Glucokinase as a therapeutic target based on findings from the analysis of mouse models.

I investigated mouse models to elucidate the pathophysiology and to establish a new treatment strategy for type 2 diabetes, with a particular focus on glucokinase. The decrease in pancreatic beta-cell function and mass are important factors in the pathophysiology of type 2 diabetes. My group have shown that glucokinase plays an important role in high-fat diet-induced and high-starch diet-induced beta-cell expansion. The findings indicated that the mechanism of short-term high-fat diet-induced beta-cell proliferation involved a glucokinase-independent pathway, suggesting that there are different pathways and mechanisms in the proliferation of pancreatic beta-cells during short-term versus long-term high-fat diets. Because enhancement of glucose signals via glucokinase is important for beta-cell proliferation, it was thought that beta-cell mass would be increased and insulin secretion would be maintained by glucokinase activators. However, sub-chronic administration of a glucokinase activator in db/db mice produced an unsustained hypoglycemic effect and promoted hepatic fat accumulation without changes in beta-cell function and mass. In contrast, my group have shown that inactivating glucokinase in beta-cells prevented beta-cell failure and led to an improvement in glucose tolerance in db/db mice. Regulation of glucokinase activity has an influence on the pathophysiology of type 2 diabetes and can be one of the therapeutic targets.

Autonomic control of pancreatic beta cells: What is known on the regulation of insulin secretion and beta-cell proliferation in rodents and humans

Insulin secretion and pancreatic beta-cell proliferation are tightly regulated by several signals such as hormones, nutrients, and neurotransmitters. However, the autonomic control of beta cells is not fully understood. In this review, we describe mechanisms involved in insulin secretion as well as metabolic and mitogenic actions on its target tissues. Since pancreatic islets are physically connected to the brain by nerves, parasympathetic and sympathetic neurotransmitters can directly potentiate or repress insulin secretion and beta-cell proliferation. Finally, we highlight the role of the autonomic nervous system in metabolic diseases such as diabetes and obesity.

Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway.

Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-β-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-α and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-κB signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-α and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-α signaling pathway, which may provide novel insight into beta cell failure and T1D development.

Intermittent cold exposure improves glucose homeostasis despite exacerbating diet‐induced obesity in mice housed at thermoneutrality

Ambient cold exposure is often regarded as a promising anti-obesity treatment in mice. However, most preclinical studies aimed at treating obesity via cold-induced thermogenesis have been confounded by subthermoneutral housing temperatures. Therefore, the ability of ambient cold to combat diet-induced obesity in mice housed under humanized thermoneutral conditions is currently unknown. Moreover, mammals such as mice are rarely exposed to chronic ambient cold without reprieve, yet mice are often subjected to experimental conditions of chronic rather than intermittent cold exposure (ICE), despite ICE being more physiologically relevant. In the present study, we provide novel evidence that thermoneutral housing uncouples the effects of ICE on glucose and energy homeostasis suggesting that ICE, despite improving glucose tolerance, is not an effective obesity treatment when mice are housed under humanized thermoneutral conditions. The present study examines whether a physiologically relevant model of ambient cold exposure, intermittent cold exposure (ICE), could ameliorate the metabolic impairments of diet-induced obesity in male and female mice housed under humanized thermoneutral conditions. Male and female C57BL/6J mice housed at thermoneutrality (29°C) were fed a low-fat diet or high-fat diet for 6weeks before being weight matched into groups that remained unperturbed or underwent ICE for 4 weeks (4°C for 60minday-1 ; 5daysweek-1 ) when being maintained on their respective diets. ICE induced rapid and persistent hyperphagia exacerbating rather than attenuating high-fat diet-induced obesity over time. These ICE-induced increases in adiposity were found to be energy intake-dependent via pair-feeding. Despite exacerbating high-fat diet-induced obesity, ICE improved glucose tolerance, independent of diet, in a sex-specific manner. The effects of ICE on glucose tolerance were not attributed to improvements in whole-body insulin tolerance, tissue specific insulin action, nor differences in markers of hepatic insulin clearance or pancreatic beta cell proliferation. Instead, ICE increased serum concentrations of insulin and C-peptide in response to glucose, suggesting that ICE may improve glucose tolerance by potentiating pancreatic glucose-stimulated insulin secretion. These data suggest that ICE, despite improving glucose tolerance, is not an effective obesity treatment in mice housed under humanized conditions.

TRAIL induces proliferation in rodent pancreatic beta cells via AKT activation.

Strategies to increase functional pancreatic beta cell mass is of great interest in diabetes-related research. TNF-related apoptosis-inducing ligand (TRAIL) is well known to promote proliferation and survival in various cell types, including vascular smooth muscle and endothelial cells. Correlation between the protective nature of TRAIL on these cells and its proliferative effect is noteworthy. TRAIL's seemingly protective/therapeutic effect in diabetes prompted us to question whether it may act as an inducer of proliferation in pancreatic beta cells. We used rat primary islet cells and MIN6 mouse beta cell line to investigate TRAIL-induced proliferation. Cell viability and/or death was analyzed by MTT, WST-1, and Annexin-V/PI assays, while proliferation rates and pathways were assessed via immunocytochemical and Western blot analyses. Receptor neutralization antibodies identified the mediator receptors. Recombinant soluble TRAIL (sTRAIL) treatment led to 1.6-fold increased proliferation in insulin-positive cells in dispersed rat islets compared to the untreated group, while adenovirus-mediated overexpression of TRAIL increased the number of proliferating beta cells up to more than six-fold. sTRAIL or adenoviral vector-mediated TRAIL overexpression induced proliferation in MIN6 cells also. TRAIL's proliferative effect was mediated via AKT activation, which was suppressed upon specific inhibition. Neutralization of each TRAIL receptor reversed the proliferative effect to some degree, with the highest level of inhibition in death receptor 5 (DR5) blockage in MIN6 cells and in decoy receptor 1 (DcR1) blockage in primary rat beta cells. Thus, TRAIL induces proliferation in rodent pancreatic beta cells through activation of the AKT pathway.