Protein kinase C epsilon (PKCε) plays a causative role in the development of glucose intolerance, and is a potential target for the treatment of type 2 diabetes. Here, we examined the effects of the PKCε inhibitor CIDD-0150612 (CP612) on insulin action in palmitate-treated HepG2 hepatocytes in vitro and on glucose homeostasis in fat-fed mice in vivo.

HepG2 cells were treated with palmitate and CP612 and stimulated with insulin. Insulin signalling was examined by immunoblotting and glucose incorporation into glycogen was measured using glucose tracer. Mice were fed a high-fat diet and treated with CP612 prior to glucose tolerance tests and tissue harvest. Proteomic analysis of liver was carried out by mass spectrometry.

CP612 promoted Akt phosphorylation in a highly insulin-dependent manner and reversed the inhibition of insulin-stimulated Akt phosphorylation and glucose incorporation into glycogen by palmitate. Fat-fed mice treated with CP612 had reduced fat mass, but not lean mass, compared with vehicle-treated littermates. Mice treated acutely with CP612 exhibited elevated fasting blood glucose. However, mice studied 24h after the last dose had lower fasting glucose and improved glucose tolerance with a lower insulin excursion. Proteomic analysis of liver from CP612-treated fat-fed mice indicated a reduction in gluconeogenic gene expression and decreased phosphorylation of the transcription factor Foxk1.

The PKCε inhibitor CP612 had beneficial effects on insulin action in hepatocytes and on fat mass and glucose homeostasis in mice. Because certain effects were not previously observed in genetically PKCε-deficient mice, off-target effects may be partly responsible.

Diabetes is a global health burden characterised by incremental beta cell loss. Islet transplantation is a recognised treatment for individuals with type 1 diabetes and hypoglycaemia unawareness but broader application is constrained by limited islet survival and function post-transplantation. The underlying molecular mechanisms that induce beta cell dysfunction and demise remain unclear, and therapeutic agents that protect against cellular loss and maintain insulin secretion are in demand as potential treatment options. CD47 is a cell surface protein implicated in cellular stress responses but its role in beta cell function remains relatively unexplored. We hypothesised that modulating CD47 expression would demonstrate a cytoprotective effect in beta cells.

We used primary murine islets with/without genetic deletion of CD47, as well as human islets and MIN6 cells subjected to pharmacological disruption of CD47 signalling (siRNA or blocking antibody). Metabolic stress was induced in cells by exposure to hypoxia, hyperglycaemia or thapsigargin, and markers of the unfolded protein response, cell survival and insulin secretory function were assessed. Human pancreases from individuals with and without diabetes were examined for evidence of CD47 signalling.

Expression of CD47 and its high affinity ligand thrombospondin-1 (TSP1) was robustly upregulated by exogenous stressors. Limiting CD47 signalling improved markers of senescence, apoptosis, endoplasmic reticulum stress, unfolded protein response, self-renewal and autophagy, and maintained insulin secretory responses. We also found concurrent upregulated expression of CD47 and senescence markers in the endocrine pancreas of aged donors and those with type 2 diabetes. Both CD47 and TSP1 expression were increased in pancreases of humans with type 1 diabetes, as were plasma levels of TSP1.

Our study provides key insights into the essential role of CD47 as a novel regulator of islet dysfunction, regulating cytoprotective responses to stress. CD47 may contribute to beta cell damage during the development of diabetes and failure of islet transplant function. Therefore, limiting CD47 activation may be a potential therapeutic tool in conditions where islet function is inadequate.

Under insulin-resistant conditions, such as obesity, pancreatic β cells adaptively proliferate and secrete more insulin to prevent blood glucose elevation. We previously reported hepatic ERK activation during obesity development to stimulate a neuronal relay system, consisting of afferent splanchnic nerves from the liver and efferent vagal nerves to the pancreas, thereby triggering adaptive β cell proliferation. However, the mechanism linking obesity with the interorgan system originating in hepatic ERK activation remains unclear. Herein, we clarified that colonic inflammation promotes β cell proliferation through this interorgan system from the liver to the pancreas. First, dextran sodium sulfate (DSS) treatment induced colonic inflammation and hepatic ERK activation as well as β cell proliferation, all of which were suppressed by blockades of the neuronal relay system by several approaches. In addition, treatment with anti-lymphocyte Peyer's patch adhesion molecule-1 (anti-LPAM1) antibody suppressed β cell proliferation induced by DSS treatment. Importantly, high-fat diet (HFD) feeding also elicited colonic inflammation, and its inhibition by anti-LPAM1 antibody administration suppressed hepatic ERK activation and β cell proliferation induced by HFD. Thus, colonic inflammation triggers adaptive β cell proliferation via the interorgan mechanism originating in hepatic ERK activation. The present study revealed a potentially novel role of the gastrointestinal tract in the maintenance of β cell regulation.

Type 2 diabetes is partially caused by insufficient pancreatic β cell insulin secretion. Previous studies show therapeutic ultrasound (TUS) evokes insulin secretion from β cells as a potential treatment for type 2 diabetes; however, how β cells sense TUS and the broad effects of this treatment on cells remain unknown. Here, we identified mechanosensitive channels (MSC) expressed by β cells and TUS-mediated gene downregulation and reactive oxygen species (ROS) formation.

For all experiments, 1 W/cm2 intensity and 800 kHz frequency TUS were continuously applied for 5 minutes with a 100% duty cycle. RNA and protein isolation of human pancreatic islets and the rat insulinoma INS 832/13 cell line were used for rtqPCR and western blot, respectively, to determine MSC expression. INS cells treated with MSC agonists and/or antagonists during TUS were visualized via fluorescent microscopy to track ROS formation. Using the same treatments, rtPCR analysis of INS insulin and IAPP encoding insulin and islet amyloid polypeptide (IAPP), respectively, was performed. TUS treatments were replicated in rats from which pancreatic sections were collected for immunohistochemistry analysis.

We found the expression of TRPV2, TRPV5, and piezo1 in human islets and INS cells. TUS increased ROS formation in INS cells compared to sham-treated controls (P < .0001); however, modulation of MSC mitigated this effect (P < .001). TUS decreased the expression of the genes insulin and IAPP in INS cells compared to sham-treated controls (P < .001 and P < .01, respectively); however, complete MSC inhibition reversed this effect (P < .01 and P < .05, respectively). In our rat model, pancreatic and duodenal homeobox 1 (PDX1) expression was decreased by TUS compared to sham-treated controls (*P < .05); however, TUS did not decrease insulin or IAPP levels (P > .05).

We report the expression of TRPV2, TRPV5, and piezo1 in human and rodent pancreatic β cells that are implicated in both TUS-mediated ROS formation and the downregulation of essential β cell genes.

A disintegrin and metalloproteinase Domain 9 (ADAM9) is a zinc-dependent proteinase involved in various biological processes. However, its role in the pathophysiology of metabolic syndrome remains unclear, and studies exploring the association between ADAM9 polymorphisms and metabolic traits are limited. In this study, we investigated the potential link between ADAM9 variants and metabolic syndrome traits in a cohort of adult participants from Kuwait. Using a genome-wide association study (GWAS), followed by a replication study, we identified two ADAM9 variants-ADAM9-E76K (rs61753672) and ADAM9-P750L (rs144750648)-that were associated with various metabolic traits. The replication phase confirmed the association of ADAM9-P750L with HbA1c levels and revealed new associations with systolic blood pressure, waist-to-hip ratio, fasting blood glucose, triglycerides, and cholesterol. Functional analysis showed that both variants exhibited reduced proteolytic activity, potentially contributing to the pathogenesis of Type 2 diabetes. These findings suggest that ADAM9 variants may play a significant role in metabolic health and diabetes risk.

The natural sweeteners of steviol glycosides (SGs) have been widely used as a substitute for sugar due to their high sweetness, low-calorie properties, and potential health benefits. Some studies reported that SGs could regulate glucose metabolism and prevent Type 2 diabetes mellitus (T2DM); however, the detailed mechanisms remained further elucidated. Therefore, in this review, we aimed to systematically summarize the effects and mechanisms of SGs on glucose metabolism based on evidence from preclinical studies. We searched PubMed and Web of Science (up to March 31, 2024), and included a total of 40 animal and 5 cell studies for review. Results showed that SGs could improve glucose metabolism by enhancing insulin secretion, simulating insulin effects, improving insulin resistance, advancing key enzyme activities, or regulating gut microbiota. To conclude, if further validated in clinical trials and population studies, the sugar substitute of SGs may serve as a potential nutritional strategy for effective prevention and treatment of T2DM.

Cardiovascular diseases are a major comorbidity factor in patients with type 2 diabetes and a leading cause of death among them. Yet, mechanistically, how impairment in pancreatic islets alters cardiac function under different metabolic states remains largely unknown. Here, we investigate the role of the G-protein-coupled receptor kinase 2 (GRK2) in regulating islet adaptations to an obesogenic diet and its impact on myocardial function. Using a novel inducible β-cell-specific GRK2 knockout mouse model (βGRK2KO), we establish that loss of adult β-cell GRK2 delays metabolic islet maladaptation, protecting the heart against obesity-induced cardiac dysfunction. βGRK2KO are more insulin-sensitive than control mice and have improved cardiac function and myocardial morphology. Thus, genetic ablation of GRK2 in adult β-cells during an obesogenic diet play a cardioprotective role. This study prompts a novel therapeutic window for GRK2 intervention strategies for diabetic patients prone to cardiac dysfunction.

Significance: Type 2 diabetes as a world-wide epidemic is characterized by the insulin resistance concomitant to a gradual impairment of β-cell mass and function (prominently declining insulin secretion) with dysregulated fatty acids (FAs) and lipids, all involved in multiple pathological development. Recent Advances: Recently, redox signaling was recognized to be essential for insulin secretion stimulated with glucose (GSIS), branched-chain keto-acids, and FAs. FA-stimulated insulin secretion (FASIS) is a normal physiological event upon postprandial incoming chylomicrons. This contrasts with the frequent lipotoxicity observed in rodents. Critical Issues: Overfeeding causes FASIS to overlap with GSIS providing repeating hyperinsulinemia, initiates prediabetic states by lipotoxic effects and low-grade inflammation. In contrast the protective effects of lipid droplets in human β-cells counteract excessive lipids. Insulin by FASIS allows FATP1 recruitment into adipocyte plasma membranes when postprandial chylomicrons come late at already low glycemia. Future Directions: Impaired states of pancreatic β-cells and peripheral organs at prediabetes and type 2 diabetes should be revealed, including the inter-organ crosstalk by extracellular vesicles. Details of FA/lipid molecular physiology are yet to be uncovered, such as complex phenomena of FA uptake into cells, postabsorptive inactivity of G-protein-coupled receptor 40, carnitine carrier substrate specificity, the role of carnitine-O-acetyltransferase in β-cells, and lipid droplet interactions with mitochondria. Antioxid. Redox Signal. 42, 566-622.

Over-nutrition and lipid metabolic abnormalities are correlated with obesity and type 2 diabetes mellitus (T2DM). Individuals with long-term hyperglycemia and dyslipidemia are susceptible to life-threatening complications such as atherosclerosis. Excess amounts of modified low density lipoprotein (mLDL) attract circulating monocytes to resident at arterial wall and differentiate into pro-inflammatory M1 macrophages. M1 cells uptake mLDL through scavenger receptors-mediated endocytosis, leading to increased lipids influx, cholesterol accumulation and foam cell formation. Besides, macrophages are attracted and infiltrated into the hypertrophic adipose tissue to mediate microenvironmental lipid metabolism. Our previous studies demonstrate that anti-inflammatory interleukin-4 (IL-4) regulates lipid metabolism by inhibiting lipid accumulation and promoting lipolysis of mature adipocytes. The effects of IL-4-polarized M2 macrophages on 3T3-L1 adipogenesis and macrophage-adipocyte interaction were explored in the present study. Our results showed lipid deposits and lipid droplets (LDs)-anchored perilipin of adipocytes cultured in IL-4-polarized M2-conditioned medium (M2-CM) were decreased, while adipogenesis-driving transcription factors and critical lipid metabolic enzymes remained unaffected. It indicates that M2-secreted mediators down-regulate lipid deposits and LDs formation in late adipogenic phase rather than interfering early programming phase and lipid synthesis machinery. In addition, IL-4 reduced intracellular lipid loads by up-regulating cholesterol efflux ATP-binding cassette transporter A1 (ABCA1) and ABCG1 despite cholesterol influx CD36 was also elevated. Accordingly, IL-4 shows beneficial effects to prevent atherosclerosis via promoting catabolism of the internalized lipids and cholesterol efflux, thus efficiently reduces lipid overload and foam cell formation. These findings illustrate novel roles and protective function of IL-4 to reduce the risk of atherosclerosis incidence by efficiently promoting macrophage cholesterol efflux and lipid homeostasis.

This research investigated how physical activity (PA) might impact the expression of several microRNAs, specifically miR-126, miR-146a, miR-34a, miR-124a, miR-155, and miR-221, in the blood of elderly individuals with type 2 diabetes (T2D). Additionally, the study examined the relationship between these microRNAs and markers of vascular endothelial dysfunction, including vascular endothelial growth factor (VEGF), apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB), to assess their potential in the prevention, early detection, and treatment of diabetes.

This correlational observational study involved 100 male participants, aged between 18 and 65 years, all of whom had been living with type 2 diabetes (T2D) for over six years. The participants were divided into three groups: inactive, moderate, and active, depending on their level of physical activity (PA). Real-time PCR and immunoassays were employed to measure the expression of selected miRNAs, as well as VEGF, apoA-I, apoB, and diabetic management indicators. PA levels were determined using ACTi graph GT1M accelerometer (model WAM 7164; Fort Walton Beach, FL) and energy expenditure was measured in the form of metabolic equivalent (MET) by indirect calorimetry method.

The expression levels of miR-146a, miR-34a, and miR-124a were significantly higher in patients with higher physical activity, while no such increase was observed for the other miRNAs in less active participants. Additionally, PA-active individuals showed a more pronounced decrease in fasting blood sugar (FBS), insulin resistance (IR), fasting insulin (FINS), HOMA-IR, HbA1c (%), and levels of VEGF, apoAI, apoB, and the apoB/apoA-I ratio. The alteration in miRNA expression was positively associated with physical activity, VEGF, apoAI, apoB, the apoB/apoA-I ratio, and diabetes-related metrics, while being inversely related to BMI.

In diabetic patients with higher physical activity levels, circulating miR-146a, miR-34a, and miR-124a showed elevated expression, accompanied by a notable decrease in vascular biomarkers, including apoAI, apoB, and the apoB/apoA-I ratio. The findings revealed a strong correlation between these vascular biomarkers and the physiological responses of miR-146a, miR-34a, and miR-124a, though larger studies are required to validate these results further.

Not applicable.

Androgen exposure (AE) poses a profound health threat to women, yet its transgenerational impacts on male descendants remain unclear. Here, employing a large-scale mother-child cohort, we show that maternal hyperandrogenism predisposes sons to β-cell dysfunction. Male offspring mice with prenatal AE exhibited hyperglycemia and glucose intolerance across three generations, which were further exacerbated by aging and a high-fat diet. Mechanistically, compromised insulin secretion underlies this transgenerational susceptibility to diabetes. Integrated analyses of methylome and transcriptome revealed differential DNA methylation of β-cell functional genes in AE-F1 sperm, which was transmitted to AE-F2 islets and further retained in AE-F2 sperm, leading to reduced expression of genes related to insulin secretion, including Pdx1, Irs1, Ptprn2, and Cacna1c. The methylation signatures in AE-F1 sperm were corroborated in diabetic humans and the blood of sons with maternal hyperandrogenism. Moreover, caloric restriction and metformin treatments normalized hyperglycemia in AE-F1 males and blocked their inheritance to offspring by restoring the aberrant sperm DNA methylations. Our findings highlight the transgenerational inheritance of impaired glucose homeostasis in male offspring from maternal AE via DNA methylation changes, providing methylation biomarkers and therapeutic strategies to safeguard future generations' metabolic health.

Diabetic wounds (DWs) are the most devastating complication, resulting in significant mortality and morbidity in diabetic patients. Although the pathophysiology of DWs is multifaceted, evidence has revealed that prolonged inflammation with infections, extracellular matrix (ECM) degradation, and unnecessary NETosis impair DW healing. This theoretical problem highlights the necessity of developing a novel strategy focused on targeting the "specific" molecular modalities of DWs. The primary culprits, matrix metalloproteinase (MMP)-9 and protein kinase C (PKC)-βII, are responsible for impaired angiogenesis, NETosis, and ECM degradation. Thus, interest in identifying selective inhibitors for the effective management of DW has increased. The current study exemplified human β-defensin-2 (HBD-2), a biological macromolecule that functions as a dual inhibitor of MMP-9 and PKC-βII, via protein-protein docking and molecular dynamics simulation studies. Overall, the data analysis revealed that HBD-2 possesses strong binding affinity and stability against MMP-9 and PKC-βII, suggesting that HBD-2 may be an ideal therapeutic for the accelerated healing of DW. Our findings suggest HBD-2's potential as an innovative therapeutic for accelerated DW healing, offering valuable insights into its molecular mechanisms. However, in vitro and in vivo studies are required to bridge the gap between computational modeling and clinical application.

Glucose-stimulated insulin release from pancreatic β-cells is critical for maintaining blood glucose homeostasis. An abrupt increase in blood glucose concentration evokes a rapid and transient rise in insulin secretion followed by a prolonged, slower phase. A diminished first phase is one of the earliest indicators of β-cell dysfunction in individuals predisposed to develop type 2 diabetes. Consequently, researchers have explored the underlying mechanisms for decades, starting with plasma insulin measurements under physiological conditions and advancing to single-vesicle exocytosis measurements in individual β-cells combined with molecular manipulations. Based on a chain of evidence gathered from genetic manipulation to in vivo mouse phenotyping, a widely accepted theory posits that distinct functional insulin vesicle pools in β-cells regulate biphasic glucose-stimulated insulin secretion (GSIS) via activation of different metabolic signal pathways. Recently, we developed a high-resolution imaging technique to visualize single vesicle exocytosis from β-cells within an intact islet. Our findings reveal that β-cells within the islet exhibit heterogeneity in their secretory capabilities, which also differs from the heterogeneous Ca2+ signals observed in islet β-cells in response to glucose stimulation. Most importantly, we demonstrate that biphasic GSIS emerges from the interactions among α-, β-, and δ-cells within the islet and is driven by a small subset of hypersecretory β-cells. Finally, we propose that a shift from reductionism to holism may be required to fully understand the etiology of complex diseases such as diabetes.

Pancreatic β-cells are susceptible to inflammation, leading to decreased insulin production/secretion and cell death. Previously, we have identified a novel triceps-derived myokine, DECORIN, which plays a pivotal role in skeletal muscle-to-pancreas interorgan communication. However, whether DECORIN can directly impact β-cell function and susceptibility to inflammation remains unexplored.

The effect of DECORIN was assessed in sorted human and rat β-cell and human islets from healthy and type 2 diabetes (T2D) donors. We assessed glucose-stimulated insulin secretion (GSIS) and cytokine-mediated cell death. We then challenged sorted β-cells and human islets with inflammatory cytokines commonly associated with diabetes, such as tumor necrosis factor-α (TNF-α) alone or in combination with interleukin1-β (IL1-β) and interferon-γ (cytomix).

DECORIN enhanced cell spreading and the localization of phosphorylated FAK at adhesions, promoting GSIS under basal conditions. It also increased insulin granule docking adhesion length and countered the inhibitory effects of TNF-α on adhesion and actin remodeling at the β-cell surface, resulting in preserved GSIS. DECORIN protected from cell death in sorted β-cells and islets challenged with TNF-α alone or TNF-α + cytomix. Interestingly, DECORIN increased both insulin content and secretion in human islets from T2D individuals. Additionally, DECORIN treatment reversed the impaired gene expression caused by T2D and enhanced the expression of genes essential for islet function and metabolism.

Collectively, we have shown that DECORIN had a beneficial effect on human islets, protecting them from inflammation-induced cell death. In T2D islets, DECORIN restores islet function and reverses the expression of T2D-associated genes. Based on our data, we propose that DECORIN is a promising therapeutic target for diabetes-associated inflammation and diabetes itself.

Type 2 diabetes mellitus (T2DM) is marked by insulin resistance, low grade chronic inflammation, and endothelial dysfunction. Vitamin K2, especially menaquinone-7 (MK-7), might delay T2DM progression and alleviate its consequences. Hence, this study evaluated the effects of MK-7 on serum and urine markers of diabetes in an animal model of T2DM.

Hetero- (fa/+, control) and homozygous (fa/fa, diabetic) male Zucker diabetic fatty (ZDF) rats were supplemented or not with MK-7 for 12 weeks. After euthanasia, vitamin K1, menaquinone-4 and MK-7 serum concentrations were analyzed via reversed phase high pressure liquid chromatography. Glucose (serum), fructosamine (serum) and creatinine (serum and urine) levels were assessed photometrically, serum cystatin C and urinary total protein were turbidimetrically determined. Serum transforming growth factor beta 1 (TGF-β1) and procollagen type III N-terminal peptide (PIIINP) were quantified with enzyme-linked immunosorbent assay. Urinary marker proteins were analyzed via sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Nephropathy was assessed histologically.

Supplementation led to significantly elevated MK-7 serum levels and a significant reduction of PIIINP serum levels in both hetero- and homozygous ZDF rats. Additionally, not statistically significant reductions of TGF-β1 serum levels, proteinuria as well as the nephropathy score were observed. In vivo body mass, serum fructosamine, glucose, cystatin C and creatinine levels were unaffected.

MK-7 reduced serum markers of fibrosis, histological features of nephropathy and urinary protein excretion, but failed to affect serum markers of T2DM. The therapeutic potential of MK-7 in T2DM and its mode of action should be further investigated in more detail.

A systematic literature review and meta-analysis was performed to evaluate the effects of dapagliflozin on low-density lipoprotein (LDL) cholesterol in type 2 diabetes mellitus. Data on changes in LDL cholesterol, adverse cardiac events (ACEs), glycated hemoglobin (HbA1c), and fasting blood glucose (FBG) were pooled in a meta-analysis. Data from dose comparison trials were separately pooled, and meta-analysis was conducted by using RevMan (5.4.1) and R (4.1.2). Dapagliflozin increased LDL cholesterol by 2.33 mg/dL (95% CI, 1.46 to 3.19; I2 = 0%; P < .00001), increased risk of ACEs by 1.56 (95% CI, 1.02 to 2.39; I2 = 0%; P < .04), decreased HbA1c by -0.41% (95% CI, -0.44 to -0.39; I2 = 85%; P < .00001), and decreased FBG by -13.51 mg/dL (95% CI, -14.43 to -12.59; I2 = 92%; P < .00001) versus any placebo or active comparator. Dapagliflozin 10 mg monotherapy increased LDL cholesterol by 1.71 mg/dL (95% CI, -1.20 to 4.62; I2 = 53%; P = .25) versus a 5 mg dose and by 1.04 mg/dL (95% CI, -1.17 to 3.26; I2 = 62%; P = .36) versus a 2.5 mg dose. Dapagliflozin 10 mg monotherapy increased LDL cholesterol by 3.13 mg/dL (95% CI, 1.31 to 4.95; I2 = 0%; P = .0008), increased the risk of ACEs by 1.26 (95% CI, 0.56 to 2.87; I2 = 0%; P = .58), decreased HbA1c by -0.4% (95% CI, -0.45 to -0.35; I2 = 89%; P < .00001), and decreased FBG by -8.39 mg/dL (95% CI, -10 to -6.77; I2 = 96%; P < .00001) versus a placebo or active comparator. Dapagliflozin monotherapy resulted in a minimal but statistically significantly (P = .0002) increase in LDL cholesterol. However, this minor change does not increase the risk of ACEs (P = .17) when compared with placebo or active comparator.

Comorbid diseases complicate patient outcomes and escalate healthcare costs, necessitating the need for a deeper mechanistic understanding. Neuropsychiatric disorders (NPDs) such as Neurotic Disorder, Major Depression, Bipolar Disorder, Anxiety Disorder, and Schizophrenia significantly exacerbate Type 2 Diabetes Mellitus (DM2), often leading to suboptimal treatment outcomes. The neurobiological mechanisms underlying this comorbidity remain poorly understood. To address this gap, we developed a novel pathway-based network computational framework to identify critical shared disease mechanisms between DM2 and these five prevalent comorbid NPDs. Our approach involves reconstructing an integrated DM2 ∩ NPDs KEGG pathway-pathway network and employs two complementary analytical methods, including the "minimum path to comorbidity" method to identify the shortest path fostering comorbid development. This analysis uncovered shared pathways like the PI3K-Akt signaling pathway and highlighted key nodes such as calcium signaling, MAPK, estrogen signaling, and apoptosis pathways. Dysregulation of these pathways likely contributes to the development of DM2-NPDs comorbidity. These findings have significant clinical implications, as they identify promising therapeutic targets that could lead to more effective treatments addressing both DM2 and NPDs simultaneously. Our model not only elucidates the intricate molecular interactions driving this comorbidity but also identifies promising therapeutic targets, paving the way for innovative treatment strategies. Additionally, the framework developed in this study can be adapted to study other complex comorbid conditions, advancing personalized medicine for comorbidities and improving patient care.

We investigated potential antihyperglycemic effects of HM-chromanone (HMC), a homoisoflavonoid isolated from Portulaca oleracea, in mice fed a high-fat diet (HFD).

Five-week-old male C57BL/6J mice (n = 24) were divided into three groups: controls, mice fed an HFD (11 weeks), and HFD-fed mice receiving HMC supplementation (8 weeks). Various analyses assessed liver and skeletal muscle proteins, pancreatic β-cell histology, blood glucose and HbA1c levels, and homeostatic index of insulin resistance (HOMA-IR).

HMC supplementation significantly reduced fasting blood glucose and postprandial blood glucose levels in HFD-fed mice. HbA1c and serum insulin levels reduced significantly, and HOMA-IR improved. Compensatory β-cell hyperplasia was reduced, and pancreatic β-cell function improved. AMP-activated protein kinase (AMPK) was significantly activated in skeletal muscle and liver tissues. IRS-1tyr612 expression increased significantly. PI3K activation and Akt phosphorylation in skeletal muscles improved insulin signaling. Forkhead box protein O1 phosphorylation increased through hepatic AMPK activation. Phosphoenolpyruvate carboxykinase and glucose-6-phosphatase expression was inhibited. Glycogen synthase kinase 3β phosphorylation increased.

HMC supplementation alleviated hyperglycemia by activating the AMPK and PI3K/Akt pathways in skeletal muscles and the AMPK pathway in the liver of HFD-fed mice.

To identify the pathways that are coordinately regulated in pancreatic β cells, muscle, liver, and fat to control fasting glycemia we fed C57Bl/6, DBA/2, and Balb/c mice a regular chow or a high fat diet for 5, 13, and 33 days. Physiological, transcriptomic and lipidomic data were used in a data fusion approach to identify organ-specific pathways linked to fasting glycemia across all conditions investigated. In pancreatic islets, constant insulinemia despite higher glycemic levels was associated with reduced expression of hormone and neurotransmitter receptors, OXPHOS, cadherins, integrins, and gap junction mRNAs. Higher glycemia and insulin resistance were associated, in muscle, with decreased insulin signaling, glycolytic, Krebs' cycle, OXPHOS, and endo/exocytosis mRNAs; in hepatocytes, with reduced insulin signaling, branched chain amino acid catabolism and OXPHOS mRNAs; in adipose tissue, with increased innate immunity and lipid catabolism mRNAs. These data provide a resource for further studies of interorgan communication in glucose homeostasis.

The Metabolic Insulin Resistance Score (METS-IR) is a non-invasive proxy for insulin resistance (IR) that has been newly developed in recent years and has been shown to be associated with diabetes risk. Our aim was to assess the predictive value of METS-IR for the future development of diabetes and its temporal differences in people of different sex, age, and body mass index (BMI).

The current study included 15,453 baseline non-diabetic subjects in the NAGALA cohort and then grouped according to the World Health Organization's (WHO) recommended criteria for age and BMI. Multivariate Cox regression and time-dependent receiver operator characteristics (ROC) curves were used to analyze the value of METS-IR in assessing and predicting the risk of diabetes in people of different sexes, ages, and BMIs.

373 individuals developed diabetes during the observation period. By multivariate COX regression analysis, the development of future diabetes was significantly associated with increased METS-IR, and this positive association was stronger in women than in men and in individuals < 45 years than in individuals ≥ 45 years; while no significant differences were observed between non-obese and overweight/obesity individuals. Using time-dependent ROC analysis we also assessed the predictive value of METS-IR for future diabetes at a total of 11-time points between 2 and 12 years. The results showed that METS-IR had a higher predictive value for the future development of diabetes in women or individuals < 45 years of age compared to men or individuals ≥ 45 years of age for almost the entire follow-up period. Furthermore, across different BMI categories, we also found that in the short term (3-5 years), METS-IR had a higher predictive value for the development of diabetes in individuals with overweight/obesity, while in the medium to long term (6-12 years), METS-IR was more accurate in predicting the development of diabetes in non-obese individuals.

Our study showed that METS-IR was independently associated with the development of future diabetes in a non-diabetic population. METS-IR was a good predictor of diabetes, especially for women and individuals < 45 years old for predicting the future risk of developing diabetes at all times.

Pancreatic ß-cells are glucose sensors in charge of regulated insulin delivery to the organism, achieving glucose homeostasis and overall energy storage. The latter function promotes obesity when nutrient intake chronically exceeds daily expenditure. In case of ß-cell failure, such weight gain may pave the way for the development of Type-2 diabetes. However, the causal link between excessive body fat mass and potential degradation of ß-cells remains largely unknown and debated. Over the last decades, intensive research has been conducted on the role of lipids in the pathogenesis of ß-cells, also referred to as lipotoxicity. Among various lipid species, the usual suspects are essentially the non-esterified fatty acids (NEFA), in particular the saturated ones such as palmitate. This review describes the fundamentals and the latest advances of research on the role of fatty acids in ß-cells. This includes intracellular pathways and receptor-mediated signaling, both participating in regulated glucose-stimulated insulin secretion as well as being implicated in ß-cell dysfunction. The discussion extends to the contribution of high glucose exposure, or glucotoxicity, to ß-cell defects. Combining glucotoxicity and lipotoxicity results in the synergistic and more deleterious glucolipotoxicity effect. In recent years, alternative roles for intracellular lipids have been uncovered, pointing to a protective function in case of nutrient overload. This requires dynamic storage of NEFA as neutral lipid droplets within the ß-cell, along with active glycerolipid/NEFA cycle allowing subsequent recruitment of lipid species supporting glucose-stimulated insulin secretion. Overall, the latest studies have revealed the two faces of the same coin.

Glucose homeostasis is mainly under the control of the pancreatic islet hormones insulin and glucagon, which, respectively, stimulate glucose uptake and utilization by liver, fat, and muscle and glucose production by the liver. The balance between the secretions of these hormones is under the control of blood glucose concentrations. Indeed, pancreatic islet β-cells and α-cells can sense variations in glycemia and respond by an appropriate secretory response. However, the secretory activity of these cells is also under multiple additional metabolic, hormonal, and neuronal signals that combine to ensure the perfect control of glycemia over a lifetime. The central nervous system (CNS), which has an almost absolute requirement for glucose as a source of metabolic energy and thus a vital interest in ensuring that glycemic levels never fall below ∼5 mM, is equipped with populations of neurons responsive to changes in glucose concentrations. These neurons control pancreatic islet cell secretion activity in multiple ways: through both branches of the autonomic nervous system, through the hypothalamic-pituitary-adrenal axis, and by secreting vasopressin (AVP) in the blood at the level of the posterior pituitary. Here, we present the autonomic innervation of the pancreatic islets; the mechanisms of neuron activation by a rise or a fall in glucose concentration; how current viral tracing, chemogenetic, and optogenetic techniques allow integration of specific glucose sensing neurons in defined neuronal circuits that control endocrine pancreas function; and, finally, how genetic screens in mice can untangle the diversity of the hypothalamic mechanisms controlling the response to hypoglycemia.

So far, biocomputation strictly follows traditional design principles of digital electronics, which could reach their limits when assembling gene circuits of higher complexity. Here, by creating genetic variants of tristate buffers instead of using conventional logic gates as basic signal processing units, we introduce a tristate-based logic synthesis (TriLoS) framework for resource-efficient design of multi-layered gene networks capable of performing complex Boolean calculus within single-cell populations. This sets the stage for simple, modular, and low-interference mapping of various arithmetic logics of interest and an effectively enlarged engineering space within single cells. We not only construct computational gene networks running full adder and full subtractor operations at a cellular level but also describe a treatment paradigm building on programmable cell-based therapeutics, allowing for adjustable and disease-specific drug secretion logics in vivo. This work could foster the evolution of modern biocomputers to progress toward unexplored applications in precision medicine.

This review seeks to address major gaps and delays between our rapidly evolving body of knowledge on type 2 diabetes and its translation into real-world practice. Through updated and improved best practices informed by recent evidence and described herein, we stand to better attain A1c targets, help preserve beta cell integrity and moderate glycemic variability, minimize treatment-emergent hypoglycemia, circumvent prescribing to "treatment failure," and prevent long-term complications. The first topic addressed in this review concerns updates in the 2023 and 2024 diabetes treatment guidelines for which further elaboration can help facilitate integration into routine care. The second concerns advances in diabetes research that have not yet found their way into guidelines, though they are endorsed by strong evidence and are ready for real-world use in appropriate patients. The final theme addresses lingering misconceptions about the underpinnings of type 2 diabetes-fundamental fallacies that continue to be asserted in the textbooks and continuing medical education upon which physicians build their approaches. A corrected and up-to-date understanding of the disease state is essential for practitioners to both conceptually and translationally manage initial onset through late-stage type 2 diabetes.

Gestational diabetes mellitus (GDM) is a major pregnancy metabolic disorder and is strongly linked with obesity. Kisspeptin is a hormone that increases several thousand-fold in the maternal circulation during human pregnancy, with placenta as its main source. Studies have suggested that kisspeptin regulates trophoblast invasion and promotes pancreatic insulin secretion and peripheral insulin sensitivity.

In a well-characterized cohort of pregnant South African women and molecular and histological techniques, this study explored the impact and interaction of maternal obesity and GDM on kisspeptin (KISS1) signalling in relation to placental morphology and maternal and neonatal parameters.

We found that GDM had no effect on placental KISS1 and KISS1R (KISS1 receptor) mRNA and/or protein expression. However, obesity reduced placental KISS1R mRNA expression even though overall KISS1 protein abundance or localization was not different from the non-obese group. Maternal and cord circulating KISS1 concentrations did not vary with obesity or GDM, but maternal circulating KISS1 was positively correlated with placenta weight in non-GDM obese women, and negatively correlated with placental intervillous space volume in non-GDM non-obese women. Cord serum KISS1 was positively correlated with infant weight in GDM obese women, but negatively correlated with maternal BMI in the non-obese GDM group. Placental syncytiotrophoblast extracellular vesicles exhibited detectable KISS1 and its abundance was ∼50 % lower in those from obese GDM compared to non-GDM women.

This study shows maternal obesity and GDM can modulate placental kisspeptin signalling and placental morphological development with potential pathophysiological implications for clinically-relevant pregnancy and perinatal outcomes.

Type 2 diabetes mellitus (T2DM) is a metabolic disease that is characterized by chronic hyperglycaemia. MicroRNAs (miRNAs) are single-stranded, small non-coding RNAs that play important roles in post-transcriptional gene regulation. They are negative regulators of their target messenger RNAs (mRNAs), in which they bind either to inhibit mRNA translation, or to induce mRNA decay. Similar to proteins, miRNAs exist in different isoforms (isomiRs). miRNAs and isomiRs are selectively loaded into small extracellular vesicles, such as the exosomes, to protect them from RNase degradation. In T2DM, exosomal miRNAs produced by different cell types are transported among the primary sites of insulin action. These interorgan crosstalk regulate various T2DM-associated pathways such as adipocyte inflammation, insulin signalling, and β cells dysfunction among many others. In this review, we first focus on the mechanism of exosome biogenesis, followed by miRNA biogenesis and isomiR formation. Next, we discuss the roles of exosomal miRNAs and isomiRs in the development of T2DM and provide evidence from clinical studies to support their potential roles as T2DM biomarkers. Lastly, we highlight the use of exosomal miRNAs and isomiRs in personalized medicine, as well as addressing the current challenges and future opportunities in this field. This review summarizes how research on exosomal miRNAs and isomiRs has developed from the very basic to clinical applications, with the goal of advancing towards the era of personalized medicine.

To investigate the effects of the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine at therapeutically relevant concentrations on beta-cell mass and function.

Viability was quantified in mouse insulinoma (MIN6) beta cells and mouse islets after 48-h exposure to sertraline (1-10 μM) or paroxetine (0.01-1 μM) using the Trypan blue exclusion test. The effects of therapeutic concentrations of these SSRIs on insulin secretion were determined by static incubation and perifusion experiments, while islet apoptosis was investigated by Caspase-Glo 3/7 assay, TUNEL staining and quantitative PCR analysis. Finally, proliferation of MIN6 and mouse islet beta cells was assessed by bromodeoxyuridine (BrdU) enzyme-linked immunosorbent assay and immunofluorescence.

Sertraline (0.1-1 μM) and paroxetine (0.01-0.1 μM) were well tolerated by MIN6 beta cells and islets, whereas 10 μM sertraline and 1 μM paroxetine were cytotoxic. Exposure to 1 μM sertraline and 0.1 μM paroxetine significantly potentiated glucose-stimulated insulin secretion from mouse and human islets. Moreover, they showed protective effects against cytokine- and palmitate-induced apoptosis of islets, they downregulated cytokine-induced Stat1 and Traf1 mRNA expression, and they significantly increased proliferation of mouse beta cells.

Our data demonstrate that sertraline and paroxetine act directly on beta cells to enhance glucose-stimulated insulin secretion and stimulate beta-cell mass expansion by increasing proliferation and decreasing apoptosis. These drugs are therefore likely to be appropriate for treating depression in people with type 2 diabetes.

Physiological variability in pancreatic cell type gene regulation and the impact on diabetes risk is poorly understood. In this study we mapped gene regulation in pancreatic cell types using single cell multiomic (joint RNA-seq and ATAC-seq) profiling in 28 non-diabetic donors in combination with single cell data from 35 non-diabetic donors in the Human Pancreas Analysis Program. We identified widespread associations with age, sex, BMI, and HbA1c, where gene regulatory responses were highly cell type- and phenotype-specific. In beta cells, donor age associated with hypoxia, apoptosis, unfolded protein response, and external signal-dependent transcriptional regulators, while HbA1c associated with inflammatory responses and gender with chromatin organization. We identified 10.8K loci where genetic variants were QTLs for cis regulatory element (cRE) accessibility, including 20% with lineage- or cell type-specific effects which disrupted distinct transcription factor motifs. Type 2 diabetes and glycemic trait associated variants were enriched in both phenotype- and QTL-associated beta cell cREs, whereas type 1 diabetes showed limited enrichment. Variants at 226 diabetes and glycemic trait loci were QTLs in beta and other cell types, including 40 that were statistically colocalized, and annotating target genes of colocalized QTLs revealed genes with putatively novel roles in disease. Our findings reveal diverse responses of pancreatic cell types to phenotype and genotype in physiology, and identify pathways, networks, and genes through which physiology impacts diabetes risk.

Insulin resistance is the primary contributor to the disruption in glucose homeostasis in the body, playing a significant causative role in many metabolic diseases. Insulin resistance is characterized by compensatory insulin secretion and reduced insulin responsiveness in target organs. Dysregulation of the interaction between insulin-secreting cells and insulin-responsive target organs is an important factor driving the progression of insulin resistance. Circulating endocrine hormones are important mediators mediating the interaction between insulin-secreting cells and insulin-responsive target organs. In addition to the classical hormones secreted by endocrine glands and organ-specific hormones secreted by metabolism-related organs (adipose tissue, muscle, liver, etc.), extracellular vesicles have been recognized as a novel class of endocrine hormones with a complex composition. Extracellular vesicles can transport signaling molecules, such as miRNAs and LncRNAs, to vital organs related to insulin resistance, in a manner akin to conventional hormones. The significant role in regulating the development of insulin resistance underscores the increasing interest in extracellular vesicles as essential contributors to this process. In this review, we summarize the three types of hormones (classical hormones, organokines and extracellular vesicles) that play a regulatory role in insulin resistance, and focus on the novel endocrine hormones, extracellular vesicles, to elaborate the mechanism of extracellular vesicles' regulation of insulin resistance progress from two aspects: the impact on insulin-secreting cells and the influence on insulin-responsive target organs. In addition, this paper outlines the clinical applications of extracellular vesicles in insulin resistance. A comprehensive understanding of the regulatory mechanisms and diagnostic status of the inter-organ network in insulin resistance has great potential to advance targeted therapeutic interventions and diagnostic markers, thereby benefiting both the prevention and treatment of insulin resistance.

In-hospital dysglycemia is associated with adverse outcomes. Identifying patients at risk of in-hospital dysglycemia early on admission may improve patient outcomes.

We analysed 117 inpatients admitted with pneumonia and type 2 diabetes monitored by continuous glucose monitoring. We assessed potential risk factors for in-hospital dysglycemia and adverse clinical outcomes.

Time in range (3.9-10.0 mmol/l) decreased by 2.9 %-points [95 % CI 0.7-5.0] per 5 mmol/mol [2.6 %] increase in admission haemoglobin A1c, 16.2 %-points if admission diabetes therapy included insulin therapy [95 % CI 2.9-29.5], and 2.4 %-points [95 % CI 0.3-4.6] per increase in the Charlson Comorbidity Index (CCI) (integer, as a measure of severity and amount of comorbidities). Thirty-day readmission rate increased with an IRR of 1.24 [95 % CI 1.06-1.45] per increase in CCI. In-hospital mortality risk increased with an OR of 1.41 [95 % CI 1.07-1.87] per increase in Early Warning Score (EWS) (integer, as a measure of acute illness) at admission.

Dysglycemia among hospitalised patients with pneumonia and type 2 diabetes was associated with high haemoglobin A1c, insulin treatment before admission, and the amount and severity of comorbidities (i.e., CCI). Thirty-day readmission rate increased with high CCI. The risk of in-hospital mortality increased with the degree of acute illness (i.e., high EWS) at admission. Clinical outcomes were independent of chronic glycemic status, i.e. HbA1c, and in-hospital glycemic status.

Obesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. Here, we screen the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity. We discover a complex interplay between muscle, neuronal, and adipose tissues, mediated by Bone Morphogenetic Protein (BMP) signaling and the hormone Bursicon, that enhances insulin signaling and sugar tolerance. Muscle-derived BMP signaling, induced by sugar, governs neuronal Bursicon signaling. Bursicon, through its receptor Rickets, a Leucine-rich-repeat-containing G-protein coupled receptor (LGR), improves insulin secretion and insulin sensitivity in adipose tissue, mitigating hyperglycemia. In mouse adipocytes, loss of the Rickets ortholog LGR4 blunts insulin responses, showing an essential role of LGR4 in adipocyte insulin sensitivity. Our findings reveal a muscle-neuronal-fat-tissue axis driving metabolic adaptation to high-sugar conditions, identifying LGR4 as a critical mediator in this regulatory network.

The tropical and subtropical regions of the world support the growth of the Indian plant Moringa oleifera. It usually goes by the name drumstick tree or horseradish tree and thrives in warm climates. The leaves of the M. oleifera tree are now frequently used as nutrients and nutraceuticals due to their availability of various minerals. While having only very minor antinutritional effects, the leaves are abundant in many beneficial compounds. A recent review of the bioactive components and activity of moringa leaves has focused on both in vivo and in vitro studies. Drumstick leaves have antidiabetic qualities, anti-inflammatory, anticancer, and antibacterial qualities among other health benefits. Phytochemicals, in addition to minerals and vitamins, are abundant in this vegetable. The majority of these effects, according to a review in the literature, are mostly brought on by the presence of carotenoids, glucosinolates, and phytochemicals. As a value-added component in the production of wholesome meals, moringa is becoming more popular. Despite extensive research into locating and quantifying these advantageous elements in drumstick leaves, bioavailability and bioaccessibility studies were carried out. Beneficial photochemicals are absorbed and digested through incredibly intricate processes that involve several physicochemical and physiological interactions. Therefore, the biological impact of food may be attributed to its various metabolites that can access particular areas of action rather than its original substances. This body of literature offers the most recent findings in scientific research on the bioavailability, health advantages, nutritional profiles, and bioactive activities of moringa leaves as they relate to their use in a range of food products. Drumsticks are frequently used as a food element that promotes health because of their potent protection against a variety of ailments and the presence of environmental pollutants.

Epinephrine influences the function of pancreatic β-cells, primarily through the α2A-adrenergic receptor (α2A-AR) on their plasma membrane. Previous studies indicate that epinephrine transiently suppresses insulin secretion, whereas prolonged exposure induces its compensatory secretion. Nonetheless, the impact of epinephrine-induced α2A-AR signaling on the survival and function of pancreatic β-cells, particularly the impact of reprogramming after their removal from sustained epinephrine stimulation, remains elusive. In the present study, we applied MIN6, a murine insulinoma cell line, with 3 days of high concentration epinephrine incubation and 2 days of standard incubation, explored cell function and activity, and analyzed relevant regulatory pathways. The results showed that chronic epinephrine incubation led to the desensitization of α2A-AR and enhanced insulin secretion. An increased number of docked insulin granules and impaired Syntaxin-2 was found after chronic epinephrine exposure. Growth curve and cell cycle analyses showed the inhibition of cell proliferation. Transcriptome analysis showed the occurrence of endoplasmic reticulum stress (ER stress) and oxidative stress, such as the presence of BiP, CHOP, IRE1, ATF4, and XBP, affecting cellular endoplasmic reticulum function and survival, along with UCP2, OPA1, PINK, and PRKN, associated with mitochondrial dysfunction. Consequently, we conclude that chronic exposure to epinephrine induces α2A-AR desensitization and leads to ER and oxidative stress, impairing protein processing and mitochondrial function, leading to modified pancreatic β-cell secretory function and cell fate.

Insulin resistance (IR) is becoming a worldwide medical and public health challenge as an increasing prevalence of obesity and metabolic disorders. Accumulated evidence has demonstrated a strong relationship between IR and a higher incidence of several dramatically vision-threatening retinal diseases, including diabetic retinopathy, age-related macular degeneration, and glaucoma. In this review, we provide a schematic overview of the associations between IR and certain ocular diseases and further explore the possible mechanisms. Although the exact causes explaining these associations have not been fully elucidated, underlying mechanisms of oxidative stress, chronic low-grade inflammation, endothelial dysfunction and vasoconstriction, and neurodegenerative impairments may be involved. Given that IR is a modifiable risk factor, it may be important to identify patients at a high IR level with prompt treatment, which may decrease the risk of developing certain ocular diseases. Additionally, improving IR through the activation of insulin signaling pathways could become a potential therapeutic target.

Craniopharyngiomas are rare tumors of the central nervous system that typically present with symptoms such as headache and visual impairment, and those reflecting endocrine abnormalities, which seriously affect the quality of life of patients. Patients with craniopharyngiomas are at higher cardiometabolic risk, defined as conditions favoring the development of type 2 diabetes and cardiovascular disease. However, the underlying common pathogenic mechanisms of craniopharyngiomas and type 2 diabetes are not clear. Especially due to the difficulty of conducting in vitro or in vivo experiments on craniopharyngioma, we thought the common pathway analysis between craniopharyngioma and type 2 diabetes based on bioinformatics is a powerful and feasible method. In the present study, using public datasets (GSE94349, GSE68015, GSE38642 and GSE41762) obtained from the GEO database, the gene expression associated with adamantinomatous craniopharyngioma, a subtype of craniopharyngioma, and type 2 diabetes were analyzed using a bioinformatic approach. We found 11 hub genes using a protein-protein interaction network analysis. Of these, seven (DKK1, MMP12, KRT14, PLAU, WNT5B, IKBKB, and FGF19) were also identified by least absolute shrinkage and selection operator analysis. Finally, single-gene validation and receptor operating characteristic analysis revealed that four of these genes (MMP12, PLAU, KRT14, and DKK1) may be involved in the common pathogenetic mechanism of adamantinomatous craniopharyngioma and type 2 diabetes. In addition, we have characterized the differences in immune cell infiltration that characterize these two diseases, providing a reference for further research.

Autophagy is a well-preserved mechanism essential in minimizing endoplasmic reticulum stress (ER)-related cell death. Defects in β-cell autophagy have been linked to type 1 diabetes, particularly deficits in the secretion of insulin, boosting ER stress sensitivity and possibly promoting pancreatic β-cell death. Quercetin (QU) is a potent antioxidant and anti-diabetic flavonoid with low bioavailability, and the precise mechanism of its anti-diabetic activity is still unknown. Aim This study aimed to design an improved bioavailable form of QU (liposomes) and examine the impact of its treatment on the alleviation of type 1 diabetes induced by STZ in rats.

Seventy SD rats were allocated into seven equal groups 10 rats of each: control, STZ, STZ + 3-MA, STZ + QU-Lip, and STZ + 3-MA + QU-Lip. Fasting blood glucose, insulin, c-peptide, serum IL-6, TNF-α, pancreatic oxidative stress, TRAF-6, autophagy, endoplasmic reticulum stress (ER stress) markers expression and their regulatory microRNA (miRNA) were performed. As well as, docking analysis for the quercetin, ER stress, and autophagy were done. Finally, the histopathological and immunohistochemical analysis were conducted.

QU-Lip significantly decreased glucose levels, oxidative, and inflammatory markers in the pancreas. It also significantly downregulated the expression of ER stress and upregulated autophagic-related markers. Furthermore, QU-Lip significantly ameliorated the expression of several MicroRNAs, which both control autophagy and ER stress signaling pathways. However, the improvement of STZ-diabetic rats was abolished upon combination with an autophagy inhibitor (3-MA). The findings suggest that QU-Lip has therapeutic promise in treating type 1 diabetes by modulating ER stress and autophagy via an epigenetic mechanism.

The endocrine pancreas is composed of clusters of cell groups called pancreatic islets. These cells are responsible for the synthesis and secretion of hormones crucial for glycemic homeostasis, such as insulin and glucagon. Therefore, these cells were the targets of many studies. One method to study and/or understand endocrine pancreatic physiology is the isolation of these islets and stimulation of hormone production using different concentrations of glucose, agonists, and/or antagonists of specific secretagogues and mimicking the stimulation of hormonal synthesis and secretion. Many researchers studied pancreatic physiology in murine models due to their ease of maintenance and rapid development. However, the isolation of pancreatic islets involves meticulous processes that may vary between rodent species. The present study describes a simple and effective technical protocol for isolating intact islets from mice and rats for use as a practical guide for researchers. The method involves digestion of the acinar parenchyma by intraductal collagenase. Isolated islets are suitable for in vitro endocrine secretion analyses, microscopy techniques, and biochemical analyses.