Aggravated Glucose Intolerance Research Articles

Trans, trans‐2,4‐decadienal, a lipid peroxidation product, aggravates insulin resistance in obese mice by promoting adipose inflammation

AbstractPeroxidation of polyunsaturated fatty acids results in the creation of numerous α, β‐unsaturated aldehydes, many of which are complicated by the development of diabetes. Trans, trans‐2,4‐decadienal (DDE) is a dietary α, β‐unsaturated aldehyde that is commonly found in food and the environment. However, it is unknown whether DDE exposure has some negative effects on glucose homeostasis and insulin sensitivity. This study investigated the biological effects of long‐term DDE exposure in normal chow diet (NCD)‐fed non‐obese mice and high‐fat diet (HFD)‐fed obese mice. Results showed that oral administration of DDE for 14 weeks did not cause severe toxicity in NCD‐fed non‐obese mice but had significant adverse effects in HFD‐fed obese mice. It was found that DDE exposure caused significant increases in LDL and ALT levels and aggravated glucose intolerance and insulin resistance in obese mice. Moreover, DDE robustly accumulated in adipose tissue and promoted the impairment of the insulin signaling pathway in the adipose tissue of obese mice while not affecting the skeletal muscle or liver. Mechanistically, DDE aggravated adipose tissue inflammation by promoting M1 macrophage accumulation and increasing proinflammatory cytokines in the adipocytes of obese mice, thus leading to impaired systemic insulin resistance. These findings provide crucial insights into the potential health impacts of long‐term DDE exposure.

The Efficacy of HGF/VEGF Gene Therapy for Limb Ischemia in Mice with Impaired Glucose Tolerance: Shift from Angiogenesis to Axonal Growth and Oxidative Potential in Skeletal Muscle

Combined non-viral gene therapy (GT) of ischemia and cardiovascular disease is a promising tool for potential clinical translation. In previous studies our group has developed combined gene therapy by vascular endothelial growth factor 165 (VEGF165) + hepatocyte growth factor (HGF). Our recent works have demonstrated that a bicistronic pDNA that carries both human HGF and VEGF165 coding sequences has a potential for clinical application in peripheral artery disease (PAD). The present study aimed to test HGF/VEGF combined plasmid efficacy in ischemic skeletal muscle comorbid with predominant complications of PAD-impaired glucose tolerance and type 2 diabetes mellitus (T2DM). Male C57BL mice were housed on low-fat (LFD) or high-fat diet (HFD) for 10 weeks and metabolic parameters including FBG level, ITT, and GTT were evaluated. Hindlimb ischemia induction and plasmid administration were performed at 10 weeks with 3 weeks for post-surgical follow-up. Limb blood flow was assessed by laser Doppler scanning at 7, 14, and 21 days after ischemia induction. The necrotic area of m.tibialis anterior, macrophage infiltration, angio- and neuritogenesis were evaluated in tissue sections. The mitochondrial status of skeletal muscle (total mitochondria content, ETC proteins content) was assessed by Western blotting of muscle lysates. At 10 weeks, the HFD group demonstrated impaired glucose tolerance in comparison with the LFD group. HGF/VEGF plasmid injection aggravated glucose intolerance in HFD conditions. Blood flow recovery was not changed by HGF/VEGF plasmid injection either in LFD or HFD conditions. GT in LFD, but not in HFD conditions, enlarged the necrotic area and CD68+ cells infiltration. However, HGF/VEGF plasmid enhanced neuritogenesis and enlarged NF200+ area on muscle sections. In HFD conditions, HGF/VEGF plasmid injection significantly increased mitochondria content and ETC proteins content. The current study demonstrated a significant role of dietary conditions in pre-clinical testing of non-viral GT drugs. HGF/VEGF combined plasmid demonstrated a novel aspect of potential participation in ischemic skeletal muscle regeneration, through regulation of innervation and bioenergetics of muscle. The obtained results made HGF/VEGF combined plasmid a very promising tool for PAD therapy in impaired glucose tolerance conditions.

ChREBP-regulated lipogenesis is not required for the thermogenesis of brown adipose tissue.

ObjectivesBrown adipose tissue (BAT) plays a critical role in energy expenditure by uncoupling protein 1 (UCP1)-mediated thermogenesis and represents an important therapeutic target for metabolic diseases. Carbohydrate response element-binding protein (ChREBP) is a key transcription factor regulating de novo lipogenesis, and its activity is associated with UCP1 expression and thermogenesis in BAT. However, the exact physiological role of endogenous ChREBP in BAT thermogenesis remains unclear.MethodsWe used the Cre/LoxP system to generate ChREBP BAT-specific knockout mice, and examined their BAT thermogenesis under acute cold exposure and long-term cold acclimation. Gene expression was analyzed at the mRNA and protein levels, and lipogenesis was examined by 3H-H2O incorporation assay.ResultsThe mice lacking ChREBP specifically in BAT displayed a significant decrease in the expression levels of lipogenic genes and the activity of de novo lipogenesis in BAT after cold exposure, with UCP1 expression decreased under thermoneutral conditions or after acute cold exposure but not chronic cold acclimation. Unexpectedly, BAT-specific ChREBP deletion did not significantly affect body temperature as well as local temperature or morphology of BAT after acute cold exposure or chronic cold acclimation. Of note, ChREBP deletion mildly aggravated glucose intolerance induced by a high-fat diet.ConclusionsOur work indicates that ChREBP regulates de novo lipogenesis in BAT and glucose tolerance, but is not required for non-shivering thermogenesis by BAT under acute or long-term cold exposure.

MON-635 FDXR Regulates Iron Metabolism and Glucose Metabolism in Liver

Iron is an essential cofactor for many proteins that function in electron transport or oxygen transport as heme or iron-sulfur cluster. On the contrary, iron also has the potential to cause oxidative damage if not carefully regulated and when in labial iron excess. Clinical studies show that elevated serum ferritin levels are observed in most patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). In this context, p53 is shown to induces some mitochondrial iron regulatory genes. The role of crosstalk between p53 and iron metabolism has not been sufficiently examined in the pathogenesis of diabetes and NAFLD.Here, we examined the role of ferredoxin reductase (FDXR), a key mitochondrial regulator for iron metabolism, as p53-inducible gene with focusing on the hepatocyte and liver. We confirmed that p53 induced FDXR expression in HepG2 cells and SKEHP1 cells. Biochemical analysis demonstrated that FDXR regulated ROS levels via iron metabolism. In vivo analysis, high-fat diet activated the p53-FDXR pathway in mice liver. We generated transgene expression in mice liver using adenovirus infection carrying shRNA or CRISPR Cas9 system. Treatment with the FDXR knockdown increased hepatic iron content and aggravated glucose intolerance. Besides, forkhead box protein O1 (FOXO1), a key transcriptional factor that induces phosphoenolpyruvate carboxylase and glucose-6-phosphatase increased ratio of nuclear localization, indicating hepatic gluconeogenesis activation. Consistently, biochemical analysis in HepG2 cells demonstrated that FDXR regulated insulin-dependent FOXO1 nuclear exclusion through oxidative stress.In conclusion, p53-inducible FDXR regulates iron metabolism and oxidative stress. FDXR inhibits iron accumulation and oxidative stress in liver and links to suppression of hepatic gluconeogenesis via insulin-dependent FOXO1 nuclear exclusion. The results of this study provide important new insights into relationship between iron metabolism and glucose metabolism as well as potentially identify novel therapeutic targets for the treatment of diabetes and NAFLD.

Hepatic Neuronal Nitric Oxide Synthase Impaired Hepatic Insulin Sensitivity Through Activation of p38 MAPK

Background: nNOS contains PZD domain and binds with NOS1AP. We reported previously that NOS1AP enhanced hepatic insulin activity on its PZD binding domain suggesting an involvement of nNOS in NOS1AP effect. In present study, we aimed to explore the role of nNOS on hepatic insulin activity and the mechanism underlined. Methods: Liver specific nNOS overexpression was achieved by tail-vein-injection of adenovirus-nNOS in C57BL/6 mice fed with a high-fat diet for 8 weeks. nNOS specific inhibitor (L-NPA) was used to inhibit its activity. Findings: nNOS co-localized with NOS1AP in liver. Its phosphorylation in Ser1417 increased in the livers of ob/ob and diet-induced obese (DIO) mice and mice with liver NOS1AP deletion. It decreased in mice with NOS1AP overexpression. Overexpression of nNOS in the livers of DIO mice aggravated glucose intolerance, increased intrahepatic lipid accumulation, decreased glycogen storage, and blunted insulin-induced phosphorylation of IRβ and Akt in livers. Similarly, overexpression of nNOS increased triglyceride production, decreased glucose utilization, and insulin-induced p-IRβ, p-Akt and p-GSK3β in HepG2 cells. In contrast, inhibition of nNOS with L-NPA in ob/ob mice improved glucose tolerance and increased insulin-induced phosphorylation of IRβ and Akt in livers. Moreover, overexpression of nNOS in HepG2 cells increased p-p38 MAPK expression, and inhibition of p38 MAPK with SB203580 significantly reversed the defect in insulin signaling activation. Interpretation: Hepatic nNOS inhibited insulin signaling activity through activation of p38 MAPK in obesity, suggesting a role of nNOS in the development of hepatic insulin resistance, and a potential therapeutic target for the prevention of diabetes. Funding: This work was supported by the National Natural Science Foundation of China (81670707 to C. Wang). Funding Statement: This study was supported by the National Natural Science Foundation of China (81670707 to C. Wang). Declaration of Interests: The authors declared that they have no conflict of interest. Ethics Approval Statement: The protocol was approved by the Ethics Committee of Shanghai Jiao Tong University (2018-KY-026 (K)). Informed consent was given by all subjects and principles of the Declaration of Helsinki were followed. Procedures involving the care and use of animals were carried out in accordance with the Guidelines for the Care and Use of Laboratory Animals of Shanghai Jiao Tong University and approved by the Animal Ethics Committee of the University Affiliated Sixth People’s Hospital (DWSY2011-096/DWLL2019-0274).

Vitamin K2 Alleviates Insulin Resistance in Skeletal Muscle by Improving Mitochondrial Biogenesis Through Modulating SIRT1 Signaling

Background: High-fat diet (HFD)-induced insulin resistance (IR) impairs skeletal muscle mitochondrial biogenesis and functions, adversely affecting human health and lifespan. Vitamin K2 (VK2) has a beneficial role in improving insulin sensitivity and glucose metabolism. However, the underlying molecular mechanisms of VK2 on insulin sensitivity have not been well established. We investigated VK2's modulation of mitochondrial function to protect against IR in mice and cell models. Method: C57BL/6J mice were fed HFD for sixteen weeks, and different doses of VK2 were supplemented by oral gavage for the last eight weeks. Mouse skeletal muscle C2C12 cells were exposed to palmitic acid (PA) for 16 h to mimic insulin resistance. Findings: VK2 supplementation could effectively ameliorate the development of IR by improving mitochondrial function in both HFD-fed mice and PA-exposed cells. FFA caused mitochondrial dysfunction and aggravated glucose intolerance that could be reversed by VK2 treatment. Moreover, VK2 improved the function of mitochondria and increased mitochondrial biogenesis. Interestingly, the benefits of VK2 were abrogated in C2C12 transfected with SIRT1 siRNA. VK2 and SRT1720, a specific agonist of SIRT1, had the same effect on improving IR via SIRT1 signaling. Thus, VK2 suppresses skeletal muscle IR in an SIRT1-dependent manner. Furthermore, the beneficial effect of VK2 on inhibiting IR contributes to geranylgeraniol, which also activates the SIRT1 signaling pathway. Interpretation: Naturally occurring VK2 ameliorates IR by improving mitochondrial biogenesis and decreasing FFA accumulation through modulating SIRT1 signaling. These effects of VK2 are promising therapeutic targets that can ameliorate HFD-induced IR and mitochondrial dysfunction. Funding Statement: This study was funded by National Natural Science Funds (No, 8157120149 ) and our study also was supported by Shaanxi Key Laboratory of Free Radical Biology and Medicine and Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment. Declaration of Interests: All authors declare no competing interest. Ethics Approval Statement: Experimental protocols were reviewed and approved by the Fourth Military Medical University Institutional Animal Care and Use Committee.

The effect of dicarbonyl stress on the development of kidney dysfunction in metabolic syndrome \u2013 a transcriptomic and proteomic approach

Background and aimsDicarbonyl stress plays an important role in the pathogenesis of microvascular complications that precede the formation of advanced glycation end products, and contributes to the development of renal dysfunction. In renal cells, toxic metabolites like methylglyoxal lead to mitochondrial dysfunction and protein structure modifications.In our study, we investigated the effect of methylglyoxal on metabolic, transcriptomic, metabolomic and proteomic profiles in the context of the development of kidney impairment in the model of metabolic syndrome.Materials and methodsDicarbonyl stress was induced by intragastric administration of methylglyoxal (0.5 mg/kg bw for 4 weeks) in a strain of hereditary hypertriglyceridaemic rats with insulin resistance and fatty liver.ResultsMethylglyoxal administration aggravated glucose intolerance (AUC0–120p < 0.05), and increased plasma glucose (p < 0.01) and insulin (p < 0.05). Compared to controls, methylglyoxal-treated rats exhibited microalbuminuria (p < 0.01). Targeted proteomic analysis revealed increases in urinary secretion of pro-inflammatory parameters (MCP-1, IL-6, IL-8), specific collagen IV fragments and extracellular matrix proteins. Urine metabolomic biomarkers in methylglyoxal-treated rats were mainly associated with impairment of membrane phospholipids (8-isoprostane, 4-hydroxynonenal).Decreased levels of glutathione (p < 0.01) together with diminished activity of glutathione-dependent antioxidant enzymes contributed to oxidative and dicarbonyl stress. Methylglyoxal administration elevated glyoxalase 1 expression (p < 0.05), involved in methylglyoxal degradation. Based on comparative transcriptomic analysis of the kidney cortex, 96 genes were identified as differentially expressed (FDR < 0.05). Network analysis revealed an over-representation of genes related to oxidative stress and pro-inflammatory signalling pathways as well as an inhibition of angiogenesis suggesting its contribution to renal fibrosis.ConclusionOur results support the hypothesis that dicarbonyl stress plays a key role in renal microvascular complications. At the transcriptome level, methylglyoxal activated oxidative and pro-inflammatory pathways and inhibited angiogenesis. These effects were further supported by the results of urinary proteomic and metabolomic analyses.

Dibutyl phthalate exposure aggravates type 2 diabetes by disrupting the insulin-mediated PI3K/AKT signaling pathway

Epidemiological studies suggest a positive relationship between phthalate exposure and diabetes. However, little is known about the impact of dibutyl phthalate (DBP) exposure on the development of diabetes. To determine the role of DBP exposure on the development of type 2 diabetes, mice were orally exposed to DBP dosages of 0.5, 5, 50 mg/kg/day for 7 weeks, combined with a high fat diet and injections of a low dose of streptozotocin (STZ). The results showed that exposure to 50 mg/kg/day DBP alone induced a marked decrease in insulin secretion and glucose intolerance, but had no influence on insulin resistance. However, combined with a high fat diet and STZ treatment, DBP exposure markedly aggravated glucose intolerance, insulin tolerance and insulin resistance and induced lesions in the pancreas and kidney. Investigation of the role of DBP on the insulin signaling pathway, we found that DBP exposure could disrupt the PI3K expression and AKT phosphorylation, and decrease the level of GLUT-2 in the pancreas. Administering demethylasterriquinone B1, significantly increased the level of PI3K, AKT phosphorylation and GLUT-2 expression, effectively inhibiting the aggravation of diabetes. Our results suggested that DBP aggravated type 2 diabetes by disrupting the insulin signaling pathway and impairing insulin secretion.

Fixed combination of bisoprolol and a low-dose hydrochlorothiazide in arterial hypertension

Beta-blockers showed better results in lowering elevated blood pressure in the younger age group of patients with higher renin plasma levels. Actual recommendations from the European Society of Cardiology for treatment of arterial hypertension from 2013 insist that heart rate should always be measured along with blood pressure. These recommendations point out the significance of resting heart rate as an independent predictor of cardiovascular morbidity and mortality in patients with arterial hypertension. Beta-blockers have a compelling indication for treatment of arterial hypertension in patients with coexistence of coronary artery disease, especially post myocardial infarction, as well as in patients with systolic heart failure. Bisoprolol, a highly selective beta-blocker with a long half-life and a prolonged antihypertensive effect, has shown consistent blood pressure control over a period of 24 hours. It has been demonstrated in placebo-controlled studies that administration of thiazide diuretics, in addition to lowering blood pressure levels, had also been associated with a reduction of cardiovascular morbidity and mortality rates. It is evident that effectiveness of thiazide diuretics is dose-dependent; however, undesirable effects of drugs are also dose-dependent. Depending on the dose, they aggravate glucose intolerance, increase lipid levels, cause hypokalemia, hyponatremia, and hypomagnesemia, and increase levels of uric acid. Administration of very low doses of a thiazide diuretic is acceptable in combination with other antihypertensive drugs, because it potentiates the action of other drugs without causing undesirable metabolic effects. The effectiveness and safety of the combination of bisoprolol (in various doses) and a thiazide diuretic in a small dose has been proven in clinical trials.

Administration of roasted barley and roasted horse gram powders pacified chronic sucrose-induced dysglycemia and dyslipidemia in rats and exerted In Vitro potent antioxidative stress effect

Background: Sugar-enriched diets/beverages consumption aggravates dysglycemia, dyslipidemia, insulin resistance, glucose intolerance, and weight gain. If unchecked, these disturbances culminate into diabetes. Indian medical classics advise consumption of roasted barley (BR) and roasted horse gram (HG) to resolve such issues. Objective: To investigate impact of BR and HG in chronic sucrose-induced dysglycemic rats. Materials and Methods: Dysglycemia was induced in rats by oral feeding of 40% sucrose solution continuously for 2 months. Later, rats were treated with test samples at a dose of 4 g/kg body weight twice a day for 1 month after withdrawal of sucrose feeding. Oral glucose tolerance test was performed at the end of experimental period. Biochemical and hematological parameters were analyzed accordingly. Nutritional contents and antioxidative stress activities in food grain powders were evaluated. Results: Chronic sucrose feeding induced glucose intolerance and weight gain. Mere sucrose withdrawal in the absence of supportive therapy aggravated glucose intolerance. Increase in plasma triglycerides, aspartate transaminase, and alanine transaminase and disturbances in hematological parameters were also observed. BR and HG treatment pacified sucrose-induced biochemical metabolic disturbances and improved hematological parameters. BR was superior in normalizing disturbances than horse gram. These grains possess potent antioxidant activities and antioxidative stress properties and are rich source of micronutrient vitamins, minerals, essential amino acids, and fatty acids. Conclusion: Consumption of these food grains may resolve and normalize sucrose-induced metabolic, biochemical, and hematological disturbances. Multiple therapeutic properties originating through phytochemicals, vitamins, minerals, amino acids, and fatty acids in totality may be responsible for observed beneficial effects. Abbreviations used: ABTS+: 2,2'-azinobis-(3-ethylbenzothiazoline -6- sulfonic acid) radical cation; AGEs: Advanced glycation end-products; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BR: Roasted barley; CHO: Chinese hamster ovary cells; DCFDA: 2',7'-dichlorofluorescein diacetate; DPPH: 2,2-diphenyl-1-picrylhydrazyl; DMEM: Dulbecco's modified Eagle's medium; EDTA: Ethylenediaminetetraacetic acid; FeCl3: Ferric chloride; HEK: Human embryonic kidney cells; HG: Roasted horse gram; H2O2: Hydrogen peroxide; MTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NBT: Nitro-blue tetrazolium; OGTT: Oral glucose tolerance test; SW: Sucrose-withdrawn rats; S60: Sixty-day sucrose-fed rats; TC: Plasma total cholesterol; TG: Plasma triglyceride; VC: Vehicle control normal rats.

Hepatocyte-specific sirtuin 6 deletion predisposes to nonalcoholic steatohepatitis by up-regulation of Bach1, an Nrf2 repressor.

Sirtuin (Sirt)6 has been implicated in negative regulation of inflammation and lipid metabolism, although its function in the progression from simple steatosis to nonalcoholic steatohepatitis (NASH) remains to be defined. To explore the role of hepatocyte Sirt6 in NASH development, we generated hepatocyte-specific Sirt6-knockout (KO) mice that were fed a high-fat and high-fructose (HFHF) diet for 16 wk. HFHF-fed KO mice had increased hepatic steatosis and inflammation and aggravated glucose intolerance and insulin resistance compared with wild-type mice. HFHF-induced liver fibrosis and oxidative stress and related gene expression were significantly elevated in KO mice. In the livers of KO mice, nuclear factor erythroid 2-related factor 2 (Nrf2) was down-regulated; conversely, BTB domain and CNC homolog 1 (Bach1), a nuclear repressor of Nrf2, were up-regulated. We discovered that Sirt6, which interacts with Bach1 under basal condition, induces its detachment from the antioxidant response element (ARE) region of heme oxygenase 1 promoter. Furthermore, we found that Sirt6 promotes Nrf2 binding to ARE in response to oxidative stimuli, which leads to the expression of phase II/antioxidant enzymes. Finally, we showed that HFHF-induced steatosis, inflammation, and fibrosis were ameliorated by adenoviral Sirt6 overexpression. Sirt6 may be a useful therapeutic target for amelioration of NASH by curbing inflammation and oxidative stress.-Ka, S.-O, Bang, I. H., Bae, E. J., Park, B.-H. Hepatocyte-specific sirtuin 6 deletion predisposes to nonalcoholic steatohepatitis by up-regulation of Bach1, an Nrf2 repressor.

Human gut microbes impact host serum metabolome and insulin sensitivity.

Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individuals is characterized by increased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus are identified as the main species driving the association between biosynthesis of BCAAs and insulin resistance, and in mice we demonstrate that P. copri can induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs. Our findings suggest that microbial targets may have the potential to diminish insulin resistance and reduce the incidence of common metabolic and cardiovascular disorders.

Chronic stress aggravates glucose intolerance in leptin receptor-deficient (db/db) mice.

Genetic predisposition and environmental challenges interact to determine individual vulnerability to obesity and type 2 diabetes. We previously established a mouse model of chronic subordination stress-induced hyperphagia, obesity, metabolic like-syndrome and insulin resistance in the presence of a high-fat diet. However, it remains to be established if social stress could also aggravate glucose intolerance in subjects genetically predisposed to develop obesity and type 2 diabetes. To answer this question, we subjected genetically obese mice due to deficiency of the leptin receptor (db/db strain) to chronic subordination stress. Over five weeks, subordination stress in db/db mice led to persistent hyperphagia, hyperglycemia and exacerbated glucose intolerance altogether suggestive of an aggravated disorder when compared to controls. On the contrary, body weight and fat mass were similarly affected in stressed and control mice likely due to the hyperactivity shown by subordinate mice. Stressed db/db mice also showed increased plasma inflammatory markers. Altogether our results suggest that chronic stress can aggravate glucose intolerance but not obesity in genetically predisposed subjects on the basis of a disrupted leptin circuitry.

Characterization of Bglu3, a mouse fasting glucose locus, and identification of Apcs as an underlying candidate gene

Bglu3 is a quantitative trait locus for fasting glucose on distal chromosome 1 identified in an intercross between C57BL/6 (B6) and C3H/HeJ (C3H) apolipoprotein E-deficient (apoE(-/-)) mice. This locus was subsequently replicated in two separate mouse intercrosses. The objective of this study was to characterize Bglu3 through construction and analysis of a congenic strain and identify underlying candidate genes. Congenic mice were constructed by introgressing a genomic region harboring Bglu3 from C3H.apoE(-/-) into B6.apoE(-/-) mice. Mice were started with a Western diet at 6 wk of age and maintained on the diet for 12 wk. Gene expression in the liver was analyzed by microarrays. Congenic mice had significantly higher fasting glucose levels and developed more significant glucose intolerance compared with B6.apoE(-/-) mice on the Western diet. Microarray analysis revealed 336 genes to be differentially expressed in the liver of congenic mice. Further pathway analysis suggested a role for acute phase response signaling in regulating glucose intolerance. Apcs, encoding an acute phase response protein serum amyloid P (SAP), is located underneath the linkage peak of Bglu3. Multiple single nucleotide polymorphisms between B6 and C3H mice were detected within and surrounding Apcs. Apcs expression in the liver was significantly higher in congenic and C3H mice compared with B6 mice. The Western diet consumption led to a gradual rise in plasma SAP levels, which was accompanied by rising fasting glucose in both B6 and C3H apoE(-/-) mice. Expression of C3H Apcs in B6.apoE(-/-) mice aggravated glucose intolerance. Bglu3 is confirmed to be a locus affecting diabetes susceptibility, and Apcs is a probable candidate gene.

Augmented reduction of islet β-cell mass in Goto-Kakizaki rats fed high-fat diet and its suppression by pitavastatin treatment.

Aims/Introduction: High fat diet (HFD) is known to be a risk for development of type 2 diabetes. It is unclear, however, how it affects the glucose tolerance or the islet structure in type 2 diabetes. The aim of this study is: (i) to examine the effects of HFD on the islet in GK rats, non-obese type 2 diabetic model; and (ii) to explore if pitavastatin treatment influences the change. To see the effects of HFD on islet changes in type 2 diabetes, 4-week old male GK and Wistar rats were fed HFD for 16 weeks and subjected to glucose tolerance tests and pathological studies of the islet. The effects of pitavastatin (3 mg/kg/day for 16 weeks, oral), one of the lipophilc statins, were also examined in both GK and Wistrar rats fed with or without HFD. The HFD induced hyperlipidemia and aggravated glucose intolerance in both GK and Wistar rats. Pitavastatin treatment did not influence the glucose tolerance in HFD-fed animals. HFD caused an increase in hepatic lipid contents in all the animals, which was partially suppressed by pitavastatin treatment. GK rats showed reduced β-cell mass, and fibrosis and macrophage migration in the islets. HFD feeding in GK rats augmented these changes which were associated with enhanced expression of 8-hydroxydeoxyguanosine and an increase in apoptotic cells. Pitavastatin treatment improved the HFD-induced islet pathology, and pancreatic insulin contents paralleled the structural changes. HFD feeding worsened the islet pathology in GK rats which was suppressed by pitavastatin treatment. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00173.x, 2011).

High prevalence of diabetes mellitus in patients with liver cirrhosis

The reported prevalence of Type 2 diabetes mellitus in patients with liver cirrhosis is five times higher than in the general population. However, these data were never adjusted for classical risk factors for Type 2 diabetes. We therefore investigated the association between cirrhosis and Type 2 diabetes and adjusted for known risk factors for Type 2 diabetes. We reviewed medical files for presence of Type 2 diabetes and potential confounders in 94 patients with cirrhosis (cases) and compared these with a control group of 107 patients with non-ulcer dyspepsia. Multiple logistic regression analysis was used to adjust for potential confounders. The aetiology of our cirrhosis population was alcohol (59%), viral hepatitis (10%), biliary cirrhosis (3%) or cryptogenic (28%). Prevalence of Type 2 diabetes was significantly higher in patients with cirrhosis than in control subjects: 35/94 (37%) vs. 7/107 (7%) (OR 8.5, 95% CI 3.5–20.2, P < 0.001). After adjustment for age, sex, family history of Type 2 diabetes, alcohol use and BMI, cirrhosis remained significantly associated with Type 2 diabetes (OR 13.6, 95% CI 4.3–42.9, P < 0.001). Most cases of Type 2 diabetes were already diagnosed before diagnosis of cirrhosis (21/35, 60%) or were incidentally found together with cirrhosis (5/35, 14%). Liver cirrhosis had a strong, independent association with Type 2 diabetes. Classical risk factors such as family history and BMI could not explain the high Type 2 diabetes prevalence in cirrhosis. Therefore, a liver-derived factor might aggravate glucose intolerance and cause Type 2 diabetes in cirrhosis. In addition, Type 2 diabetes might also cause cirrhosis through liver steatosis and fibrosis.

Insulin sensitivity and body composition in cirrhosis: changes after TIPS

Insertion of a transjugular intrahepatic porto-systemic shunt (TIPS) increases body cell mass (BCM) in patients with liver cirrhosis. The responsible mechanism is unidentified, but may involve changes in insulin sensitivity and glucose metabolism. Eleven patients with liver cirrhosis were examined before and 6 mo after a TIPS procedure with bioimpedance analyses, 2-h oral glucose tolerance tests, and two-step hyperinsulinemic euglycemic clamp with tracer-determined endogenous glucose production. After TIPS, BCM increased by 4.8 kg [confidence interval (CI): 2.7-7.3]. Fasting (f)-insulin increased from 123 +/- 81 to 193 +/- 124 pmol/l (P = 0.03), whereas f-glucose was unchanged (6.0 +/- 0.8 vs. 6.2 +/- 1.0 mmol/l). Glucose and insulin oral glucose tolerance test area under the curve increased by 14% (CI: 7-22%) and 53% (CI: 14-90%), respectively, P < 0.05. The C-peptide-to-insulin ratio decreased by 21% (CI: 8-35%, P = 0.01). Insulin sensitivity based on glucose infusion rate (4.69 +/- 1.82 vs. 4.85 +/- 2.37 mg.kg(-1).min(-1)) and glucose tracer-based rate of disappearance were unchanged (5.01 +/- 1.61 vs. 4.97 +/- 2.13 mg.kg(-1).min(-1)). Despite a further increase in peripheral hyperinsulinemia, f-endogenous glucose production did not change between study days (2.01 +/- 0.42 vs. 2.42 +/- 0.58 mg.kg(-1).min(-1)) and was suppressed equally by insulin (1.1 +/- 0.1 vs. 1.0 +/- 0.1 mg.kg(-1).min(-1)). Insulin clearance, growth hormone, cortisol, and glucagon levels were unchanged. BCM improvement did not correlate with the measured variables. After TIPS, BCM rose, despite enhanced hyperinsulinemia and aggravated glucose intolerance, but unchanged peripheral and hepatic insulin sensitivity. This apparent discrepancy may be ascribed to shunt-related decreased insulin exposure to the liver cells. However, the anabolic effect of TIPS seems not to be related to improvements in insulin sensitivity and remains mechanistically unexplained.

Effects of a late evening snack combined with α‐glucosidase inhibitor on liver cirrhosis

A late evening snack (LES) is recommended for protein-energy malnutrition in patients with liver cirrhosis. However, many cases of liver cirrhosis have accompanying impaired glucose tolerance and there are concerns that LESs might aggravate glucose intolerance. In this study, we concomitantly used an alpha-glucosidase inhibitor with a LES and examined the effects on glucose tolerance. In addition, we examined whether or not there was an improvement in energy metabolism by slowing glucose absorption with the concomitant use of the alpha-glucosidase inhibitor. The subjects were 11 patients with liver cirrhosis. From before the study, all the patients had been taking a LES supplementation with a branched-chain amino acid (BCAA)-enriched nutrient mixture. The patients were started on the concomitant use of alpha-glucosidase inhibitor (0.2 mg) taken just prior to the LES. The change of glucose tolerance and energy metabolism were examined using a 75-g oral glucose tolerance test and indirect calorimetry. One week and three months after the start of the concomitant use of the alpha-glucosidase inhibitor, the area under the concentration curve for plasma glucose was significantly decreased. Three months after the concomitant use, the non-protein respiratory quotient was significantly improved. There were no serious side effects during the follow-ups. The concomitant use of the alpha-glucosidase inhibitor use with LES showed the possibility of improving glucose tolerance and energy metabolism. In patients with impaired glucose tolerance, the concomitant use of an alpha-glucosidase inhibitor with LES might be a useful measure for nutritional management.

Effect of a late evening snack on outpatients with liver cirrhosis

We have reported that one-week administration of a late evening snack (LES) improved not only malnutrition but also glucose intolerance in hospitalized patients with liver cirrhosis. Thus, we investigated whether long-term LES administration to outpatients for 3 months could reproduce the results obtained from hospitalized patients, especially improved glucose intolerance. If this treatment aggravated glucose intolerance, we tried to find any marker predicting this aggravation before the treatment. Outpatients were prescribed one pack of oral supplementation of a branched-chain amino acid (BCAA)-enriched nutrient, Aminoleban EN (210 kCal) as a LES without dietician supervision. Both before LES administration and after 3 months, glucose tolerance and liver function were examined using a 75 g oral glucose tolerance test (OGTT), biochemical parameters in blood and the relationship between glucose tolerance (area under the curve (AUC)) and the following serum markers. Branched-chain amino acid/tyrosine ratio (BTR), the number of red blood cells (RBC), and hematocrit (Ht) significantly increased, with significant reduction of blood NH(3) level in patients with a blood glucose level less than 200 mg/dL 2 h after 75 g OGTT. However, the increase of AUC was seen after 3 months of LES administration in patients who had blood glucose higher than 200 mg/dL 2 h after 75 g OGTT. AUC weakly correlated positively with serum 7S collagen and negatively with choline esterase (ChE) and albumin (Alb). 75 g OGTT is a useful marker to predict the worst outcome and avoid the adverse effect of LES treatment in liver cirrhosis patients if performed without adequate nutrient conduct by a dietician.

Metabolic aspects of continuous renal replacement therapies

Metabolic aspects of continuous renal replacement therapies