Β-cell Dysfunction Research Articles

Prenatal air pollution, fetal β-cell dysfunction and neurodevelopmental delay

BackgroundEmerging evidence has reported significant associations of prenatal air pollution exposure with neurodevelopmental delay in offspring. Sensitive exposure windows and the modifiable factor remain elusive. ObjectiveWe aim to identify sensitive windows of air pollution during pregnancy on neurodevelopmental delay, and examine whether cord blood C-peptide mediates the relationship. MethodsThis study included 7438 mother-newborn pairs in Hefei, China, from 2015 to 2021. Weekly exposure to particulate matter of aerodynamic diameter <2.5 µm, 10 µm (PM2.5, PM10), nitrogen dioxide (NO2) and carbon monoxide (CO) was estimated at regulatory air monitoring stations in Hefei. Denver Developmental Screening Test-II and the Gesell Developmental Schedules were applied to assess the neurodevelopmental delay in children 6–36 mon of age. Distributed lag nonlinear models examined sensitive time windows of prenatal air pollutants exposure. Mediation analysis estimated the mediating role of cord blood C-peptide. ResultsThe sensitive PM2.5, PM10, NO2, and CO exposure windows associated with neurodevelopmental delay were throughout pregnancy. Weekly air pollutants exposure was related to higher neurodevelopmental delay risks [cumulative odds ratio (OR): 1.40(1.29,1.53) in PM2.5 (per 10 μg/m3), 1.40(1.28,1.53) in PM10 (per 10 μg/m3), 1.41(1.30,1.52) in CO (per 0.1 mg/m3), and 1.49(1.29,1.72) in NO2 (per 5 μg/m3)]. Mediation analysis indicated 18.3 % contributions of cord C-peptide to the relationship [average mediation effect: 0.04(0.01.0.06); average direct effect: 0.15(0.07.0.25)]. Conclusions: Exposure to air pollution throughout pregnancy is linked to neurodevelopmental delay mediated by poorer fetal β-cell function. Screening and treatment of abnormal glucose metabolism in infants could benefit the prevention of air pollution-associated neurodevelopment delay.

Increased Insulin Secretion and Glucose Effectiveness in Obese Patients with Type 2 Diabetes following Bariatric Surgery.

β-cell dysfunction and insulin resistance are the main mechanisms causing glucose intolerance in type 2 diabetes (T2D). Bariatric surgeries, i.e., sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), are procedures both known to induce weight loss, increase insulin action, and enhance β-cell function, but hepatic insulin extraction and glucose effectiveness may also play a role. To determine the contribution of these regulators on glucose tolerance after bariatric surgery, an oral glucose tolerance test (OGTT) was performed before and 2 months after surgery in 9 RYGB and 7 SG subjects. Eight healthy subjects served as metabolic controls. Plasma glucose, insulin, C-peptide, GLP-1, and GIP were measured during each OGTT. Insulin sensitivity and secretion, glucose effectiveness, and glucose rate of appearance were determined via oral minimal models. RYGB and SG resulted in similar weight reductions (13%, RYGB (p < 0.01); 14%, SG (p < 0.05)). Two months after surgery, insulin secretion (p < 0.05) and glucose effectiveness both improved equally in the two groups (11%, RYGB (p < 0.01); 8%, SG (p > 0.05)), whereas insulin sensitivity remained virtually unaltered. Bariatric surgery resulted in a comparable increase in the GLP-1 response during the OGTT, whereas GIP concentrations remained unaltered. Following surgery, oral glucose intake resulted in a comparable increase in hepatic insulin extraction, the response in both RYGB and SG patients significantly exceeding the response observed in the control subjects. These results demonstrate that the early improvement in glucose tolerance in obese T2D after RYGB and SG surgeries is attributable mainly to increased insulin secretion and glucose effectiveness, while insulin sensitivity seems to play only a minor role. This trial is registered with NCT02713555.

In Silico identification of novel phytochemicals that target SFRP4: An early biomarker of diabesity.

The simultaneous coexistence of complicated metabolic conditions like obesity and diabetes within an individual is known as diabesity. Obesity is the key factor for many chronic diseases, including insulin resistance and type 2 diabetes (T2D). Metabolic stress due to nutrient overload releases different inflammatory mediators. Secreted frizzled-related protein 4 (SFRP4) is also an inflammatory mediator that impairs insulin secretion. SFRP4 acts as an early biomarker for diabesity expressed with interleukin-1 beta (IL-1β) in the adipose tissues that hinder the exocytosis of insulin-secreting granules from the pancreatic β-cells and is a potential target for preserving β-cell dysfunction and the diabesity treatment. The current study aimed to screen potential bioactive compounds targeting and inhibiting the diabesity-linked SFRP4 protein through an in silico approach. The three-dimensional (3D) structure of human SFRP4 was predicted through comparative modeling techniques and evaluated by various online bioinformatics tools. The molecular docking and MD simulation investigations were carried out against phytochemicals with anti-diabetic and anti-obesity properties to shortlist the best SFRP4 inhibitor. Hesperetin, Curcumin, Isorhamnetin, Embelin, Epicatechin, and Methyl Eugenol interacted strongly with SFRP4 by displaying zero RMSD and binding affinities of -6.5, -6.4, -6.3, -5.3, -6.3 and -5.8 kcal/mol respectively. Additionally, the root mean square fluctuation and root mean square deviation graphs from the MD simulation results demonstrated that hesperetin has good variations throughout the simulation period as compared to others. This dynamic stability and control behavior of hesperetin, when it interacts with SFRP4, shows that it has the potential to modulate the function and activity of the protein. Therefore, hesperetin is identified as an effective and top drug candidate through this analysis for preserving beta-cell function and treating diabesity by targeting SFRP4. The findings of this study could be useful in the design and development of diabesity drugs.

'Oxidative stress'-A new target in the management of diabetes mellitus.

Diabetes mellitus (DM) is a chronic condition that poses a mammoth challenge for the healthcare system in developing as well as developed nations. Diabetes mellitus is associated with damage to the vasculature which leads to microvascular and macrovascular complications. Oxidative stress is a consequence of glucotoxicity and lipotoxicity, which are associated with diabetes. Glucotoxicity and lipotoxicity play a part in the pathogenesis of β-cell dysfunction. The hyperglycemic state in DM leads to oxidative stress which further hampers insulin secretion. In diabetes, the biological antioxidants also get depleted along with a reduction in glutathione (GSH), an increase in the oxidized glutathione (GSSG)/GSH ratio, and a depletion of non-enzymatic antioxidants. This results in the formation of a viscous circle of hyperglycemia leading to increased oxidative stress that further hampers insulin secretion which in turn results in hyperglycemia. Antioxidants are efficacious in reducing diabetic complications. The antioxidants produced biologically fall short, hence external supplements are required. In this review, the authors have discussed the relationship between oxidative stress in DM and the advantages of antioxidant supplements in controlling blood glucose levels and also in deaccelerating the complications related to DM.

Failure to repair endogenous DNA damage in β-cells causes adult-onset diabetes in mice.

Age is the greatest risk factor for the development of type 2 diabetes mellitus (T2DM). Age-related decline in organ function is attributed to the accumulation of stochastic damage, including damage to the nuclear genome. Islets of T2DM patients display increased levels of DNA damage. However, whether this is a cause or consequence of the disease has not been elucidated. Here, we asked if spontaneous, endogenous DNA damage in β-cells can drive β-cell dysfunction and diabetes, via deletion of Ercc1, a key DNA repair gene, in β-cells. Mice harboring Ercc1-deficient β-cells developed adult-onset diabetes as demonstrated by increased random and fasted blood glucose levels, impaired glucose tolerance, and reduced insulin secretion. The inability to repair endogenous DNA damage led to an increase in oxidative DNA damage and apoptosis in β-cells and a significant loss of β-cell mass. Using electron microscopy, we identified β-cells in clear distress that showed an increased cell size, enlarged nuclear size, reduced number of mature insulin granules, and decreased number of mitochondria. Some β-cells were more affected than others consistent with the stochastic nature of spontaneous DNA damage. Ercc1-deficiency in β-cells also resulted in loss of β-cell function as glucose-stimulated insulin secretion and mitochondrial function were impaired in islets isolated from mice harboring Ercc1-deficient β-cells. These data reveal that unrepaired endogenous DNA damage is sufficient to drive β-cell dysfunction and provide a mechanism by which age increases the risk of T2DM.

The Impact of Taurine on Obesity-Induced Diabetes Mellitus: Mechanisms Underlying Its Effect.

This review explores the potential benefits of taurine in ameliorating the metabolic disorders of obesity and type 2 diabetes (T2D), highlighting the factors that bridge these associations. Relevant articles and studies were reviewed to conduct a comprehensive analysis of the relationship between obesity and the development of T2D and the effect of taurine on those conditions. The loss of normal β-cell function and development of T2D are associated with obesity-derived insulin resistance. The occurrence of diabetes has been linked to the low bioavailability of taurine, which plays critical roles in normal β-cell function, anti-oxidation, and anti-inflammation. The relationships among obesity, insulin resistance, β-cell dysfunction, and T2D are complex and intertwined. Taurine may play a role in ameliorating these metabolic disorders through different pathways, but further research is needed to fully understand its effects and potential as a therapeutic intervention.

Inter-organ crosstalk during development and progression of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is characterized by tissue-specific insulin resistance and pancreatic β-cell dysfunction, which result from the interplay of local abnormalities within different tissues and systemic dysregulation of tissue crosstalk. The main local mechanisms comprise metabolic (lipid) signalling, altered mitochondrial metabolism with oxidative stress, endoplasmic reticulum stress and local inflammation. While the role of endocrine dysregulation in T2DM pathogenesis is well established, other forms of inter-organ crosstalk deserve closer investigation to better understand the multifactorial transition from normoglycaemia to hyperglycaemia. This narrative Review addresses the impact of certain tissue-specific messenger systems, such as metabolites, peptides and proteins and microRNAs, their secretion patterns and possible alternative transport mechanisms, such as extracellular vesicles (exosomes). The focus is on the effects of these messengers on distant organs during the development of T2DM and progression to its complications. Starting from the adipose tissue as a major organ relevant to T2DM pathophysiology, the discussion is expanded to other key tissues, such as skeletal muscle, liver, the endocrine pancreas and the intestine. Subsequently, this Review also sheds light on the potential of multimarker panels derived from these biomarkers and related multi-omics for the prediction of risk and progression of T2DM, novel diabetes mellitus subtypes and/or endotypes and T2DM-related complications.

Periostin deficiency attenuates kidney fibrosis in diabetic nephropathy by improving pancreatic β-cell dysfunction and reducing kidney EMT

Diabetic nephropathy (DN) is associated with kidney fibrosis. A previous study revealed that periostin (POSTN) contributes to kidney fibrosis. This study examined the role of POSTN in DN. The urinary concentrations of POSTN and TNC increased according to the severity of DN in human samples. Streptozotocin (STZ) was administered after unilateral nephrectomy (UNXSTZ) to induce DN in wild-type and Postn-null mice. Four experimental groups were generated: wild-typeham (WT Sham), wild-type UNXSTZ (WT STZ), Postn-null Sham (KO Sham), and Postn-null UNXSTZ (KO STZ). After 20 weeks, the KO STZ group had lower levels of urine albumin excretion, glomerular sclerosis, and interstitial fibrosis than those of the WT STZ group. Additionally, the KO STZ group had lower expression of fibrosis markers, including TNC. The KO STZ group showed better glucose regulation than the WT STZ model. Furthermore, the KO STZ group exhibited significantly preserved pancreatic islet integrity and insulin expression. HK-2 cells were used to observe the aggravation of fibrosis caused by POSTN under TGF-β conditions. We stimulated INS-1 cells with streptozotocin and evaluated the viability of these cells. The anti-POSTN antibody treatment of INS-1 cells with streptozotocin resulted in higher cell viability than that with treatment with streptozotocin alone. The absence of POSTN in DN contributes to renal fibrosis alleviation by improving pancreatic β-cell function. Additionally, there is an association between POSTN and TNC.

Slc12a2 loss in insulin-secreting β-cells links development of overweight and metabolic dysregulation to impaired satiation control of feeding.

Male mice lacking the Na+-K+-2Cl- cotransporter Slc12a2 (Nkcc1) specifically in insulin-secreting β-cells (Slc12a2βKO) have reduced β-cell mass and mild β-cell secretory dysfunction associated with overweight, glucose intolerance, insulin resistance, and metabolic abnormalities. Here, we confirmed and extended previous results to female Slc12a2βKO mice, which developed a similar metabolic syndrome-like phenotype as males, albeit milder. Notably, male and female Slc12a2βKO mice developed overweight without consuming excess calories. Analysis of the feeding microstructure revealed that young lean Slc12a2βKO male mice ate meals of higher caloric content and at a relatively lower frequency than normal mice, particularly during the night. In addition, overweight Slc12a2βKO mice consumed significantly larger meals than lean mice. Therefore, the reduced satiation control of feeding precedes the onset of overweight and is worsened in older Slc12a2βKO mice. However, the time spent between meals remained intact in lean and overweight Slc12a2βKO mice, indicating conserved satiety responses to ad libitum feeding. Nevertheless, satiety was intensified during and after refeeding only in overweight males. In lean females, satiety responses to refeeding were delayed relative to age- and body weight-matched control mice but normalized in overweight mice. Since meal size did not change during refeeding, these data suggested that the satiety control of eating after fasting is impaired in lean Slc12a2βKO mice before the onset of overweight and independently of their reduced satiation responses. Therefore, our results support the novel hypothesis that reduced satiation precedes the onset of overweight and the development of metabolic dysregulation.NEW & NOTEWORTHY Obesity, defined as excess fat accumulation, increases the absolute risk for metabolic diseases. Although obesity is usually attributed to increased food intake, we demonstrate that body weight gain can be hastened without consuming excess calories. In fact, impaired meal termination control, i.e., satiation, is detectable before the development of overweight in an animal model that develops a metabolic syndrome-like phenotype.

Astragalus polysaccharide restores insulin secretion impaired by lipopolysaccharides through the protein kinase B /mammalian target of rapamycin/glucose transporter 2 pathway

BackgroundLipopolysaccharide (LPS)-induced dysfunction of pancreatic β-cells leads to impaired insulin (INS) secretion. Astragalus polysaccharide (APS) is a bioactive heteropolysaccharide extracted from Astragalus membranaceus and is a popular Chinese herbal medicine. This study aimed to elucidate the mechanisms by which APS affects INS secretion from β-cells under LPS stress.MethodsRat insulinoma (INS-1) cells were treated with LPS at a low, medium, or high concentration of APS. Glucose-stimulated insulin secretion (GSIS) was evaluated using an enzyme-linked immunosorbent assay (ELISA). Transcriptome sequencing was used to assess genome-wide gene expression. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to determine the signaling pathways affected by APS. Quantitative reverse transcription–polymerase chain reaction (qRT-PCR) was performed to evaluate the gene expression of glucose transporter 2 (GLUT2), glucokinase (GCK), pancreatic duodenal homeobox-1 (PDX-1), and INS. Western blot analysis was used to detect the protein expression of phosphorylated protein kinase B (p-Akt), total Akt (t-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), total mTOR (t-mTOR), and GLUT2.ResultsLPS decreased GLUT2, GCK, PDX-1, and INS expression and reduced GSIS. These LPS-induced decreases in gene expression and GSIS were restored by APS treatment. In addition, transcriptome sequencing in combination with KEGG enrichment analysis revealed changes in the INS signaling pathway following APS treatment. LPS decreased p-Akt and p-mTOR expression, which was restored by APS treatment. The restorative effects of APS on GSIS as well as on the expression of GLUT2, GCK, PDX-1, and INS were abolished by treatment with the Akt inhibitor MK2206 or the mTOR inhibitor rapamycin (RPM).ConclusionsAPS restored GSIS in LPS-stimulated pancreatic β-cells by activating the Akt/mTOR/GLUT2 signaling pathway.

THU317 Study Of Risk Factors For The Development Of Various Subtypes Of Gestational Diabetes Mellitus

Abstract Disclosure: N.I. Volkova: None. I. Davidenko: None. J. Sorokina: None. J. Degtyareva: None. V. Kovalenko: None. Abstract: Gestational diabetes mellitus (GDM) poses a threat to the health of the mother and a high risk of perinatal complications, however, achieving normoglycemia will significantly improve the prognosis in such pregnant women. One of the factors determining the most optimal management tactics is based on the pathophysiological mechanism of GDM formation. According to modern concepts, the processes associated with pancreatic β-cell dysfunction, insulin resistance (IR) or a combination of these factors may prevail in the basis of the formation of GDM, forming various subtypes of GDM. Identification of risk factors for the development of various subtypes of GDM in pregnant women may be important for timely verification and selection of therapy. In order to study risk factors for the development of various subtypes of GDM 130 pregnant women were examined without a history of carbohydrate metabolism disorders. The subjects were divided into: group I - 45 pregnant women with GDM and β-cell dysfunction, group II - 43 pregnant women with GDM and IR, group III - 42 pregnant women without GDM (control). The risk factors, whose contribution to the development of GDM is already well known, and the factors that, in our opinion, can influence the development of GDM, were studied. We conducted a full clinical examination. Carbohydrate metabolism was assessed according to fasting venous plasma glucose, oral glucose tolerance test with 75 g of glucose. The function of β-cells was evaluated and IR was detected. According to the Matsuda index, subtypes of GDM were identified. Statistical processing was carried out using comparative analysis. The data are presented in the form of medians and interquartile intervals of quantitative indicators in the groups, the data were considered reliable at p&amp;lt;0.05. Pregnant women with GDM and IR are characterized by an older age at the onset of pregnancy [32 (29; 35) y.o, p = 0.009], a large body weight [84 (76; 91) kg, p &amp;lt;0.001], signs of acanthosis nigricans (14%, p=0.03), weight of 1 child at birth (p= 0.047), rarer intake of folic acid (p&amp;lt; 0.001), low physical activity before pregnancy (p&amp;lt;0.001). Patients with GDM and β-cell dysfunction are characterized by a younger age [29 (27; 31) y.o.; p= 0.02], lower body weight [59.8 (55.9; 76.4) kg, p &amp;lt;0.001] and BMI [21.9 (20.7; 26.6) kg/m2, p &amp;lt;0.001], absence of regular MC before pregnancy (93%, p=0.02) and more frequent use of folic acid (p=0.048). Both groups of patients were characterized by the absence of pre-gravidar preparation (p=0.03).Thus, we have studied known risk factors for GDM, as well as factors that could potentially cause the development of hyperglycemia during pregnancy. And it turned out that in addition to the influence of the patient's age and body weight before pregnancy, an important contribution to the development of various subtypes of GDM is provided by low physical activity and lack of pregravidar preparation. Presentation: Thursday, June 15, 2023

THU279 Long duration Of CFTR Modulators Consistently Improve Glucose Metabolism Parameters In Patients With Cystic Fibrosis

Abstract Disclosure: A. Cohen: None. A. Mass: None. D. Zangen: None. M. Cohen-Cymberknoh: None. Background: Impaired glycemic control and consequently Cystic fibrosis Related Diabetes (CFRD) due to gradual pancreatic β-cell dysfunction is a common complication (upto 50% in adults) in patients with cystic fibrosis (CF.) The novel use of CFTR modulators (CFTRm), improve pulmonary function and reduce disease exacerbations. Data regarding the long-term effect of CFTRm on glycemic control is limited. In this observational-retrospective study, we evaluate the effect of CFTRm on the classical pathophysiological deterioration in glucose tolerance in patients with CF. Methods and Results: 15 patients with CF (ages 13-37) treated with CFTRm were followed by routine Oral Glucose Tolerance Test (OGTT). OGTT Results of Pre and 3-81 months (mean 28) post initiation of CFTRm therapy were compared and also classified to 4 classic categories: normal glucose tolerance (NGT), indeterminate (INDET), impaired glucose tolerance (IGT) and diabetes (CFRD). The end point of OGTT at 120 minutes significantly improved post CFTRm therapy being 159.7 (80-419.4) compared to 130.4 (54-286) pre-CFTRm (p = 0.047). Regarding the categories sub-classification of patients: Two patients with CFRD improved after CFTRm therapy to NGT or INDET. 2 with INDET pre-therapy improved to NGT post therapy.Of 3 patients with IGT, 2 improved to NGT or INDET and 1 worsened to CFRD. Out of the 6 patients who had NGT pre CFTRm therapy, 4 remained NGT, one worsened to INDET, and one became CFRD. Conclusions: This is the first and largest study so far demonstrating consistent significant improvement in glycemic control in CFRD after CFTRm treatment of at least 3 months duration. Treatment seems to delay and possibly reverse the deterioration in glycemic control that is typical to the natural history of patients with cystic fibrosis. Larger studies are indicated but awareness to the current findings may prevent hypoglycemic events while staying on a fixed insulin dose while on CFTRm therapy. Presentation: Thursday, June 15, 2023

A high throughput screen for pharmacological inhibitors of the carbohydrate response element

A central regulator of metabolism, transcription factor carbohydrate response element binding protein (ChREBP) senses and responds to dietary glucose levels by stimulating the transcription of glycolytic and lipogenic enzymes. Genetic depletion of ChREBP rescues β-cell dysfunction arising from high glucose levels, suggesting that inhibiting ChREBP might represent an attractive therapeutic approach to manage diabetes and other metabolic diseases. However, the molecular mechanisms governing ChREBP activation are poorly understood and chemical tools to probe the cellular activity of ChREBP are lacking. Here, we report a high-throughput pharmacological screen in INS-1E β-cells that identified novel inhibitors of ChREBP-driven transcription at carbohydrate response element sites, including three putative covalent inhibitors and two likely non-covalent chemical scaffolds. This work affords a pharmacological toolkit to help uncover the signaling logic controlling ChREBP activation and may ultimately reveal potential therapeutic approaches for treating metabolic disease.

Urokinase-type plasminogen activator receptor as a predictive marker for cardiac disease among type 2 diabetic patients

Abstract Background: Type 2 diabetes mellitus is a progressive and chronic disease manifested by β-cell dysfunction and improved insulin resistance. Higher levels of urokinase-type plasminogen activator receptors have been found to predict morbidity and mortality among diabetic patients with cardiac disease. Objective: This study aims to explore the role of serum urokinase-type plasminogen activator receptor levels as a prognostic marker among type 2 diabetic Iraqi patients. Materials and Methods: A total of 70 type 2 diabetic patients (40 male and 30 female) (mean age: 46.20 ± 7.56 years) participated in this study; 35 patients were with cardiovascular disease and 35 were without cardiovascular disease; their ages range were 40–55 years. They were collected from Baghdad Teaching Hospital/Medical City, Baghdad, Iraq through the period from October 2022 to February 2023. Moreover, 30 individuals who were apparent healthy were selected as control group. Results: There was significant increase in blood glucose, lipid levels with their ratios, and C-reactive protein in diabetic patients as compared to the control. Also, the present results reveal high levels of urokinase-type plasminogen activator receptor (2500.72 ± 12.36 vs. 2255.32 ± 10.15) ρg/mL with OR = 1.80, 95% CI: 1.2, and P = 0.0001 in type 2 diabetic patients with and without cardiovascular disease, respectively, as compared to healthy control (229.00 ± 14.48) ρg/mL. Moreover, this study reveals that female patients had higher levels of serum urokinase-type plasminogen activator receptor as compared to the male patients. Conclusion: It demonstrated that urokinase-type plasminogen activator receptor levels reliably predict morbidity among type 2 diabetic patients presenting with symptoms suggestive of cardiovascular disease.

Inhibition of hyaluronan synthesis prevents β-cell loss in obesity-associated type 2 diabetes

Pancreatic β-cell dysfunction and death are central to the pathogenesis of type 2 diabetes (T2D). We identified a novel role for the inflammatory extracellular matrix polymer hyaluronan (HA) in this pathophysiology. Low concentrations of HA were present in healthy pancreatic islets. However, HA substantially accumulated in cadaveric islets of T2D patients and islets of the db/db mouse model of T2D in response to hyperglycemia. Treatment with 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, or the deletion of the main HA receptor CD44, preserved glycemic control and insulin concentrations in db/db mice despite ongoing weight gain, indicating a critical role for this pathway in T2D pathogenesis. 4-MU treatment and the deletion of CD44 likewise preserved glycemic control in other settings of β-cell injury including streptozotocin treatment and islet transplantation. Mechanistically, we found that 4-MU increased the expression of the apoptosis inhibitor survivin, a downstream transcriptional target of CD44 dependent on HA/CD44 signaling, on β-cells such that caspase 3 activation did not result in β-cell apoptosis. These data indicated a role for HA accumulation in diabetes pathogenesis and suggested that it may be a viable target to ameliorate β-cell loss in T2D. These data are particularly exciting, because 4-MU is already an approved drug (also known as hymecromone), which could accelerate translation of these findings to clinical studies.

Deletion of Ascl1 in pancreatic β-cells improves insulin secretion, promotes parasympathetic innervation, and attenuates dedifferentiation during metabolic stress

ObjectiveASCL1, a pioneer transcription factor, is essential for neural cell differentiation and function. Previous studies have shown that Ascl1 expression is increased in pancreatic β-cells lacking functional KATP channels or after feeding of a high fat diet (HFD) suggesting that it may contribute to the metabolic stress response of β-cells. MethodsWe generated β-cell-specific Ascl1 knockout mice (Ascl1βKO) and assessed their glucose homeostasis, islet morphology and gene expression after feeding either a normal diet or HFD for 12 weeks, or in combination with a genetic disruption of Abcc8, an essential KATP channel component. ResultsAscl1 expression is increased in response to both a HFD and membrane depolarization and requires CREB-dependent Ca2+ signaling. No differences in glucose homeostasis or islet morphology were observed in Ascl1βKO mice fed a normal diet or in the absence of KATP channels. However, male Ascl1βKO mice fed a HFD exhibited decreased blood glucose levels, improved glucose tolerance, and increased β-cell proliferation. Bulk RNA-seq analysis of islets from Ascl1βKO mice from three studied conditions showed alterations in genes associated with the secretory function. HFD-fed Ascl1βKO mice showed the most extensive changes with increased expression of genes necessary for glucose sensing, insulin secretion and β-cell proliferation, and a decrease in genes associated with β-cell dysfunction, inflammation and dedifferentiation. HFD-fed Ascl1βKO mice also displayed increased expression of parasympathetic neural markers and cholinergic receptors that was accompanied by increased insulin secretion in response to acetylcholine and an increase in islet innervation. ConclusionsAscl1 expression is induced by stimuli that cause Ca2+-signaling to the nucleus and contributes in a multifactorial manner to the loss of β-cell function by promoting the expression of genes associated with cellular dedifferentiation, attenuating β-cells proliferation, suppressing acetylcholine sensitivity, and repressing parasympathetic innervation of islets. Thus, the removal of Ascl1 from β-cells improves their function in response to metabolic stress.

Modulation of PPAR-γ, SREBP-1c and inflammatory mediators by luteolin ameliorates β-cell dysfunction and renal damage in a rat model of type-2 diabetes mellitus.

Natural products have been recommended as a complementary therapy for type 2 diabetes mellitus (T2DM) due to constraints of safety and tolerability of existing anti-diabetic agents. Luteolin exhibits anti-diabetic and anti-inflammatory effects. Hence, the impact of luteolin on glucose homoeostasis and organ damage was investigated in high-fat diet (HFD) and streptozotocin (STZ) induced T2DM in rats. Male Wistar rats were maintained on HFD (provided 55% energy as fat) for 10days. Subsequently, a single dose of 40mg/kg STZ was injected intraperitoneally on the 11th day. Seventy-two hours after STZ administration, diabetic rats with established hyperglycemia (fasting serum glucose > 200mg/dL) were randomized into different groups having six rats each and orally administered either 0.5% hydroxy propyl cellulose or pioglitazone (10mg/kg) or luteolin (50mg/kg or 100mg/kg) once daily for 28days, while continuing HFD for respective groups. Luteolin significantly reduced hyperglycaemia, homoeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) levels, and improved hypoinsulinemia and HOMA of b-cell function (HOMA-B) in a dose-dependent manner. Increased TNF-α, IL-6 and NFκB levels in diabetic rats were significantly regulated. Additionally, luteolin significantly augmented PPAR-γ expression while attenuating sterol regulatory element binding protein-1c (SREBP-1c) expression. Histopathological scrutiny validated that luteolin effectively attenuated HFD-STZ-induced injury in pancreatic β-cells and kidneys to near normalcy. Our study showed that luteolin ameliorated hyperglycemia and improved hypoinsulinemia, β-cell dysfunction, and renal impairment in HFD-STZ-induced diabetic rats by attenuating inflammation and dysregulated cytokine secretion through modulation of PPAR-γ, TNF-α, IL-6 and NF-kB expression and down-regulation of SREBP-1c.

IL-33 promotes pancreatic β-cell survival and insulin secretion under diabetogenic conditions through PPARγ

Pancreatic β-cell dysfunction plays a vital role in the development of diabetes. IL-33 exerts anti-diabetic effects via its anti-inflammatory properties and has been demonstrated to increase insulin secretion in animal models. However, IL-33, as a pleiotropic cytokine, may also exert a deleterious effect on β-cells, which has not been rigorously studied. In the present study, we found that IL-33 promoted cell survival and insulin secretion in MIN6 (a mouse pancreatic β-cell line) cells under diabetogenic conditions. IL-33 increased the expression of its receptor ST2 and the transcription factor PPARγ, whereas PPARγ inhibition impaired IL-33-mediated β-cell survival and insulin release. IL-33 did not repress the expression of pro-inflammatory mediators, including Tf, Icam1, Cxcl10, and Il1b, whereas it significantly reduced the expression of Ccl2. IL-33 decreased TNF-α secretion and increased IL-10 secretion; these effects were completely reversed by PPARγ inhibition. IL-33 increased glucose uptake and expression of Glut2. It upregulated the expression of glycolytic enzyme genes, namely, Pkm2, Hk2, Gpi1, and Tpi, and downregulated the expression of Gck, Ldha, and Mct4. However, it did not alter hexokinase activity. Moreover, IL-33 increased the number and activity of mitochondria, accompanied by increased ATP production and reduced accumulation of ROS. IL-33 upregulated the expression of PGC-1α and cytochrome c, and mitochondrial fission- and fusion-associated genes, including Mfn1, Mfn2, and Dnm1l. IL-33-mediated mitochondrial homeostasis was partially reversed by PPARγ inhibition. Altogether, IL-33 protects β-cell survival and insulin secretion that could be partially driven via PPARγ, which regulates glucose uptake and promotes mitochondrial function and anti-inflammatory responses.

M6 A mRNA methylation: Biological features, mechanisms, and therapeutic potentials in type 2 diabetes mellitus.

As the most common internal post-transcriptional RNA modification in eukaryotic cells, N6-methyladenosine (m6 A) performs a dynamic and reversible role in a variety of biological processes mediated by methyltransferases (writers), demethylases (erasers), and m6 A binding proteins (readers). M6 A methylation enables transcriptome conversion in different signals that regulate various physiological activities and organ development. Over the past few years, emerging studies have identified that mRNA m6 A regulators defect in β-cell leads to abnormal regulation of the target mRNAs, thereby resulting in β-cell dysfunction and loss of β-cell identity and mass, which are strongly associated with type 2 diabetes mellitus (T2DM) pathogenesis. Also, mRNA m6 A modification has been implicated with insulin resistance in muscles, fat, and liver cells/tissues. In this review, we elaborate on the biological features of m6 A methylation; provide a comprehensive overview of the underlying mechanisms that how it controls β-cell function, identity, and mass as well as insulin resistance; highlight its connections to glucose metabolism and lipid metabolism linking to T2DM; and further discuss its role in diabetes complications and its therapeutic potentials for T2DM diagnosis and treatment.

Endoplasmic reticulum stress in pancreatic β cells induces incretin desensitization and β-cell dysfunction via ATF4-mediated PDE4D expression.

Pancreatic β-cell dysfunction and eventual loss are key steps in the progression of type 2 diabetes (T2D). Endoplasmic reticulum (ER) stress responses, especially those mediated by the protein kinase RNA-like ER kinase and activating transcription factor 4 (PERK-ATF4) pathway, have been implicated in promoting these β-cell pathologies. However, the exact molecular events surrounding the role of the PERK-ATF4 pathway in β-cell dysfunction remain unknown. Here, we report our discovery that ATF4 promotes the expression of PDE4D, which disrupts β-cell function via a downregulation of cAMP signaling. We found that β-cell-specific transgenic expression of ATF4 led to early β-cell dysfunction and loss, a phenotype that resembles accelerated T2D. Expression of ATF4, rather than C/EBP homologous protein (CHOP), promoted PDE4D expression, reduced cAMP signaling, and attenuated responses to incretins and elevated glucose. Furthermore, we found that β-cells of leptin receptor-deficient diabetic (db/db) mice had elevated nuclear localization of ATF4 and PDE4D expression, accompanied by impaired β-cell function. Accordingly, pharmacological inhibition of the ATF4 pathway attenuated PDE4D expression in the islets and promoted incretin-simulated glucose tolerance and insulin secretion in db/db mice. Finally, we found that inhibiting PDE4 activity with selective pharmacological inhibitors improved β-cell function in both db/db mice and β-cell-specific ATF4 transgenic mice. In summary, our results indicate that ER stress causes β-cell failure via ATF4-mediated PDE4D production, suggesting the ATF4-PDE4D pathway could be a therapeutic target for protecting β-cell function during the progression of T2D.NEW & NOTEWORTHY Endoplasmic reticulum stress has been implied to cause multiple β-cell pathologies during the progression of type 2 diabetes (T2D). However, the precise molecular events underlying this remain unknown. Here, we discovered that elevated ATF4 activity, which was seen in T2D β cells, attenuated β-cell proliferation and impaired insulin secretion via PDE4D-mediated downregulation of cAMP signaling. Additionally, we demonstrated that pharmacological inhibition of the ATF4 pathway or PDE4D activity alleviated β-cell dysfunction, suggesting its therapeutic usefulness against T2D.