Increased Plasma Glucose Research Articles

Potential role of cinnamaldehyde and costunolide to counteract metabolic syndrome induced by excessive fructose consumption

BackgroundOne of the serious public health problems in the world is metabolic syndrome. It includes visceral obesity, dyslipidemia, insulin resistance, hyperglycemia, and hypertension. As a contributor to almost all the classic signs of metabolic syndrome, fructose was the ideal choice. There are certain shortcomings with existing drugs for insulin-resistant treatment. Plants still represent the main source of most available medicines. Cinnamaldehyde (CNA) is an active principle of Cinnamomum zeylanicum. Costunolide (CE) is natural sesquiterpene lactones, which is the main bioactive constituent of Saussurea lappa. The main aim of the present study is to investigate the effect of the synthetic antidiabetic agent (metformin) in comparison with natural constituents (cinnamaldehyde, costunolide) after developing a reliable model for insulin resistance by using high fructose diet (HFD).ResultsIt was found that HFD increased plasma glucose, insulin, glycosylated hemoglobin, HbA1c, serum total cholesterol, LDL-cholesterol, triglyceride, ALT, AST, creatinine, and uric acid. Moreover, HFD decreased hepatic reduced glutathione and superoxide dismutase levels. While oral administration of cinnamaldehyde and costunolide significantly decreased plasma glucose, HbA1c, total cholesterol, LDL-cholesterol, triglyceride, and increased level of hepatic reduced glutathione and superoxide dismutase activity. Also, cinnamaldehyde and costunolide restored the altered plasma levels of ALT, AST, creatinine, and uric acid to normal.ConclusionsThe results of this experimental study showed that cinnamaldehyde and costunolide could be used as safe drugs for treating different abnormalities of metabolic syndrome.

The toxic effects of titanium dioxide nanoparticles on plasma glucose metabolism are more severe in developing mice than in adult mice.

Titanium dioxide nanoparticles (TiO2 NPs) are authorized food additives, and children have the highest exposure. Therefore, children are likely more susceptible to the adverse effects of TiO2 NPs than adults. Previous study showed that oral administration of 50 mg/kg body weight (bw) TiO2 NPs increase plasma glucose in mice. However, few studies have directly compared the adverse effects of exposure to TiO2 NPs on plasma glucose metabolism of different age groups. In this study, the developing (age 3 weeks) and adult mice (age 10 weeks) were orally administered with 50 mg/kg bw TiO2 NPs per day. The TiO2 NPs induced hyperglycemia earlier in the developing mice than in the adult mice. Then mechanisms were analyzed after mice were oral administration of TiO2 NPs for 8 weeks and 26 weeks, respectively. Results showed that the treatment with TiO2 NPs activated xenobiotic biodegradation in livers of both developing and adult mice at the early stage. However, only in the developing mice, TiO2 NPs induced endoplasmic reticulum (ER) stress in livers and increased reactive oxygen species in livers and sera in the early stage. The ER stress and ROS activated an inflammation response and mitogen-activated protein kinase pathways, thereby inducing insulin resistance in the livers of developing mice at the early stage. The response of the adult mice was delayed, and these changes were observed in the late stage of the study. The results of this study all suggest that children are more susceptible than adults to the toxicity of orally administered TiO2 NPs.

Platelet-rich plasma improves impaired glucose hemostasis, disrupted insulin secretion, and pancreatic oxidative stress in streptozotocin-induced diabetic rat

Our study aimed to investigate the effects of platelet-rich plasma (PRP) on impaired glucose homeostasis, disrupted islet insulin secretion, and pancreatic oxidative status in streptozotocin (STZ)-diabetic rats. A total of 64 Sprague-Dawley male were randomized to four groups including controls, diabetes, control-PRP, and diabetes-PRP. The rats received the PRP (0.5 ml/kg, SC injection) twice weekly for 4 weeks. Plasma glucose and insulin levels, pancreatic oxidative stress markers and islet insulin secretion and content were measured. Compared with the control group, in the diabetic group, increased plasma glucose and malondialdehyde (MDA) levels and decreased plasma insulin level, islet insulin secretion, pancreatic superoxide dismutase (SOD), and catalase activities were observed. PRP treatment significantly reduced plasma glucose and MDA levels and enhanced plasma insulin, antioxidant enzyme activity, islet insulin secretion, and content in the diabetic rats. These findings showed that PRP can improve pancreatic islet insulin secretion, pancreatic oxidative stress and regulate plasma insulin and glucose levels in diabetic rats.

The effect of dietary glycerol supplementation on milk production and composition, blood parameters and performance of lactating sows

Modern lactating sows have an increased demand for nutrients for the large litter size compared to the traditional genotypes. Glycerol is considered to be a good alternative to moderate the energy deficiency and provide energy supply in the feed of lactating sow. The aim of our study was to evaluate the effect of a liquid “feed grade” glycerol source on the milk production and milk composition of sows including its fatty acid profile, on the major physiological indicators of sows, and on the digestibility of nutrients. The trial was conducted with Danish Landrace×Danish Yorkshire (323±17.0 kg) sows (n = 12/treatment) and their litters. 5% glycerol supplementation increased the milk yield on d 21 of lactation [control (C): 8.94±2.27 kg/d vs. 5% glycerol (G): 10.39±1.56 kg/d; P<0.05], but had no effect on the milk production of the total lactation period (P>0.05). Glycerol inclusion decreased the milk protein content on d 14 and d 21 and had a decreasing effect on the milk protein (CP) content in the total lactation period, either (C: 5.33±0.40 g/100 g milk vs. G: 5.15.±0.33 g/100 g milk; P<0.05). Glycerol supplementation did not influence the dry matter (DM), ether extract (EE) and lactose content. 5% glycerol did not have any effect on the feed intake, live weight, back-fat thickness, and weaning-to-oestrus interval of lactating sows and neither did significantly influence the weaning weight of the piglets. There was no difference between control and experimental groups in total protein, albumin and triglyceride concentration of blood samples of sows and in the activity of liver enzymes (ALT, AST, GGT), but there was a tendency (P<0.10) for increased plasma glucose (C: 4.94±0.29 mmol/L vs. G: 5.17±0.55 mmol/L) and cholesterol (C: 2.10±0.27 mmol/L vs. G: 2.34±0.33 mmol/L) in the experimental group. Due to the 5% glycerol supplementation, the ratio of total saturated fatty acids (SFAs) of the milk fat decreased (C: 43.47±3.37 g/100 g fatty acid vs. G: 39.39±4.51 g/100 g fatty acid; P<0.05). In the SFAs group the ratio of C14:0 and C16:0 fatty acids decreased significantly compared with the control group (P<0.05). In contrast, there was a tendency for increased total monounsaturated fatty acids (MUFAs) content of the milk (C: 43.62±2.54 g/100 g fatty acid vs. G: 47.11±4.29 g/100 g fatty acid; P<0.10) but the total polyunsaturated fatty acids (PUFAs) content was not affected (C: 12.88±1.23 g/100 g fatty acid vs. G: 13.50±0.64 g/100 g fatty acid;). The total n-3 PUFAs proportion in the milk increased (C: 0.63±0.06 vs. G: 0.68±0.05; P<0.05). No differences were observed in the apparent total tract digestibility of DM, CP, EE and crude fiber between control and experimental groups. Our findings have shown that 5% “feed grade” glycerol can be fed with lactating sows without having a negative effect on the performance. Additional dose trials are needed to be performed in order to further study the effect of glycerol supplementation on milk production and on metabolic processes of lactating sows.

The influence of exogenous phytase on the post-enteral availability of amino acids in broiler chickens offered wheat-based diets

To investigate the influence of exogenous phytase inclusions in poultry diets on the post-enteral availability of amino acids, wheat-soybean meal diets containing 0, 500, 1000 and 2000 phytase units (FTU)/kg were offered to eight replicate cages (six birds per cage) or a total of 192 male Ross 308 chicks from 7 to 28 days post-hatch. The parameters determined included growth performance, nutrient utilisation, bone mineralization, parameters of gizzard functionality, apparent ileal digestibility coefficients and disappearance rates (g/bird/day) of amino acids, plus concentrations of amino acids, glucose and ammonia in plasma from the portal circulation (anterior mesenteric vein). The inclusion of 500 FTU/kg significantly improved weight gain by 8.39% (1485 versus 1370 g/bird) and feed conversion ratio (FCR) by 5.10% (1.397 versus 1.472 g/g) in comparison to the control. Phytase inclusions significantly increased gizzard pH but not toe ash. The 2000 FTU/kg phytase inclusion significantly increased digestibility of 15 from 16 amino acids by an average of 5.29% (0.716 versus 0.680) and significantly increased apparent metabolisable energy (AME) by 0.45 MJ (12.43 versus 12.88 MJ) and N-corrected AME (AMEn) by 0.45 MJ (11.43 versus 11.88 MJ) relative to the control. The 500 FTU/kg phytase inclusion significantly increased free concentrations of seven amino acids (isoleucine, leucine, lysine, phenylalanine, tryptophan, valine and serine) in plasma from the anterior mesenteric vein based on pairwise comparisons and numerically increased concentrations of a further six amino acids. Phytase inclusions linearly reduced concentrations of glutamic acid and glutamine in the portal circulation, and there was a logarithmic relationship between phytase inclusions and increased plasma glucose concentrations. Reductions in the ratio of glutamate plus glutamine to glucose concentrations in portal plasma were significantly related to improvements in FCR. The outcomes of this study indicate that phytase can positively influence the post-enteral availability of amino acids. The inference is that phytase is manipulating the metabolic fates of amino acids and glucose in the gut mucosa and consideration is given to the possible responsible mechanisms for the observed outcomes.

Physiological responses to central and peripheral injections of compound 48/80 and histamine in chicks

Mast cells are a type of immune cell widely distributed in the body of vertebrates. Mast cells have many granules that contain several bioactive molecules such as histamine, and these molecules are released through degranulation when the mast cell receives certain stimuli. Because the number of mast cells increases during infection in chickens (Gallus gallus), the activity of mast cells might be related to non-specific symptoms such as anorexia under an infectious condition. Therefore, the purpose of the present study was to investigate whether intraperitoneal (IP) and intracerebroventricular (ICV) injections of compound 48/80, which induces degranulation of mast cells, affects feeding, voluntary activity, cloacal temperature, and the concentrations of plasma corticosterone (CORT) and glucose in chicks. The effect of histamine, which is found in mast cell granules, on these parameters was also investigated. IP injection of compound 48/80 significantly decreased food intake, voluntary activity, and cloacal temperature, and increased plasma CORT concentration in the chicks. While ICV injection of compound 48/80 also decreased food intake, it increased cloacal temperature and plasma glucose concentration. Both IP and ICV injections of histamine significantly decreased food intake, cloacal temperature, and plasma CORT concentration. However, only IP injection of histamine significantly decreased voluntary activity and increased plasma glucose concentration. The results suggest that degranulation of mast cells is related to non-specific symptoms in chicks, although the mechanism seems to be different between peripheral and central tissues. In addition, the effect of peripherally-injected compound 48/80 may be partly mediated by histamine.

Combined effects of dietary quercetin and resveratrol on growth performance, antioxidant capability and innate immunity of blunt snout bream (Megalobrama amblycephala)

This study was conducted to investigate the effects of resveratrol (R) and quercetin (Q) supplementation on growth performance, antioxidant capability and hepatic apoptosis of juvenile blunt snout bream (average initial weight 4.6 ± 0.10 g) fed a high-fat diet (HFD). Eight experimental diets were formulated to contain normal fat diet (NFD, 5% fat), a HFD (11% fat), or a HFD supplemented with three resveratrol levels (0, 0.5% and 1.0%) and two quercetin levels (0.4% and 0.8%), designated diets as D1, D2, D3, D4, D5, D6, D7, and D8, respectively. After an 8-week feeding trial, the results showed that fish fed a HFD developed hepatic steatosis, as shown by elevated hepatic and plasma triglycerides (TG), total cholesterol (TC), and by increased plasma glucose (GLU), apoptosis index (AI) and liver fat content. Also, hepatocyte mRNA expressions of sirtuin-1 (SIRT1), copperezinc superoxide dismutase (Cu/Zn-SOD) and catalase (CAT) in fish fed a HFD were significantly decreased compared to fish fed a NFD (P < 0.05). Tumor necrosis factor-α (TNF-α) level was significantly increased in fish fed D2 compared to those fed D1. Dietary resveratrol and quercetin supplementation decreased plasma GLU, TG and TC, increased nitric oxide (NO) content, upregulated the mRNA expressions of SIRT1, Cu/Zn-SOD, CAT and glutathione peroxidase (GPx), and downregulated Caspase8 and TNF-a mRNA expressions. Weight gain rate (WGR) significantly increased in fish fed a HFD supplemented with 0.8% quercetin alone compared to other treatments (except for fish fed HFD supplemented with 0.4% quercetin alone). At the same quercetin concentration, the growth performance decreased with increasing resveratrol. Compared with D2 (HFD) and D7 (HFD supplemented with 0.8% quercetin and 0.5% resveratrol), the combination of 0.4% quercetin and 1.0% resveratrol supplementation significantly decreased hepatic TG and TC (P < 0.05). Additionally, compared with D2, the combination of 0.8% quercetin and 1.0% resveratrol supplementation significantly increased hepatic endothelial nitric oxide synthase (e-NOS) and inducible nitric oxide synthase (i-NOS) contents (P < 0.05). The results of this study indicated that dietary quercetin and resveratrol association could improve immunity, antioxidant capability and lipid metabolism of blunt snout bream, and high concentration of resveratrol would inhibit the growth of this species, while relatively high concentration of quercetin alone could promote its growth.

Abstract P2025: Primary Aldosteronism Decreases Insulin Secretion and Increases Insulin Clearance in Humans

Primary aldosteronism is associated with an increased risk of diabetes, but the mechanism is uncertain. We enrolled 9 patients with primary aldosteronism and assessed insulin secretion and insulin sensitivity beforte and after 3-12 months after either adrenalectomy (n-6) or medical treatment (n=3). Plasma 8AM Aldosterone ( p =0.02) and 11-deoxycorticosterone ( p =0.02) decreased after treatment, whereas cortisol was unchanged ( p =0.57). Systolic blood pressure (131.1±3.6 vs 124.3±7.7; p =0.43), serum potassium (3.7±0.1 vs 4.1±0.1 mEq/L; p =0.063), and creatinine (1.1±0.1 vs 1.2±0.1 mg/dL; p =0.35) were similar after treatment. During hyperglycemic clamps, we infused glucose to increase plasma glucose to a target of 200mg/dL ( a ). The insulin response ( b , 218.6±39.8 vs 403.1±42.0 pM insulin mean at 90-120 min, p =0.004) and L-arginine stimulated insulin response ( c) increased compared to Pre-Treatment assessment. C-peptide results were similar to insulin alterations. Comparison to control subjects matched for age, race, sex, and BMI ( Figure , gray line and area indicating mean±95%CI) indicated that insulin secretion after treatment was comparable to healthy individuals. During hyperinsulinemic-euglycemic clamps, insulin clearance (steady state insulin divided by insulin infusion rate) increased after treatment (855±68 vs 615±57 mL/min, p =0.031). Insulin sensitivity decreased after treatment (30.7±2.1 vs 18.5±1.6 M/I; p =0.016), but disposition index was unchanged (acute insulin response x M/I; p =0.81).

Temporal effects of ruminal infusion of propionic acid on hepatic metabolism in cows in the postpartum period

A faster rate of infusion of propionic acid into the rumen of cows in the postpartum period increased meal size compared with a slower rate of infusion in a previous experiment. Because propionate is anaplerotic and stimulates oxidation of acetyl coenzyme A (CoA) in the liver, and hepatic oxidation has been linked to satiety, this result was opposite to our expected response. We then hypothesized that the faster rate of infusion might have saturated the pathway for propionate metabolism in hepatocytes resulting in lower first-pass extraction by the liver. Because we were measuring feeding behavior, we could not sample blood and liver tissue over time in that experiment. Therefore, to determine the temporal effects of propionic acid (PA) infusion on hepatic metabolism and plasma metabolites over the time course of a meal, we infused 1.25 mol of PA (2.5 L of 0.5M PA) over 5 min (FST) or 15 min (SLW) into the rumen. We evaluated response to PA infusions both before feeding, when ruminal PA production by rumen microbes is lower and hepatic acetyl CoA concentration is greater, and 4 h after feeding, when PA production is greater and hepatic acetyl CoA concentration is lower. Blood and liver samples were collected before, and after 5, 15, and 30 min of infusion. Contrary to our hypothesis, the rate of PA infusion into the rumen did not affect plasma propionate concentration, indicating the FST effects on feeding behavior were not because of a limitation on propionate uptake by the liver. However, FST increased plasma glucose and insulin concentrations faster than SLW, resulting in a reduction in plasma nonesterified fatty acid concentration during the time frame of meals. Decreased plasma nonesterified fatty acid concentration during infusion likely decreased the supply of acetyl CoA for oxidation in the liver. The FST treatment also increased fumarate concentration at 5 min after the initiation of infusion but did not affect oxaloacetate concentration compared with SLW, consistent with a limitation to propionate metabolism at that reaction. A metabolic bottleneck at the malate dehydrogenase reaction for FST compared with SLW would further contribute to a reduction in hepatic oxidation within the time frame of a meal, allowing greater meal size, consistent with the hepatic oxidation theory and our previous results.

The effect of length of storage and sodium benzoate on the nutritive value of reconstituted sorghum grain silages for dairy cows

Twenty Holstein cows at 168 ± 87 d in milk (mean ± SD) were assigned to a 4 × 4 Latin square design with a 2 × 2 factorial arrangement to evaluate the effects of 2 storage lengths (30 or 90 d) and the presence of sodium benzoate (control or 0.2% as fed) on the nutritive value of reconstituted sorghum grain silages (RSGS). For each treatment, dry ground sorghum grain was rehydrated to 35% moisture and ensiled in 200-L plastic drums. The treatments were RSGS stored for 30 d without sodium benzoate (30 CON), RSGS stored for 30 d with sodium benzoate (30 BEN), RSGS stored for 90 d without sodium benzoate (90 CON) and RSGS stored for 90 d with sodium benzoate (90 BEN). Diets contained 16.3% RSGS. Silages stored for 90 d had higher concentrations of 1,2-propanediol, soluble protein, and ammonia nitrogen than did those stored for 30 d. Sodium benzoate reduced ethanol and ethyl-ester formation. Silages stored for 90 d had higher starch (89.3 vs. 86.9%) and protein (57.1 vs. 54.0%) digestibility compared with silages stored for 30 d. The ruminal acetate-to-propionate ratio tended to be lower in RSGS stored for 90 d than in RSGS stored for 30 d (3.75 vs. 3.34). Milk yield increased from 30.0 kg/d in cows fed RSGS stored for 30 d to 31.2 kg/d in cows fed RSGS stored for 90 d, without a change in dry matter intake (23.5 kg/d on average). Hence, feed efficiency and milk N efficiency also had tendencies to increase in cows fed RSGS stored for 90 d. Sodium benzoate did not alter cow performance but slightly increased plasma glucose (65.2 vs. 63.6 mg/dL). In conclusion, increasing the storage period of RSGS from 30 to 90 d improved starch and protein digestibility, milk yield, and feed efficiency.

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.

Mechanisms of titanium dioxide nanoparticle-induced oxidative stress and modulation of plasma glucose in mice.

Titanium dioxide nanoparticles (TiO2 NPs) are reported to increase plasma glucose levels in mice at specific doses. The production and accumulation of reactive oxygen species (ROS) is potentially the most important factor underlying the biological toxicity of TiO2 NPs but the underlying mechanisms are unclear at present. Data from genome-wide analyses showed that TiO2 NPs induce endoplasmic reticulum (ER) stress and ROS generation, leading to the inference that TiO2 NP-induced ER stress contributes to enhancement of ROS in mice. Resveratrol (Res) effectively relieved TiO2 NP-induced ER stress and ROS generation by ameliorating expression of a common set of activated genes for both processes, signifying that ER stress and ROS are closely related. TiO2 NP-induced ER stress occurred earlier than ROS generation. Upon treatment with 4-phenylbutyric acid to relieve ER stress, plasma glucose levels tended toward normal and TiO2 NP increased ROS production was inhibited. These results suggest that TiO2 NP-induced ER stress promotes the generation of ROS, in turn, triggering increased plasma glucose levels in mice. In addition, Res that displays the ability to reduce ER stress presents a dietary polyphenol antioxidant that can effectively prevent the toxicological effects of TiO2 NPs on plasma glucose metabolism.

Effect of dietary sodium butyrate on growth performance, enzyme activities and intestinal proliferation‐related gene expression of juvenile golden pompanoTrachinotus ovatus

The present study was conducted to investigate the effects of dietary sodium butyrate on growth performance, intestine enzyme activities and intestinal proliferation‐related gene expression of juvenile golden pompano Trachinotus ovatus. A basal diet was supplemented with sodium butyrate at 0.0 (control), 0.25, 0.5, 1, 2 and 4 g/kg feed for 8 weeks. The final body weight, weight gain (WG), specific growth rate (SGR) and condition factor (CF) increased with increasing dietary sodium butyrate up to 2.0 g/kg, and thereafter declined, while feed conversion ratio exhibited an opposite trend. Compared with the control, the 2.0 g/kg sodium butyrate group had higher condition factor (CF) significantly (p < 0.05). Whole body ash decreased with increasing dietary sodium butyrate level, with the lowest whole body ash content in 4.0 g/kg sodium butyrate (p < 0.05). Compared with the control, the 2.0 g/kg sodium butyrate group had significantly increased plasma glucose, cholesterol, albumin level, A/G ratio, ALT and AST contents (p < 0.05), while significantly decreased plasma ALT/AST ratio (p < 0.05). As for the intestinal digestive and brush border enzymes activities, compared with the control, the 2.0 and 4.0 g/kg sodium butyrate groups had significantly increased intestinal protease, amylase, AKP and Na⁺‐K⁺‐ATPase activities (p < 0.05), respectively. The relative level of intestinal CDX2 mRNA of fish significantly increased with dietary sodium butyrate level. Compared with the control, the 2.0 g/kg sodium butyrate groups had significantly increased the expression of intestinal CDX2 and CREB mRNA (p < 0.05), respectively. In conclusion, these results suggested that the optimum sodium butyrate level for juvenile golden pompano could be 2.0 g/kg of the diet.

Glutamine administration promotes hepatic glucose homeostasis through regulating the PI3K/Akt pathway in high-fat diet-induced obese mice with limb ischemia

High-fat diet-induced obesity can lead to hepatic insulin resistance (IR) and alter glucose metabolism. The decreased protein expression involved in the PI3K-Akt pathway may enhance hepatic glycogenolysis and gluconeogenesis. Obesity-associated glucose dysregulation and IR are risk factors for the development of peripheral arterial disease. Glutamine (Gln) has immunomodulatory properties and was found to attenuate IR and hyperglycemia in diabetic condition. Thus, in this study we hypothesized that Gln administration modulates hepatic glucose metabolism and improve IR via PI3K-Akt pathway in obese mice with limb ischemia. Mice were divided into a high-fat group (HC), and a high-fat Gln group (HG). Mice in the HC group were fed the high-fat diet for 8 weeks, while the HG group was initially fed the high-fat diet for 4 weeks followed by a high-fat diet with Gln for an additional 4 weeks. Part of the mice in the HC and HG groups were subjected to a limb ischemic operation and were euthanized after the operation. Liver tissues and blood samples were collected for analysis. The results showed that high-fat diet-induced obesity resulted in increased plasma glucose and insulin levels. Also, impairment of hepatic insulin signaling by downregulating PI3K-Akt pathway-associated protein expression was observed. Administration of Gln increased protein expression associated with PI3K-Akt signaling pathway, while reducing G6PC and FOXO1 expression in the hepatocytes that may promote glycogen synthesis and inhibit gluconeogenesis. These findings suggest that obese mice treated with Gln-containing high-fat diet may normalize blood glucose and improve IR in response to limb ischemia.

Low intake of digestible carbohydrates ameliorates duodenal absorption of carbohydrates in mice with glucose metabolism disorders induced by artificial sweeteners.

Long-term artificial sweetener consumption has been reported to induce glucose intolerance, and the intestinal microbiota seems as an important target. While the impacts of artificial sweeteners on energy balance remain controversial, this work aimed to evaluate the protective effects in mice of a low digestible carbohydrate (LDC) diet on plasma glucose, plasma fasting insulin, sweet taste receptors, glucose transporters, and absorption of carbohydrates, together with consumption of acesulfame potassium (AK) or saccharin (SAC). Artificial sweetener was administered to mice for 12 weeks to induce glucose metabolism disorders; mice were treated with an LDC diet for the final 6weeks. The experimental groups were treated with an LDC diet that had the same energy as the normal-diet group. Prolonged administration of artificial sweeteners led to metabolic dysfunction, characterized by significantly increased plasma glucose, insulin resistance, sweet taste receptors, glucose transporters, and absorption of carbohydrates. Treatment with an LDC diet positively modulated these altered parameters, suggesting overall beneficial effects of an LDC diet on detrimental changes associated with artificial sweeteners. Reducing digestible carbohydrates in the diet can significantly reduce the absorption of carbohydrates and improve glucose metabolism disorders caused by dietary factors. These effects may be due to the fact that reducing the amount of digestible carbohydrates in the feed can reduce the number of intestinal sweet receptors induced by exposure to artificial sweeteners. © 2019 Society of Chemical Industry.

Absence of the β1 subunit of AMP-activated protein kinase reduces myofibroblast infiltration of the kidneys in early diabetes.

Activation of the heterotrimeric energy-sensing kinase AMP-activated protein kinase (AMPK) has been reported to improve experimental diabetic kidney disease. We examined the effect of type 1 diabetes in wild-type (WT) mice and mice lacking the β1 subunit of AMPK (AMPK β1-/- mice), which have reduced AMPK activity in kidneys and other organs. Diabetes was induced using streptozotocin (STZ) and the animals followed up for 4weeks. Hyperglycaemia was more severe in diabetic AMPK β1-/- mice, despite the absence of any difference in serum levels of insulin, adiponectin and leptin. There was no change in AMPK activity in the kidneys of diabetic WT mice by AMPK activity assay, or phosphorylation of either the αT172 activation site on the α catalytic subunit of AMPK or the AMPK-specific phosphosite S79 on acetyl CoA carboxylase 1 (ACC1). Phosphorylation of the inhibitory αS485 site on the α subunit of AMPK was significantly increased in the WT diabetic mice compared to non-diabetic controls. Despite increased plasma glucose levels in the diabetic AMPK β1-/- mice, there were fewer myofibroblasts in the kidneys compared to diabetic WT mice, as evidenced by reduced α-smooth muscle actin (α-SMA) protein by Western blot, mRNA by qRT-PCR and fewer α-SMA-positive cells by immunohistochemical staining. Albuminuria was also reduced in the AMPK β1-/- mice. In contrast to previous studies, therefore, myofibroblasts were reduced in the kidneys of AMPK β1-/- diabetic mice compared to diabetic WT mice, despite increased circulating glucose, suggesting that AMPK can worsen renal fibrosis in type 1 diabetes.

A New Player in Intra‐islet Communication: The Hyperglycemic Effects of Neuronostatin through Increased Glucagon Production and Reduced Insulin Release

The tight regulation of blood glucose with insulin and antidiabetic agents greatly increases the risk and dangers of hypoglycemia in patients with Type 1 and Type 2 Diabetes. In addition, repeated bouts of hypoglycemia diminish the sympathetic arms of the counterregulatory response and blunt awareness of symptoms, creating a vicious cycle of unawareness and increasingly severe hypoglycemia. The only option in preventing or reversing hypoglycemia unawareness is careful avoidance of hypoglycemia through close monitoring– an often unobtainable goal. There is great need for other therapies and better understanding of diabetic hypoglycemia. We recently identified a novel peptide, neuronostatin (NST), encoded in the somatostatin preprohormone and found in all somatostatin‐positive tissues and cells. However, the activity of NST is functionally distinct from other preprosomatostatin products. Furthermore, it appears the physiologic stimuli of the peptides are different and that the peptides are sequestered in separate secretory vesicles. Our group identified the orphan GPCR, GPR107, as a cognate receptor of NST. Through an interaction with GPR107, NST enhanced proglucagon mRNA expression and glucagon release from isolated islets and immortalized alpha cells. NST also reduced beta cell release of insulin in response to high glucose conditions in isolated islets. Based off our findings, we hypothesized that NST is a pancreatic component of the counterregulatory response to hypoglycemia. In support of our hypothesis, an infusion of NST substantially increased plasma glucose levels over a 30‐minute time period in male rats. Additionally, NST delayed glucose clearance and diminished the insulin response to hyperglycemia in a glucose tolerance test. Fasting blood glucose raised plasma NST levels in rats, and exposure to low glucose stimulated NST release from human islets. Further experiments will confirm the role of NST in preventing or reversing hypoglycemia and determine how NST plays a role in the complex relationships of islet regulation and signaling. We propose that NST could represent a novel therapeutic target for the treatment and prevention of hypoglycemia in diabetes.Support or Funding InformationThis work was completed with funding support from the NIH and NIDDK, and the Helmsley Charitable Trust.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A diet rich in menhaden oil has the hypolipidemic effect but increases plasma glucose and insulin levels in rats

A diet rich in menhaden oil has the hypolipidemic effect but increases plasma glucose and insulin levels in rats

Chronic mercury at low doses impairs white adipose tissue plasticity

IntroductionThe toxic effects of mercury (Hg) are involved in homeostasis of energy systems such as lipid and glucose metabolism, and white adipose tissue dysfunction is considered as a central mechanism leading to metabolic disorders. Objective: The aim of this study was to determine the effects of chronic inorganic Hg exposure at low doses on the lipid and glycemic metabolism. MethodsMale Wistar rats were divided into two groups and treated for 60 days with: saline solution, i.m. (Untreated) and mercury chloride, i.m. - 1st dose 4.6 μg/kg, subsequent doses 0.07 μg/kg/day - (Mercury). Histological analyses, Hg levels measurement and GRP78, CHOP, PPARα, PPARγ, leptin, adiponectin and CD11 mRNA expressions were performed in epididymal white adipose tissue (eWAT). Glucose, triglycerides, total cholesterol and insulin plasma levels were also measured. ResultsHg exposure reduced the absolute and relative eWAT weights, adipocyte size, plasma insulin levels, glucose tolerance, antioxidant defenses and increased plasma glucose and triglyceride levels. In addition, CHOP, GRP78, PPARα, PPARγ, leptin and adiponectin mRNA expressions were increased in Hg-treated animals. No differences in Hg concentration were found in eWAT between the untreated and Hg groups. These results suggest that the reduction in adipocyte size is related to the impaired antioxidant defenses, endoplasmic reticulum (ER) stress, the disrupted PPARs and adipokines mRNA expression induced by the metal in eWAT. These disturbances possibly induced a decrease in circulating insulin levels, an imbalance between lipolysis and lipogenesis mechanisms in eWAT, with an increase in fatty acids mobilization, a reduction in glucose uptake and an activation of pro-apoptotic pathways, leading to hyperglycemia and hyperlipidemia. ConclusionsHg is a powerful environmental WAT disruptor that influences signaling events and impairs metabolic activity and hormonal balance of adipocytes.

Mild Physiologic Hyperglycemia Induces Hepatic Insulin Resistance in Healthy Normal Glucose-Tolerant Participants.

Chronic hyperglycemia worsens skeletal muscle insulin resistance and β-cell function. However, the effect of sustained physiologic hyperglycemia on hepatic insulin sensitivity is not clear. To examine the effect of sustained physiologic hyperglycemia (similar to that observed in patients with type 2 diabetes) on endogenous (primarily reflecting hepatic) glucose production (EGP) in healthy individuals. Volunteers participated in a three-step hyperinsulinemic (10, 20, 40 mU/m2 per minute) euglycemic clamp before and after a 48-hour glucose infusion to increase plasma glucose concentration by ∼40 mg/dL above baseline. EGP was measured with 3-3H-glucose before and after chronic glucose infusion. Sixteen persons with normal glucose tolerance [eight with and eight without a family history (FH) of diabetes] participated in the study. EGP. Basal EGP increased following 48 hours of glucose infusion (from a mean ± SEM of 2.04 ± 0.08 to 3.06 ± 0.29 mg/kgffm⋅ min; P < 0.005). The hepatic insulin resistance index (basal EGP × fasting plasma insulin) markedly increased following glucose infusion (20.1 ± 1.8 to 51.7 ± 6.6; P < 0.005) in both FH+ and FH- subjects. Sustained physiologic hyperglycemia for as little as 48 hours increased the rate of basal hepatic glucose production and induced hepatic insulin resistance in health persons with normal glucose tolerance, providing evidence for the role of glucotoxicity in the increase in hepatic glucose production in type 2 diabetes.