(-)-Epicatechin Reverses Glucose Intolerance in Rats Housed at Thermoneutrality.

Diabetes is a life-threatening and debilitating disease with pathological hallmarks, including glucose intolerance and insulin resistance. Plant compounds are a source of novel and effective therapeutics, and the flavonoid (-)-epicatechin, common to popular foods worldwide, has been shown to improve carbohydrate metabolism in both clinical studies and preclinical models. We hypothesized that (-)-epicatechin would alleviate thermoneutral housing-induced glucose intolerance. Male rats were housed at either thermoneutral (30 °C) or room temperature (24 °C) for 16 weeks and gavaged with either 1 mg/kg body weight or vehicle for the last 15 days before sacrifice. Rats housed at thermoneutrality had a significantly elevated serum glucose area under the curve (p < 0.05) and reduced glucose-mediated insulin secretion. In contrast, rats at thermoneutrality treated with (-)-epicatechin had improved glucose tolerance and increased insulin secretion (p < 0.05). Insulin tolerance tests revealed no differences in insulin sensitivity in any of the four groups. Pancreatic immunohistochemistry staining showed significantly greater islet insulin positive cells in animals housed at thermoneutrality. In conclusion, (-)-epicatechin improved carbohydrate tolerance via increased insulin secretion in response to glucose challenge without a change in insulin sensitivity.

High-dose saccharin supplementation does not induce gut microbiota changes or glucose intolerance in healthy humans and mice.

BACKGROUND: Non-caloric artificial sweeteners (NCAS) are widely used as a substitute for dietary sugars to control body weight or glycemia. Paradoxically, some interventional studies in humans and rodents have shown unfavorable changes in glucose homeostasis in response to NCAS consumption. The causative mechanisms are largely unknown, but adverse changes in gut microbiota have been proposed to mediate these effects. These findings have raised concerns about NCAS safety and called into question their broad use, but further physiological and dietary considerations must be first addressed before these results are generalized. We also reasoned that, since NCAS are bona fide ligands for sweet taste receptors (STRs) expressed in the intestine, some metabolic effects associated with NCAS use could be attributed to a common mechanism involving the host. RESULTS: We conducted a double-blind, placebo-controlled, parallel arm study exploring the effects of pure saccharin compound on gut microbiota and glucose tolerance in healthy men and women. Participants were randomized to placebo, saccharin, lactisole (STR inhibitor), or saccharin with lactisole administered in capsules twice daily to achieve the maximum acceptable daily intake for 2 weeks. In parallel, we performed a 10-week study administering pure saccharin at a high dose in the drinking water of chow-fed mice with genetic ablation of STRs (T1R2-KO) and wild-type (WT) littermate controls. In humans and mice, none of the interventions affected glucose or hormonal responses to an oral glucose tolerance test (OGTT) or glucose absorption in mice. Similarly, pure saccharin supplementation did not alter microbial diversity or composition at any taxonomic level in humans and mice alike. No treatment effects were also noted in readouts of microbial activity such as fecal metabolites or short-chain fatty acids (SCFA). However, compared to WT, T1R2-KO mice were protected from age-dependent increases in fecal SCFA and the development of glucose intolerance. CONCLUSIONS: Short-term saccharin consumption at maximum acceptable levels is not sufficient to alter gut microbiota or induce glucose intolerance in apparently healthy humans and mice. TRIAL REGISTRATION: Trial registration number NCT03032640 , registered on January 26, 2017. Video abstract.

Tissue-dependent effects of cis-9,trans-11- and trans-10,cis-12-CLA isomers on glucose and lipid metabolism in adult male mice.

Mixtures of the two major conjugated linoleic acid (CLA) isomers trans-10,cis-12-CLA and cis-9,trans-11-CLA are used as over the counter supplements for weight loss. Because of the reported adverse effects of CLA on insulin sensitivity in some mouse studies, we sought to compare the impact of dietary t10c12-CLA and c9t11-CLA on liver, adipose tissue, and systemic metabolism of adult lean mice. We fed 8 week-old C57Bl/6J male mice with low fat diets (10.5% Kcal from fat) containing 0.8% t10c12-CLA or c9t11-CLA for 9 or 38 days. Diets containing c9t11-CLA had minimal impact on the endpoints studied. However, 7 days after starting the t10c12-CLA diet, we observed a dramatic reduction in fat mass measured by NMR spectroscopy, which interestingly rebounded by 38 days. This rebound was apparently due to a massive accumulation of lipids in the liver, because adipose tissue depots were visually undetectable. Hepatic steatosis and the disappearance of adipose tissue after t10c12-CLA feeding was associated with elevated plasma insulin levels and insulin resistance, compared to mice fed a control diet or c9t11-CLA diet. Unexpectedly, despite being insulin resistant, mice fed t10c12-CLA had normal levels of blood glucose, without signs of impaired glucose clearance. Hepatic gene expression and fatty acid composition suggested enhanced hepatic de novo lipogenesis without an increase in expression of gluconeogenic genes. These data indicate that dietary t10c12-CLA may alter hepatic glucose and lipid metabolism indirectly, in response to the loss of adipose tissue in mice fed a low fat diet.

Substitution of linoleic acid with α-linolenic acid or long chain n-3 polyunsaturated fatty acid prevents Western diet induced nonalcoholic steatohepatitis.

Imbalance in the n-6 polyunsaturated fatty acids (PUFA) and n-3 PUFA in the Western diet may increase the risk of nonalcoholic fatty liver disease (NAFLD). This study investigates the impact of substitution of linoleic acid with α-linolenic acid (ALA) or long chain (LC) n-3 PUFA and hence decreasing n-6:n-3 fatty acid ratio on high fat, high fructose (HFHF) diet induced nonalcoholic steatohepatitis (NASH). Male Sprague-Dawley rats were divided into four groups and fed control diet, HFHF diet (n-6:n-3 ratio of 200), HFHF diet with ALA (n-6:n-3 ratio of 2) or HFHF diet with LC n-3 PUFA (n-6:n-3 ratio of 5) for 24 weeks. Rats fed HFHF diet with n-6:n-3 ratio of 200 resulted in hepatic steatosis, induced glucose intolerance, insulin resistance and oxidative stress accompanied by increase in markers of inflammation, plasma lipids and aminotransferase levels. Histopathological examination of liver further confirmed the establishment of NASH. ALA and LC n-3 PUFA supplementation prevented hepatic steatosis and dyslipidemia by inhibiting lipogenesis and increasing insulin sensitivity. Furthermore, n-3 PUFA supplementation attenuated hepatic oxidative stress by restoring antioxidant status, decreased inflammation and preserved hepatic architecture. These finding suggest that decreasing n-6:n-3 ratio prevented HFHF induced NASH by attenuating oxidative stress and inflammation.

Southern Brazilian native fruit shows neurochemical, metabolic and behavioral benefits in an animal model of metabolic syndrome.

In this work, we evaluated the effects of Psidium cattleianum (Red Type) (PcRT) fruit extract on metabolic, behavioral, and neurochemical parameters in rats fed with a highly palatable diet (HPD) consisted of sucrose (65% carbohydrates being 34% from condensed milk, 8% from sucrose and 23% from starch, 25% protein and 10% fat). Animals were divided into 4 groups: standard chow, standard chow + PcRT extract (200 mg/Kg/day by gavage), HPD, HPD + extract. The animals were treated for 150 days. Concerning chemical profiling, LC/PDA/MS/MS analysis revealed cyanidin-3-O-glucoside as the only anthocyanin in the PcRT extract. Our results showed that the animals exposed to HPD presented glucose intolerance, increased weight gain and visceral fat, as well as higher serum levels of glucose, triacylglycerol, total cholesterol, LDL-cholesterol and interleukin-6. These alterations were prevented by PcRT. In addition, HPD caused an increase in immobility time in a forced swimming test and the fruit extract prevented this alteration, indicating an antidepressant-like effect. PcRT treatment also prevented increased acetylcholinesterase activity in the prefrontal cortex caused by HPD consumption. Moreover, PcRT extract was able to restore Ca2+-ATPase activity in the prefrontal cortex, hippocampus, and striatum, as well as Na+,K+-ATPase activity in the prefrontal cortex and hippocampus. PcRT treatment decreased thiobarbituric acid-reactive substances, nitrite, and reactive oxygen species levels and prevented the reduction of superoxide dismutase activity in all cerebral structures of the HPD group. Additionally, HPD decreased catalase in the hippocampus and striatum. However, the extract prevented this change in the hippocampus. Our results showed that this berry extract has antihyperglycemic and antihyperlipidemic effects, and neuroprotective properties, proving to be a potential therapeutic agent for individuals with metabolic syndrome.

Dietary yeast-derived mannan oligosaccharides have immune-modulatory properties but do not improve high fat diet-induced obesity and glucose intolerance.

The indigestible mannan oligosaccharides (MOS) derived from the outer cell wall of yeast Saccharomyces cerevisiae have shown potential to reduce inflammation. Since inflammation is one of the underlying mechanisms involved in the development of obesity-associated metabolic dysfunctions, we aimed to determine the effect of dietary supplementation with MOS on inflammation and metabolic homeostasis in lean and diet-induced obese mice. Male C57BL/6 mice were fed either a low fat diet (LFD) or a high fat diet (HFD) with, respectively, 10% or 45% energy derived from lard fat, with or without 1% MOS for 17 weeks. Body weight and composition were measured throughout the study. After 12 weeks of intervention, whole-body glucose tolerance was assessed and in week 17 immune cell composition was determined in mesenteric white adipose tissue (mWAT) and liver by flow cytometry and RT-qPCR. In LFD-fed mice, MOS supplementation induced a significant increase in the abundance of macrophages and eosinophils in mWAT. A similar trend was observed in hepatic macrophages. Although HFD feeding induced a classical shift from the anti-inflammatory M2-like macrophages towards the pro-inflammatory M1-like macrophages in both mWAT and liver from control mice, MOS supplementation had no effect on this obesity-driven immune response. Finally, MOS supplementation did not improve whole-body glucose homeostasis in both lean and obese mice.Altogether, our data showed that MOS had extra-intestinal immune modulatory properties in mWAT and liver. However these effects were not substantial enough to significantly ameliorate HFD-induced glucose intolerance or inflammation.

Eugenia uniflora fruit (red type) standardized extract: a potential pharmacological tool to diet-induced metabolic syndrome damage management.

The aim of this study was to investigate the effect of Eugenia uniflora fruit (red type) extract on metabolic status, as well as on neurochemical and behavioral parameters in an animal model of metabolic syndrome induced by a highly palatable diet (HPD). Rats were treated for 150days and divided into 4 experimental groups: standard chow (SC) and water orally, SC and E. uniflora extract (200mg/kg daily, p.o), HPD and water orally, HPD and extract. Our data showed that HPD caused glucose intolerance, increased visceral fat, weight gain, as well as serum glucose, triacylglycerol, total cholesterol and LDL cholesterol; however, E. uniflora prevented these alterations. The extract decreased lipid peroxidation and prevented the reduction of superoxide dismutase and catalase activities in the prefrontal cortex, hippocampus and striatum of animals submitted to HPD. We observed a HPD-induced reduction of thiol content in these cerebral structures. The extract prevented increased acetylcholinesterase activity in the prefrontal cortex caused by HPD and the increase in immobility time observed in the forced swim test. Regarding chemical composition, LC/MS analysis showed the presence of nine anthocyanins as the major compounds. In conclusion, E. uniflora extract showed benefits against metabolic alterations caused by HPD, as well as exhibited antioxidant and antidepressant-like effects.

Alantolactone improves palmitate-induced glucose intolerance and inflammation in both lean and obese states in vitro: Adipocyte and adipocyte-macrophage co-culture system.

Obesity is characterized by a massive infiltration of the adipose tissue by macrophages. Adipocytes, together with macrophages create a crosstalk between inflammation and insulin resistance. Excess saturated FFA, such as palmitate, absorbed via the portal system may cause glucose intolerance and inflammation, which leads to insulin resistance. In this study, we aimed to evaluate the potency of alantolactone (AL), a sesquiterpene lactone isolated from Inula helenium in reducing palmitate-induced glucose intolerance, fat accumulation, and inflammation in 3T3-L1 adipocytes and adipocyte-macrophage co-culture system (3T3-L1-RAW264.7). We observed that palmitate reduced glucose uptake and increased fat accumulation, which indicated dysfunctional adipocytes with inadequate lipid storage. However, AL treatment reversed these changes in a dose-dependent manner (P<0.05). Palmitate activated c-Jun N-terminal kinases (JNK) and IκB kinase ß/α (IKKß/α) phosphorylation, and increased the levels of the proinflammatory cytokines (tumor necrosis factor-α and interleukin-6 [IL-6]) and chemokines (monocyte chemoattractant protein-1 [MCP-1]). AL treatment selectively reduced JNK-associated mitogen-activated protein kinase pathway (JNK and extracellular signal-regulated kinase phosphorylation). However, it did not affect NF-κB pathway in adipocytes. In addition, AL decreased the gene expression of JNK upregulating factor, toll-like receptor-4 (TLR4), suggesting inhibition of TLR4-JNK signaling. Moreover, it reduced inflammation-associated IL-6 and MCP-1 mRNA levels in both adipocytes and adipocyte-macrophage system. Our study showed that palmitate treatment led to adipocyte dysfunction and macrophage infiltration; however, AL improved palmitate-induced glucose intolerance and inflammation. These findings suggest that AL may inhibit obesity-induced insulin resistance and improve glucose homeostasis and inflammation in insulin target tissues.

Dimethylesculetin ameliorates maternal glucose intolerance and fetal overgrowth in high-fat diet-fed pregnant mice via constitutive androstane receptor.

The constitutive androstane receptor (CAR) has been reported to decrease insulin resistance along with obesity. 6,7-dimethylesculetin (DE) is an active component of Yin Zhi Huang which is a traditional Asian medicine used to treat neonatal jaundice via CAR. In this study, we examined whether DE could affect the expression of gluconeogenic and lipogenic genes via human CAR pathway using human HepG2 cells in vitro. We also studied whether DE treatment during pregnancy could prevent maternal hypertension, glucose intolerance and hyperlipidemia, and fetal overgrowth in high-fat diet (HFD)-induced obese pregnant mice. Dimethylesculetin suppressed the mRNA expression of gluconeogenic genes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, and lipogenic genes, sterol regulatory element-binding protein 1 and stearoyl-CoA desaturase 1, and enhanced CAR-mediated transcription. Blocking the CAR-mediated pathway abolished the effect of DE in vitro. DE treatment during pregnancy could prevent maternal hypertension, glucose intolerance and hyperlipidemia, and fetal overgrowth in HFD-induced obese pregnant mice in vivo. Our data indicate that DE might be a potential therapeutic agent for obese pregnant patients with insulin resistance through CAR to prevent the perinatal outcomes such as preeclampsia, gestational diabetes, and macrosomia. Further analysis of possible complications and side effects using animal models is required.

The impact of altered carnitine availability on acylcarnitine metabolism, energy expenditure and glucose tolerance in diet-induced obese mice.

AIM: Acylcarnitines are fatty acid oxidation (FAO) intermediates, which have been implicated in diet-induced insulin resistance. Elevated acylcarnitine levels are found in obese, insulin resistant humans and rodents, and coincide with lower free carnitine. We hypothesized that increasing free carnitine levels by administration of the carnitine precursor γ-butyrobetaine (γBB) could facilitate FAO, thereby improving insulin sensitivity. METHODS: C57BL/6N mice were fed with a high fat or chow diet with or without γBB supplementation (n=10 per group). After 8weeks of diet, indirect calorimetry, glucose tolerance and insulin sensitivity tests were performed. AC profiles and carnitine biosynthesis intermediates were analyzed in plasma and tissues by tandem mass spectrometry (MS) and liquid chromatography tandem MS. RESULTS: γBB supplementation did not facilitate FAO, was unable to curb bodyweight and did not prevent impaired glucose homeostasis in the HFD fed mice in spite of marked alterations in the acylcarnitine profiles in plasma and liver. Remarkably, γBB did not affect the acylcarnitine profile in other tissues, most notably muscle. Administration of a bolus acetylcarnitine also caused significant changes in plasma and liver, but not in muscle acylcarnitine profiles, again without effect on glucose tolerance. CONCLUSION: Altogether, increasing carnitine availability affects acylcarnitine profiles in plasma and liver but does not modulate glucose tolerance or insulin sensitivity. This may be due to the lack of an effect on muscle acylcarnitine profiles, as muscle tissue is an important contributor to whole body insulin sensitivity. These results warrant caution on making associations between plasma acylcarnitine levels and insulin resistance.

Long-term oral administration of osteocalcin induces insulin resistance in male mice fed a high-fat, high-sucrose diet.

Uncarboxylated osteocalcin (GluOC), a bone-derived hormone, regulates energy metabolism by stimulating insulin secretion, pancreatic ß-cell proliferation, and adiponectin expression in adipocytes. Previously, we showed that long-term intermittent or daily oral administration of GluOC reduced the fasting blood glucose level, improved glucose tolerance, and increased the fasting serum insulin concentration as well as pancreatic ß-cell area in female mice fed a normal or high-fat, high-sucrose diet. We have now performed similar experiments with male mice and found that such GluOC administration induced glucose intolerance, insulin resistance, and adipocyte hypertrophy in those fed a high-fat, high-sucrose diet. In addition, GluOC increased the circulating concentration of testosterone and reduced that of adiponectin in such mice. These phenotypes were not observed in male mice fed a high-fat, high-sucrose diet after orchidectomy, but they were apparent in orchidectomized male mice or intact female mice that were fed such a diet and subjected to continuous testosterone supplementation. Our results thus reveal a sex difference in the effects of GluOC on glucose homeostasis. Given that oral administration of GluOC has been considered a potentially safe and convenient option for the treatment or prevention of metabolic disorders, this sex difference will need to be taken into account in further investigations.

Impaired Glucose Tolerance in Healthy Men Treated with St. John's Wort.

The purpose of this study was to examine whether the over-the-counter herbal medicinal plant St. John's wort affects glucose tolerance in healthy men. To do this, we included 10 healthy men who were examined by a 2-hr oral glucose tolerance test on three occasions: A: baseline; B: after 21 days of treatment with St. John's wort; and C: at least 6 weeks after the last capsule of St. John's wort was ingested. Plasma glucose, serum insulin and C-peptide levels were measured during an oral glucose tolerance test and used for estimation of area under the concentration-time curve (AUC) as well as indices of insulin sensitivity and insulin secretion. We found that treatment with St. John's wort increased total and incremental glucose AUC and 2-hr plasma glucose levels. Surprisingly, this effect was sustained and even further increased 6 weeks after the last capsule of St. John's wort was taken. No effect on indices of insulin sensitivity was seen, but indices of insulin secretion were reduced even after adjustment for insulin sensitivity. In conclusion, this study indicates that long-term treatment with St. John's wort may impair glucose tolerance by reducing insulin secretion in young, healthy men. The unregulated use of this over-the-counter drug might be a risk factor for impaired glucose tolerance and type 2 diabetes.

Effects of genistein in combination with conjugated estrogens on endometrial hyperplasia and metabolic dysfunction in ovariectomized mice.

Tissue-selective estrogen complex (TSEC), which combines a selective estrogen receptor modulator (SERM) with one or more estrogens, is a novel approach to menopausal therapy. It has been demonstrated that the phytoestrogen genistein (GEN) exhibits mixed estrogen receptor agonist and antagonist activity, suggesting that GEN may have potential for use as a natural SERM. We evaluated, for the first time, the effects of GEN, conjugated estrogens (CE), and their pairing effects as a TSEC treatment on estrogen-induced endometrial hyperplasia and metabolic dysfunction in ovariectomized (OVX) mice fed a high-fat diet. CE replacement prevented fat accumulation in the adipose tissue and liver, improved glucose homeostasis, and induced endometrial hyperplasia in OVX mice. GEN at 100 mg/kg showed CE mimetic effects in preventing ovariectomy-induced metabolic dysfunctions without endometrial stimulation. Combination treatments with CE and GEN prevented metabolic dysfunctions more strongly than CE alone, but at both low and high doses, GEN did not reverse CE-induced endometrial hyperplasia. In addition, we found that in a TSEC regimen, a typical SERM raloxifene maintains the metabolic benefits of CE while simultaneously protecting the endometrium in OVX mice. These findings indicate that GEN acts as an estrogen agonist in metabolic regulation, but has no SERM function in the uteri of OVX mice.

Beneficial effects of calcitriol on hypertension, glucose intolerance, impairment of endothelium-dependent vascular relaxation, and visceral adiposity in fructose-fed hypertensive rats.

Besides regulating calcium homeostasis, the effects of vitamin D on vascular tone and metabolic disturbances remain scarce in the literature despite an increase intake with high-fructose corn syrup worldwide. We investigated the effects of calcitriol, an active form of vitamin D, on vascular relaxation, glucose tolerance, and visceral fat pads in fructose-fed rats. Male Wistar-Kyoto rats were divided into 4 groups (n = 6 per group). Group Con: standard chow diet for 8 weeks; Group Fru: high-fructose diet (60% fructose) for 8 weeks; Group Fru-HVD: high-fructose diet as Group Fru, high-dose calcitriol treatment (20 ng / 100 g body weight per day) 4 weeks after the beginning of fructose feeding; and Group Fru-LVD: high-fructose diet as Group Fru, low-dose calcitriol treatment (10 ng / 100 g body weight per day) 4 weeks after the beginning of fructose feeding. Systolic blood pressure was measured twice a week by the tail-cuff method. Blood was examined for serum ionized calcium, phosphate, creatinine, glucose, triglycerides, and total cholesterol. Intra-peritoneal glucose intolerance test, aortic vascular reactivity, the weight of visceral fat pads, adipose size, and adipose angiotensin II levels were analyzed at the end of the study. The results showed that the fructose-fed rats significantly developed hypertension, impaired glucose tolerance, heavier weight and larger adipose size of visceral fat pads, and raised adipose angiotensin II expressions compared with the control rats. High- and low-dose calcitriol reduced modestly systolic blood pressure, increased endothelium-dependent aortic relaxation, ameliorated glucose intolerance, reduced the weight and adipose size of visceral fat pads, and lowered adipose angiotensin II expressions in the fructose-fed rats. However, high-dose calcitriol treatment mildly increased serum ionized calcium levels (1.44 ± 0.05 mmol/L). These results suggest a protective role of calcitriol treatment on endothelial function, glucose tolerance, and visceral adiposity in fructose-fed rats.

Murraya koenigii (L.) Spreng. ameliorates insulin resistance in dexamethasone-treated mice by enhancing peripheral insulin sensitivity.

BACKGROUND: Murraya koenigii (L.) Spreng. is an important medicinal plant used traditionally as an antiemetic, antidiarrhoeal agent and blood purifier and as a medicine for a variety of ailments. This study investigated the effects of ethanolic extract of M. koenigii (MK) on diabetes-associated insulin resistance induced in mice by chronic low-dose injection of dexamethasone. RESULTS: Mice treated with dexamethasone exhibited hyperglycaemia and impaired glucose tolerance. Treatment with MK reduced the extent of dexamethasone-induced hyperglycaemia and decreased insulin resistance as indicated by improved glucose tolerance and increased insulin-stimulated AKT phosphorylation in skeletal muscle tissue. Further evaluation in clonal skeletal muscle cell lines suggested that MK increased glucose uptake in L6 skeletal muscle cells by increasing cell surface GLUT4 density via an AKT-mediated pathway. CONCLUSION: MK can ameliorate dexamethasone-induced hyperglycaemia and insulin resistance in part by increasing glucose disposal into skeletal muscle.

Nicotinamide supplementation induces detrimental metabolic and epigenetic changes in developing rats.

Ecological evidence suggests that niacin (nicotinamide and nicotinic acid) fortification may be involved in the increased prevalence of obesity and type 2 diabetes, both of which are associated with insulin resistance and epigenetic changes. The purpose of the present study was to investigate nicotinamide-induced metabolic changes and their relationship with possible epigenetic changes. Male rats (5 weeks old) were fed with a basal diet (control group) or diets supplemented with 1 or 4 g/kg of nicotinamide for 8 weeks. Low-dose nicotinamide exposure increased weight gain, but high-dose one did not. The nicotinamide-treated rats had higher hepatic and renal levels of 8-hydroxy-2'-deoxyguanosine, a marker of DNA damage, and impaired glucose tolerance and insulin sensitivity when compared with the control rats. Nicotinamide supplementation increased the plasma levels of nicotinamide, N1-methylnicotinamide and choline and decreased the levels of betaine, which is associated with a decrease in global hepatic DNA methylation and uracil content in DNA. Nicotinamide had gene-specific effects on the methylation of CpG sites within the promoters and the expression of hepatic genes tested that are responsible for methyl transfer reactions (nicotinamide N-methyltransferase and DNA methyltransferase 1), for homocysteine metabolism (betaine-homocysteine S-methyltransferase, methionine synthase and cystathionine ß-synthase) and for oxidative defence (catalase and tumour protein p53). It is concluded that nicotinamide-induced oxidative tissue injury, insulin resistance and disturbed methyl metabolism can lead to epigenetic changes. The present study suggests that long-term high nicotinamide intake (e.g. induced by niacin fortification) may be a risk factor for methylation- and insulin resistance-related metabolic abnormalities.

Coffee consumption attenuates insulin resistance and glucose intolerance in rats fed on high-sucrose diet.

Several epidemiological evidences indicate that consumption of coffee is associated with a lower risk of type 2 diabetes mellitus (T2DM) however; there is dearth of experimental data to support these observations. Given that associations do not necessarily infer causality, the present study was designed to investigate the effect of coffee consumption on glucose regulation, T2DM and the probable mechanisms of action, using an animal model. The effect of coffee (2-fold dilution) by oral gavage on normal and high sucrose-solution (HSS) fed (30 % w/v) rats was evaluated. The results showed that consumption of coffee significantly increase glucose tolerance and insulin sensitivity (p<0.05) along with significant improvement in SOD and GSH activities. In addition, lipid indices such as TG and LDL as well as the lipid peroxidation marker (MDA) were markedly reduced (p<0.05) in rats fed with coffee compared with that of the HSS fed rats. These findings suggest that coffee consumption improves insulin sensitivity, glucose tolerance in HSS-fed rat possibly via inhibition of oxidative stress.

The dietary flavonoids naringenin and quercetin acutely impair glucose metabolism in rodents possibly via inhibition of hypothalamic insulin signalling.

Secondary metabolites of herbs and spices are widely used as an alternative strategy in the therapy of various diseases. The polyphenols naringenin, quercetin and curcumin have been characterised as anti-diabetic agents. Conversely, in vitro, naringenin and quercetin are described to inhibit phosphoinositide-3-kinase (PI3K), an enzyme that is essential for the neuronal control of whole body glucose homoeostasis. Using both in vitro and in vivo experiments, we tested whether the inhibitory effect on PI3K occurs in neurons and if it might affect whole body glucose homoeostasis. Quercetin was found to inhibit basal and insulin-induced phosphorylation of Akt (Ser473), a downstream target of PI3K, in HT-22 cells, whereas naringenin and curcumin had no effect. In Djungarian hamsters (Phodopus sungorus) naringenin and quercetin (10 mg/kg administered orally) diminished insulin-induced phosphorylation of Akt (Ser473) in the arcuate nucleus, indicating a reduction in hypothalamic PI3K activity. In agreement with this finding, glucose tolerance in naringenin-treated hamsters (oral) and mice (oral and intracerebroventricular) was reduced compared with controls. Dietary quercetin also impaired glucose tolerance, whereas curcumin was ineffective. Circulating levels of insulin and insulin-like growth factor-binding protein were not affected by the polyphenols. Oral quercetin reduced the respiratory quotient, suggesting that glucose utilisation was impaired after treatment. These data demonstrate that low doses of naringenin and quercetin acutely and potently impair glucose homoeostasis. This effect may be mediated by inhibition of hypothalamic PI3K signalling. Whether chronic impairments in glucose homoeostasis occur after long-term application remains to be identified.

[A case of fatal clinical course with reversible acute cardiac failure and glucose intolerance during sorafenib therapy for metastatic renal cell carcinoma].

A 72-year-old man was diagnosed with right renal cell carcinoma (RCC) with multiple brain and lung metastases (cT3aN0M1). He underwent γ-knife treatment for brain metastases, palliative right renal artery embolization for primary RCC, and interferon- alpha treatment for residual lung metastases. Although the interferon-alpha treatment was effective, it was discontinued because of side effects. He received sorafenib (800 mg/daily) therapy for 2 months. Suddenly, he developed left cardiac failure, and he died 6 days later through a rapid clinical course that included circulatory failure, abnormal glucose tolerance, disseminated intravascular coagulation, and multiple organ failure. A pathological examination could not explain the cause of death. It is important to carefully observe metastatic RCC patients receiving a tyrosine kinase inhibitor, especially sorafenib, because critical side effects may appear.

Effects of long-term feeding of chitosan on postprandial lipid responses and lipid metabolism in a high-sucrose-diet-impaired glucose-tolerant rat model.

This study was designed to investigate the effects of long-term feeding of chitosan on postprandial lipid response and lipid metabolism in a high-sucrose (HS)-diet-impaired glucose-tolerant rat model. As the results, HS-diet-fed rats supplemented with 5 and 7% chitosan in diets for 9 weeks had lower postprandial plasma total cholesterol (TC) levels, but 7% chitosan in the diet had higher postprandial plasma triglyceride (TG) and TG-rich lipoprotein TG levels. Supplementation of chitosan significantly decreased the postprandial ratio of apolipoprotein B (apoB)48/apoB100 in TG-rich lipoprotein fractions of HS-diet-fed rats. Long-term supplementation of 5 and 7% chitosan in diets for 16 weeks had lower plasma TC, low-density lipoprotein cholesterol (LDL-C) + very low density lipoprotein cholesterol (VLDL-C), TC/high-density lipoprotein (HDL-C) ratio, leptin, and tumor necrosis factor-α (TNF-α) levels in HS-diet-fed rats. Moreover, it was noticed that the VLDL receptor (VLDLR) protein expression in skeletal muscles of HS-diet-fed rats was significantly decreased, which could be significantly reversed by supplementation of 5 and 7% chitosan. Rats supplemented with 7% chitosan in the diet significantly elevated the lipolysis rate and decreased the accumulation of TG in epididymal fat pads of HS-diet-fed rats. The plasma angiopoietin-like 4 (ANGPTL4) protein expression was not affected in HS-diet-fed rats, but it was significantly increased in 7% chitosan-supplemented HS-diet-fed rats. Taken together, these results indicate that supplementation of chitosan in the diet can improve the impairment of lipid metabolism in a HS-diet-fed rat model, but long-term high-dose chitosan feeding may enhance postprandial plasma TG and TG-rich lipoprotein TG levels in HS-diet-fed rats through an ANGPTL4-regulated pathway.