Islet Β-cells Research Articles

Extracellular Vesicles in Type 1 Diabetes: A Versatile Tool.

Type 1 diabetes is a chronic autoimmune disease affecting nearly 35 million people. This disease develops as T-cells continually attack the β-cells of the islets of Langerhans in the pancreas, which leads to β-cell death, and steadily decreasing secretion of insulin. Lowered levels of insulin minimize the uptake of glucose into cells, thus putting the body in a hyperglycemic state. Despite significant progress in the understanding of the pathophysiology of this disease, there is a need for novel developments in the diagnostics and management of type 1 diabetes. Extracellular vesicles (EVs) are lipid-bound nanoparticles that contain diverse content from their cell of origin and can be used as a biomarker for both the onset of diabetes and transplantation rejection. Furthermore, vesicles can be loaded with therapeutic cargo and delivered in conjunction with a transplant to increase cell survival and long-term outcomes. Crucially, several studies have linked EVs and their cargos to the progression of type 1 diabetes. As a result, gaining a better understanding of EVs would help researchers better comprehend the utility of EVs in regulating and understanding type 1 diabetes. EVs are a composition of biologically active components such as nucleic acids, proteins, metabolites, and lipids that can be transported to particular cells/tissues through the blood system. Through their varied content, EVs can serve as a flexible aid in the diagnosis and management of type 1 diabetes. In this review, we provide an overview of existing knowledge about EVs. We also cover the role of EVs in the pathogenesis, detection, and treatment of type 1 diabetes and the function of EVs in pancreas and islet β-cell transplantation.

Morus alba L. (Sangzhi) Alkaloids Promote Insulin Secretion, Restore Diabetic β-Cell Function by Preventing Dedifferentiation and Apoptosis.

Background: Morus alba L. (Sangzhi) alkaloids (SZ-A), extracted from the Chinese herb Morus alba L. (mulberry twig), have been shown to ameliorate hyperglycemia in type 2 diabetes and have been approved for diabetes treatment in the clinic. However, their versatile pharmacologic effects and regulatory mechanisms are not yet completely understood. Purpose: This study explored the protective effects of SZ-A on islet β cells and the underlying mechanism. Methods: Type 2 diabetic KKAy mice were orally administered SZ-A (100 or 200 mg/kg, once daily) for 11 weeks, and oral glucose tolerance, insulin tolerance, intraperitoneal glucose tolerance and hyperglycemia clamp tests were carried out to evaluate the potency of SZ-A in vivo. The morphology and β-cell dedifferentiation marker of KKAy mouse islets were detected via immunofluorescence. The effect of SZ-A on glucose-stimulated insulin secretion was investigated in both the islet β-cell line MIN6 and mouse primary islets. Potential regulatory signals and pathways in insulin secretion were explored, and cell proliferation assays and apoptosis TUNEL staining were performed on SZ-A-treated MIN6 cells. Results: SZ-A alleviated hyperglycemia and glucose intolerance in type 2 diabetic KKAy mice and improved the function and morphology of diabetic islets. In both MIN6 cells and primary islets, SZ-A promoted insulin secretion. At a normal glucose level, SZ-A decreased AMPKα phosphorylation, and at high glucose, SZ-A augmented the cytosolic calcium concentration. Additionally, SZ-A downregulated the β-cell dedifferentiation marker ALDH1A3 and upregulated β-cell identifying genes, such as Ins1, Ins2, Nkx2.2 and Pax4 in KKAy mice islets. At the same time, SZ-A attenuated glucolipotoxicity-induced apoptosis in MIN6 cells, and inhibited Erk1/2 phosphorylation and caspase 3 activity. The major active fractions of SZ-A, namely DNJ, FAG and DAB, participated in the above regulatory effects. Conclusion: Our findings suggest that SZ-A promotes insulin secretion in islet β cells and ameliorates β-cell dysfunction and mass reduction under diabetic conditions both in vivo and in vitro, providing additional supportive evidence for the clinical application of SZ-A.

Long-term exposure of Bisphenol A impairs metabolism and develop insulin resistance

Bisphenol A (BPA) is a well-recognized endocrine disruptor which has wide applications in current age. This is an industrial compound which is being used in the preparation of juice cans, water containers and various other household plastic products. The main objective of this study was to investigate the mechanism of BPA-induced metabolic pathways disturbance and other key risk factors that can may lead to the development of impaired insulin secretion from β-cells of pancreatic islets and insulin resistance peripheral tissues. The methodology involved the oral administration of BPA in different doses i.e., 50, 500, 2500 and 5000 for 3 months. The predefined BPA induced metabolic risk factors that lead towards the insulin resistance were measured by using ELISA kits. The association of long-term exposure of BPA with, significant reduction (P<0.05) of antioxidant enzymes, such as superoxide dismutase (SOD), glutathione (GSH), catalase (CAT) and, considerable higher levels (P<0.05) of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), can exacerbate the chances of insulin resistance and impaired insulin secretion. Furthermore, we found a significant correlation (P<0.05) between the long-term exposure of BPA and various enzymes that control the metabolism of carbohydrates such as α-glucosidase, glucose-6-phosphatase, hexokinase, α-amylase. The same correlation (P<0.05) was also found to be existed in between the enzymes involved in the biosynthesis of cholesterol such as HMG-CoA reductase and long-term exposure of BPA. It can be concluded that long-term exposure of BPA can disrupt the various metabolic pathways by inducing the oxidative stress which provokes various inflammatory responses that ultimately lead to impair the β-cells of pancreatic islets and insulin resistance peripheral tissues.

Effects of a prolonged diet regimen on autophagic function in rat islets with aging

The prevalence of type 2 diabetes increases with age-associated increased susceptibility of islet β-cells and altered dietary patterns, in part because of insufficient compensation of β-cell functional mass in the face of increasing insulin resistance. However, the underlying mechanisms have not been fully elucidated. In the present study, we investigated the effects of a long-term calorie-restricted (CR) or high-fat (HF) diet compared to a normal ad libitum diet on β-cell structure-function relationships and autophagy in the islets of 3- and 24-month-old Fischer 344 rats. Aging and the HF diet decreased the β-cell-to-islet area ratio, disorganized the islet structure, and increased the expression of senescence markers. Aging and the long-term HF diet also decreased autophagy-related proteins, which suggests compromised autophagic function. These findings were further corroborated by increased p62 accumulation and polyubiquitin aggregates observed with aging and the HF diet intervention; these are cardinal markers of attenuated autophagic function. It is important to note that the 24-month-old rats maintained on the CR diet closely mimicked the 3-month-old rats, which indicates that a long-term CR diet can delay islet aging and prevent the decline in the autophagic function of islets during the aging process. Taken together, our results indicate an autophagy-dependent mechanism responsible for islet function in older people or those with altered dietary patterns and lay the foundations for future research leading to novel therapeutic strategies for treating diabetes.

GIPR Is Predominantly Localized to Nonadipocyte Cell Types Within White Adipose Tissue.

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) augments glucose-dependent insulin secretion through its receptor expressed on islet β-cells. GIP also acts on adipose tissue; yet paradoxically, both enhanced and reduced GIP receptor (GIPR) signaling reduce adipose tissue mass and attenuate weight gain in response to nutrient excess. Moreover, the precise cellular localization of GIPR expression within white adipose tissue (WAT) remains uncertain. We used mouse genetics to target Gipr expression within adipocytes. Surprisingly, targeting Cre expression to adipocytes using the adiponectin (Adipoq) promoter did not produce meaningful reduction of WAT Gipr expression in Adipoq-Cre:Giprflx/flx mice. In contrast, adenoviral expression of Cre under the control of the cytomegalovirus promoter, or transgenic expression of Cre using nonadipocyte-selective promoters (Ap2/Fabp4 and Ubc) markedly attenuated WAT Gipr expression. Analysis of single-nucleus RNA-sequencing, adipose tissue data sets localized Gipr/GIPR expression predominantly to pericytes and mesothelial cells rather than to adipocytes. Together, these observations reveal that adipocytes are not the major GIPR+ cell type within WAT-findings with mechanistic implications for understanding how GIP and GIP-based co-agonists control adipose tissue biology.

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production.

Pancreatic islet β-cells exhibit tremendous plasticity for secretory adaptations that coordinate insulin production and release with nutritional demands. This essential feature of the β-cell can allow for compensatory changes that increase secretory output to overcome insulin resistance early in Type 2 diabetes (T2D). Nutrient-stimulated increases in proinsulin biosynthesis may initiate this β-cell adaptive compensation; however, the molecular regulators of secretory expansion that accommodate the increased biosynthetic burden of packaging and producing additional insulin granules, such as enhanced ER and Golgi functions, remain poorly defined. As these adaptive mechanisms fail and T2D progresses, the β-cell succumbs to metabolic defects resulting in alterations to glucose metabolism and a decline in nutrient-regulated secretory functions, including impaired proinsulin processing and a deficit in mature insulin-containing secretory granules. In this review, we will discuss how the adaptative plasticity of the pancreatic islet β-cell’s secretory program allows insulin production to be carefully matched with nutrient availability and peripheral cues for insulin signaling. Furthermore, we will highlight potential defects in the secretory pathway that limit or delay insulin granule biosynthesis, which may contribute to the decline in β-cell function during the pathogenesis of T2D.

Effect of sodium butyrate on glucose and lipid metabolism, insulin expression and apoptosis of β-cells in obese pregnant rats

&#x0D; &#x0D; &#x0D; &#x0D; Purpose: To study the influence of sodium butyrate on the metabolism of lipid and glucose, insulin expression and apoptosis of β-cells in obese pregnant rats.&#x0D; Methods: Three groups of one hundred and twenty 4-week-old female C5BL/6J mice were used: control, high-fat diet and sodium butyrate groups. Insulin, triglycerides and total cholesterol were evaluated by enzyme-linked immunosorbent assay (ELISA). Insulin levels, as well as area and quality of islet β-cells were assessed using Image Pro Plus software. The number of DAPI-positive islet cells, positive expression of bcl-2 in each islet cell, and apoptosis of islet β-cells in each group were determined.&#x0D; Results: The expression levels of insulin in high-fat diet group and butyrate group were significantly reduced, relative to control, but insulin expression level in Na butyrate group increased, relative to high- fat diet mice (p &lt; 0.01). The area and quality of islet β-cells in high-fat diet and sodium butyrate groups were markedly higher in sodium butyrate group than in high-fat diet group (p &lt; 0.01). The bcl-2 expression in islet β-cells rose in mice given high-fat diet, relative to control and sodium butyrate groups (p &lt; 0.01).&#x0D; Conclusion: Sodium butyrate facilitates glucose and lipid metabolism, but increases insulin expression, and effectively inhibits apoptosis of islet β-cells in obese pregnant mice. Thus, sodium butyrate may be useful in the prevention and treatment of metabolic disorders due to diabetes mellitus (DM).&#x0D; &#x0D; &#x0D; &#x0D;

Immunohistochemical and Histochemical Studies of Β-Cells Insulin Up-Regulation in Pancreatic Tissues of Streptozotocin-Induced Diabetic Albino Rats Treated with Melatonin and Magnesium

Background: Improve insulin secretion and cellular availability to reduced blood glucose levels in diabetic subjects by bioactive compound especially antioxidants are the new focus to ameliorate the complication with diabetes mellitus. Aims and objectives: The aim of this study was to evaluate the effects of administration of melatonin and magnesium on the cytoarchitecture of the pancreatic tissue and to access immunohistochemically insulin release in streptozotocin-induced diabetic Albino rats. Materials and methods: To achieve this aim six normoglycaemic rats and fourty eight Streptozotocin (STZ) induced diabetic rats was used in the study after two weeks acclimatization period. The animals were assigned into nine groups as follows, Normal control group (NC), Diabetic control (DC) group, Melatonin at 10 mg/kgb (MLD), magnesium dose group of 240 mg/kgbw (MgLD), melatonin and magnesium combined group of 10mg/kgbw+240mg/kgbw (MMgLD), melatonin group of 20mg/kgbw (MHD), melatonin and magnesium high dose combined group of 20mg/kgbw+480mg/kgbw (MMgHD) and insulin at 500mg/kgbw group (IN). Melatonin and insulin were administered through intraperitoneal injections (IP) while magnesium was by oral administration. The control groups were given placebo and all groups’ treatment was for twenty-one days. At the end of the study, the animals were aestheticized and euthanized to harvest pancreatic organ. The organs were fixed in neutral buffered formaldehyde (NBF). They were histologically prepared and stained using haematoxylin and eosin and immunohistochemically stained using insulin antibody to access insulin release. Results: Melatonin treatment at 10mg/kgbw and at 20 mg/kgbw showed histological improvement in histological tissues and insulin release while when combined with magnesium at dose of 10mg/kgbw and at 240 mg/kgbw showed better results. The administration of magnesium at 240 mg/kgbw, 480 mg/kgbw and when combined with melatonin at high doses does not show significant improvement in islet β-cell proliferation and insulin release. Conclusion: The administration of melatonin and magnesium at low doses regenerates pancreatic islet histoarchitecture and augments insulin release from treated diabetic albino rats.

Molecular Mechanisms of Amylin Turnover, Misfolding and Toxicity in the Pancreas.

Amyloidosis is a common pathological event in which proteins self-assemble into misfolded soluble and insoluble molecular forms, oligomers and fibrils that are often toxic to cells. Notably, aggregation-prone human islet amyloid polypeptide (hIAPP), or amylin, is a pancreatic hormone linked to islet β-cells demise in diabetics. The unifying mechanism by which amyloid proteins, including hIAPP, aggregate and kill cells is still matter of debate. The pathology of type-2 diabetes mellitus (T2DM) is characterized by extracellular and intracellular accumulation of toxic hIAPP species, soluble oligomers and insoluble fibrils in pancreatic human islets, eventually leading to loss of β-cell mass. This review focuses on molecular, biochemical and cell-biology studies exploring molecular mechanisms of hIAPP synthesis, trafficking and degradation in the pancreas. In addition to hIAPP turnover, the dynamics and the mechanisms of IAPP–membrane interactions; hIAPP aggregation and toxicity in vitro and in situ; and the regulatory role of diabetic factors, such as lipids and cholesterol, in these processes are also discussed.

From barnyard to bedside: using interspecies variants to inform the rational design of novel analogs of islet amyloid polypeptide

Islet amyloid polypeptide (IAPP, also known as amylin) is a 37-residue, neuropancreatic hormone that is co-secreted with insulin by islet β-cells and plays an important role in glycemic control. The peptide is linked to diabetes mellitus, forming extracellular amyloid deposits in type 2 disease and largely absent in type 1 disease. IAPP is found in all vertebrates and the sequence is well conserved, but some variants exhibit decreased in vitro amyloidogenicity and enhanced solubility in formulation.

Pathogenic Mechanism of Autoimmune Diabetes Mellitus in Humans: Potential Role of Streptozotocin-Induced Selective Autoimmunity against Human Islet β-Cells.

Human type 1 diabetes mellitus is a chronic autoimmune disease characterized by the selective loss of insulin-producing β-cells in pancreatic islets of genetically susceptible individuals. In this communication, a new hypothesis is postulated which is based on the observations that streptozotocin (STZ), a chemically reactive and cytotoxic compound produced by certain gram-positive bacteria, can be preferentially taken up into islet β-cells and induce cytotoxicity and autoimmunity. It is hypothesized that humans might be occasionally exposed to STZ through opportunistic infections with the STZ-producing bacteria and/or through ingestion of certain food products that contain STZ. In addition, the potential presence of the STZ-producing bacteria in the gut microbiota of some individuals might be another source of long-term STZ exposure. Because of the high chemical reactivity of STZ and its breakdown products, these chemicals can covalently modify certain cellular macromolecules (e.g., DNA and proteins), and the covalently modified cellular components would serve as new antigens, potentially capable of inducing both humoral and cellular autoimmune responses in the islets of certain individuals. In addition to STZ exposure, the eventual development of autoimmunity against STZ-exposed islet β-cells also depends critically on the genetic predisposition of the susceptible individuals plus the opportunistic presence of a conducive, strong environmental trigger, which often is presented as severe febrile viral infections subsequently inducing strong aberrant reactions of the body’s immune system. The proposed pathogenic hypothesis is supported by a considerable body of direct and indirect evidence from laboratory animal studies and clinical observations. Certainly, more experimental and clinical studies are needed to carefully further examine each of the key components of the proposed pathogenic hypothesis.

Dapagliflozin diminishes memory and cognition impairment in Streptozotocin induced diabetes through its effect on Wnt/β-Catenin and CREB pathway

Diabetic neuropathy is a chronic condition that affects a significant number of individuals with diabetes. Streptozotocin injection intraperitoneally to rodents produces pancreatic islet β-cell destruction causing hyperglycemia, which affect the brain leading to memory and cognition impairment. Dapagliflozin may be able to reverse beta-cell injury and alleviate this impairment. This effect may be via neuroprotective effect or possible involvement of the antioxidant, and anti-apoptotic properties. Forty rats were divided into four groups as follows: The normal control group, STZ-induced diabetes group, STZ-induced diabetic rats followed by treatment with oral dapagliflozin group and normal rats treated with oral dapagliflozin. Behavioral tests (Object location memory task and Morris water maze) were performed. Serum biomarkers (blood glucose and insulin) were measured and then the homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. In the hippocampus the followings were determined; calmodulin, ca-calmodulin kinase Ⅳ (CaMKIV), protein kinase A (PKA) and cAMP-responsive element-binding protein to determine the transcription factor CREB and its signaling pathway also Wnt signaling pathway and related parameters (WnT, B-catenin, lymphoid enhancer binding factor LEF, glycogen synthase kinase 3β). Moreover, nuclear receptor-related protein-1, acetylcholine and its hydrolyzing enzyme acetylcholine esterase, oxidative stress parameter malondialdehyde (MDA) and apoptotic parameter caspase-3 were determined. STZ was able to cause destruction to pancreatic β-cells which was reflected on glucose levels causing diabetes. Diabetic neuropathy was clear in the rats performing the behavioral tests. Memory and cognition parameters in the hippocampus were negatively affected. Oxidative stress and apoptotic parameter were elevated while the electrical activity was declined. Dapagliflozin was able to reverse the previously mentioned parameters and behavior. Thus, to say dapagliflozin significantly showed neuroprotective action along with antioxidant, and anti-apoptotic properties.

Anti-Inflammatory and Pro-Autophagy Effects of the Cannabinoid Receptor CB2R: Possibility of Modulation in Type 1 Diabetes.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease resulting from loss of insulin-secreting β-cells in islets of Langerhans. The loss of β-cells is initiated when self-tolerance to β-cell-derived contents breaks down, which leads to T cell-mediated β-cell damage and, ultimately, β-cell apoptosis. Many investigations have demonstrated the positive effects of antagonizing cannabinoid receptor 1 (CB1R) in metabolic diseases such as fatty liver disease, obesity, and diabetes mellitus, but the role of cannabinoid receptor 2 (CB2R) in such diseases is relatively unknown. Activation of CB2R is known for its immunosuppressive roles in multiple sclerosis, rheumatoid arthritis, Crohn’s, celiac, and lupus diseases, and since autoimmune diseases can share common environmental and genetic factors, we propose CB2R specific agonists may also serve as disease modifiers in diabetes mellitus. The CNR2 gene, which encodes CB2R protein, is the result of a gene duplication of CNR1, which encodes CB1R protein. This ortholog evolved rapidly after transitioning from invertebrates to vertebrate hundreds of million years ago. Human specific CNR2 isoforms are induced by inflammation in pancreatic islets, and a CNR2 nonsynonymous SNP (Q63R) is associated with autoimmune diseases. We collected evidence from the literature and from our own studies demonstrating that CB2R is involved in regulating the inflammasome and especially release of the cytokine interleukin 1B (IL-1β). Furthermore, CB2R activation controls intracellular autophagy and may regulate secretion of extracellular vesicles from adipocytes that participate in recycling of lipid droplets, dysregulation of which induces chronic inflammation and obesity. CB2R activation may play a similar role in islets of Langerhans. Here, we will discuss future strategies to unravel what roles, if any, CB2R modifiers potentially play in T1DM.

Tolerogenic Delivery of a Hybrid Insulin Peptide Markedly Prolongs Islet Graft Survival in the NOD Mouse.

The induction of antigen (Ag)-specific tolerance and replacement of islet β-cells are major ongoing goals for the treatment of type 1 diabetes (T1D). Our group previously showed that a hybrid insulin peptide (2.5HIP) is a critical autoantigen for diabetogenic CD4+ T cells in the NOD mouse model. In this study, we investigated whether induction of Ag-specific tolerance using 2.5HIP-coupled tolerogenic nanoparticles (NPs) could protect diabetic NOD mice from disease recurrence upon syngeneic islet transplantation. Islet graft survival was significantly prolonged in mice treated with 2.5HIP NPs, but not NPs containing the insulin B chain peptide 9-23. Protection in 2.5HIP NP-treated mice was attributed both to the simultaneous induction of anergy in 2.5HIP-specific effector T cells and the expansion of Foxp3+ regulatory T cells specific for the same Ag. Notably, our results indicate that effector function of graft-infiltrating CD4+ and CD8+ T cells specific for other β-cell epitopes was significantly impaired, suggesting a novel mechanism of therapeutically induced linked suppression. This work establishes that tolerance induction with an HIP can delay recurrent autoimmunity in NOD mice, which could inform the development of an Ag-specific therapy for T1D.

Intracellular Toxic Advanced Glycation End-Products in 1.4E7 Cell Line Induce Death with Reduction of Microtubule-Associated Protein 1 Light Chain 3 and p62.

Background: The death of pancreatic islet β-cells (β-cells), which are the insulin-producing cells, promote the pathology in both Type 1 and Type 2 diabetes mellitus (DM) (T1DM and T2DM), and they are protected by autophagy which is one of the mechanisms of cell survival. Recently, that some advanced glycation end-products (AGEs), such as methylglyoxial-derived AGEs and Nε-carboxymethyllysine, induced the death of β-cells were revealed. In contrast, we had reported AGEs derived from glyceraldehyde (GA, the metabolism intermediate of glucose and fructose) are considered to be toxic AGEs (TAGE) due to their cytotoxicity and role in the pathogenesis of T2DM. More, serum levels of TAGE are elevated in patients with T1 and T2DM, where they exert cytotoxicity. Aim: We researched the cytotoxicity of intracellular and extracellular TAGE in β-cells and the possibility that intracellular TAGE were associated with autophagy. Methods: 1.4E7 cells (a human β-cell line) were treated with GA, and analyzed viability, quantity of TAGE, microtubule-associated protein 1 light chain 3 (LC3)-I, LC3-II, and p62. We also examined the viability of 1.4E7 cells treated with TAGE-modified bovine serum albumin, a model of TAGE in the blood. Results: Intracellular TAGE induced death of 1.4E7 cells, decrease of LC3-I, LC3-II, and p62. Extracellular TAGE didn’t show cytotoxicity in the physiological concentration. Conclusion: Intracellular TAGE induced death of β-cells more strongly than extracellular TAGE, and may suppress autophagy via reduction of LC3-I, LC3-II, and p62 to inhibit the degradation of them.

Perioperative Management of a Rare Pancreatic Insulinoma Resection: Anaesthetic Challenge!

Insulinoma is a rare, mostly benign and solitary neuroendocrine tumour of the β-cells of islets of langerhans of pancreas. Clinically it presents with a classical ‘Whipple Triad’ encompassing symptomatic hypoglycemia, fasting hypoglycemia (&lt;50 mg/dl) and immediate relief of symptoms after glucose administration. Definitive treatment is laparoscopic or open surgical excision of the tumour. We report and discuss the distinctive anaesthetic considerations and implications during perioperative period. A comprehensive approach including preoperative optimization of blood glucose levels with various drugs and dietary modifications, scrupulous hemodynamic and blood sugar monitoring with prompt initiation of dextrose infusion during surgical handling of tumour and meticulous management of rebound hyperglycemia with insulin infusion in postoperative period remains the essence for better outcome in these subset of patients.

ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis

AbstractMitochondrial homeostasis is crucial for the function of pancreatic β-cells. ATP synthase inhibitory factor subunit 1 (IF1) is a mitochondrial protein interacting with ATP synthase to inhibit its enzyme activity. IF1 may also play a role in maintaining ATP synthase oligomerization and mitochondrial inner membrane formation. A recent study confirmed IF1 expresses in β-cells. IF1 knockdown in cultured INS-1E β-cells enhances glucose-induced insulin release. However, the role of IF1 in islet β-cells remains little known. The present study investigates islets freshly isolated from mouse lines with global IF1 knockout (IF1−/−) and overexpression (OE). The glucose-stimulated insulin secretion was increased in islets from IF1−/− mice but decreased in islets from IF1 OE mice. Transmitted Electronic Microscopic assessment of isolated islets revealed that the number of matured insulin granules (with dense core) was relatively higher in IF1−/−, but fewer in IF1 OE islets than those of controlled islets. The mitochondrial ultrastructure within β-cells of IF1 overexpressed islets was comparable with those of wild-type mice, whereas those in IF1−/− β-cells showed increased mitochondrial mass. Mitochondrial network analysis in cultured INS-1 β-cells showed a similar pattern with an increased mitochondrial network in IF1 knockdown cells. IF1 overexpressed INS-1 β-cells showed a compromised rate of mitochondrial oxidative phosphorylation with attenuated cellular ATP content. In contrast, INS-1 cells with IF1 knockdown showed markedly increased cellular respiration with improved ATP production. These results support that IF1 is a negative regulator of insulin production and secretion via inhibiting mitochondrial mass and respiration in β-cells. Therefore, inhibiting IF1 to improve β-cell function in patients can be a novel therapeutic strategy to treat diabetes.

Роль вкусовых рецепторов T1R в регуляции потребления и метаболизма углеводов у млекопитающих

Taste receptors type 1, T1R, encoded by Tas1 genes play a key role in sweet and amino acid taste perception in vertebrates. Significant differences in food preferences, described in different groups of animals, could be associated with interruption of expression of some genes encoding these proteins. Numerous polymorphisms of these genes were found in mammals, including humans and mice. These polymorphisms entail an increase in the preference and consumption of sweet substances and affect receptor sensitivity. This makes the study of this system highly relevant in light of the current situation with diabetes and obesity. Although T1Rs were originally cloned in taste cells, the subsequent studies have significantly expanded the understanding of their expression and suggested they had a functional role in parts of the body other than the oral cavity. Their expression is found along the digestive tract and in endocrine tissues (in enteroendocrine and absorptive intestinal cells, α and β-cells of pancreatic islet), liver, adipocytes, in brain structures involved in metabolism and nutrition regulation, osteocytes, and this list is constantly expanding. At the same time, metabolic gene effects still remain poorly understood. This review summarizes the latest data showing that T1R receptors not only influence food choices, but are also involved in controlling hormonal responses that regulate carbohydrate intake and metabolism in body tissues and fat accumulation.

Histochemical revealing and estimation of zinc and insulin content in b-cells of pancreatic islets, prostate and in glandules submandibularis of animals

Histochemical revealing and estimation of zinc and insulin content in b-cells of pancreatic islets, prostate and in glandules submandibularis of animals

Direct Reprogramming of Somatic Cells into Induced β-Cells: An Overview.

The persistent shortage of insulin-producing islet mass or β-cells for transplantation in the ever-growing diabetic population worldwide is a matter of concern. To date, permanent cure to this medical complication is not available and soon after the establishment of lineage-specific reprogramming, direct β-cell reprogramming became a viable alternative for β-cell regeneration. Direct reprogramming is a straightforward and powerful technique that can provide an unlimited supply of cells by transdifferentiating terminally differentiated cells toward the desired cell type. This approach has been extensively used by multiple groups to reprogram non-β-cells toward insulin-producing β-cells. The β-cell identity has been achieved by various studies via ectopic expression of one or more pancreatic-specific transcription factors in somatic cells, bypassing the pluripotent state. This work highlights the importance of the direct reprogramming approaches (both integrative and non-integrative) in generating autologous β-cells for various applications. An in-depth understanding of the strategies and cell sources could prove beneficial for the efficient generation of integration-free functional insulin-producing β-cells for diabetic patients lacking endogenous β-cells.