Defects In Insulin Secretion Research Articles

Study of the Relationship between Insulin Resistance, Iron Status Markers and Body Weight in a Sample of Egyptian Population

Abstract Background Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Aim of the Work The aim of this study is to investigate the relationship between insulin Resistance, iron Status Markers and body Weight in a sample of Egyptian population. Patients and Methods Our study was case control study conducted on 90 subjects their age was ranging form18 to 70 from diabetes outpatient clinic, and they were divided into 3 groups: Group (1): Non-obese non-diabetic as a control group, Group (2): Obese non diabetic and group (3): Obese diabetic. Results In our study, there was no statistical significant difference found between the three studied groups regarding iron study, Also our study showed that there was statistically non significant correlation between (ferritin level and TIBC), and (ferritin level, HOMA IR), but there was statistical significant positive correlation found between TIBC and FBS (p- value 0.045),Similarly, we did not observe either abnormally high or low ferritin values in our study on subjects with obesity. We found no association between this marker and body weight, in contrast with others. In our study, the higher insulin and HOMA-IR values observed in the subjects with TSAT<20% = 4.2(1.4-11.6) than those with TSAT >20% =2.4 (1.15-6.95), but statistically non significant p- value. The present study also showed that There was statistical significant positive correlation between (T.SAT, serum ferritin), (T.SAT, S.iron) and (T.SAT,SBP) (with p-value 0.03). Our study also showed that there was no statistical significant difference found between patients with T.sat ≤ 20% and those with T.sat > 20% regarding all the studied parameters except ferritin level and iron level was found higher in patients with T.sat >20% than those with T. sat ≤20% with p-value <0.001 and <0.001 respectively. Conclusion Characteristics of iron deficiency or iron overload were not observed in subjects with overweight/obesity and diabetic patients. Our results suggest a complex metabolic dysregulation.

Development and Evaluation of PEG-gelatin-based Microparticles to Enhance the Oral Delivery of Insulin

Background: Diabetes mellitus is a global disease identified by hyperglycemia due to defects in insulin secretion, insulin action, or both. Objective: The main objective of this research was to evaluate the ability of gelatinized Poly(ethylene glycol) (PEG) microparticles to be used as carriers for oral insulin delivery via double emulsion preparation. Methods: Five different batches of the formulation consisting of gelatin:PEG were prepared as follows: 0:1 (W1), 1:0 (W2), 1:1 (W3), 1:3 (W4), and 3:1 (W5). The prepared microparticles (from insulin-loaded batches) had particle sizes ranging from 19.5 ± 0.32-23.9 ± 0.22 μm and encapsulation and loading capacities ranging from 78.8 ± 0.24-88.9 ± 0.95 and 22.2 ± 0.96-29.7 ± 0.86%, respectively. The minimum and maximum in vitro release rates were 8.0 and 66.0%, respectively, for batches W1 and W2 at 8 h. Results: Insulin-loaded MPs induced a significant decrease in glucose levels, with a reduction from 100 to 33.35% in batch W5 at 9 h compared to that of subcutaneous insulin (100 to 22.63%). A liver function study showed that the formulation caused no obvious toxicity to the experimental rats. Conclusion: Gelatinized PEG-based microparticles as insulin delivery systems may open a new window into the development of oral insulin for diabetic treatment.

Antidiabetic Advancements In Silico: Pioneering Novel Heterocyclic Derivatives through Computational Design

Background:: Deficiency of insulin signaling in type 2 diabetes results from insulin resistance or defective insulin secretion and induced hyperglycemia. By reducing glycated hemoglobin, SGLT2 inhibitors improve hyperuricemia, blood lipids, and weight loss without increasing the risk of hypoglycemia. By targeting this pathway, SGLT2 inhibitors can become a prominent target in the management of type 2 diabetes. Objective:: This study aimed to carry out the molecular docking and ADMET prediction of novel imidazo(2,1-b)-1,3,4 thiadiazole derivatives as SGLT2 inhibitors. Methods:: The chemical structures of 108 molecules were drawn by using ChemDraw Professional 15.0. Further, their energy minimization was also carried out by using Chem Bio Draw three-dimensional (3D) Ultra 12.0. Molecular docking was also carried out using a Molegro Virtual Docker to identify the best-fitting molecules and to identify the potential leads on the basis of dock score. The predicted parameters of drug-likeness according to Lipinski’s rule of five, such as molecular weight, log P, hydrogen bond acceptor, hydrogen bond donors, and number of rotatable bonds of the selected compounds, were predicted using pKCSM software. Results:: About 108 molecules were designed by employing different substitutions on imidazothiadiazole nucleus as SGLT2 inhibitors. Out of these, 10 compounds were found to have better interactions with the active site of SGLT2 protein and the highest dock scores compared to canagliflozin. Compounds 39a and 39b demonstrated good interactions and the highest docking scores of -155.428 and -142.786, respectively. The in silico physicochemical properties of the best compounds were also determined. Additionally, these compounds suggested a good pharmacokinetic profile as per Lipinski's rule of five (orally active drugs). Conclusion:: Novel imidazo (2,1-b)-1,3,4 thiadiazole derivatives were strategically designed, and their binding affinity was meticulously evaluated against the SGLT2 protein. This endeavor yielded pioneering lead compounds characterized by ultimate binding affinity, coupled with optimal ADMET properties in adherence to Lipinski's rule of five and favourable noncarcinogenic profile.

Maturity-onset diabetes of the young type 3 complicated with type 5: A case report and literature review.

This report describes a case of maturity-onset diabetes of the young (MODY) type 3 (MODY3) complicated with type 5 (MODY5), including the patient's clinical features, diagnosis, and treatment, and reviews relevant literature. Using next-generation sequencing of MODY (types 1-14) gene exons and Sanger sequencing for verification, the patient and her mother were assessed. Based on the clinical phenotype and genetic test results, the patient was diagnosed as MODY3 combined with MODY5. Treatment included insulin and linagliptin, with monitoring of blood glucose changes. Clinicians should enhance their understanding of MODY clinical phenotypes. In adolescents with diabetes who have congenital pancreatic and renal developmental defects, elevated high-density lipoprotein cholesterol, no spontaneous ketosis, insulin secretion defects, negative pancreatic autoantibodies, no significant insulin resistance, and who are not obese, gene testing should be conducted to screen for MODY. Accurate diagnosis and personalized treatment can aid in achieving glycemic control, improving quality of life, and optimizing reproductive planning.

Understanding Gut Health: Probiotics, Dysbiosis, and their Connection to Type 2 Diabetes - A Review

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both. The pathophysiology of T2DM involves a multifaceted interplay of genetic, behavioural, and environmental factors. Beta cells play a central role in regulating blood glucose levels through intricate mechanisms involving insulin secretion triggered by elevated glucose concentrations and other factors. Dysfunction of beta cells in T2DM encompasses various molecular pathways influenced by factors such as hyperglycaemia, hyperlipidaemia, chronic inflammation, and genetic susceptibility, leading to impaired insulin secretion and insulin resistance. Recent research has highlighted the role of gut dysbiosis in the pathogenesis of T2DM, with alterations in gut microbiome composition impacting glucose metabolism. Dysbiosis-induced intestinal permeability can lead to systemic inflammation, contributing to insulin resistance and diabetes progression. Conversely, a diverse and rich gut microbiome has been associated with protection against obesity, diabetes, and metabolic syndrome. Probiotics, defined as live bacteria conferring health benefits when administered in adequate amounts, hold promise in mitigating T2DM-related metabolic derangements through various mechanisms, including modulation of gut microbiota, regulation of the gut-brain axis, and reduction of chronic low-grade inflammation. This provides a comprehensive overview of the mechanisms through which probiotics may positively impact glucose metabolism and discusses current evidence on the efficacy of probiotic supplementation in improving glycemic parameters and highlights the need for further research to elucidate strain-specific effects, optimal dosages, and long-term outcomes. Additionally, the translation of research findings into clinical practice and the potential of microbiome-targeted therapies for precision management of T2DM are explored, underscoring the importance of evidence-based guidelines for healthcare practitioners.

1218-P: A Critique of Defective Insulin Secretion and Insulin Sensitivity as a Precision Approach to Gestational Diabetes

1218-P: A Critique of Defective Insulin Secretion and Insulin Sensitivity as a Precision Approach to Gestational Diabetes

Insulin Management for Gestational and Type 2 Diabetes in Pregnancy.

Insulin is preferred as the first-line agent for glucose management of gestational diabetes mellitus and type 2 diabetes in pregnancy when nutritional and lifestyle modifications are unable to achieve pregnancy-specific glucose targets. Individual heterogeneity in defects of insulin secretion or sensitivity in liver and muscle, unique genetic influences on pregnancy glycemic regulation, and variable cultural and lifestyle behaviors that affect meal, activity, sleep, and occupational schedules necessitate a personalized approach to insulin regimens. Newer insulin preparations have been developed to mimic the physiologic release of endogenous insulin, maintaining appropriate basal levels to cover hepatic gluconeogenesis and simulate the rapid, meal-related, bolus rise of insulin. Such physiologic basal-bolus dosing of insulin can be administered safely, achieving tighter glycemic control while reducing episodes of hypoglycemia. Insulin initiation and titration require understanding the pharmacodynamics of different insulin preparations in addition to a patient's glycemic profiles, effect of variable nutritional intake and mealtimes, physical activity, stress, timing of sleep cycles, and cultural habits. Educating and empowering patients to learn how their glucose responds to insulin, portion and content of meals, and physical activity can increase personal engagement in therapy, flexibility in eating patterns, and improved glycemic control. This Clinical Expert Series article is focused on optimizing insulin management (initiation, dosing, and titration) of gestational and type 2 diabetes in pregnancy.

Immune-Mediated Ocular Surface Disease in Diabetes Mellitus-Clinical Perspectives and Treatment: A Narrative Review.

Diabetes mellitus (DM) is a chronic metabolic disorder marked by hyperglycemia due to defects in insulin secretion, action, or both, with a global prevalence that has tripled in recent decades. This condition poses significant public health challenges, affecting individuals, healthcare systems, and economies worldwide. Among its numerous complications, ocular surface disease (OSD) is a significant concern, yet understanding its pathophysiology, diagnosis, and management remains challenging. This review aims to explore the epidemiology, pathophysiology, clinical manifestations, diagnostic approaches, and management strategies of diabetes-related OSD. The ocular surface, including the cornea, conjunctiva, and associated structures, is vital for maintaining eye health, with the lacrimal functional unit (LFU) playing a crucial role in tear film regulation. In DM, changes in glycosaminoglycan metabolism, collagen synthesis, oxygen consumption, and LFU dysfunction contribute to ocular complications. Persistent hyperglycemia leads to the expression of cytokines, chemokines, and cell adhesion molecules, resulting in neuropathy, tear film abnormalities, and epithelial lesions. Recent advances in molecular research and therapeutic modalities, such as gene and stem cell therapies, show promise for managing diabetic ocular complications. Future research should focus on pathogenetically oriented therapies for diabetic neuropathy and keratopathy, transitioning from animal models to clinical trials to improve patient outcomes.

Evaluation of glycemic response of ten local meals commonly consumed from Chad

Diabetes mellitus is a metabolic disorder characterized by the presence of chronic hyperglycaemia accompanied by greater or lesser impairment in the metabolism of carbohydrates, lipids and proteins, including defects in either insulin secretion or response. The function of pancreatic cells gradually declines before the onset of clinical hyperglycemia. Its prevalence is increasing everywhere, especially in the developing countries due to the consumption of unknown glycemic index (GI) foods. Thus, the present study aimed to determine the GI of some local meals from Chad. In this purpose, ten meals were investigated and 60 non-diabetic volunteers were recruited in the present study. The proximate composition and the GI of these meals were determined. Results showed that 5 main ingredients (Hibiscus esculentus, Ipomea batata, Hibiscus sabdariffa, Corchorus oletorius and seeds of Parkia biglobosa) differentiate the meals. Soluble sugars and total carbohydrates levels showed a significant (p < 0.05) difference between meals (staples and sauces). The highest value of total carbohydrate of staples was found in Peeled dried sorghum ((BD); 31.80 %) while Cooked rice ((RZ); 19.82 %) has the lowest amount. Then, total carbohydrate content of sauces was in the range of 3.95 % (Leaves of Corchorus oletorius (MLK)) and 8.76 % (Dried okra + Fresh meat (GSV)) while, Sorrel leaves + Smoked fish ((OSP); 2.51 %) and Dried okra + Smoked fish ((GSP); 1.31 %) recorded the highest and lower values of soluble sugars, respectively. Moreover, Peeled dried maize + Dried okra + Fresh meat (MD/GSV) meal showed the highest GI (115.76 %) while the lowest value was found with Cooked rice + Sorrel leaves + Smoked fish (RZ/OZP) meal (31.08 %). The GI of Peeled dried maize + Fresh okra + Fresh meat (MD/GFV) attained a peak of 140 at 40 min while the peak of 130 was obtained with Peeled dried maize + Fresh okra + Smoked fish (MD/GFP) meal at the same time compared to glucose (160 at 40 min). Five meals (OSP/RZ; MD/GFP; MD/GFV; BD/GFP and BD/MLK) were low GI foods and were the best meals for human-being in terms of preventing diabetes mellitus. The consumption of such meals can provide a substantial contribution to the improvement of the Chadian diets.

Formulation &amp; Evaluation of Syzynium jambolanam extract for treatment of diabetes mellitus

Diabetes mellitus has become a serious and chronic metabolic disorder that results from a complex interaction of genetic and environmental factors. The patient of diabetes had polyuria (passing excessive urine) Diabetes can be caused by too little insulin, resistance to insulin, or both. Diabetes is a chronic disease marked by high level of sugar in the blood. Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia with disturbances of carbohydrates, fats and protein metabolism resulting from the defect in insulin secretion, insulin action or both. More than 300 million individuals worldwide are affected by this condition, and the number is growing rapidly because current medical technology has no permanent cure Homoeopathy is one such area of medicine that has had some success in the treatment of diabetes. Diabetes can be caused by too little insulin, resistance to insulin, or both. Diabetes is a chronic disease marked by high level of sugar in the blood Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia with disturbances of carbohydrates, fats and protein metabolism resulting from the defect in insulin secretion, insulin action or both. There are two major types of diabetes that is Type 1 DM, Type 2 DM. other types are Homoeopathy uses natural materials such as plants, animals, minerals to prepare medicines from. Plants form a major portion of homoeopathic medicines. Plants such as Syzygiumjambolanum, Gymnemasylvestre, etc. have long been used to treat diabetes traditionally as well as in homoeopathy. These plants act in reducing the blood glucose level.

Cardioprotective effect of cemtirestat treatment in male Zucker diabetic fatty rats: a pilot study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Slovak Research and Development under the contract no. 21-0410 (APVV) and 20-0411 (APVV) and VEGA grant no. 2/0006/23 Introduction Type 2 Diabetes Mellitus (T2DM), the most common metabolic disorder in human population is caused by defective insulin secretion and reduced tissue responsiveness to insulin. T2DM is characterized by hyperglycaemia accompanied by oxidative stress and inflammation that results in organopathy. The Zucker diabetic fatty rats (ZDF) are established animal model for research of T2DM associated with obesity, and for efficacy of novel treatments. Myocardial electrical coupling protein, connexin43 (Cx43) is one of the key factors affecting heart function and arrhythmogenesis. We have previously shown upregulation of Cx43 in type 1 DM rats that was associated with reduced susceptibility to malignant arrhythmias. However, it is not known whether T2DM affects Cx43 expression and/or function in the heart as well as in brown adipose tissue (BAT). The purpose of our study was to examine expression of Cx43 in heart and BAT as well as the effect of treatment with highly selective and efficient aldose reductase inhibitor enriched with antioxidant activity, Cemtirestat. Methods: Forty 4-month-old male ZDF rats (fa/+ and fa/fa) were divided into 4 groups: 1) untreated control lean rats (fa/+), 2) control lean rats treated with Cemtirestat, 3) untreated diabetic fatty rats (fa/fa), 4) diabetic fatty rats treated with Cemtirestat (2,55 mg/kg/day). After 6 months of treatment, biometric parameters were registered and left ventricle (LV) + BAT were used for Western blot analysis of Cx43, PKCɛ (phosphorylates Cx43) and PKCδ (implicated in pro­apoptotic signaling). BAT and LV tissue sections were also used for immunolabeling of Cx43 to examine its topology. Results: Increase of body weight, heart weight, LV weight, adiposity, plasma triglycerides, cholesterol and blood glucose were registered in ZDF fa/fa rats. T2DM resulted in altered localisation of Cx43 that was not affected by treatment with Cemtirestat. Expression of Cx43 was significantly decreased in LV of fa/fa rats and restored with Cemtirestat. Moreover, BAT exhibited significantly lower expression of total Cx43 in fa/fa rats, that was moderately increased by Cemtirestat. The expression of PKCɛ was significantly decreased in both, LV and BAT of fa/fa rats with mild elevation of PKCɛ in LV of treated fa/fa rats. Cemtirestat slightly normalized increased expression of PKCδ in LV of fa/fa rats, but had no effect on lower PKCδ levels in BAT of fa/fa rats. Echocardiographic examination did not show significant difference between treated and untreated groups of rats and showed mild differences between diabetic and control rats. In conclusions, findings point out that T2DM downregulates Cx43 in the heart and BAT, however further studies are necessary for understanding the mechanisms implicated in every step in the development of T2DM cardiopathy and arrhythmogenesis as well as BAT alterations. Further research is required to determine factors involved in cardioprotective effects of Cemtirestat.

Modulation of nuclear receptor 4A1 expression improves insulin secretion in a mouse model of chronic pancreatitis.

Diabetes secondary to chronic pancreatitis (CP) presents clinical challenges due to insulin secretory defects and associated metabolic alterations. Owing to lack of molecular understanding, no pharmacotherapies to treat insulin secretory defects have been approved to date. We aimed to delineate the molecular mechanism of β-cell dysfunction in CP. Transcriptomic analysis was conducted to identify endocrine specific receptor expression in mice and human CP on microarray. The identified receptor (NR4A1) was overexpressed in MIN6 cells using PEI linear transfection. RNA-Seq analysis on NovaSeq 6000 of NR4A1 overexpressed (OE) MIN6 cells was performed to identify aberrant metabolic pathways. Upstream trigger for NR4A1OE was studied by InBio Discover and cytokine exposure. Downstream effect of NR4A1OE was examined by Fura2 AM based fluorometric and imaging studies of intracellular calcium. Mice with CP were treated with IFN-γ neutralizing monoclonal antibodies to assess NR4A1 expression and insulin secretion. Increased expression of NR4A1 associated with decreased insulin secretion in islets (humans: controls 9 ± 0.2, CP 3.7 ± 0.2, mice: controls 8.5 ± 0.2, CP 2.1 ± 0.1 μg/L). NR4A1OE in MIN6 cells (13.2 ± 0.1) showed reduction in insulin secretion (13 ± 5 to 0.2 ± 0.1 μg/mg protein/minute, p = 0.001) and downregulation of calcium and cAMP signaling pathways. IFN-γ was identified as upstream signal for NR4A1OE in MIN6. Mice treated with IFN-γ neutralizing antibodies showed decreased NR4A1 expression 3.4 ± 0.11-fold (p = 0.03), improved insulin secretion (4.4 ± 0.2-fold, p = 0.01), associated with increased Ca2+ levels (2.39 ± 0.06-fold, p = 0.009). Modulating NR4A1 expression can be a promising therapeutic strategy to improve insulin secretion in CP.

Novel Approaches to Control Diabetes.

Diabetes is a chronic, long-term, incurable, but controllable condition. Diabetes mellitus (DM) is a group of metabolic disorders characterized by hyperglycemia that results from defects in insulin secretion, insulin action, or both. People who have diabetes often experience a variety of symptoms, including blurry vision, excessive thirst, fatigue, frequent urination, hunger, and weight loss. This review article includes a discussion on diabetes types, symptoms, diagnostic tests, and various therapies for treating, controlling, and managing blood glucose levels, with a focus on its most recent innovation of therapies and medications. Diabetes management will also be reviewed, along with clinical pharmacodynamics, bioavailability, advantages, and complications of combined drugs/medications.

Effectiveness of Oral Health Education and Interventions in Improving Oral Health Outcomes in Type II Diabetes Mellitus Patients: A Prospective Study.

Introduction Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The study aimed to evaluate the effectiveness of oral health education and intervention in improving oral health outcomes in type 2 DM (T2DM) patients. Methods The present study was conducted in the Department of Oral Medicine and Radiology between February 2023 and August 2023 at Saveetha Dental College and Hospitals in Chennai, India. All of the patients in the study had T2DM with oral manifestations. This study enrolled 105 participants, of whom 63 were female and 42 were male. A standard pro forma was given to all the participants, and the findings were recorded. The pro forma comprises different oral manifestations, blood glucose levels, the Decayed, Missing, and Filled Teeth (DMFT) index, and Russell's periodontal index. The results were then statistically analyzed. Results This study of 105 individuals with T2DM (60% females and 40% males) revealed significant oral health challenges: 33% had periodontitis, 20% had gingivitis, 5% had lichenoid reactions, 23% had xerostomia, 11% had halitosis, and 8% had candidiasis, illustrating diabetes' impact on dental health. Following appropriate, tailor-made treatment for individual patients, such as scaling, root planning, oral hygiene education, pharmacotherapy, and post-intervention, the prevalence of complications notably decreased by 61%. A total of 7% of patients had gingivitis, 11% had periodontitis, 12% had xerostomia, 4% had halitosis, 2% had candidiasis, and 1% had lichenoid reactions, respectively. This highlights the importance of regular oral care positively impacting diabetes patients, with 61% experiencing improved oral health and 39% experiencing no improvement. Conclusion This study provides compelling evidence for the effectiveness of oral health education and interventions in improving oral health outcomes in T2DM patients. This approach offers a promising strategy for managing the oral health complications associated with diabetes and improving this population's overall health and well-being.

Transcriptomic profiling analysis of the effect of palmitic acid on 3D spheroids of β-like cells derived from induced pluripotent stem cells

Type 2 diabetes (T2D) is posing a serious public health concern with a considerable impact on human life and health expenditures worldwide. The disease develops when insulin plasma level is insufficient for coping insulin resistance, caused by the decline of pancreatic β-cell function and mass. In β-cells, the lipotoxicity exerted by saturated free fatty acids in particular palmitate (PA), which is chronically elevated in T2D, plays a major role in β-cell dysfunction and mass. However, there is a lack of human relevant in vitro model to identify the underlying mechanism through which palmitate induces β-cell failure. In this frame, we have previously developed a cutting-edge 3D spheroid model of β-like cells derived from human induced pluripotent stem cells. In the present work, we investigated the signaling pathways modified by palmitate in β-like cells derived spheroids. When compared to the 2D monolayer cultures, the transcriptome analysis (FDR set at 0.1) revealed that the 3D spheroids upregulated the pancreatic markers (such as GCG, IAPP genes), lipids metabolism and transporters (CD36, HMGSC2 genes), glucose transporter (SLC2A6). Then, the 3D spheroids are exposed to PA 0.5 mM for 72 h. The differential analysis demonstrated that 32 transcription factors and 135 target genes were mainly modulated (FDR set at 0.1) including the upregulation of lipid and carbohydrates metabolism (HMGSC2, LDHA, GLUT3), fibrin metabolism (FGG, FGB), apoptosis (CASP7). The pathway analysis using the 135 selected targets extracted the fibrin related biological process and wound healing in 3D PA treated conditions. An overall pathway gene set enrichment analysis, performed on the overall gene set (with pathway significance cutoff at 0.2), highlighted that PA perturbs the citrate cycle, FOXO signaling and Hippo signaling as observed in human islets studies. Additional RT-PCR confirmed induction of inflammatory (IGFBP1, IGFBP3) and cell growth (CCND1, Ki67) pathways by PA. All these changes were associated with unaffected glucose-stimulated insulin secretion (GSIS), suggesting that they precede the defect of insulin secretion and death induced by PA. Overall, we believe that our data demonstrate the potential of our spheroid 3D islet-like cells to investigate the pancreatic-like response to diabetogenic environment.

Roles of β-Cell Hypoxia in the Progression of Type 2 Diabetes.

Type 2 diabetes is a chronic disease marked by hyperglycemia; impaired insulin secretion by pancreatic β-cells is a hallmark of this disease. Recent studies have shown that hypoxia occurs in the β-cells of patients with type 2 diabetes and hypoxia, in turn, contributes to the insulin secretion defect and β-cell loss through various mechanisms, including the activation of hypoxia-inducible factors, induction of transcriptional repressors, and activation of AMP-activated protein kinase. This review focuses on advances in our understanding of the contribution of β-cell hypoxia to the development of β-cell dysfunction in type 2 diabetes. A better understanding of β-cell hypoxia might be useful in the development of new strategies for treating type 2 diabetes.

Antidiabetic Evaluation of Kigelia pinnata Root Bark Extract in Streptozotocin-Induced Type-2 Diabetes Model of Rats.

Diabetes mellitus (DM) is the most common endocrine disorder characterized by increased blood glucose levels resulting from defective insulin secretion, resistance to insulin action, or both. DM is often associated with severe complications, and there is an increasing appreciation that cognitive function declines in DM. The aim of this research work was to evaluate Kigelia pinnata root bark extract in Streptozotocin (STZ)-induced type-2 diabetes. Experimental diabetes was induced by a single administration of STZ (60 mg/kg, intraperitoneal [i.p.]), immediately after the STZ administration, and all animals were fed with normal food and water. Nicotinamide was administered (120 mg/kg, i.p.) 15 min before STZ. The development of hyperglycemia was confirmed by the elevated blood glucose levels determined at fixed intervals, which was confirmed by measuring fasting blood glucose levels in rats' blood taken from the tail vein. Supplementation with ethanolic extract of K. pinnata root bark (EEKP) significantly reduced the elevated blood glucose in STZ-induced hyperglycemia in rats. EEKP significantly restored the biochemical and antioxidant defense system. On the final day of the protocol, the extract also reduced inflammatory cytokines in the blood serum.

Camel milk; A potent superfood for diabetes complications

Currently, camel milk has been considered around the world due to awareness of its unique health benefits. Camel milk is considered a superfood with special nutrients and therapeutic values. In diabetes or hyperglycemia, the cells may not respond properly to insulin or defects in insulin secretion by the pancreas, therefore glucose level of blood is excessive. Chronic hyperglycemia is associated with dysfunction in the eyes, heart, nerves, kidneys, liver, and blood vessels. Insulin and oral hypoglycemic drugs are used for diabetes, but a high percentage of patients cannot use allopathic drugs and rely on natural alternative healings. Furthermore, coagulation of oral insulin in an acidic environment neutralizes and decreases the efficacy of insulin. Camel milk contains insulin-like proteins and may be an effective alternative for insulin to treat type 1 and 2 and gestational diabetes. Camel milk may prepare about 60% of the insulin in diabetic patients and reduce blood sugar and required insulin doses of about 30% - 35% in type 1 diabetes patients. This milk is believed to be a suitable hypoglycemic agent in improving long-term glycemic control in experimental animals and diabetic patients, as well as improving diabetes risk factors such as liver and kidney failures and cardiovascular challenges. It appears that more scientific studies are needed to confirm the efficacy of processed camel milk on diabetes. This review represents scientific studies on how camel milk as a superfood can be effective in diabetes.

Insufficient TRPM5 Mediates Lipotoxicity-induced Pancreatic β-cell Dysfunction.

While the reduction of transient receptor potential channel subfamily M member 5 (TRPM5) has been reported in islet cells from type 2 diabetic (T2D) mouse models, its role in lipotoxicity-induced pancreatic β-cell dysfunction remains unclear. This study aims to study its role. Pancreas slices were prepared from mice subjected to a high-fat-diet (HFD) at different time points, and TRPM5 expression in the pancreatic β cells was examined using immunofluorescence staining. Glucose-stimulated insulin secretion (GSIS) defects caused by lipotoxicity were mimicked by saturated fatty acid palmitate (Palm). Primary mouse islets and mouse insulinoma MIN6 cells were treated with Palm, and the TRPM5 expression was detected using qRT-PCR and Western blotting. Palm-induced GSIS defects were measured following siRNA-based Trpm5 knockdown. The detrimental effects of Palm on primary mouse islets were also assessed after overexpressing Trpm5 via an adenovirus-derived Trpm5 (Ad-Trpm5). HFD feeding decreased the mRNA levels and protein expression of TRPM5 in mouse pancreatic islets. Palm reduced TRPM5 protein expression in a time- and dose-dependent manner in MIN6 cells. Palm also inhibited TRPM5 expression in primary mouse islets. Knockdown of Trpm5 inhibited insulin secretion upon high glucose stimulation but had little effect on insulin biosynthesis. Overexpression of Trpm5 reversed Palm-induced GSIS defects and the production of functional maturation molecules unique to β cells. Our findings suggest that lipotoxicity inhibits TRPM5 expression in pancreatic β cells both in vivo and in vitro and, in turn, drives β-cell dysfunction.

Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity

Aims/hypothesisBeta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of cells make distinct contributions to the overall control of insulin secretion. These include a subpopulation of highly connected ‘hub’ cells, important for the propagation of intercellular Ca2+ waves. Functional subpopulations have also been demonstrated in human beta cells, with an altered subtype distribution apparent in type 2 diabetes. At present, the molecular mechanisms through which beta cell hierarchy is established are poorly understood. Changes at the level of the epigenome provide one such possibility, which we explore here by focusing on the imprinted gene Nnat (encoding neuronatin [NNAT]), which is required for normal insulin synthesis and secretion.MethodsSingle-cell RNA-seq datasets were examined using Seurat 4.0 and ClusterProfiler running under R. Transgenic mice expressing enhanced GFP under the control of the Nnat enhancer/promoter regions were generated for FACS of beta cells and downstream analysis of CpG methylation by bisulphite sequencing and RNA-seq, respectively. Animals deleted for the de novo methyltransferase DNA methyltransferase 3 alpha (DNMT3A) from the pancreatic progenitor stage were used to explore control of promoter methylation. Proteomics was performed using affinity purification mass spectrometry and Ca2+ dynamics explored by rapid confocal imaging of Cal-520 AM and Cal-590 AM. Insulin secretion was measured using homogeneous time-resolved fluorescence imaging.ResultsNnat mRNA was differentially expressed in a discrete beta cell population in a developmental stage- and DNA methylation (DNMT3A)-dependent manner. Thus, pseudo-time analysis of embryonic datasets demonstrated the early establishment of Nnat-positive and -negative subpopulations during embryogenesis. NNAT expression is also restricted to a subset of beta cells across the human islet that is maintained throughout adult life. NNAT+ beta cells also displayed a discrete transcriptome at adult stages, representing a subpopulation specialised for insulin production, and were diminished in db/db mice. ‘Hub’ cells were less abundant in the NNAT+ population, consistent with epigenetic control of this functional specialisation.Conclusions/interpretationThese findings demonstrate that differential DNA methylation at Nnat represents a novel means through which beta cell heterogeneity is established during development. We therefore hypothesise that changes in methylation at this locus may contribute to a loss of beta cell hierarchy and connectivity, potentially contributing to defective insulin secretion in some forms of diabetes.Data availabilityThe mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD048465.Graphical