ß-cell keratin 8 maintains islet mechanical integrity, mitochondrial ultrastructure and ß-cell glucose transporter 2 plasma membrane targeting.

Islet ß-cell dysfunction is an underlying factor for type I diabetes (T1D) development. Insulin sensing and secretion is tightly regulated in ß-cells at multiple subcellular levels. The epithelial intermediate filament protein keratin (K) 8 is the main ß-cell keratin, constituting the filament network with K18. To identify the cell-autonomous functions of K8 in ß-cells, mice with targeted deletion of ß-cell K8 (K8flox/flox; Ins-Cre) were analyzed for islet morphology, ultrastructure and integrity, as well as blood glucose regulation and streptozotocin (STZ)-induced diabetes development. Glucose transporter 2 (GLUT2) localization was studied in ß-cells in vivo and in MIN6 cells with intact or disrupted K8/K18 filaments. Loss of ß-cell K8 leads to a major reduction in K18. Islets without ß-cell K8 are more fragile and these ß-cells display disjointed plasma membrane organization with less membranous E-cadherin and smaller mitochondria, with diffuse cristae. Lack of ß-cell K8 also leads to a reduced glucose stimulated insulin secretion response in vivo, despite undisturbed systemic blood glucose regulation. K8flox/flox; Ins-Cre mice have a decreased sensitivity to STZ compared to K8 wild-type mice, which is in line with decreased membranous GLUT2 expression observed in vivo, as GLUT2 is required for STZ uptake in ß-cells. In vitro, MIN6 cell plasma membrane GLUT2 is rescued in cells overexpressing K8/K18 filaments, but mistargeted in cells with disrupted K8/K18 filaments. ß-cell K8 is required for islet and ß-cell structural integrity, normal mitochondrial morphology and GLUT2 plasma membrane targeting, and has implications on STZ sensitivity as well as systemic insulin responses.

A mathematical model of obesity-induced type 2 diabetes and efficacy of anti-diabetic weight reducing drug.

The dominant paradigm for modeling the obesity-induced T2DM (type 2 diabetes mellitus) today focuses on glucose and insulin regulatory systems, diabetes pathways, and diagnostic test evaluations. The problem with this approach is that it is not possible to explicitly account for the glucose transport mechanism from the blood to the liver, where the glucose is stored, and from the liver to the blood. This makes it inaccurate, if not incorrect, to properly model the concentration of glucose in the blood in comparison to actual glycated hemoglobin (A1C) test results. In this paper, we develop a mathematical model of glucose dynamics by a system of ODEs. The model includes the mechanism of glucose transport from the blood to the liver, and from the liver to the blood, and explains how obesity is likely to lead to T2DM. We use the model to evaluate the efficacy of an anti-T2DM drug that also reduces weight.

An insight into the mechanistic role of (-)-Ampelopsin F from Vatica chinensis L. in inducing insulin secretion in pancreatic beta cells.

Resveratrol oligomers, ranging from dimers to octamers, are formed through regioselective synthesis involving the phenoxy radical coupling of resveratrol building blocks, exhibiting remarkable therapeutic potential, including antidiabetic properties. In this study, we elucidate the mechanistic insights into the insulin secretion potential of a resveratrol dimer, (-)-Ampelopsin F (AmF), isolated from the acetone extract of Vatica chinensis L. stem bark in Pancreatic Beta-TC-6 cell lines. The AmF (50 µM) treated cells exhibited a 3.5-fold increase in insulin secretion potential as compared to unstimulated cells, which was achieved through the enhancement of mitochondrial membrane hyperpolarization, elevation of intracellular calcium concentration, and upregulation of GLUT2 and glucokinase expression in pancreatic Beta-TC-6 cell lines. Furthermore, AmF effectively inhibited the activity of DPP4, showcasing a 2.5-fold decrease compared to the control and a significant 6.5-fold reduction compared to the positive control. These findings emphasize AmF as a potential lead for the management of diabetes mellitus and point to its possible application in the next therapeutic initiatives.

Fanconi-Bickel syndrome complicated by nephrocalcinosis and GFR decline.

Fanconi-Bickel syndrome (FBS) is a rare genetic disorder of carbohydrate metabolism due to pathogenic variants in SLC2A2, a gene encoding glucose transporter 2 (GLUT2), which leads to accumulation of glycogen in the kidney and liver. While consequential complex proximal tubular dysfunction is well acknowledged in the literature, long-term trajectories of kidney function in patients with FBS have not been well characterized, and kidney biopsy is performed infrequently. Here, we report on a patient with FBS followed from infancy through young adulthood who presented early on with hypercalciuria, phosphaturia, and hypophosphatemia, complicated by chronic kidney disease development during childhood. Kidney biopsy, in addition to a widespread glycogen accumulation in proximal tubular epithelial cells, demonstrated medullary nephrocalcinosis. Screening for nephrocalcinosis may be warranted in pediatric patients with FBS, along with close surveillance of their kidney function.

Wfs1 loss-of-function disrupts the composition of mouse pancreatic endocrine cells from birth and impairs Glut2 localization to cytomembrane in pancreatic ß cells.

Wfs1 is an endoplasmic reticulum (ER) membrane located protein highly expressed in pancreatic ß cells and brain. Wfs1 deficiency causes adult pancreatic ß cells dysfunction following ß cells apoptosis. Previous studies mainly focus on the Wfs1 function in adult mouse pancreatic ß cells. However, whether Wfs1 loss-of-function impairs mouse pancreatic ß cell from its early development is unknown. In our study, Wfs1 deficiency disrupts the composition of mouse pancreatic endocrine cells from early postnatal day 0 (P0) to 8 weeks old, with decreased percentage of ß cells and increased percentage of α and δ cells. Meanwhile, Wfs1 loss-of-function leads to reduced intracellular insulin content. Notably, Wfs1 deficiency impairs Glut2 localization and causes the accumulation of Glut2 in mouse pancreatic ß cell cytoplasm. In Wfs1-deficient mice, glucose homeostasis is disturbed from early 3 weeks old to 8 weeks old. This work reveals that Wfs1 is significantly required for the composition of pancreatic endocrine cells and is essential for Glut2 localization in mouse pancreatic ß cells.

Sex Dimorphic Glucose Transporter-2 Regulation of Hypothalamic Astrocyte Glucose and Energy Sensor Expression and Glycogen Metabolism.

The plasma membrane glucose transporter-2 (GLUT2) monitors brain cell uptake of the critical nutrient glucose, and functions within astrocytes of as-yet-unknown location to control glucose counter-regulation. Hypothalamic astrocyte-neuron metabolic coupling provides vital cues to the neural glucostatic network. Current research utilized an established hypothalamic primary astrocyte culture model along with gene knockdown tools to investigate whether GLUT2 imposes sex-specific regulation of glucose/energy sensor function and glycogen metabolism in this cell population. Data show that GLUT2 stimulates or inhibits glucokinase (GCK) expression in glucose-supplied versus -deprived male astrocytes, but does not control this protein in female. Astrocyte 5'-AMP-activated protein kinaseα1/2 (AMPK) protein is augmented by GLUT2 in each sex, but phosphoAMPKα1/2 is coincidently up- (male) or down- (female) regulated. GLUT2 effects on glycogen synthase (GS) diverges in the two sexes, but direction of this control is reversed by glucoprivation in each sex. GLUT2 increases (male) or decreases (female) glycogen phosphorylase-brain type (GPbb) protein during glucoprivation, yet simultaneously inhibits (male) or stimulates (female) GP-muscle type (GPmm) expression. Astrocyte glycogen accumulation is restrained by GLUT2 when glucose is present (male) or absent (both sexes). Outcomes disclose sex-dependent GLUT2 control of the astrocyte glycolytic pathway sensor GCK. Data show that glucose status determines GLUT2 regulation of GS (both sexes), GPbb (female), and GPmm (male), and that GLUT2 imposes opposite control of GS, GPbb, and GPmm profiles between sexes during glucoprivation. Ongoing studies aim to investigate molecular mechanisms underlying sex-dimorphic GLUT2 regulation of hypothalamic astrocyte metabolic-sensory and glycogen metabolic proteins, and to characterize effects of sex-specific astrocyte target protein responses to GLUT2 on glucose regulation.

Cryptosporidium parvumcompetes with the intestinal epithelial cells for glucose and impairs systemic glucose supply in neonatal calves.

Cryptosporidiosis is one of the main causes of diarrhea in children and young livestock. The interaction of the parasite with the intestinal host cells has not been characterized thoroughly yet but may be affected by the nutritional demand of the parasite. Hence, we aimed to investigate the impact of C. parvum infection on glucose metabolism in neonatal calves. Therefore, N = 5 neonatal calves were infected with C. parvum on the first day of life, whereas a control group was not (N = 5). The calves were monitored clinically for one week, and glucose absorption, turnover and oxidation were assessed using stable isotope labelled glucose. The transepithelial transport of glucose was measured using the Ussing chamber technique. Glucose transporters were quantified on gene and protein expression level using RT-qPCR and Western blot in the jejunum epithelium and brush border membrane preparations. Plasma glucose concentration and oral glucose absorption were decreased despite an increased electrogenic phlorizin sensitive transepithelial transport of glucose in infected calves. No difference in the gene or protein abundance of glucose transporters, but an enrichment of glucose transporter 2 in the brush border was observed in the infected calves. Furthermore, the mRNA for enzymes of the glycolysis pathway was increased indicating enhanced glucose oxidation in the infected gut. In summary, C. parvum infection modulates intestinal epithelial glucose absorption and metabolism. We assume that the metabolic competition of the parasite for glucose causes the host cells to upregulate their uptake mechanisms and metabolic machinery to compensate for the energy losses.

Exploring of the ameliorative effects of Nerium (Nerium oleander L.) ethanolic flower extract in streptozotocin induced diabetic rats via biochemical, histological and molecular aspects.

BACKGROUND: Nerium oleander L. is ethnopharmacologically used for diabetes. Our aim was to investigate the ameliorative effects of ethanolic Nerium flower extract (NFE) in STZ-induced diabetic rats. METHODS: Seven random groups including control group, NFE group (50 mg/kg), diabetic group, glibenclamide group and NFE treated groups (25 mg/kg, 75 mg/kg, and 225 mg/kg) were composed of forty-nine rats. Blood glucose level, glycated hemoglobin (HbA1c), insulin level, liver damage parameters and lipid profile parameters were investigated. Antioxidant defense system enzyme activities and reduced glutathione (GSH) and malondialdehyde (MDA) contents and immunotoxic and neurotoxic parameters were determined in liver tissue. Additionally, the ameliorative effects of NFE were histopathologically examined in liver. mRNA levels of SLC2A2 gene encoding glucose transporter 2 protein were measured by quantitative real time PCR. RESULTS: NFE caused decrease in glucose level and HbA1c and increase in insulin and C-peptide levels. Additionally, NFE improved liver damage biomarkers and lipid profile parameters in serum. Moreover, lipid peroxidation was prevented and antioxidant enzyme activities in liver were regulated by NFE treatment. Furthermore, anti-immunotoxic and anti-neurotoxic effects of NFE were determined in liver tissue of diabetic rats. Histopathogically, significant liver damages were observed in the diabetic rats. Histopathological changes were decreased partially in the 225 mg/kg NFE treated group. SLC2A2 gene expression in liver of diabetic rats significantly reduced compared to healthy rats and NFE treatment (25 mg/kg) caused increase in gene expression. CONCLUSION: Flower extract of Nerium plant may have an antidiabetic potential due to its high phytochemical content.

The role of GLUT2 in glucose metabolism in multiple organs and tissues.

The glucose transporter family has an important role in the initial stage of glucose metabolism; Glucose transporters 2 (GLUTs, encoded by the solute carrier family 2, SLC2A genes) is the major glucose transporter in ß-cells of pancreatic islets and hepatocytes but is also expressed in the small intestine, kidneys, and central nervous system; GLUT2 has a relatively low affinity to glucose. Under physiological conditions, GLUT2 transports glucose into cells and allows the glucose concentration to reach balance on the bilateral sides of the cellular membrane; Variation of GLUT2 is associated with various endocrine and metabolic disorders; In this study, we discussed the role of GLUT2 in participating in glucose metabolism and regulation in multiple organs and tissues and its effects on maintaining glucose homeostasis.

Loss of function of renal Glut2 reverses hyperglycaemia and normalises body weight in mouse models of diabetes and obesity.

AIMS/HYPOTHESIS: Renal GLUT2 is increased in diabetes, thereby enhancing glucose reabsorption and worsening hyperglycaemia. Here, we determined whether loss of Glut2 (also known as Slc2a2) specifically in the kidneys would reverse hyperglycaemia and normalise body weight in mouse models of diabetes and obesity. METHODS: We used the tamoxifen-inducible CreERT2-Lox system in mice to knockout Glut2 specifically in the kidneys (Ks-Glut2 KO) to establish the contribution of renal GLUT2 to systemic glucose homeostasis in health and in insulin-dependent as well as non-insulin-dependent diabetes. We measured circulating glucose and insulin levels in response to OGTT or IVGTT under different experimental conditions in the Ks-Glut2 KO and their control mice. Moreover, we quantified urine glucose levels to explain the phenotype of the mice independently of insulin actions. We also used a transcription factor array to identify mechanisms underlying the crosstalk between renal GLUT2 and sodium-glucose cotransporter 2 (SGLT2). RESULTS: The Ks-Glut2 KO mice exhibited improved glucose tolerance and massive glucosuria. Interestingly, this improvement in blood glucose control was eliminated when we knocked out Glut2 in the liver in addition to the kidneys, suggesting that the improvement is attributable to the lack of renal GLUT2. Remarkably, induction of renal Glut2 deficiency reversed hyperglycaemia and normalised body weight in mouse models of diabetes and obesity. Longitudinal monitoring of renal glucose transporters revealed that Sglt2 (also known as Slc5a2) expression was almost abolished 3 weeks after inducing renal Glut2 deficiency. To identify a molecular basis for this crosstalk, we screened for renal transcription factors that were downregulated in the Ks-Glut2 KO mice. Hnf1α (also known as Hnf1a) was among the genes most downregulated and its recovery restored Sglt2 expression in primary renal proximal tubular cells isolated from the Ks-Glut2 KO mice. CONCLUSIONS/INTERPRETATION: Altogether, these results demonstrate a novel crosstalk between renal GLUT2 and SGLT2 in regulating systemic glucose homeostasis via glucose reabsorption. Our findings also indicate that inhibiting renal GLUT2 is a potential therapy for diabetes and obesity.

Developmental alterations of intestinal SGLT1 and GLUT2 induced by early weaning coincides with persistent low-grade metabolic inflammation in female pigs.

Early-life adversity (ELA) is linked with the increased risk for inflammatory and metabolic diseases in later life, but the mechanisms remain poorly understood. Intestinal epithelial glucose transporters sodium-glucose-linked transporter 1 (SGLT1) and glucose transporter 2 (GLUT2) are the major route for intestinal glucose uptake but have also received increased attention as modulators of inflammatory and metabolic diseases. Here, we tested the hypothesis that early weaning (EW) in pigs, an established model of ELA, alters the development of epithelial glucose transporters and coincides with elevated markers of metabolic inflammation. The jejunum and ileum of 90-day-old pigs previously exposed to EW (16 days wean age), exhibited reduced SGLT1 activity (by ∼ 30%, P < 0.05) than late weaned (LW, 28 days wean age) controls. In contrast, GLUT2-mediated glucose transport was increased (P = 0.003) in EW pigs than in LW pigs. Reciprocal changes in SGLT1- and GLUT2-mediated transport coincided with transporter protein expression in the intestinal brush-border membranes (BBMs) that were observed at 90 days and 150 days of age. Ileal SGLT1-mediated glucose transport and BBM expression were inhibited by the ß-adrenergic receptor (ßAR) blocker propranolol in EW and LW pigs. In contrast, propranolol enhanced ileal GLUT2-mediated glucose transport (P = 0.015) and brush-border membrane vesicle (BBMV) abundance (P = 0.035) in LW pigs, but not in EW pigs. Early-weaned pigs exhibited chronically elevated blood glucose and C-reactive protein (CRP) levels, and adipocyte hypertrophy and upregulated adipogenesis-related gene expression in visceral adipose tissue. Altered development of intestinal glucose transporters by EW could underlie the increased risk for later life inflammatory and metabolic diseases.NEW & NOTEWORTHY These studies reveal that early-life adversity in the form of early weaning in pigs causes a developmental shift in intestinal glucose transport from SGLT1 toward GLUT2-mediated transport. Early weaning also induced markers of metabolic inflammation including persistent elevations in blood glucose and the inflammatory marker CRP, along with increased visceral adiposity. Altered intestinal glucose transport might contribute to increased risk for inflammatory and metabolic diseases associated with early-life adversity.

Soat2 ties cholesterol metabolism to ß-oxidation and glucose tolerance in male mice.

BACKGROUND: Sterol O-acyltransferase 2 (Soat2) encodes acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2), which synthesizes cholesteryl esters in hepatocytes and enterocytes fated either to storage or to secretion into nascent triglyceride-rich lipoproteins. OBJECTIVES: We aimed to unravel the molecular mechanisms leading to reduced hepatic steatosis when Soat2 is depleted in mice. METHODS: Soat2-/- and wild-type mice were fed a high-fat, a high-carbohydrate, or a chow diet, and parameters of lipid and glucose metabolism were assessed. RESULTS: Glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), oral glucose tolerance (OGTT), and insulin tolerance tests significantly improved in Soat2-/- mice, irrespective of the dietary regimes (2-way ANOVA). The significant positive correlations between area under the curve (AUC) OGTT (r = 0.66, p < 0.05), serum fasting insulin (r = 0.86, p < 0.05), HOMA-IR (r = 0.86, p < 0.05), Adipo-IR (0.87, p < 0.05), hepatic triglycerides (TGs) (r = 0.89, p < 0.05), very-low-density lipoprotein (VLDL)-TG (r = 0.87, p < 0.05) and the hepatic cholesteryl esters in wild-type mice disappeared in Soat2-/- mice. Genetic depletion of Soat2 also increased whole-body oxidation by 30% (p < 0.05) compared to wild-type mice. CONCLUSION: Our data demonstrate that ACAT2-generated cholesteryl esters negatively affect the metabolic control by retaining TG in the liver and that genetic inhibition of Soat2 improves liver steatosis via partitioning of lipids into secretory (VLDL-TG) and oxidative (fatty acids) pathways.

Enzyme kinetic approach for mechanistic insight and predictions of in vivo starch digestibility and the glycaemic index of foods.

BACKGROUND: Starch is a principal dietary source of digestible carbohydrate and energy. Glycaemic and insulinaemic responses to foods containing starch vary considerably and glucose responses to starchy foods are often described by the glycaemic index (GI) and/or glycaemic load (GL). Low GI/GL foods are beneficial in the management of cardiometabolic disorders (e.g., type 2 diabetes, cardiovascular disease). Differences in rates and extents of digestion of starch-containing foods will affect postprandial glycaemia. SCOPE AND APPROACH: Amylolysis kinetics are influenced by structural properties of the food matrix and of starch itself. Native (raw) semi-crystalline starch is digested slowly but hydrothermal processing (cooking) gelatinises the starch and greatly increases its digestibility. In plants, starch granules are contained within cells and intact cell walls can limit accessibility of water and digestive enzymes hindering gelatinisation and digestibility. In vitro studies of starch digestion by α-amylase model early stages in digestion and can suggest likely rates of digestion in vivo and expected glycaemic responses. Reports that metabolic responses to dietary starch are influenced by α-amylase gene copy number, heightens interest in amylolysis. KEY FINDINGS AND CONCLUSIONS: This review shows how enzyme kinetic strategies can provide explanations for differences in digestion rate of different starchy foods. Michaelis-Menten and Log of Slope analyses provide kinetic parameters (e.g., K m and k cat /K m ) for evaluating catalytic efficiency and ease of digestibility of starch by α-amylase. Suitable kinetic methods maximise the information that can be obtained from in vitro work for predictions of starch digestion and glycaemic responses in vivo.

Characterisation of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice.

AIMS/HYPOTHESIS: Pancreatic polypeptide (PP) cells, which secrete PP (encoded by the Ppy gene), are a minor population of pancreatic endocrine cells. Although it has been reported that the loss of beta cell identity might be associated with beta-to-PP cell-fate conversion, at present, little is known regarding the characteristics of Ppy-lineage cells. METHODS: We used Ppy-Cre driver mice and a PP-specific monoclonal antibody to investigate the association between Ppy-lineage cells and beta cells. The molecular profiles of endocrine cells were investigated by single-cell transcriptome analysis and the glucose responsiveness of beta cells was assessed by Ca2+ imaging. Diabetic conditions were experimentally induced in mice by either streptozotocin or diphtheria toxin. RESULTS: Ppy-lineage cells were found to contribute to the four major types of endocrine cells, including beta cells. Ppy-lineage beta cells are a minor subpopulation, accounting for 12-15% of total beta cells, and are mostly (81.2%) localised at the islet periphery. Unbiased single-cell analysis with a Ppy-lineage tracer demonstrated that beta cells are composed of seven clusters, which are categorised into two groups (i.e. Ppy-lineage and non-Ppy-lineage beta cells). These subpopulations of beta cells demonstrated distinct characteristics regarding their functionality and gene expression profiles. Ppy-lineage beta cells had a reduced glucose-stimulated Ca2+ signalling response and were increased in number in experimental diabetes models. CONCLUSIONS/INTERPRETATION: Our results indicate that an unexpected degree of beta cell heterogeneity is defined by Ppy gene activation, providing valuable insight into the homeostatic regulation of pancreatic islets and future therapeutic strategies against diabetes. DATA AVAILABILITY: The single-cell RNA sequence (scRNA-seq) analysis datasets generated in this study have been deposited in the Gene Expression Omnibus (GEO) under the accession number GSE166164 ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE166164 ).

Early postnatal stress impairs insulin secretion in response to psychological stress in adult rats.

PURPOSE: Adversity in early life can induce metabolic defects in exposure to stress in adulthood. Therefore, the exploration of involving mechanisms can be helpful in the treatment of metabolic disorders. So, the present study was conducted in terms of exploring the effects of interaction between early postnatal stress and young adulthood psychological stress on insulin secretion and pancreatic GLUT-2 levels in male rats. METHODS: Footshock as a model of early life stress (at 2 weeks of age) and psychological stress induced by communication box as a model of young adulthood stress (at 8-10 weeks of age) were induced in male Wistar rats for five consecutive days (2 times/day). Blood samples were drawn to measure glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of ß-cell dysfunction (HOMA-B), before and after stress protocol in young adult rats. Corticosterone was measured on days 1 and 5 of stress induction. The day after the stress period, factors including glucose tolerance, TNF-alpha, isolated islets' insulin output and levels of pancreatic GLUT-2 protein via western blotting were determined. RESULTS: The combination of early footshock exposure and psychological stress during adulthood did not affect plasma corticosterone, but increased plasma insulin, HOMA-IR, HOMA-B and TNF-alpha levels. Plasma TNF was not only increased by the combination of both stressors, but also after only E STR exposure. HOMA-IR was increased in both Psy STR and E + Psy-STR groups. Plasma glucose just increased in Psy STR group. The combination of these two life stressors further increased the in vitro insulin secretion from isolated islets in response to 16.7-mM glucose. The level of Glut2 was increased in Psy STR and decreased in both E STR and E + Psy STR groups. Finally, glucose tolerance was impaired and glucose-stimulated insulin secretion was increased in E + Psy STR group. CONCLUSIONS: In conclusion, inducing stress in early life makes the organism more susceptible to metabolic defects in exposure to psychological stress later in life.

Alzheimer's disease improved through the activity of mitochondrial chain complexes and their gene expression in rats by boswellic acid.

The foremost neurodegenerative disease is Alzheimer's (AD), which is characterized as a gradual decrease in memory, cognitive function, and also personal changes occurred. This study aims to assess the role of boswellic bioactive component in control Alzheimer's disease through enhancing mitochondrial electron transport chain complexes in the rat model. Rats were divided into five equal groups: the control group (G1), boswellic acid control group (G2), AD disease group (G3), boswellic acid -pre-treated group (G4) and boswellic acid-treated group (G5). At the end of the experiment, blood glucose level, tau protein, different neurochemicals parameters (dopamine, acetylcholine), L-malondialdehyde (MDA) levels, and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities was determined. Also, GLUT2 and mitochondrial electron transport chain complexes were evaluated. As a result, an increase in hippocampus glucose, tau protein expression, MDA and GLUT2 in the AD group (G3) compared to control groups (G1 and G2) has been recorded. These parameters were declined after pre (G4) and treated (G5) by boswellic acid. The neurochemicals, antioxidants parameters, four mitochondrial chain complexes activities and their gene expression in the hippocampus of the AD group were decreased compared to the control groups (G1 and G2). In contrast, pre and treated groups by boswellic acid (G4 and G5, respectively) have shown an increase in antioxidants parameters, and the activities of four mitochondrial complexes, with the best improvement in the pre-treated group (G4), then treated group (G5). In conclusion; the boswellic acid improved the antioxidant and mitochondrial complexes in Alzheimer's disease.

Berberine Decreases Intestinal GLUT2 Translocation and Reduces Intestinal Glucose Absorption in Mice.

Postprandial hyperglycemia is an important causative factor of type 2 diabetes mellitus, and permanent localization of intestinal GLUT2 in the brush border membrane is an important reason of postprandial hyperglycemia. Berberine, a small molecule derived from Coptidis rhizome, has been found to be potent at lowering blood glucose, but how berberine lowers postprandial blood glucose is still elusive. Here, we investigated the effect of berberine on intestinal glucose transporter 2 (GLUT2) translocation and intestinal glucose absorption in type 2 diabetes mouse model. Type 2 diabetes was induced by feeding of a high-fat diet and injection of streptozotocin and diabetic mice were treated with berberine for 6 weeks. The effects of berberine on intestinal glucose transport and GLUT2 translocation were accessed in isolated intestines and intestinal epithelial cells (IEC-6), respectively. We found that berberine treatment improved glucose tolerance and systemic insulin sensitivity in diabetic mice. Furthermore, berberine decreased intestinal glucose transport and inhibited GLUT2 translocation from cytoplasm to brush border membrane in intestinal epithelial cells. Mechanistically, berberine inhibited intestinal insulin-like growth factor 1 (IGF-1R) phosphorylation and thus reduced localization of PLC-ß2 in the membrane, leading to decreased GLUT2 translocation. These results suggest that berberine reduces intestinal glucose absorption through inhibiting IGF-1R-PLC-ß2-GLUT2 signal pathway.

The Postnatal Offspring of Finasteride-Treated Male Rats Shows Hyperglycaemia, Elevated Hepatic Glycogen Storage and Altered GLUT2, IR, and AR Expression in the Liver.

BACKGROUND: A growing body of data indicates that the physiology of the liver is sex-hormone dependent, with some types of liver failure occurring more frequently in males, and some in females. In males, in physiological conditions, testosterone acts via androgen receptors (AR) to increase insulin receptor (IR) expression and glycogen synthesis, and to decrease glucose uptake controlled by liver-specific glucose transporter 2 (GLUT-2). Our previous study indicated that this mechanism may be impaired by finasteride, a popular drug used in urology and dermatology, inhibiting 5α-reductase 2, which converts testosterone (T) into dihydrotestosterone (DHT). Our research has also shown that the offspring of rats exposed to finasteride have an altered T-DHT ratio and show changes in their testes and epididymides. Therefore, the goal of this study was to assess whether the administration of finasteride had an trans-generational effect on (i) GLUT-2 dependent accumulation of glycogen in the liver, (ii) IR and AR expression in the hepatocytes of male rat offspring, (iii) a relation between serum T and DHT levels and the expression of GLUT2, IR, and AR mRNAs, (iv) a serum glucose level and it correlation with GLUT-2 mRNA. METHODS: The study was conducted on the liver (an androgen-dependent organ) from 7, 14, 21, 28, and 90-day old Wistar male rats (F1:Fin) born by females fertilized by finasteride-treated rats. The control group was the offspring (F1:Control) of untreated Wistar parents. In the histological sections of liver the Periodic Acid Schiff (PAS) staining (to visualize glycogen) and IHC (to detect GLUT-2, IR, and AR) were performed. The liver homogenates were used in qRT-PCR to assess GLUT2, IR, and AR mRNA expression. The percentage of PAS-positive glycogen areas were correlated with the immunoexpression of GLUT-2, serum levels of T and DHT were correlated with GLUT-2, IR, and AR transcript levels, and serum glucose concentration was correlated with the age of animals and with the GLUT-2 mRNA by Spearman's rank correlation coefficients. RESULTS: In each age group of F1:Fin rats, the accumulation of glycogen was elevated but did not correlate with changes in GLUT-2 expression. The levels of GLUT-2, IR, and AR transcripts and their immunoreactivity statistically significantly decreased in F1:Fin animals. In F1:Fin rats the serum levels of T and DHT negatively correlated with androgen receptor mRNA. The animals from F1:Fin group have statistically elevated level of glucose. Additionally, in adult F1:Fin rats, steatosis was observed in the liver (see Appendix A). CONCLUSIONS: It seems that treating male adult rats with finasteride causes changes in the carbohydrate metabolism in the liver of their offspring. This can lead to improper hepatic energy homeostasis or even hyperglycaemia, insulin resistance, as well as some symptoms of metabolic syndrome and liver steatosis.

[Molecular mechanism of geniposide in regulating GLUT2 glycosylation in pancreatic ß cells].

Type 2 diabetes mellitus( T2 DM) is a common chronic metabolic disease characterized by persistent hyperglycemia and insulin resistance. In pancreatic ß-cells,glucose-stimulated insulin secretion( GSIS) plays a pivotal role in maintaining the balance of blood glucose level. Previous studies have shown that geniposide,one of the active components of Gardenia jasminoides,could quickly regulate the absorption and metabolism of glucose,and affect glucose-stimulated insulin secretion in pancreatic ß cells,but the specific mechanism needs to be further explored. Emerging evidence indicated that glycosylation of glucose transporter( GLUT) has played a key role in sensing cell microenvironmental changes and regulating glucose homeostasis in eucaryotic cells. In this study,we studied the effects of geniposide on the key molecules of GLUT2 glycosylation in pancreatic ß cells. The results showed that geniposide could significantly up-regulate the mRNA and protein levels of Glc NAc T-Ⅳa glycosyltransferase( Gn T-Ⅳa) and galectin-9 but had no signi-ficant effect on the expression of clathrin,and geniposide could distinctively regulate the protein level of Gn T-Ⅳa in a short time( 1 h) under the conditions of low and medium glucose concentrations,but had no significant effect on the protein level of galectin-9. In addition,geniposide could also remarkably affect the protein level of glycosylated GLUT2 in a short-time treatment. The above results suggested that geniposide could quickly regulate the protein level of Gn T-Ⅳa,a key molecule of protein glycosylation in INS-1 rat pancreatic ßcells and affect the glycosylation of GLUT2. These findings suggested that the regulation of geniposide on glucose absorption,metabolism and glucose-stimulated insulin secretion might be associated with its efficacy in regulating GLUT2 glycosylation and affecting its distribution on the cell membrane and cytoplasm in pancreatic ß cells.

A novel role for farnesoid X receptor in the bile acid-mediated intestinal glucose homeostasis.

The farnesoid X receptor (FXR), as a bile acid (BA) sensor, plays an important role in the regulation of lipid metabolism. However, the effects and underlying molecular mechanisms of FXR on intestinal glucose homeostasis remain elusive. Herein, we demonstrated that FXR and glucose transporter 2 (GLUT2) are essential for BA-mediated glucose homeostasis in the intestine. BA-activated FXR enhanced glucose uptake in intestinal epithelial cells by increasing the expression of GLUT2, which depended on ERK1/2 phosphorylation via S1PR2. However, it also reduced the cell energy generation via inhibition of oxidative phosphorylation, which is crucial for intestinal glucose transport. Moreover, BA-activated FXR signalling potently inhibited specific glucose flux through the intestinal epithelium to the circulation, which reduced the increase in blood glucose levels in mice following oral glucose administration. This trend was supported by the changed ratio of GLUT2 to SGLT1 in the brush border membrane (BBM), including especially decreased GLUT2 abundance in the BBM. Furthermore, impaired intestinal FXR signalling was observed in the patients with intestinal bile acid deficiency (IBAD). These findings uncover a novel function by which FXR sustains the intestinal glucose homeostasis and provide a rationale for FXR agonists in the treatment of IBAD-related hyperglycaemia.