Effect of (poly)phenol-rich 'Daux Belan' apple supplementation on diet-induced obesity and glucose intolerance in C57BL/6NCrl mice.

Obesity is a state of metabolic dysfunction that can lead to dyslipidemia and impaired glucose homeostasis. Apple polyphenols have been shown to ameliorate dyslipidemia/metabolic dysfunction in humans. The influence of apple (poly)phenols on energy metabolism in high-fat (HF) diet-induced obese mice remains controversial. This study examined the effect of dietary supplementation of (poly)phenol-rich 'Daux Belan' apple (DB; 6.2 mg gallic acid equivalence (GAE)/mouse/day; 0.15% (poly)phenol) in the form of freeze-dried powder on glucose and lipid metabolism in male HF-fed C57BL/6NCrl mice, in comparison to low-(poly)phenol-containing 'Zestar' apple (Z; 0.4 mg GAE/mouse/day). Obesity, glucose intolerance, hypertriglyceridemia, and hepatic lipid vacuolation were induced by HF feeding while circulating cholesterol levels remained unchanged. DB apple supplementation did not protect against HF-induced body weight gain, hyperglycemia, hepatic triglyceride level elevation, and hepatic lipid vacuolation at the tested dosage. Future studies should be conducted with increased DB dosage and employ apple (poly)phenols supplemented in the form of extracts or sugar-free powder.

Effect of different dietary fats on inflammation and glucose intolerance in high fructose and high fat fed experimental animals.

OBJECTIVES: Diet is the major modifiable risk factor for the onset of insulin resistance and its progression into diabetes. In the present study the effect of various dietary fats on inflammatory homeostasis and glucose tolerance is investigated in high fat and high fructose fed mice model. METHODS: C57/BL6J mice were divided into four groups and fed a casein-based diet containing high fructose (45%) and high fat (24%) (clarified butter oil [CBO]; safflower oil [SFFO] and lard oil [LO]) for 120 days; oral glucose tolerance (OGTT), plasma lipid profile and plasma & adipose tissue cytokines levels were compared with the control diet (10% groundnut oil and 59.5% starch) fed animals. RESULTS: The total cholesterol and triglycerides were higher in CBO and LO fed animals with glucose intolerance and increased body weights; liver and white adipose tissue weights were higher in CBO and LO fed animals respectively. CBO feeding increased the plasma (IFN-γ) and adipose tissue cytokines (IFN-γ, IL-10, IL-6 & TNF-α). LO feeding increased plasma IFN-γ, TNF-α and IL-1ß and adipose tissue IL-6. SFFO feeding decreased body weight and tissue cytokines and increased plasma IFN-γ levels without causing impairment in the glucose tolerance. CONCLUSIONS: Consumption of a high fructose and high fat diet which mimic the present-day dietary pattern resulted in altered inflammatory homeostasis and impairment in glucose tolerance in 24% CBO and LO fed animals. The deleterious effects of high fructose feeding were reversed in SFFO fed mice possibly due to the presence of oleic and linoleic acids.

Sexually Dimorphic Effects of a Western Diet on Brain Mitochondrial Bioenergetics and Neurocognitive Function.

A Western diet (WD), high in sugars and saturated fats, impairs learning and memory function and contributes to weight gain. Mitochondria in the brain provide energy for neurocognitive function and may play a role in body weight regulation. We sought to determine whether a WD alters behavior and metabolic outcomes in male and female rodents through impacting hippocampal and hypothalamic mitochondrial bioenergetics. Results revealed a sexually dimorphic macronutrient preference, where males on the WD consumed a greater percentage of calories from fat/protein and females consumed a greater percentage of calories from a sugar-sweetened beverage. Both males and females on a WD gained body fat and showed impaired glucose tolerance when compared to same-sex controls. Males on a WD demonstrated impaired hippocampal functioning and an elevated tendency toward a high membrane potential in hippocampal mitochondria. Comprehensive bioenergetics analysis of WD effects in the hypothalamus revealed a tissue-specific adaption, where males on the WD oxidized more fat, and females oxidized more fat and carbohydrates at peak energy demand compared to same-sex controls. These results suggest that adult male rats show a susceptibility toward hippocampal dysfunction on a WD, and that hypothalamic mitochondrial bioenergetics are altered by WD in a sex-specific manner.

Differential Effects of Dietary Components on Glucose Intolerance and Non-Alcoholic Steatohepatitis.

Pharmacological treatment modalities for non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are scarce, and discoveries are challenged by lack of predictive animal models adequately reflecting severe human disease stages and co-morbidities such as obesity and type 2 diabetes. To mimic human NAFLD/NASH etiology, many preclinical models rely on specific dietary components, though metabolism may differ considerably between species, potentially affecting outcomes and limiting comparability between studies. Consequently, understanding the physiological effects of dietary components is critical for high translational validity. This study investigated the effects of high fat, cholesterol, and carbohydrate sources on NASH development and metabolic outcomes in guinea pigs. Diet groups (n = 8/group) included: low-fat low-starch (LF-LSt), low-fat high-starch (LF-HSt), high-fat (HF) or HF with 4.2%, or 8.4% sugar water supplementation. The results showed that caloric compensation in HF animals supplied with sugar water led to reduced feed intake and a milder NASH phenotype compared to HF. The HF group displayed advanced NASH, weight gain and glucose intolerance compared to LF-LSt animals, but not LF-HSt, indicating an undesirable effect of starch in the control diet. Our findings support the HF guinea pig as a model of advanced NASH and highlights the importance in considering carbohydrate sources in preclinical studies of NAFLD.

Fortifying Butterfat with Soybean Oil Attenuates the Onset of Diet-Induced Non-Alcoholic Steatohepatitis and Glucose Intolerance.

The addition of plant oils such as soybean oil (S) to a diet rich in saturated fatty acids is discussed as a possible route to prevent or diminish the development of metabolic disease. Here, we assessed whether a butterfat-rich diet fortified with S affects the development of early non-alcoholic steatohepatitis (NASH) and glucose intolerance. Female C57BL/6J mice were fed a standard-control diet (C); a fat-, fructose-, and cholesterol-rich diet (FFC, 25E% butterfat, 50% (wt./wt.) fructose, 0.16% (wt./wt.) cholesterol); or FFC supplemented with S (FFC + S, 21E% butterfat + 4E% S) for 13 weeks. Indicators of liver damage, inflammation, intestinal barrier function, and glucose metabolism were measured. Lipopolysaccharide (LPS)-challenged J774A.1 cells were incubated with linolenic and linoleic acids (ratio 1:7.1, equivalent to S). The development of early NASH and glucose intolerance was significantly attenuated in FFC + S-fed mice compared to FFC-fed mice associated with lower hepatic toll-like receptor-4 mRNA expression, while markers of intestinal barrier function were significantly higher than in C-fed mice. Linolenic and linoleic acid significantly attenuated LPS-induced formation of reactive nitrogen species and interleukin-1 beta mRNA expression in J774A.1 cells. Our results indicate that fortifying butterfat with S may attenuate the development of NASH and glucose intolerance in mice.

Wild blueberry proanthocyanidins shape distinct gut microbiota profile and influence glucose homeostasis and intestinal phenotypes in high-fat high-sucrose fed mice.

Blueberries are a rich source of polyphenols, widely studied for the prevention or attenuation of metabolic diseases. However, the health contribution and mechanisms of action of polyphenols depend on their type and structure. Here, we evaluated the effects of a wild blueberry polyphenolic extract (WBE) (Vaccinium angustifolium Aiton) on cardiometabolic parameters, gut microbiota composition and gut epithelium histology of high-fat high-sucrose (HFHS) diet-induced obese mice and determined which constitutive polyphenolic fractions (BPF) was responsible for the observed effects. To do so, the whole extract was separated in three fractions, F1) Anthocyanins and phenolic acids, F2) oligomeric proanthocyanidins (PACs), phenolic acids and flavonols (PACs degree of polymerization DP < 4), and F3) PACs polymers (PACs DP > 4) and supplied at their respective concentration in the whole extract. After 8 weeks, WBE reduced OGTT AUC by 18.3% compared to the HFHS treated rodents and the F3 fraction  contributed the most to this effect. The anthocyanin rich F1 fraction did not reproduce this response. WBE and the BPF restored the colonic mucus layer. Particularly, the polymeric PACs-rich F3 fraction increased the mucin-secreting goblet cells number. WBE caused a significant 2-fold higher proportion of Adlercreutzia equolifaciens whereas oligomeric PACs-rich F2 fraction increased by 2.5-fold the proportion of Akkermansia muciniphila. This study reveals the key role of WBE PACs in modulating the gut microbiota and restoring colonic epithelial mucus layer, providing a suitable ecological niche for mucosa-associated symbiotic bacteria, which may be crucial in triggering health effects of blueberry polyphenols.

Prenatal Choline Supplementation during High-Fat Feeding Improves Long-Term Blood Glucose Control in Male Mouse Offspring.

Maternal obesity increases the risk of metabolic dysregulation in rodent offspring, especially when offspring are exposed to a high-fat (HF), obesogenic diet later in life. We previously demonstrated that maternal choline supplementation (MCS) in HF-fed mouse dams during gestation prevents fetal overgrowth and excess adiposity. In this study, we examined the long-term metabolic influence of MCS. C57BL/6J mice were fed a HF diet with or without choline supplementation prior to and during gestation. After weaning, their pups were exposed to either a HF or control diet for 6 weeks before measurements. Prenatal and post-weaning dietary treatments led to sexually dimorphic responses. In male offspring, while post-weaning HF led to impaired fasting glucose and worse glucose tolerance (p < 0.05), MCS in HF dams (HFCS) attenuated these changes. HFCS (versus maternal normal fat control) appeared to improve metabolic functioning of visceral adipose tissue during post-weaning HF feeding, preventing the elevation in leptin and increasing (p < 0.05) mRNA expression of insulin receptor substrate 1 (Irs1) that promotes peripheral insulin signaling in male offspring. In contrast, MCS had minimal effects on metabolic outcomes of female offspring. In conclusion, MCS during HF feeding in mice improves long-term blood glucose homeostasis in male offspring when they are faced with a postnatal obesogenic environment.

Effect of Aruncus dioicus var. kamtschaticus Extract on Neurodegeneration Improvement: Ameliorating Role in Cognitive Disorder Caused by High-Fat Diet Induced Obesity.

This study was performed to estimate the possibility of using an ethyl acetate fraction from Aruncus dioicus var. kamtschaticus (EFAD) on metabolic syndrome that is induced by a high-fat diet (HFD). It was demonstrated that EFAD suppresses lipid accumulation and improves insulin resistance (IR) caused by Tumor necrosis factor alpha (TNF-α) in in-vitro experiments using the 3T3-L1 cell. In in-vivo tests, C57BL/6 mice were fed EFAD at 20 and 40 mg/kg body weight (BW) for four weeks after the mice were fed HFD for 15 weeks to induce obesity. EFAD significantly suppressed the elevation of BW and improved impaired glucose tolerance in obese mice. Additionally, this study showed that EFAD has an ameliorating effect on obesity-induced cognitive disorder with behavioral tests. The effect of EFAD on peripheral-IR improvement was confirmed by serum analysis and western blotting in peripheral tissues. Additionally, EFAD showed an ameliorating effect on HFD-induced oxidative stress, impaired cholinergic system and mitochondrial dysfunction, which are interrelated symptoms of neurodegeneration, such as Alzheimer's disease and central nervous system (CNS)-IR in brain tissue. Furthermore, we confirmed that EFAD improves CNS-IR by confirming the IR-related factors in brain tissue. Consequently, this study suggests the possibility of using EFAD for the prevention of neurodegeneration by improving metabolic syndrome that is caused by HFD.

Passive heating and glycaemic control in non-diabetic and diabetic individuals: A systematic review and meta-analysis.

OBJECTIVE: Passive heating (PH) has begun to gain research attention as an alternative therapy for cardio-metabolic diseases. Whether PH improves glycaemic control in diabetic and non-diabetic individuals is unknown. This study aims to review and conduct a meta-analysis of published literature relating to PH and glycaemic control. METHODS: Electronic data sources, PubMed, Embase and Web of Science from inception to July 2018 were searched for randomised controlled trials (RCT) studying the effect of PH on glycaemic control in diabetic or non-diabetic individuals. To measure the treatment effect, standardised mean differences (SMD) with 95% confidence intervals (CI) were calculated. RESULTS: Fourteen articles were included in the meta-analysis. Following a glucose load, glucose concentration was greater during PH in non-diabetic (SMD 0.75, 95% CI 1.02 to 0.48, P < 0.001) and diabetic individuals (SMD 0.27, 95% CI 0.52 to 0.02, P = 0.030). In non-diabetic individuals, glycaemic control did not differ between PH and control only (SMD 0.11, 95% CI 0.44 to -0.22, P > 0.050) and a glucose challenge given within 24 hours post-heating (SMD 0.30, 95% CI 0.62 to -0.02, P > 0.050). CONCLUSION: PH preceded by a glucose load results in acute glucose intolerance in non-diabetic and diabetic individuals. However, heating a non-diabetic individual without a glucose load appears not to affect glycaemic control. Likewise, a glucose challenge given within 24 hours of a single-bout of heating does not affect glucose tolerance in non-diabetic individuals. Despite the promise PH may hold, no short-term benefit to glucose tolerance is observed in non-diabetic individuals. More research is needed to elucidate whether this alternative therapy benefits diabetic individuals.

Taurine supplementation in high-fat diet fed male mice attenuates endocrine pancreatic dysfunction in their male offspring.

Obesity in fathers leads to DNA damage and epigenetic changes in sperm that may carry potential risk factors for metabolic diseases to the next generation. Taurine (TAU) supplementation has demonstrated benefits against testicular dysfunction and pancreatic islet impairments induced by obesity, but it is not known if these protective actions prevent the propagation of metabolic disruptions to the next generation; as such, we hypothesized that paternal obesity may increase the probability of endocrine pancreatic dysfunction in offspring, and that this could be prevented by TAU supplementation in male progenitors. To test this, male C57Bl/6 mice were fed on a control diet (CTL) or a high-fat diet (HFD) without or with 5% TAU in their drinking water (CTAU and HTAU) for 4 months. Subsequently, all groups of mice were mated with CTL females, and the F1 offspring were identified as: CTL-F1, CTAU-F1, HFD-F1, and HTAU-F1. HFD-fed mice were normoglycemic, but glucose intolerant and their islets hypersecreted insulin. However, at 90 days of age, HFD-F1 offspring displayed normal glucose homeostasis and adiposity, but reduced glucose-induced insulin release. HFD-F1 islets also exhibited ß- and α-cell hypotrophy, and lower δ-cell number per islet. Paternal TAU supplementation prevented the decrease in glucose-induced insulin secretion and normalized ß-cell size and δ-cell number, and increased α-cell size/islet in HTAU-F1 mice. In conclusion, HFD consumption by male founders decreases ß-cell secretion and islet-cell distribution in their offspring. TAU attenuates the deleterious effects of paternal obesity on insulin secretion and islet-cell morphology in F1 offspring.

Maternal resistin predisposes offspring to hypothalamic inflammation and body weight gain.

Resistin promotes hypothalamic neuroinflammation and insulin resistance through Toll like receptor 4 (TLR4), this hormone is thought to be a link between obesity and insulin-resistance. Indeed, resistin plasma levels are higher in obese and insulin resistant subjects. However, the impact of maternal resistin on the predisposition of offspring to hypothalamic neuroinflammation is unknown. Here, female mice were treated with resistin during gestation/lactation periods, then hypothalamic neuroinflammation was investigated in male offspring at p28 and p90. At p28, resistin increased the expression of inflammation markers (IL6, TNFα and NFκB) and TLR4 in the hypothalamus and decreased both hypothalamic insulin and leptin receptors' expression. The hypothalamic up-regulation IL6, TNFα and TLR4 was sustained until p90 promoting most likely hypothalamic inflammation. Maternal resistin also increased IL6 and TNFα in the adipose tissue of offspring at p90 associated with a higher body weight gain. In contrast, liver and muscle were not affected. These findings reveal that the augmentation of maternal resistin during gestation and lactation promotes hypothalamic and adipose tissue inflammation of offspring as evidenced by sustained increase of inflammation markers from weaning to adulthood. Thus, maternal resistin programs offspring hypothalamic and adipose tissue inflammation predisposing then offspring to body weight gain.

Vitamin D deficiency in the aetiology of obesity-related insulin resistance.

The obese insulin-resistant state is often associated with low circulating concentration of vitamin D 25-hydroxyvitamin D3 [25(OH)D3 ]. Fat sequestration of vitamin D in the expanded obese adipose tissue mass has been pointed out as a plausible explanation for this circulating vitamin D deficiency. However, the putative mechanisms behind this hypovitaminosis D remain to be elucidated. The presence of vitamin D receptor and vitamin D-metabolizing enzymes in insulin-sensitive organs suggests that vitamin D may be involved in glucose and lipid metabolism and may be related to insulin sensitivity. Indeed, mainly in vitro studies support a role of vitamin D in regulating glucose and lipid metabolism in several insulin-sensitive tissues including adipose tissue, skeletal muscle, liver, as well as pancreatic insulin secretion. A potential role of vitamin D in gut barrier function and metabolism has also been suggested. This review summarizes recent knowledge on vitamin D deficiency in the aetiology of obesity-related insulin resistance and discusses potential underlying mechanisms. Finally, the role of vitamin D supplementation on insulin sensitivity and glycaemic control is discussed.

High-Dose Perinatal Folic-Acid Supplementation Alters Insulin Sensitivity in Sprague-Dawley Rats and Diminishes the Expression of Adiponectin.

The possible intake of folate in excess of the recommended upper levels is a matter of critical importance. This study was conducted to investigate the effects of prenatal and postnatal high folic acid supplementation (FAS) on glucose tolerance, insulin sensitivity, lipid metabolism, and expression of adiponectin in rats. The study included 20 female rats divided into two groups: control group and FAS group (receiving high folic acid supplemented diet). Both groups of female rats were mated and pregnancy confirmed. At parturition, the diet of 5 dams that were fed with control diet during gestation and their litters was changed to FAS diet and continued throughout lactation. Similarly, half of the dams that were previously fed with FAS diet during gestation and their litters were also changed to control diet. The remaining 5 dams in each group continued on their respective diets throughout lactation with their litters. Other dams remained on their respective diets throughout lactation. Food and water intake, body weight, lipid concentrations, insulin, and the expression of adiponectin were determined. Glucose tolerance and insulin sensitivity were also measured to evaluate glucose homeostasis. FAS significantly increased the postweaning food, water intake, triglyceride, and insulin levels but diminished insulin sensitivity in adult offspring. The expression of adiponectin in insulin-sensitive tissues was also significantly decreased and these were consistent with insulin resistance of FAS offspring. High-dose FAS may promote insulin resistance and dyslipidemia and disrupt glucose metabolism possibly by depressing adiponectin expression. Although this is an animal model and the effects of the diets cannot be directly transposed to humans, this study provides indications of the possible adverse effects of FAS maternal diet on glucose metabolism in the offspring.

Depletion of regulator-of-G-protein signaling-10 in mice exaggerates high-fat diet-induced insulin resistance and inflammation, and this effect is mitigated by dietary green tea extract.

The interaction between insulin resistance and inflammation plays a central role in the development of chronic diseases, although the mechanism is not fully understood. We previously demonstrated that regulator of G-protein signaling-10 (RGS10) protein is a negative modulator of the inflammatory response in macrophages and microglia. Because inflammation is a critical component in the development of high fat diet-induced insulin resistance, in this study we investigated whether RGS10 is involved in the diet-dependent regulation of glucose tolerance and insulin sensitivity. We hypothesized that the absence of RGS10 would exaggerate high-fat diet (HFD)-induced insulin resistance and inflammation response. Our results showed that RGS10 knockout (KO) mice fed a HFD gained significantly more weight and developed severe insulin resistance compared to wild-type (WT) mice fed HFD. Furthermore, compared to WT HFD-fed mice, KO mice fed the HFD displayed inflammatory phenotypes such as decreased adipose tissue expression of the anti-inflammatory M2 markers YM1 and Fizz1 and increased expression of the proinflammatory M1 cytokine interleukin 6 in adipose and CD11b, CD68 and interleukin 1ß in liver tissues. The impact of RGS10 deficiency on the exaggeration of HFD-induced insulin resistance and inflammation was ameliorated by oral consumption of green tea extract. Our results demonstrate that RGS10 is an important part of a protective mechanism involved in in regulating metabolic homeostasis by reducing inflammatory responses, which could potentially lead to an innovative new approach targeting inflammation and insulin resistance.

Diet-induced obesity and associated disorders are prevented by natural bioactive type 1 fish collagen peptides (Naticol®) treatment.

To fight against metabolic disorders such as insulin resistance, new alimentary behaviors are developed. For instance, hyperproteined, gluten-free, or collagen-enriched diets could be preconized in order to reduce the consequences of obesity. In this aim, this study evaluates the potential effects of warm sea fish collagen peptides (Naticol®) on representative metabolic and inflammatory parameters. For that, male C57Bl6/J mice fed with either a chow- (CD) or high-fat diet (HFD) were submitted or not to specific collagen peptides in drinking water (4 g/kg bw/d) for 20 weeks. Weight, body composition, glucose tolerance, and insulin sensitivity were followed up. Effects of fish collagen peptides on various blood parameters reflecting the metabolism status were also measured (free fatty acids, triglycerides, cholesterol, hormones) together with adipocyte inflammation. Results showed that HFD-fed mice supplemented by fish collagen peptides exhibited a significant lower increase in body weight as soon as the twelfth week of treatment whereas no effect of the peptide was observed in CD fed mice. In line with this result, a weaker increase in fat mass in HFD-fed mice supplemented with Naticol® at both 9 and 18 weeks of treatment was also observed. In spite of this resistance to obesity promoted by fish collagen peptides treatment, no difference in glucose tolerance was found between groups whereas mice treated with Naticol® exhibited a lower basal glycemia. Also, even if no effect of the treatment on adipocyte lipolysis was found, a decrease of inflammatory cytokines was retrieved in collagen-supplemented group arguing for a potential better insulin sensitivity. Altogether, these results need to be completed but are the first describing a benefic role of warm sea fish collagen peptides in a context of metabolic disease paving the route for a potential utilization in human obesity-associated disorders.

Folate treatment partially reverses gestational low-protein diet-induced glucose intolerance and the magnitude of reversal is age and sex dependent.

OBJECTIVES: Gestational low-protein (LP) programming causes glucose intolerance (GI) and insulin resistance (IR) in adult offspring. Folate supplementation has been shown to rescue the offspring from various programming effects. The aim of this study was to investigate whether folate supplementation during pregnancy reverses LP-induced GI and IR. METHODS: Pregnant rats were fed control (20% protein), isocaloric low-protein (LP, 6%) or LP with 5 mg/kg folate (LPF) diets from gestational day 4 to delivery. The control diet was given during lactation and to pups after weaning. Glucose tolerance test was done at 1, 2, and 3 mo of age followed by euglycemic-hyperinsulinemic clamp at 4 mo. Rats were sacrificed at 4 mo and their gonadal, renal, inguinal, brown fat, and pancreas were weighed and expressed relative to their body weight. RESULTS: LP- and LPF-fed dams showed similar weight loss during late pregnancy after decreased feed intake. Both LP and LPF pups were smaller at birth but their weights caught up like that of controls by 3 mo. In males, folate supplementation reduced LP-induced GI at 2 mo (glucose area under the curve [AUC]: 1940 mmol/L × 180 min in LP, 1629 mmol/L × 180 min in LPF, and 1653 mmol/L × 180 min in controls; P <0.05, LP versus control and P <0.01, LP versus LPF) but the effect diminished at 3 mo. In females, folate reduced GI at 1 mo (glucose AUC: 1406 mmol/L × 180 min in LP, 1264 mmol/L × 180 min in LPF, and 1281 mmol/L × 180 min in controls; P <0.05, LP versus control and LP versus LPF) but had no effect at 2 and 3 mo. Interestingly, the LPF group had higher pancreatic weights than other groups, suggesting that folate helps in pancreatic development enabling the LPF rats to produce/secrete more insulin to maintain euglycemia. Euglycemic-hyperinsulinemic clamp shows both LP and LPF are insulin resistant compared with controls by 4 mo with LPF more severe than LP in males. Interestingly, females were more insulin resistant than males. CONCLUSIONS: Folate treatment partially reverses LP-induced GI and the magnitude of reversal is age and sex dependent. Furthermore, folate treatment does not reverse IR in either sex but makes it worse in males at 4 mo. The present study demonstrated that folate treatment is not sufficient to rescue the LP programming effects.

Leptin enhances hypothalamic lactate dehydrogenase A (LDHA)-dependent glucose sensing to lower glucose production in high-fat-fed rats.

The responsiveness of glucose sensing per se to regulate whole-body glucose homeostasis is dependent on the ability of a rise in glucose to lower hepatic glucose production and increase peripheral glucose uptake in vivo In both rodents and humans, glucose sensing is lost in diabetes and obesity, but the site(s) of impairment remains elusive. Here, we first report that short-term high-fat feeding disrupts hypothalamic glucose sensing to lower glucose production in rats. Second, leptin administration into the hypothalamus of high-fat-fed rats restored hypothalamic glucose sensing to lower glucose production during a pancreatic (basal insulin)-euglycemic clamp and increased whole-body glucose tolerance during an intravenous glucose tolerance test. Finally, both chemical inhibition of hypothalamic lactate dehydrogenase (LDH) (achieved via hypothalamic LDH inhibitor oxamate infusion) and molecular knockdown of LDHA (achieved via hypothalamic lentiviral LDHA shRNA injection) negated the ability of hypothalamic leptin infusion to enhance glucose sensing to lower glucose production in high fat-fed rats. In summary, our findings illustrate that leptin enhances LDHA-dependent glucose sensing in the hypothalamus to lower glucose production in high-fat-fed rodents in vivo.

Glucose Homeostasis and Effect of Chelation on ß Cell Function in Children With ß-Thalassemia Major.

OBJECTIVE: To assess the prevalence of impaired glucose tolerance in ß-thalassemia major and correlate it with chelation therapy. MATERIALS AND METHODS: Sixty-seven subjects with ß-thalassemia major, aged 1 to 20 years, were enrolled in our prospective cohort. Clinical details were recorded. Baseline oral glucose tolerance test, serum insulin, C peptide, and insulin resistance were measured. The biochemical profile was repeated after 6 months. RESULTS: The mean age of subjects was 7.43±4.48 years. Eight (11.9%) subjects had impaired fasting glucose, 7 (10.4%) had impaired glucose tolerance, and 1 (1.4%) subject had diabetes at baseline. Subjects with abnormal glucose profile had longer disease duration (95% confidence interval [CI] of difference=-6.64 to -0.68; P=0.019) and higher fasting blood glucose (95% CI of difference=-32.1 to -10.5; P=0.001) and serum ferritin (95% CI of difference=-219.8 to -3.4; P=0.001) than normoglycemic subjects. Insulin resistance and serum ferritin showed significant increase at 6 months (P<0.001 and P=0.001, respectively). Patients on deferiprone alone significantly improved glucose homeostasis on follow-up than those on desferrioxamine or combination therapy of desferrioxamine and deferiprone (P<0.05). CONCLUSIONS: Prolonged disease duration and higher serum ferritin adversely affects glucose homeostasis in thalassemic children. Deferiprone was the most effective chelator to improve glucose homeostasis in chronically transfused thalassemics.

Yangxin Tongmai Formula ameliorates impaired glucose tolerance in children with Graves' disease through upregulation of the insulin receptor levels.

Graves' disease (GD) is the leading cause of hyperthyroidism, and the majority of GD patients eventually develop disorders of glucose handling, which further affects their quality of life. Yangxin Tongmai formula (YTF) is modified from a famous formula of traditional Chinese medicine for the treatment of cardiovascular diseases. In this study we investigated the potential effects of YTF in the treatment of pediatric GD patients with impaired glucose tolerance. Forty pediatric GD patients and 20 healthy children were recruited for this clinical study. Based on the glucose tolerance, the GD patients were divided into two groups: 20 patients displayed impaired glucose tolerance, while the other 20 patients displayed normal glucose tolerance. YTF was orally administered for 60 days. YTF administration significantly ameliorated the abnormal glucose tolerance and insulin sensitivity in the GD patients with impaired glucose tolerance. To determine the molecular mechanisms of this observation, the number of plasma insulin receptors was determined by ELISA. Before treatment, the fasting and postprandial levels of the insulin receptor were significantly lower in patients with impaired glucose tolerance compared with those in patients with normal glucose tolerance and healthy children. After YTF treatment, both the fasting and the postprandial circulating insulin receptor levels were upregulated, and close to those in healthy children. Therefore, YTF is a potential effective treatment to enhance glucose handling in GD children with impaired glucose tolerance.

Comparison between pre-exercise casein peptide and intact casein supplementation on glucose tolerance in mice fed a high-fat diet.

We hypothesized that along with exercise, casein peptide supplementation would have a higher impact on improving glucose tolerance than intact casein. Male 6-week-old ICR mice were provided a high-fat diet to induce obesity and glucose intolerance. The mice were randomly divided into 4 treatment groups: control (Con), endurance training (Tr), endurance training with intact casein supplementation (Cas+Tr), and endurance training with casein peptide supplementation (CP+Tr). The mice in each group were orally administrated water, intact casein, or casein peptide (1.0 mg/g body weight, every day), and then subjected to endurance training (15-25 m/min, 60 min, 5 times/week for 4 weeks) on a motor-driven treadmill 30 min after ingestion. Our results revealed that total intra-abdominal fat was significantly lower in CP+Tr than in Con (p < 0.05). Following an oral glucose tolerance test, the blood glucose area under the curve (AUC) was found to be significantly smaller for CP+Tr than for Con (p < 0.05). Moreover, in the soleus muscle, glucose transporter 4 (GLUT4) protein levels were significantly higher in CP+Tr than in Con (p < 0.01). However, intra-abdominal fat, blood glucose AUC, and GLUT4 protein content in the soleus muscle did not alter in Tr and Cas+Tr when compared with Con. These observations suggest that pre-exercise casein peptide supplementation has a higher effect on improving glucose tolerance than intact casein does in mice fed a high-fat diet.