Diabetogenic Action Research Articles

Oestrogen receptor β mediates the actions of bisphenol-A on ion channel expression in mouse pancreatic beta cells.

Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical that has been associated with type 2 diabetes development. Low doses of BPA modify pancreatic beta cell function and induce insulin resistance; some of these effects are mediated via activation of oestrogen receptors α (ERα) and β (ERβ). Here we investigated whether low doses of BPA regulate the expression and function of ion channel subunits involved in beta cell function. Microarray gene profiling of isolated islets from vehicle- and BPA-treated (100μg/kg per day for 4days) mice was performed using Affymetrix GeneChip Mouse Genome 430.2 Array. Expression level analysis was performed using the normalisation method based on the processing algorithm 'robust multi-array average'. Whole islets or dispersed islets from C57BL/6J or oestrogen receptor β (ERβ) knockout (Erβ-/-) mice were treated with vehicle or BPA (1nmol/l) for 48h. Whole-cell patch-clamp recordings were used to measure Na+ and K+ currents. mRNA expression was evaluated by quantitative real-time PCR. Microarray analysis showed that BPA modulated the expression of 1440 probe sets (1192 upregulated and 248 downregulated genes). Of these, more than 50 genes, including Scn9a, Kcnb2, Kcnma1 and Kcnip1, encoded important Na+ and K+ channel subunits. These findings were confirmed by quantitative RT-PCR in islets from C57BL/6J BPA-treated mice or whole islets treated ex vivo. Electrophysiological measurements showed a decrease in both Na+ and K+ currents in BPA-treated islets. The pharmacological profile indicated that BPA reduced currents mediated by voltage-activated K+ channels (Kv2.1/2.2 channels) and large-conductance Ca2+-activated K+ channels (KCa1.1 channels), which agrees with BPA's effects on gene expression. Beta cells from ERβ-/- mice did not present BPA-induced changes, suggesting that ERβ mediates BPA's effects in pancreatic islets. Finally, BPA increased burst duration, reduced the amplitude of the action potential and enlarged the action potential half-width, leading to alteration in beta cell electrical activity. Our data suggest that BPA modulates the expression and function of Na+ and K+ channels via ERβ in mouse pancreatic islets. Furthermore, BPA alters beta cell electrical activity. Altogether, these BPA-induced changes in beta cells might play a role in the diabetogenic action of BPA described in animal models.

A hypomorphic Ephb2 gene variant contributes to autoimmune diabetes in NOD mice associated with altered Mapk3 activities in B-lymphocytes

Abstract β-cell destruction in type 1 diabetes (T1D) is considered a T-cell mediated autoimmune disease, but based on studies in the NOD mouse model, B-lymphocytes also play a critical pathogenic role. They do so by serving as a preferential subset of pathogenic APC that expand diabetogenic T cells. Immunological tolerance induction mechanisms that normally eliminate or inactivate autoreactive B-lymphocytes are defective in NOD mice and also in T1D patients. We previously mapped a faulty NOD B-lymphocyte tolerance phenotype to a 6.22Mb region on Chromosome 4. With a combination of differential gene expression and ingenuity pathway analyses (IPA) we identified a hypomorphic Ephb2 allelic variant within this region on Chromosome 4 as a potential candidate gene interacting with human T1D susceptibility genes in a common pathway modulating Mapk3 activities. Ephrin-B1 ligand engagement of Ephb2 attenuated B-cell receptor (BCR) induced Mapk3 phosphorylation in vitro. We tested the candidacy of Ephb2 by introducing into NOD mice a transgenic higher expression variant of Ephb2 derived from the B6 strain (NOD-Ephb2B6). Elevated expression of Ephb2 afforded significant T1D protection due to changes in hematopoietic cells. Despite having enhanced proliferative capacity, B-lymphocytes from NOD-Ephb2B6 mice had diminished diabetogenic activity associated with attenuated Mek-Erk signaling. Introduction of the Ephb2 transgene into NOD BCR transgenic models expressing autoreactive peripherin (Per) specific Ig molecules also inhibited the accelerated T1D development characterizing these stocks. Thus, signaling via Ephb2 in B-lymphocytes can fine-tune BCR signaling that ultimately determine their diabetogenic activities.

Single-cell transcriptome analysis reveals diverse islet-infiltrating T cell subsets and a role for BATF in promoting the diabetogenic activity of CD8 T cells

Abstract T cells infiltrate pancreatic islets and directly mediate the destruction of insulin-producing β cells during the development of type 1 diabetes (T1D). However, islet-infiltrating T cell differentiation states and functional diversity have not been completely defined. We used unbiased single-cell RNA sequencing analyses to define the phenotypic complexity of islet-infiltrating T cells in non-obese diabetic (NOD) mice. In the CD4 T cell compartment, we identified naïve, memory, and regulatory T cells, as well as multiple Il21 expressing effector subsets positive for markers indicative of Th1 and Tfh cells. In the CD8 T cell compartment, we identified naïve cells and two activated subsets defined by Slamf6 or Cxcr6 expression, respectively resembling the self-renewing progenitor cells and terminally differentiated effectors found during chronic lymphocytic choriomeningitis virus (LCMV) infection. Single-cell regulatory network inference and clustering (SCENIC) analysis revealed that regulon activity of several transcription factors with known roles in effector CD8 T cell function including Batf were turned on in the Slamf6+ and Cxcr6+ cells. Previous studies have shown that IL-21 induced BATF expression in CD8 T cells is critical to sustain their effector function against chronic LCMV infection. Similarly, we found lower BATF expression in activated islet CD8 T cells from NOD. Il21+/− compared to NOD mice. We further demonstrated that overexpression of BATF in β cell autoreactive CD8 T cells eliminated their need for IL-21 to cause T1D. Our results reveal phenotypically diverse and novel islet-infiltrating T cell subsets and suggest a model in which the IL-21-BATF pathway is critical for the diabetogenic activity of CD8 T cells.

Diabetogenic Action of Statins: Mechanisms.

Observational studies and meta-analyses of randomized clinical trials data have revealed a 10-12% increased risk of new-onset diabetes (NOD) associated with statin therapy; the risk is increased with intensive treatment regimens and in people with features of the metabolic syndrome or prediabetes. The purpose of this review is to provide an updated summary of what is known about the potential mechanisms for the diabetogenic effect of statins. Hydroxyl methyl glutaryl coenzyme A reductase (HMGCoAR) is the target of statin therapy and the activity of this key enzyme in cholesterol synthesis is reduced by statins in a partial and reversible way. Mendelian randomization studies suggest that the effect of statins on glucose homeostasis reflect reduced activity of HMGCoAR. In vitro and in vivo data indicate that statins reduce synthesis of mevalonate pathway products and increase cholesterol loading, leading to impaired β-cell function and decreased insulin sensitivity and insulin release. While this effect has been thought to be a drug class effect, recent insights suggest that pravastatin and pitavastatin could exhibit neutral effects on glycaemic parameters in patients with and without diabetes mellitus. The mechanisms by which statins might lead to the development of NOD are unclear. The inhibition of HMGCoAR activity by statins appears to be a key mechanism. It is difficult to offer a comprehensive view regarding the diabetogenic effect of statins because our understanding of the most widely recognized potential mechanisms, i.e. underlying statin-induced reduction of insulin sensitivity and/or insulin secretion, is still far from complete. The existence of this dual mechanism is supported by the results of a study in a large group of non-diabetic men, showing that a 46% higher risk of NOD in statin users compared to non-users was accompanied by a significant 12% reduction in insulin secretion and a 24.3% increase in insulin resistance. Although statin therapy is associated with a modest increase in the risk of NOD (about one per thousand patient-years), patients should be reassured that the benefits of statins in preventing cardiovascular disease (CVD) events far outweigh the potential risk from elevation in plasma glucose.

Ceramides and diabetes mellitus: an update on the potential molecular relationships

Recent evidence suggests that ceramides can play an important pathophysiological role in the development of diabetes. Ceramides are primarily recognized as lipid bilayer building blocks, but recent work has shown that these endogenous molecules are important intracellular signalling mediators and may exert some diabetogenic effects via molecular pathways involved in insulin resistance, β-cell apoptosis and inflammation. In the present review, we consider the available evidence on the possible roles of ceramides in diabetes mellitus and introduce eight different molecular mechanisms mediating the diabetogenic action of ceramides, categorized into those predominantly related to insulin resistance vs those mainly implicated in β-cell dysfunction. Specifically, the mechanistic evidence involves β-cell apoptosis, pancreatic inflammation, mitochondrial stress, endoplasmic reticulum stress, adipokine release, insulin receptor substrate 1 phosphorylation, oxidative stress and insulin synthesis. Collectively, the evidence suggests that therapeutic agents aimed at reducing ceramide synthesis and lowering circulating levels may be beneficial in the prevention and/or treatment of diabetes and its related complications.

Coumarins ameliorate diabetogenic action of dexamethasone via Akt activation and AMPK signaling in skeletal muscle

Glucocorticoids are widely prescribed for lots of pathological conditions, however, can produce ‘Cushingoid’ side effects including central obesity, glucose intolerance, insulin resistance and so forth. Our study is intended to investigate the improving effects of coumarins on diabetogenic action of dexamethasone in vivo and in vitro and elucidate potential mechanisms. ICR mice treated with dexamethasone for 21 days exhibited decreased body weight, increased blood glucose and impaired glucose tolerance, which were prevented by fraxetin (40 mg/kg/day), esculin (40 mg/kg/day) and osthole (20 mg/kg/day), respectively. Esculin, fraxetin and osthole also could promote glucose uptake in normal C2C12 myotubes, and improve insulin resistance in myotubes induced by dexamethasone. Western blotting results indicated that esculin, fraxetin and osthole could boost Akt activation, stimulate GLUT4 translocation, thus alleviate insulin resistance. Esculin and osthole also could activate AMPK, thereby phosphorylate TBC1D1 at Ser237, and consequently ameliorate diabetogenic action of dexamethasone. Our study indicates coumarins as potential anti-diabetic candidates or leading compounds for drug development.

Growth Hormone and Metabolic Homeostasis

Pituitary growth hormone (GH) is a peptide hormone predominantly secreted by somatotrophs in the anterior pituitary under the tight control of the hypothalamic–pituitary axis and GH secretagogues. GH elicits its effects directly on target organs and cells interacting with GH receptors and through stimulation of insulin-like growth factor 1 production. GH plays critical roles in regulating somatic growth and the metabolism of carbohydrates, lipids, and protein. GH increases insulin secretion and glucose uptake. Conversely, a GH deficient state is characterised by enhanced insulin sensitivity. Diabetogenic actions of GH are evident in conditions of GH excess, such as acromegaly or poorly controlled Type 1 diabetes mellitus. In patients with GH deficiency, administration of GH resulted in impaired glucose tolerance and insulin sensitivity. Owing to its multiple and complex effects, the regulation of GH secretion and its function in normal health and metabolic diseases is a major research interest in the field of molecular endocrinology. This review provides an overview of the effects of GH on glucose, lipid, and protein metabolism, insulin resistance, and metabolic homeostasis.

How do we know that statins are diabetogenic, and why? Is it an important issue in the clinical practice?

There is no doubt nowadays that statins exert a diabetogenic action. The evidence comes from observational studies, ran-domised trials, and meta-analyses. The relationship between statin use and new-onset type 2 diabetes is associated with statin potency and dose. It seems also to be stronger if the lowering effect is stronger and the low-density lipoprotein cholesterol level achieved is lower. The mechanisms underlying the development of diabetes in statin-treated patients are not completely understood. Generally, the increased insulin resistance and decreased insulin secretion are taken into account. However, it should be kept in mind that the cardiovascular risk reduction effect of statins outweighs the harm related to diabetes induc-tion. The patients at risk of diabetes development should be monitored with regard to the parameters of glucose metabolism. The introduction of preventive lifestyle modifications to prevent diabetes is recommended. New-onset diabetes should be managed according to the guidelines.

Interleukin 27 signaling in T cells is essential for the development of type 1 diabetes

Abstract Human genome wide association studies have identified a 0.73 Mb region on chromosome 16 significantly linked to the development of type 1 diabetes (T1D) and IL27 is proposed to be the causal gene. IL27 encodes the p28 subunit of the heterodimeric cytokine interleukin 27 (IL-27). Human eQTL studies suggest a disease promoting role for IL-27 in the pathogenesis of T1D. However, the function of IL-27 in T1D has not been completely defined. The focus of this study was to test the role of IL-27 in the progression of T1D using the NOD mouse model. We generated NOD mice deficient in IL-27 or IL-27 receptor (IL-27Rα). In sharp contrast to wildtype NOD mice, both NOD.Il27−/− and NOD.Il27ra−/− strains were completely protected from T1D. Additionally, histological examination of pancreatic sections revealed that both NOD.Il27−/− and NOD.Il27ra−/− mice had significantly less insulitis compared to the wildtype NOD control. Furthermore, IL-27 production by myeloid antigen presenting cells was sufficient to drive T1D progression. Adoptive transfer of IL-27 deficient T cells into NOD.Rag1−/− recipients resulted in diabetes development indicating that IL-27 deficient mice still harbor diabetogenic T cells. However, NOD.Rag1−/− recipients of IL-27Rα deficient T cells did not develop diabetes demonstrating that direct IL-27 signaling is essential for their diabetogenic activity. We further demonstrated that direct IL-27 signaling promoted the accumulation of CD8 T cells and altered CD4 T cell subsets (reducing Foxp3+ but increasing T-BET+ frequency) in pancreatic islets. Our observations reveal that IL-27 signaling in T cells is required for diabetes development in the NOD mouse and provide additional evidence to support its potential role in human T1D.

On the mechanisms of diabetogenic activity of Xanthurenic acid

On the mechanisms of diabetogenic activity of Xanthurenic acid

Long-term Effects of high-doSe pitavaStatin on Diabetogenicity in comparison with atorvastatin in patients with Metabolic syndrome (LESS-DM): study protocol for a randomized controlled trial

BackgroundThe diabetogenic action of statins remains a concern, particularly in patients at high risk for diabetes receiving intensive statin therapy. Despite the risk of diabetes with statin use being considered a potential class effect, recent studies have suggested that pitavastatin exerts neutral or favorable effects on diabetogenicity. However, no randomized trial has compared the long-term effects of pitavastatin with those of other statins on glycemic control in populations at high risk for diabetes. Hence, we aim to assess the long-term effects of pitavastatin in comparison with atorvastatin on glucose metabolism in patients with metabolic syndrome (MetS).Methods/designThe Long-term Effects of high-doSe pitavaStatin on Diabetogenicity in comparison with atorvastatin in patients with Metabolic syndrome (LESS-DM) trial is a prospective, randomized, open-label, active control clinical trial of patients with MetS. We plan to randomize 500 patients with MetS (1:1) to receive high-dose pitavastatin (4 mg) or atorvastatin (20 mg) daily for 24 months. The primary endpoint will be the change in hemoglobin A1c after statin treatment. Secondary endpoints will include the following: (1) changes in biochemical markers, including insulin, C-peptide, homeostasis model assessment of insulin resistance and insulin secretion, and adiponectin; (2) changes in imaging parameters, including carotid elasticity metrics and indices of cardiac function; and (3) the incidence of clinical events, including new-onset diabetes and cardiovascular disease.DiscussionIn this trial, we will explore whether pitavastatin 4 mg does not disturb glucose metabolism in patients with MetS. It will also provide mechanistic information on statin type-dependent diabetogenic effects and surrogate data regarding vascular and cardiac changes achieved by intensive statin therapy.Trial registrationClinicalTrials.gov, NCT02940366. Registered on 19 October 2016.

Effects of growth hormone on glucose metabolism and insulin resistance in human.

Growth hormone (GH) is important for promotion of somatic growth and the regulation of substrate metabolism. Metabolic action of GH occurs in multiple tissues including the liver, muscle, fat and pancreas either directly or indirectly through insulin-like growth factor 1. The diabetogenic action of GH has been well-described in previous in vivo studies. In this paper, we review the metabolic effects of GH on peripheral tissues focusing on glucose metabolism and insulin resistance, and discuss results from human studies on the long-term effects of GH administration on insulin resistance and hyperglycemia.

Adipocyte JAK2 mediates growth hormone-induced hepatic insulin resistance.

For nearly 100 years, growth hormone (GH) has been known to affect insulin sensitivity and risk of diabetes. However, the tissue governing the effects of GH signaling on insulin and glucose homeostasis remains unknown. Excess GH reduces fat mass and insulin sensitivity. Conversely, GH insensitivity (GHI) is associated with increased adiposity, augmented insulin sensitivity, and protection from diabetes. Here, we induce adipocyte-specific GHI through conditional deletion of Jak2 (JAK2A), an obligate transducer of GH signaling. Similar to whole-body GHI, JAK2A mice had increased adiposity and extreme insulin sensitivity. Loss of adipocyte Jak2 augmented hepatic insulin sensitivity and conferred resistance to diet-induced metabolic stress without overt changes in circulating fatty acids. While GH injections induced hepatic insulin resistance in control mice, the diabetogenic action was absent in JAK2A mice. Adipocyte GH signaling directly impinged on both adipose and hepatic insulin signal transduction. Collectively, our results show that adipose tissue governs the effects of GH on insulin and glucose homeostasis. Further, we show that JAK2 mediates liver insulin sensitivity via an extrahepatic, adipose tissue-dependent mechanism.

A histological study of alloxan-induced diabetes on experimental male Wistar rats

Background: Alloxan is a toxic chemical which is used for induction of diabetes in experimental animals. In the light of various earlier researches which showed different dosages for induction, it has been decided to select and optimize the correct dosage. Alloxan which is a urea derivative is known for its diabetogenic action and causes damage to β-cells. A histological study is conducted for dosage selection of alloxan causing diabetes. Aims and Objectives: This study strives to establish the correct dose which is 120 mg/kg body weight (b.w) intraperitoneally to Wistar rats. Material and Methods: Male albino rats were procured and grouped as Group 1 (control), and alloxanized groups as Group II: 90 mg/kg b.w, Group III: 120 mg/kg b.w, and Group IV: 150 mg/kg b.w the biochemical parameters like blood glucose, urea, creatinine, uric acid, etc., were determined. Animals were sacrificed, and 5 mm pancreatic tissues from various groups were processed for histological examination. Results: Among all, a significant difference in biochemical parameters was observed with 120 mg/kg b.w (Group III) when compared to control group. There was marked degeneration and necrosis in the pancreatic β-cells of islets. Conclusion: Although earlier works have studied the diabetic effect of alloxan, it is pertinent to optimize and standardize the dose selection of alloxan with desirable effects.

Bisphenol A (BPA) aggravates multiple low-dose streptozotocin-induced Type 1 diabetes in C57BL/6 mice

Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disorder characterized by destruction of insulin-producing pancreatic β-cells. Whereas epidemiological data implicate environmental factors in the increasing incidence of T1D, their identity remains unknown. Though exposure to bisphenol A (BPA) has been associated with several disorders, no epidemiologic evidence has linked BPA exposure and T1D. The goal of this study was to elucidate diabetogenic potentials of BPA and underlying mechanisms in the context of T-cell immunity, in a multiple low-dose streptozotocin (MLDSTZ)-induced autoimmune mouse T1D model. C57BL/6 mice were orally exposed to 1 or 10 mg BPA/L starting at 4 wk of age; diabetes was induced at 9 wk of age with STZ. T-cell composition, function, and insulitis levels were studied at Days 11 and 50 during diabetes development (i.e. post-first STZ injection). Results showed both BPA doses increased diabetes incidence and affected T-cell immunity. However, mechanisms of diabetogenic action appeared divergent based on dose. Low-dose BPA fits a profile of an agent that exhibits pro-diabetogenic effects via T-cell immunomodulation in the early stages of disease development, i.e. decreases in splenic T-cell subpopulations [especially CD4+ T-cells] along with a trend in elevation of splenic T-cell formation of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-6). In contrast, high-dose BPA did not affect T-cell populations and led to decreased levels of IFN-γ and TNF-α. Both treatments did not affect insulitis levels at the disease early stage, but aggravated it later on. By the study end, besides decreasing T-cell proliferative capacity, low-dose BPA did not affect other T-cell-related parameters, including cytokine secretion, comparable to the effects of high-dose BPA. In conclusion, this study confirmed BPA as a potential diabetogenic compound with immunomodulatory mechanisms of action – in the context of T-cell immunity – that seemed to be dose dependent in the early immunopathogenesis of a MLDSTZ-induced model of T1D.

Congenic mapping identifies a novel Idd9 subregion regulating type 1 diabetes in NOD mice.

Type 1 diabetes (T1D) results from complex interactions between genetic and environmental factors. The nonobese diabetic (NOD) mouse develops spontaneous T1D and has been used extensively to study the genetic control of this disease. T1D is suppressed in NOD mice congenic for the C57BL/10 (B10)-derived Idd9 resistance region on chromosome 4. Previous studies conducted by other investigators have identified four subregions (Idd9.1, Idd9.2, Idd9.3, and Idd9.4) where B10-derived genes suppress T1D development in NOD mice. We independently generated and characterized six congenic strains containing B10-derived intervals that partially overlap with the Idd9.1 and Idd9.4 regions. T1D incidence studies have revealed a new B10-derived resistance region proximal to Idd9.1. Our results also indicated that a B10-derived gene(s) within the Idd9.4 region suppressed the diabetogenic activity of CD4 T cells and promoted CD103 expression on regulatory T cells indicative of an activated phenotype. In addition, we suggest the presence of a B10-derived susceptibility gene(s) in the Idd9.1/Idd9.4 region. These results provide additional information to improve our understanding of the complex genetic control by the Idd9 region.

Influence of Bisphenol A on Type 2 Diabetes Mellitus

Bisphenol A (BPA) is an organic synthetic compound employed to produce plastics and epoxy resins. It is used as a structural component in polycarbonate beverage bottles and as coating for metal surface in food containers and packaging. The adverse effects of BPA on human health are widely disputed. BPA has been recently associated with a wide variety of medical disorders and, in particular, it was identified as potential endocrine-disrupting compound with diabetogenic action. Most of the clinical observational studies in humans reveal a positive link between BPA exposure, evaluated by the measurement of urinary BPA levels, and the risk of developing type 2 diabetes mellitus. Clinical studies on humans and preclinical studies on in vivo, ex vivo, and in vitro models indicate that BPA, mostly at low doses, may have a role in increasing type 2 diabetes mellitus developmental risk, directly acting on pancreatic cells, in which BPA induces the impairment of insulin and glucagon secretion, triggers inhibition of cell growth and apoptosis, and acts on muscle, hepatic, and adipose cell function, triggering an insulin-resistant state. The current review summarizes the available evidences regarding the association between BPA and type 2 diabetes mellitus, focusing on both clinical and preclinical studies.

Abordagem e Tratamento da Hiperglicemia Induzida por Glicocorticóides

Glucocorticoids have been associated to several side effects, specially a diabetogenic action, the most common and representative effect. Glucocorticoid-induced hyperglycemia is a common medical condition, with general associated morbidity and mortality. It was performed a literature review about the management and treatment of glucocorticoid-induced hyperglycemia. Through numerous not quite fully understood mechanics, glucocorticoids promote hyperglycemia in non-diabetic patients and worsen diabetes control in diabetic individuals. Glucocorticoid-induced hyperglycemia presents key patterns, enhanced in the postprandial period and scheduled-dependent. Despite the existence of guidelines for hyperglycemia treatment in non-critic hospitalized and non-hospitalized patients, there are no guidelines respecting glucocorticoid-induced hyperglycemia. Nevertheless, it is known that glucocorticoid-induced hyperglycemia is complex and demanding, requiring a specific approach. Indeed, glucocorticoid-induced hyperglycemia treatment depends on the glucocorticoid used, its dose, frequency and schedule. Furthermore, the scheme of treatment previously used by diabetic individuals also influences the choice of the new scheme. The authors reviewed the glucocorticoid induced-hyperglycemia thematic and propose strategies to approach and treat glucocorticoid induced-hyperglycemia in diabetic and non-diabetic individuals. This review is expected to be useful in different settings and crosswise to all medical specialties.

Diabetogenic Zinc Binding B-Cytotoxic Chemicals: Mechanisms of Action and Methods for Prevention of Diabetes

Mechanisms of diabetogenic action of diabetogenic zincbinding chemicals (DZBC) as Dithizon and derivatives of 8-oxyquinolin and methods of prevention of diabetes caused by their were investigated. It was established that: a) injection of diabetogenic doses of DZBC as 30-50 mg/kg result forming in bytoplasm of B-cells of chelat complexes Zn-DZBC within a few minutes; b) by electron microscopy it was showed that presence of complex in B-cells within 15-20 min result destruction and death of majority B-cells and developing of 1 type diabetes in animals; c) destruction of B-cells started by destroying of B-granules concentrated deposited form of insulin as Zn-insulin; d) prevention of formation of comlex in B-cells by 2 ways (complete elimination of Zn-ions from B-cells by Glibenclamide or binding of Zn-ions by not diabetogenic chelators as Na salt of Diethyl-dithiocarbamic acid, by Cystein and recovered form of Glutathion completely protect B-cells of formation of complex and of developing of diabetes in 85-95% of animals for period of binding of Zn-ions (12-24 h); e) Xanthurenic Acid formed in animals and human as result of disturbances of tryptophan metabolism possess same mechanism of action as other DZBC but diabetes developed more slowly because XA is synthesised in organism more slowly that is why not possible to destroy majority of B-cells as in result of injection of diabetogenic doses of other DZBC; f) they are only one real way for prevention action of XA- partial or mo complete inhibition of endogene synthesis of XA by administration of Pyridoxine (P) within long time due to ability of P to restore amount of Pyridoxal-5-Phosphate which protect endogene synthesis of XA; two other ways (elimination of Zn-ions and not diabetogenic binding of its) not possible to use for protect developing of diabetes or to reduce its symptoms.

The diabetogenic action of statins - mechanisms and clinical implications.

Treatment with statins has transformed primary and secondary prevention of cardiovascular disease (CVD), including thrombotic stroke. Evidence-based data demonstrate the benefits and safety of statin therapy and help to guide clinicians in the management of populations at high risk of CVD. Nevertheless, clinical trials, meta-analyses and observational studies highlight a 10-12% increase in new-onset diabetes mellitus (NODM) among patients receiving statins. The risk further increases with intensive therapy and among individuals with known risk factors for NODM. Mechanisms underpinning this effect are not yet fully understood; however, Mendelian randomization studies suggest that they are related to lowered activity of HMG-CoA reductase, the target of statin therapy. In vitro research indicates that statins potentially impair β-cell function and decrease insulin sensitivity but how these findings relate to patients is unknown. In the clinic, statins should be prescribed on the basis of CVD risk and individual patient characteristics. In addition, diet and lifestyle interventions should be emphasized to help mitigate the risk of NODM. Individuals who develop NODM while taking statins do not exhibit increased microvascular disease, which is reassuring. In diabetes mellitus of long duration, the effect of statins on glycaemic control is small and unlikely to be clinically important.