The impact of prolonged hyperinsulinaemia on glucose transport in equine skeletal muscle and digital lamellae

REASONS FOR PERFORMING STUDY An increased incidence of metabolic disease in horses has led to heightened recognition of the pathological consequences of insulin resistance (IR). Laminitis, failure of the weight-bearing digital lamellae, is an important consequence. Altered trafficking of specialised glucose transporters (GLUTs) responsible for glucose uptake, are central to the dysregulation of glucose metabolism and may play a role in laminitis pathophysiology. OBJECTIVES We hypothesised that prolonged hyperinsulinaemia alters the regulation of glucose transport in insulin-sensitive tissue and digital lamellae. Our objectives were to compare the relative protein expression of major GLUT isoforms in striated muscle and digital lamellae in healthy horses and during hyperinsulinaemia. STUDY DESIGN Randomised, controlled study. METHODS Prolonged hyperinsulinaemia and lamellar damage were induced by a prolonged-euglycaemic hyperinsulinaemic clamp (p-EHC) or a prolonged-glucose infusion (p-GI) and results were compared to electrolyte-treated controls. GLUT protein expression was examined with immunoblotting. RESULTS Lamellar tissue contained more GLUT1 protein than skeletal muscle (p = 0.002) and less GLUT4 than the heart (p = 0.037). During marked hyperinsulinaemia and acute laminitis (induced by the p-EHC), GLUT1 protein expression was decreased in skeletal muscle (p = 0.029) but unchanged in the lamellae, while novel GLUTs (8; 12) were increased in the lamellae (p = 0.03), but not skeletal muscle. However, moderate hyperinsulinaemia and subclinical laminitis (induced by the p-GI) did not cause differential GLUT protein expression in the lamellae vs. control horses. CONCLUSIONS The results suggest that lamellar tissue functions independently of insulin and that IR may not be an essential component of laminitis aetiology. Marked differences in GLUT expression exist between insulin-sensitive and insulin-independent tissues during metabolic dysfunction in horses. The different expression profiles of novel GLUTs during acute and subclinical laminitis may be important to disease pathophysiology and require further investigation.

Weight-related differences in glucose metabolism and free fatty acid production in two South African population groups

OBJECTIVE The effects of free fatty acids (FFA), leptin, tumour necrosis factor (TNF) alpha and body fat distribution on in vivo oxidation of a glucose load were studied in two South African ethnic groups. DESIGN AND MEASUREMENTS Anthropometric and various metabolic indices were measured at fasting and during a 7h oral glucose tolerance test (OGTT). Body composition was measured using bioelectrical impedance analysis and subcutaneous and visceral fat mass was assessed using a five- and two-level CT-scan respectively. Glucose oxidation was evaluated by measuring the ratio of (13)CO(2) to (12)CO(2) in breath following ingestion of 1-(13)C-labelled glucose. SUBJECTS Ten lean black women (LBW), ten obese black women (OBW), nine lean white women (LWW) and nine obese white women (OWW) were investigated after an overnight fast. RESULTS Visceral fat levels were significantly higher (P < 0.01) in obese white than black women, despite similar body mass indexes (BMIs). There were no ethnic differences in glucose oxidation however; in the lean subjects of both ethnic groups the area under the curve (AUC) was higher than in obese subjects (P < 0.05 for both) and was found to correlate negatively with weight (r = -0.69, P < 0.01) after correcting for age. Basal TNF alpha concentrations were similar in all groups. Percentage suppression of FFAs at 30 min of the OCTT was 24 +/- 12% in OWW and - 38 +/- 23% (P < 0.05) in OBW, ie the 30 min FFA level was higher than the fasting level in the latter group. AUC for FFAs during the late postprandial period (120 - 420 min) was significantly higher in OWW than OBW (P < 0.01) and LWW (P < 0.01) and correlated positively with visceral fat mass independent of age (r = 0.78, P < 0.05) in the OWW only. Leptin levels were higher (P < 0.01) both at fasting and during the course of the OCTT in obese women from both ethnic groups compared to the lean women. CONCLUSIONS Glucose oxidation is reduced in obese subjects of both ethnic groups; inter- and intra-ethnic differences were observed in visceral fat mass and FFA production and it is possible that such differences may play a role in the differing prevalences of obesity-related disorders that have been reported in these two populations.

Dapagliflozin – do we need it registered for type 2 diabetes?

INTRODUCTION: Inhibitors of the sodium-glucose co-transporter 2 (SGLT2) promote the excretion of glucose to reduce glycated hemoglobin (HbA1c) levels. Canagliflozin was the first SGLT2 inhibitor to be approved by the US FDA for use in the treatment of type 2 diabetes, and recently dapagliflozin has also been approved. AREAS COVERED: We evaluated a recent Phase III clinical trial with dapagliflozin. EXPERT OPINION: Dapagliflozin was studied as add-on therapy to sitagliptin with or without metformin, and was shown to lower HbA1c levels and body weight. The incidence of hypoglycaemia was low with dapagliflozin, but it did increase the incidence of urogenital infections. As no clear benefits have been identified for dapagliflozin over canagliflozin, which was the first gliflozin registered by the FDA, we do not fully understand why it was necessary to register dapagliflozin. Given that there are no completed cardiovascular/clinical outcome studies with dapagliflozin, and therefore no evidence of beneficial effect, it also seems premature to be using it extensively or considering it as an alternative to the clinically proven metformin.

A comprehensive mechanistic kinetic model for dilute acid hydrolysis of switchgrass cellulose to glucose, 5-HMF and levulinic acid

Switchgrass was treated by 1% (w/w) H₂SO₄in batch tube reactors at temperatures ranging from 140–220°C for up to 60 minutes. In this study, release patterns of glucose, 5-hydroxymethylfurfural (5-HMF), and levulinic acid from switchgrass cellulose were investigated through a mechanistic kinetic model. The predictions were consistent with the measured products of interest when new parameters reflecting the effects of reaction limitations, such as cellulose crystallinity, acid soluble lignin–glucose complex (ASL–glucose) and humins that cannot be quantitatively analyzed, were included. The new mechanistic kinetic model incorporating these parameters simulated the experimental data with R² above 0.97. Results showed that glucose yield was most sensitive to variations in the parameter regarding the cellulose crystallinity at low temperatures (140–180°C), while the impact of crystallinity on the glucose yield became imperceptible at elevated temperatures (200–220 °C). Parameters related to the undesired products (e.g. ASL–glucose and humins) were the most sensitive factors compared with rate constants and other additional parameters in impacting the levulinic acid yield at elevated temperatures (200–220°C), while their impacts were negligible at 140–180°C. These new findings provide a more rational explanation for the kinetic changes in dilute acid pretreatment performance and suggest that the influences of cellulose crystallinity and undesired products including ASL–glucose and humins play key roles in determining the generation of glucose, 5-HMF and levulinic acid from biomass-derived cellulose.

Studies of water and electrolyte movement from oral rehydration solutions (rice- and glucose-based) across a normal and secreting gut using a dual isotope tracer technique in a rat perfusion model

Aims: To establish a model to measure bidirectional flow of water from a glucose oral rehydration solution (G-ORS) and a newly developed rice-based oral rehydration solution (R-ORS) using a dual isotope tracer technique in a rat perfusion model. To measure net water, sodium and potassium absorption from the ORS. Methods: In viva steady-state perfusion studies were carried out in normal and secreting (induced by cholera toxin) rat small intestine (n = 11 in each group). To determine bidirectional flow of water from the ORS the animals were initially labelled with tritium, and deuterium was added to the perfusion solution. Sequential perfusate and blood samples were collected after attainment of steady-state conditions and analysed for water and electrolyte content. Results: There was a significant increase in net water absorption from the R-ORS compared to the G-ORS in both the normal (P < 0.02) and secreting intestine (P < 0.05). Water efflux was significantly reduced in the R-ORS group compared to the G-ORS group in both the normal (P < 0.01) and the secreting intestine (P < 0.01). There was an increase in sodium absorption in the R-ORS group compared to the G-ORS. The G-ORS produced a significantly greater blood glucose level at 75 min compared to the R-ORS (P < 0.03) in the secreting intestine. Conclusions: This study demonstrates the improved water absorption from a rice-based ORS in both the normal and secreting intestine. Evidence that the absorption of water may be influenced by the osmolality of the ORS was also demonstrated.

A controlled trial comparing the efficacy of rice-based and hypotonic glucose oral rehydration solutions in infants and young children with gastroenteritis

A prospective randomized trial was conducted to compare the efficacy of a rice-based oral rehydration solution (ORS) with glucose ORS in infants and children under 5 years of age with acute diarrhoea and mild to moderate dehydration (<10%). One hundred children presenting to a large metropolitan teaching hospital were eligible for entry to the study and were randomized to receive rice ORS or glucose ORS. Outcome measures were stool output (SO), duration of illness (DD) and recovery time to introduction of other fluids (RTF) and diet (RTD). Significant differences were found for all outcome measures in favour of the rice ORS group. Mean SO was lower (160 vs 213 mt; P<0.02), mean DD was reduced (17.3 vs 24.3 h; P = 0.03) and median RTF was decreased (12.7 vs 18.1 h; P< 0.001) in the rice ORS group compared with the glucose ORS group. The median rime to introduction of diet and mean length of hospital stay showed similar significant reductions. Our study has shown rice ORS to be an acceptable alternative to glucose ORS in young children and have shown that it is significantly more effective in reducing the course of diarrhoeal illness and the time taken to return to normal drinking and eating habits.

A 3-hour quantitative comparison of glucose-based versus rice-based oral rehydration solution intake by children with diarrhoea in Port Moresby General Hospital

Measurements were made of the intake of a WHO/UNICEF glucose-based and a rice cereal-based oral rehydration solution (ORS) by children with diarrhoea. Twenty children who presented to the Children's Outpatient Department at Port Moresby General Hospital with acute diarrhoea and mild dehydration were randomly assigned to an ORS and measurements were taken over the following 3 hours. For data analysis, the patients were paired by weight. Testing the means of the paired samples by t test showed that there was no significant difference between the amount of rice ORS and the amount of glucose ORS taken over 3 hours. The discovery of oral rehydration solution (ORS) for the treatment of diarrheal disease has been heralded as the most important medical discovery of the century. Cereal-based ORS is able to decrease stool output and the duration of diarrheal illness more than the standard glucose-based ORS, through the increased absorption provided by oligosaccharides without the imposition of a greater osmotic penalty. Moreover, the peptides in cereals enhance amino acid and water absorption, while providing nutritional benefits. UNICEF's glucose-based ORS is becoming more widely used in Papua New Guinea (PNG). 20 children aged 6-37 months (mean age, 15 months) who presented to the Children's Outpatient Department at Port Moresby General Hospital during September-October 1993 with acute diarrhea and mild dehydration were randomly assigned to receive either a rice-based ORS or standard glucose ORS, and measurements were taken over the following 3 hours. The patients were paired by weight for analysis. No statistically significant difference was found between the amount of rice ORS and the amount of glucose ORS taken over 3 hours.

Air pollution and fasting blood glucose: A longitudinal study in China

Limited studies have examined the associations between air pollutants [particles with diameters of 10um or less (PM10), sulfur dioxide (SO2), and nitrogen dioxide (NO2)] and fasting blood glucose (FBG). We collected data for 27,685 participants who were followed during 2006 and 2008. Generalized Estimating Equation models were used to examine the effects of air pollutants on FBG while controlling for potential confounders. We found that increased exposure to NO2, SO2 and PM10 was significantly associated with increased FBG levels in single pollutant models (p<0.001). For exposure to 4 days’ average of concentrations, a 100 µg/m3 increase in SO2, NO2, and PM10 was associated with 0.17 mmol/L (95%CI: 0.15–0.19), 0.53 mmol/L (95%CI: 0.42–0.65), and 0.11 mmol/L (95%CI: 0.07–0.15) increase in FBG, respectively. In the multi-pollutant models, the effects of SO2 were enhanced, while the effects of NO2 and PM10 were alleviated. The effects of air pollutants on FBG were stronger in female, elderly, and overweight people than in male, young and underweight people. In conclusion, the findings suggest that air pollution increases the levels of FBG. Vulnerable people should pay more attention on highly polluted days to prevent air pollution-related health issues.

Associations with low rates of postpartum glucose screening after gestational diabetes among Indigenous and non-Indigenous Australian women

OBJECTIVES To explore factors associated with postpartum glucose screening among women with Gestational Diabetes Mellitus (GDM). METHODS A retrospective study using linked records from women with GDM who gave birth at Cairns Hospital in Far North Queensland, Australia, from 1 January 2004 to 31 December 2010. RESULTS The rates of postpartum Oral Glucose Tolerance Test (OGTT) screening, while having increased significantly among both Indigenous* and non-Indigenous women from 2004 to 2010 (HR 1.15 per year, 95%CI 1.08-1.22, p<0.0001), remain low, particularly among Indigenous women (10% versus 27%, respectively at six months postpartum). Indigenous women in Cairns had a longer time to postpartum OGTT than Indigenous women in remote areas (HR 0.58, 0.38-0.71, p=0.01). Non-Indigenous women had a longer time to postpartum OGTT if they: were born in Australia (HR 0.76, 0.59-1.00, 0.05); were aged <25 years (HR 0.45, 0.23-0.89, p=0.02); had parity >5 (HR 0.33, 0.12-0.90, p=0.03); smoked (HR 0.48, 0.31-0.76, p=0.001); and did not breastfeed (HR 0.09, 0.01-0.64, p=0.02). CONCLUSIONS Postpartum diabetes screening rates following GDM in Far North Queensland are low, particularly among Indigenous women, with lower rates seen in the regional centre; and among non-Indigenous women with indicators of low socioeconomic status. IMPLICATIONS Strategies are urgently needed to improve postpartum diabetes screening after GDM that reach women most at risk.

Commentary: Chronic SSRI stimulation of astrocytic 5-HT2B receptors change multiple gene expressions/editings and metabolism of glutamate, glucose and glycogen: A potential paradigm shift

Working on the serotonin (5-hydroxytryptamine, 5-HT) 5-HT2B receptor since several years, we have read with high interest the review by Hertz et al. (2015). Previous studies from our group demonstrated that a direct injection in mouse raphe nucleus of the 5-HT2B agonist BW723C86 has the ability to increase extracellular levels of serotonin, which can be blocked by the selective 5-HT2B receptor antagonist RS127445 (Doly et al., 2008, 2009). We also reported that an acute injection of paroxetine 2 mg/kg in mice knocked out for the 5-HT2B receptor gene or in wild type mice injected with RS127445 (0.5 mg/kg) triggers a strong reduction in extracellular accumulation of 5-HT in hippocampus (Diaz et al., 2012). Following these observations, we showed that acute and chronic BW723C86 injection (3 mg/kg) can mimic the fluoxetine (3 mg/kg) and paroxetine (1 mg/kg) behavioral and biochemical antidepressant effects in mice (Diaz and Maroteaux, 2011; Diaz et al., 2012)...