Normalizing HIF-1α Signaling Improves Cellular Glucose Metabolism and Blocks the Pathological Pathways of Hyperglycemic Damage

Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial superoxide generation is dispensable for diabetic complications development. Here we tested the hypothesis that hypoxia inducible factor (HIF)-1α and related bioenergetic changes (Warburg effect) play an initiating role in glucotoxicity. By using human endothelial cells and macrophages, we demonstrate that high glucose (HG) induces HIF-1α activity and a switch from oxidative metabolism to glycolysis and its principal branches. HIF1-α silencing, the carbonyl-trapping and anti-glycating agent ʟ-carnosine, and the glyoxalase-1 inducer trans-resveratrol reversed HG-induced bioenergetics/biochemical changes and endothelial-monocyte cell inflammation, pointing to methylglyoxal (MGO) as the non-hypoxic stimulus for HIF1-α induction. Consistently, MGO mimicked the effects of HG on HIF-1α induction and was able to induce a switch from oxidative metabolism to glycolysis. Mechanistically, methylglyoxal causes HIF1-α stabilization by inhibiting prolyl 4-hydroxylase domain 2 enzyme activity through post-translational glycation. These findings introduce a paradigm shift in the pathogenesis and prevention of diabetic complications by identifying HIF-1α as essential mediator of glucotoxicity, targetable with carbonyl-trapping agents and glyoxalase-1 inducers.

Possibilities of application a fixed combination of alogliptin and pioglitazone for type 2 diabetes mellitus treatment

Hyperglycemia in T2DM is based on three main mechanisms: insulin resistance, progressive β-cell dysfunction, and excess glucose production by the liver.The onset of T2DM is usually preceded by a long period of insulin resistance. Prescribing sugar drugs that affect different links of pathogenesis, reducing a steady decrease in glycemia. To date, in clinical practice, various combinations of hypoglycemic drugs are used, the choice of which is determined by the characteristics of the course of diabetes in the patient, the presence of concomitant diseases and complications of diabetes, as well as the dominant clinical problem. This resolution provides an expert council opinion on the feasibility of using a combination of alogliptin and pioglitazone in patients with type 2 diabetes.

Tauroursodeoxycholic acid/TGR5 signaling promotes survival and early development of glucose-stressed porcine embryos

Conditions of impaired energy and nutrient homeostasis, such as diabetes and obesity, are associated with infertility. Hyperglycemia increases endoplasmic reticulum (ER) stress as well as oxidative stress, and reduces the quality and development of embryos. Oxidative stress also causes DNA damage, which impairs embryo quality and development. The natural bile acid tauroursodeoxycholic acid (TUDCA) reduces ER stress and rescues developmentally-incompetent late-cleaving embryos, as well as embryos subjected to nuclear stress, suggesting the ER stress response, or unfolded protein response (UPR), and the genome damage response (GDR) are linked. TUDCA acts via the Takeda-G-protein-receptor 5 (TGR5) receptor to alleviate nuclear stress in embryos. To evaluate the role of TUDCA/TGR5 signaling in embryo UPR, we used a model of glucose-induced ER stress. Embryo development was impaired by direct injection of TUDCA into parthenogenetically activated (PA) oocytes, whereas it was improved when TUDCA was added to the culture medium. Attenuation of the TGR5 receptor precluded the positive effect of TUDCA supplementation on development of PA and fertilized embryos cultured under standard conditions, and PA embryos cultured with excess glucose. Moreover, attenuation of TUDCA/TGR5 signaling induced ER and oxidative stress as well as cell survival genes, but decreased expression of pluripotency genes in PA embryos cultured under excess glucose conditions. These data suggest that TGR5 signaling pathways link the UPR and GDR. Furthermore, this study identifies TGR5 signaling as a potential target for mitigating fertility issues caused by nutrient excess-associated blastomere stress and embryo death.

PHYTOCHEMICAL EVALUATION OF INDIGOFERA ASTRAGALINA

The word diabetes is Greek for a draw off, referring to the ejection of a more quantity of urine; and mellitus is Latin used for sugar. Consequently diabetes mellitus means the passage of huge amounts of sweet urine. This is derived from the information that excess glucose in the blood spills over into the urine, absorbing fluids with it. Based on the exhaustive literature survey, the objective of the present work focussed on the search of herb to be proved as more suitable among the reported herbs/ herbal preparations/claimed herbs, towards the control of blood glucose level in hyperglycemic condition. In the present investigation herbs; Indigofera astragalina were considered based on their literature information. In general, there is very little biological knowledge on the specific modes of action in the treatment of diabetes, but most of the plants have been found to contain substances like phenols, glycosides, alkaloids, terpenoids, flavonoids etc., that are normally concerned as having antidiabetic effect. Keywords: Keywords: Antidiabetic activity, alkaloids, Flavonoid, Phenol and Indigofera Astragalina.

Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing Beta-Cell Mass in db/db Mice

Efficacy of glucokinase activation on glycemic control is limited to a short-term period. One reason might be related with the excess glucose signalling by glucokinase activation towards beta-cells. In this study, we investigated the effect of glucokinase haploinsufficiency on glucose tolerance as well as beta-cell function and mass using a mouse model of type 2 diabetes. Our results showed that <i>db/db</i> mice with glucokinase haploinsufficiency presented amelioration of glucose tolerance by augmented insulin secretion associated with the increase in beta-cell mass when compared with <i>db/db</i> mice. Gene expression profiling, and immunohistochemical and metabolomic analyses revealed that glucokinase haploinsufficiency in the islets of <i>db/db</i> mice was associated with lower expression of stress-related genes, higher expression of transcription factors involved in the maintenance and maturation of beta-cell function, less mitochondrial damage, and a superior metabolic pattern. These effects of glucokinase haploinsufficiency could preserve beta-cell mass under diabetic conditions. These findings verified our hypothesis that optimizing excess glucose signalling in beta-cells by inhibiting glucokinase could prevent beta-cell insufficiency, leading to improving glucose tolerance in diabetes status by preserving beta-cell mass. Therefore, glucokinase inactivation in beta-cells could, paradoxically, be a potential strategy for the treatment of type 2 diabetes.

Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing Beta-Cell Mass in db/db Mice

Efficacy of glucokinase activation on glycemic control is limited to a short-term period. One reason might be related with the excess glucose signalling by glucokinase activation towards beta-cells. In this study, we investigated the effect of glucokinase haploinsufficiency on glucose tolerance as well as beta-cell function and mass using a mouse model of type 2 diabetes. Our results showed that <i>db/db</i> mice with glucokinase haploinsufficiency presented amelioration of glucose tolerance by augmented insulin secretion associated with the increase in beta-cell mass when compared with <i>db/db</i> mice. Gene expression profiling, and immunohistochemical and metabolomic analyses revealed that glucokinase haploinsufficiency in the islets of <i>db/db</i> mice was associated with lower expression of stress-related genes, higher expression of transcription factors involved in the maintenance and maturation of beta-cell function, less mitochondrial damage, and a superior metabolic pattern. These effects of glucokinase haploinsufficiency could preserve beta-cell mass under diabetic conditions. These findings verified our hypothesis that optimizing excess glucose signalling in beta-cells by inhibiting glucokinase could prevent beta-cell insufficiency, leading to improving glucose tolerance in diabetes status by preserving beta-cell mass. Therefore, glucokinase inactivation in beta-cells could, paradoxically, be a potential strategy for the treatment of type 2 diabetes.

Aldose Reductase and the Polyol Pathway in Schwann Cells: Old and New Problems

Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. AR is highly expressed by Schwann cells in the peripheral nervous system (PNS). The excess glucose flux through AR of the polyol pathway under hyperglycemic conditions has been suggested to play a critical role in the development and progression of diabetic peripheral neuropathy (DPN). Despite the intensive basic and clinical studies over the past four decades, the significance of AR over-activation as the pathogenic mechanism of DPN remains to be elucidated. Moreover, the expected efficacy of some AR inhibitors in patients with DPN has been unsatisfactory, which prompted us to further investigate and review the understanding of the physiological and pathological roles of AR in the PNS. Particularly, the investigation of AR and the polyol pathway using immortalized Schwann cells established from normal and AR-deficient mice could shed light on the causal relationship between the metabolic abnormalities of Schwann cells and discordance of axon-Schwann cell interplay in DPN, and led to the development of better therapeutic strategies against DPN.

Study of the kidney function remaining in kidney donors and its related factors in transplant center of Imam Khomeini hospital, Urmia

Introduction: Concerns about the occurrence of premature kidney failure have been expressed a few years after the kidney donation in the donor due to increase in compensatory blood flow in the remaining kidney nephrons. Objectives: This study aimed to study the kidney function remaining in living kidney donors and its related factors. Patients and Methods: Data were collected from 30 kidney donors in Imam Khomeini hospital in Urmia and evaluated using SPSS-22 software. Results: The mean duration of nephrectomy was 36.36 ± 6.22 years. The mean serum creatinine was significantly increased at the time of examination than before donation, and the glomerular filtration rate (GFR) decreased significantly (P<0.001). Male donors (P=0.025) and donors who did not have relative relationship with the recipient (P=0.44) had better kidney function. The renal function at the time of examination was 74.86% amount before donation. The glucose tolerance test (mg/dL 2 hours) of the donors increased significantly at the time of the study compared to the time before donation (P=0.049). Conclusion: The remaining kidney function of the donors has decreased significantly seven years after donation. It seems that kidney donors need more time to excrete excess glucose, so they are far from being over-carbohydrate.

Diabetes, Immunity and Defense System: A Paradox in Treatment

Hyperglycemia has been the primary metabolic condition for the origin of diabetic complications. The glucose in the cell is underutilized due to diminished entry of glucose into the cell and down-regulation of the Pentose Phosphate Pathway. The PPP is the potential pathway in maintaining the defense of the cell through GPx, GR, GSH, and GSSG. Particularly, GPx and GSH levels diminish in diabetes. Constipation in diabetes also plays an important role in decreasing the immune system as the excess glucose in the gut lining enhances the number of gut bacteria and fungi. Antioxidants have not been proved to enhance the immune and defense of cells in diabetes but the exhibitory roles of herbal medicines have been potential in exaggerating the immune and defense system by their unknown modulators and enhancers molecules. Turmeric and black pepper have been proven to enhance the immune and defense of the body in diabetics.

Lack of nutritional immunity in diabetic skin infections promotes Staphylococcus aureus virulence

Elevated blood/tissue glucose is a hallmark feature of advanced diabetes, and people with diabetes are prone to more frequent and invasive infections with Staphylococcus aureus. Phagocytes must markedly increase glucose consumption during infection to generate and oxidative burst and kill invading bacteria. Similarly, glucose is essential for S. aureus survival in an infection and competition with the host, for this limited resource is reminiscent of nutritional immunity. Here, we show that infiltrating phagocytes do not express their high-efficiency glucose transporters in modeled diabetic infections, resulting in a diminished respiratory burst and increased glucose availability for S. aureus. We show that excess glucose in these hyperglycemic abscesses significantly enhances S. aureus virulence potential, resulting in worse infection outcomes. Last, we show that two glucose transporters recently acquired by S. aureus are essential for excess virulence factor production and the concomitant increase in disease severity in hyperglycemic infections.