The phospholipase A2 inhibitor methyl indoxam suppresses diet-induced obesity and glucose intolerance in mice

Background and purpose:

Previous results have shown that mice lacking in the group 1B phospholipase A₂ (Pla2g1b) are resistant to obesity and diabetes induced by feeding a diabetogenic high-fat/high-carbohydrate diet. This study examined the potential of using the Pla2g1b inhibitor methyl indoxam as therapy to suppress diet-induced obesity and diabetes.

Experimental approach:

Male C57BL/6 mice were fed the diabetogenic diet with or without methyl indoxam supplementation. Body weight gain, fasting plasma glucose levels, glucose tolerance and postprandial lysophospholipid absorption were compared.

Key results:

Wild-type C57BL/6 mice fed the diabetogenic diet without Pla2g1b inhibitor showed 31 and 69% body weight gain after 4 and 10 weeks respectively. These animals also showed elevated plasma glucose levels and were glucose intolerant. In contrast, C57BL/6 mice fed the diabetogenic diet with 90 mg·kg⁻¹ of methyl indoxam gained only 5% body weight after 10 weeks. These animals were also euglycaemic and displayed normal glucose excursion rates in glucose tolerance test. Methyl indoxam suppression of diet-induced body weight gain and glucose intolerance was correlated with the inhibition of Pla2g1b-mediated postprandial lysophospholipid absorption.

Conclusions and implications:

These results show that oral supplementation of a diabetogenic diet with the Pla2g1b inhibitor methyl indoxam effectively suppresses diet-induced obesity and diabetes in mice. This suggests that Pla2g1b inhibition may be a potentially effective oral therapeutic option for treatment of obesity and diabetes.     

Effect of saturated fatty acid-rich dietary vegetable oils on lipid profile, antioxidant enzymes and glucose tolerance in diabetic rats

Objective:

To study the effect of saturated fatty acid (SFA)-rich dietary vegetable oils on the lipid profile, endogenous antioxidant enzymes and glucose tolerance in type 2 diabetic rats.

Materials and Methods:

Type 2 diabetes was induced by administering streptozotocin (90 mg/kg, i.p.) in neonatal rats. Twenty-eight-day-old normal (N) and diabetic (D) male Wistar rats were fed for 45 days with a fat-enriched special diet (10%) prepared with coconut oil (CO) – lauric acid-rich SFA, palm oil (PO) – palmitic acid-rich SFA and groundnut oil (GNO) – control (N and D). Lipid profile, endogenous antioxidant enzymes and oral glucose tolerance tests were monitored.

Results:

D rats fed with CO (D + CO) exhibited a significant decrease in the total cholesterol and non-high-density lipoprotein cholesterol. Besides, they also showed a trend toward improving antioxidant enzymes and glucose tolerance as compared to the D + GNO group, whereas D + PO treatment aggravated the dyslipidemic condition while causing a significant decrease in the superoxide dismutase levels when compared to N rats fed with GNO (N + GNO). D + PO treatment also impaired the glucose tolerance when compared to N + GNO and D + GNO.

Conclusion:

The type of FA in the dietary oil determines its deleterious or beneficial effects. Lauric acid present in CO may protect against diabetes-induced dyslipidemia.     

Antidiabetic activity of aqueous root extract of Ichnocarpus frutescens in streptozotocin-nicotinamide induced type-II diabetes in rats

Objective:

To evaluate the antidiabetic activity of aqueous extract of roots of Ichnocarpus frutescens in streptozotocin-nicotinamide induced type-II diabetes in rats.

Materials and Methods:

Streptozotocin-nicotinamide induced type-II diabetic rats (n = 6) were administered aqueous root extract (250 and 500 mg/kg, p.o.) of Ichnocarpus frutescens or vehicle (gum acacia solution) or standard drug glibenclamide (0.25 mg/kg) for 15 days. Blood samples were collected by retro-orbital puncture and were analyzed for serum glucose on days 0, 5, 10, and 15 by using glucose oxidase-peroxidase reactive strips and a glucometer. For oral glucose tolerance test, glucose (2 g/kg, p.o.) was administered to nondiabetic control rats and the rats treated with glibenclamide (10 mg/kg, p.o.) and aqueous root extract of Ichnocarpus frutescens. The serum glucose levels were analyzed at 0, 30, 60, and 120 min after drug administration. The effect of the extract on the body weight of the diabetic rats was also observed.

Results:

The aqueous root extract of Ichnocarpus frutescens (250 and 500 mg/kg, p.o.) induced significant reduction (P < 0.05) of fasting blood glucose levels in streptozotocin-nicotinamide induced type-II diabetic rats on the 10^th and 15^th days. In the oral glucose tolerance test, the extract increased the glucose tolerance. It also brought about an increase in the body weight of diabetic rats.

Conclusion:

It is concluded that Ichnocarpus frutescens has significant antidiabetic activity as it lowers the fasting blood sugar level in diabetic rats and increases the glucose tolerance.     

Combination of vildagliptin and rosiglitazone ameliorates nonalcoholic fatty liver disease in C57BL/6 mice

Objectives:

To evaluate the effect of vildagliptin alone and in combination with metformin or rosiglitazone on murine hepatic steatosis in diet-induced nonalcoholic fatty liver disease (NAFLD).

Materials and Methods:

Male C57BL/6 mice were fed with high fat diet (60 Kcal %) and fructose (40%) in drinking water for 60 days to induce NAFLD. After the induction period, animals were divided into different groups and treated with vildagliptin (10 mg/kg), metformin (350 mg/kg), rosiglitazone (10 mg/kg), vildagliptin (10 mg/kg) + metformin (350 mg/kg), or vildagliptin (10 mg/kg) + rosiglitazone (10 mg/kg) orally for 28 days. Following parameters were measured: body weight, food intake, plasma glucose, triglyceride (TG), total cholesterol, liver function tests, and liver TG. Liver histopathology was also examined.

Results:

Oral administration of vildagliptin and rosiglitazone in combination showed a significant reduction in fasting plasma glucose, hepatic steatosis, and liver TGs. While other treatments showed less or no improvement in the measured parameters.

Conclusions:

These preliminary results demonstrate that administration of vildagliptin in combination with rosiglitazone could be a promising therapeutic strategy for the treatment of NAFLD.KEY WORDS: Metformin, NAFLD, non-alcoholic fatty liver disease, rosiglitazone, vildagliptin     

Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats

BACKGROUND AND PURPOSE

mTOR inhibitors are currently used as immunosuppressants in transplanted patients and as promising anti-cancer agents. However, new-onset diabetes is a frequent complication occurring in patients treated with mTOR inhibitors such as rapamycin (Sirolimus). Here, we investigated the mechanisms associated with the diabetogenic effects of chronic Sirolimus administration in rats and in in vitro cell cultures.

EXPERIMENTAL APPROACH

Sirolimus was administered to rats fed either a standard or high-fat diet for 21 days. Metabolic parameters were measured in vivo and in ex vivo tissues. Insulin sensitivity was assessed by glucose tolerance tests and euglycaemic hyperinsulinaemic clamps. Rapamycin effects on glucose metabolism and insulin signalling were further evaluated in cultured myotubes.

KEY RESULTS

Sirolimus induced a decrease in food intake and concomitant weight loss. It also induced specific fat mass loss that was independent of changes in food intake. Despite these beneficial effects, Sirolimus-treated rats were glucose intolerant, hyperinsulinaemic and hyperglycaemic, but not hyperlipidaemic. The euglycaemic hyperinsulinaemic clamp measurements showed skeletal muscle is a major site of Sirolimus-induced insulin resistance. At the molecular level, long-term Sirolimus administration attenuated glucose uptake and metabolism in skeletal muscle by preventing full insulin-induced Akt activation and altering the expression and translocation of glucose transporters to the plasma membrane. In rats fed a high-fat diet, these metabolic defects were exacerbated, although Sirolimus-treated animals were protected from diet-induced obesity.

CONCLUSIONS AND IMPLICATIONS

Taken together, our data demonstrate that the diabetogenic effect of chronic rapamycin administration is due to an impaired insulin action on glucose metabolism in skeletal muscles.     

Acute and chronic administration of SHR117887, a novel and specific dipeptidyl peptidase-4 inhibitor,improves metabolic control in diabetic rodent models

Aim:

Dipeptidyl deptidase-4 (DPP-4) inhibitors are a new class of anti-diabetic agents. The purpose of this study was to assess the acute and chronic effects of SHR117887, a novel DPP-4 inhibitor, on metabolic control and pancreatic β-cell function in normal or diabetic rodent models.

Methods:

In the acute experiments, ICR mice, diet-induced obese (DIO) rats and ob/ob mice were subjected to an oral glucose tolerance test (OGTT) following a single oral administration of SHR117887 (0.1, 0.3, 1 or 3 mg/kg). Blood samples were collected to measure glucose, insulin, DPP-4 activity and active GLP-1 level. In the chronic experiments, ob/ob mice was administered SHR117887 (3, 10 or 30 mg/kg) twice daily for 33 d to assess the effects on metabolic control and pancreatic β-cell function. Vildagliptin (LAF237) was used as a positive control in all the experiments.

Results:

Acute oral administration of SHR117887 dose-dependently decreased the serum DPP-4 activity and improved glucose tolerance in ICR mice, DIO rats and ob/ob mice. This was accompanied by significant increases in the serum active GLP-1 and insulin levels. Chronic administration of SHR117887 significantly decreased fasting blood glucose level and improved the lipid profiles in ob/ob mice by reducing the serum triglyceride and free fatty acid levels, and its efficacy was comparable with that of vildagliptin at the same molarity. Moreover, chronic administration of SHR117887 increased the insulin staining of islet cells, which is suggestive of improved β-cell function.

Conclusion:

SHR117887 is a potent DPP-4 inhibitor that improves metabolic control and β-cell function in diabetic rodent models, suggesting that it could be a new therapeutic agent for the treatment of type 2 diabetes.     

Coenzyme Q10 supplementation lowers hepatic oxidative stress and inflammation associated with diet-induced obesity in mice

Background

Diabetes and obesity are metabolic disorders induced by an excessive dietary intake of fat, usually related to inflammation and oxidative stress.

Aims

The aim of the study is to investigate the effect of the antioxidant coenzyme Q10 (CoQ10) on hepatic metabolic and inflammatory disorders associated with diet-induced obesity and glucose intolerance.

Methods

C57bl6/j mice were fed for 8 weeks, either a control diet (CT) or a high-fat diet plus 21% fructose in the drinking water (HFF). CoQ10 supplementation was performed in this later condition (HFFQ).

Results

HFF mice exhibit increased energy consumption, fat mass development, fasting glycaemia and insulinemia and impaired glucose tolerance. HFF treatment promoted the expression of genes involved in reactive oxygen species production (NADPH oxidase), inflammation (CRP, STAMP2) and metabolism (CPT1α) in the liver. CoQ10 supplementation decreased the global hepatic mRNA expression of inflammatory and metabolic stresses markers without changing obesity and tissue lipid peroxides compared to HFF mice. HFF diets paradoxically decreased TBARS (reflecting lipid peroxides) levels in liver, muscle and adipose tissue versus CT group, an effect related to vitamin E content of the diet.

Conclusion

In conclusion, HFF model promotes glucose intolerance and obesity by a mechanism independent on the level of tissue peroxides. CoQ10 tends to decrease hepatic stress gene expression, independently of any modulation of lipid peroxidation, which is classically considered as its most relevant effect.     

Influence of pioglitazone on experimental heart failure and hyperlipidemia in rats

Objectives:

To investigate the effect of pioglitazone on isoproterenol-induced heart failure and high-fructose diet-induced metabolic changes in rats.

Materials and Methods:

Three doses of pioglitazone (Pio – 3, 10, 30 mg/kg, po) were tested in male Wistar rats. In the Heart Failure (HF) group, treatment was followed by Isoproterenol (ISO) injection. The markers for HF, such as enzyme estimation, relative heart weight, and antioxidant status, were evaluated. In another group, metabolic disturbances were induced by High Fructose Diet (HFD). The influence of Pio treatment on Systolic Blood Pressure (SBP), serum glucose, Triglycerides (TG), Total Cholesterol (TC), and High-Density Lipoprotein (HDL)-cholesterol (HDL-c) were determined.

Results:

The results indicated that Pio at 10 mg increased significantly (P<0.05) the Lactate Dehydrogenase (LDH), Creatinine Kinase-MB (CK-MB), and antioxidant enzyme levels as compared to ISO. The high dose of Pio (30 mg) enhanced (P<0.05) Aspartate Transaminase (AST), Alanine Transaminase (ALT), Lipid Peroxidation (LPO),and relative heart weight in addition to increased LDH, CK-MB, and antioxidant enzyme activity. In the HFD group, a dose-dependent inhibitory effect was observed. Pio at 3 mg significantly reduced (P<0.05) elevated glycemia, TG, and SBP as compared to HFD rats. Further, the higher doses of Pio (10 and 30 mg) enhanced the inhibitory effect on glucose, TG, and SBP besides elevating the HDL-c levels. However, none of the tested doses of Pio significantly altered the TC level in HFD rats.

Conclusion:

The observations suggest that Pio exhibits anti-diabetic and anti-hypertensive effects and also partially corrected the hyperlipidemia, but the treatment augmented the cardiac damage associated with ISO. The antioxidant property of Pio appears to have a limited role in protecting the ISO-mediated heart damage.KEY WORDS: Anti-hyperlipidemia, anti-hypertensive, heart failure, pioglitazone     

BITC and <Emphasis Type="Italic">S</Emphasis>-Carvone Restrain High-Fat Diet-Induced Obesity and Ameliorate Hepatic Steatosis and Insulin Resistance

Purpose

To investigate the preventative activity of benzyl isothiocyante and S-carvone against high-fat diet-induced obesity and metabolic complications.

Methods

Ten-week-old C57BL/6 male mice were fed a high-fat diet and injected intraperitoneally twice per week with benzyl isothiocyante, S-carvone, or vehicle for 8 weeks. The body weight, food intake, and body composition were monitored, and glucose tolerance and insulin tolerance tests were performed at the end of the experiment. Serum and tissue samples were studied using serum biochemistry, histological, and gene expression analysis to define the effects of benzyl isothiocyante and S-carvone treatments on lipid and glucose metabolism and inflammatory responses.

Results

Benzyl isothiocyante and S-carvone blocked high-fat diet-induced weight gain, fat accumulation in the liver, and insulin resistance. The beneficial effects were found to be associated with an improvement of expression of macrophage marker genes in white adipose tissue, including F4/80, Cd11b, Cd11c, Cd206, and Tnf-α, and reduced expression of genes (Pparγ2, Scd1, Cd36) responsible for lipid synthesis and transport in the liver.

Conclusion

Benzyl isothiocyante and S-carvone block high-fat diet-induced obesity and metabolism disorders and can be considered for management of the obesity epidemic that affects approximately 36% of adults and 17% of children in the USA.

     

Antioxidant potential of the methanol-methylene chloride extract of Terminalia glaucescens leaves on mice liver in streptozotocin-induced stress

Aim:

The antioxidant effect of the methanol–methylene chloride extract of Terminalia glaucescens (Combretaceae) leaves was investigated in streptozotocin (STZ)-induced oxidative stress.

Methods:

Oxidative stress was induced in mice by a daily dose of STZ (45 mg/kg body weight i.p.) for five days. From day one, before STZ injection, normal and diabetic-test mice received an oral dose of the extract (100 or 300 mg/kg b.w.) daily. Plasma metabolites, lipid peroxidation, and antioxidant enzymes in the liver were assessed and gain in body weight recorded.

Results:

In normal mice the plant extract reduced food and water intake, blood glucose and LDL-C level and body weight gain, did not affect the lipid peroxidation in the liver, while the antioxidant enzyme activities seemed increased. Blood glucose was decreased (P < 0.05) in normal mice treated with 300 mg/kg extract. Diabetic mice pretreated with 100 mg/kg extract as diabetic control mice (DC) showed significant (P < 0.001) body weight loss, polyphagia and polydipsia, high plasma glucose level, decrease in the liver catalase, peroxidase, and superoxide dismutase activities, and increase in lipid peroxidation. The HDL-C level was lowered (P < 0.05) whereas LDL-C increased. In 300 mg/kg extract-pretreated diabetic mice the extract prevented body weight loss, increase of blood glucose level, lipid peroxidation in liver, food and water intake, and lowering of plasma HDL-C level and liver antioxidants; this extract prevented LDL-C level increase.

Conclusion:

These results indicate that T. glaucescens protects against STZ-induced oxidative stress and could thus explain its traditional use for diabetes and obesity treatment or management.     

Metformin increases plasma ghrelin in Type 2 diabetes

AIMS

Metformin treatment of Type 2 diabetes is not usually associated with weight gain, and may assist with weight reduction. Plasma ghrelin concentrations are inversely associated with obesity and food intake. Metformin might therefore affect ghrelin concentrations, although previous studies have shown variable results in this regard. The primary aim of this study was to determine the effect of metformin on plasma ghrelin, appetite and satiety in patients with Type 2 diabetes.

METHODS

Eighteen patients with Type 2 diabetes were studied before and after 6 weeks of metformin treatment, which was titrated to 1 g b.d. On the study days patients were fed standard meals of 390 kcal at 08.00 and 12.30 h, plasma samples were collected at 15- and 30-min intervals, and appetite and satiety were measured on visual analogue scales. Changes in the area under the concentration–time curves (AUCs) of plasma ghrelin, insulin, glucose, appetite and satiety were assessed and examined for correlations with metformin AUCs. Changes in fasting adiponectin and leptin were also measured.

RESULTS

Treatment with metformin increased the mean AUC (07.30–16.30 h) of plasma ghrelin by 24% (P= 0.003), while decreasing those of glucose by 19% (P < 0.001) and insulin by 19% (P= 0.001). No changes were detected in hunger and satiety, or in fasting adiponectin or leptin concentrations. There were no clear correlations between metformin plasma concentrations (AUC) and changes in plasma glucose, insulin or ghrelin.

CONCLUSIONS

Treatment of Type 2 diabetes with metformin was associated with increased plasma ghrelin concentrations, without associated changes in hunger and satiety.     

Evaluation of antiobesity and cardioprotective effect of Gymnema sylvestre extract in murine model

Objective:

Obesity plays a central role in the insulin resistance syndrome, which is associated with hyperinsulinemia, hypertension, hyperlipidemia, type 2 diabetes mellitus, and an increased risk of atherosclerotic cardiovascular disease. The present study was done to assess the effect of Gymnema sylvestre extract (GSE) in the high fat diet (HFD)-induced cellular obesity and cardiac damage in Wistar rats.

Materials and Methods:

Adult male Wistar rats (150–200 g body weight) were used in this study. HFD was used to induce obesity. Body mass index, hemodynamic parameters, serum leptin, insulin, glucose, lipids, apolipoprotein levels, myocardial apoptosis, and antioxidant enzymes were assessed. Organ and visceral fat pad weights and histopathological studies were also carried out.

Results:

Oral feeding of HFD (20 g/day) for a period of 28 days resulted in a significant increase in body mass index, organ weights, visceral fat pad weight, cardiac caspase-3, cardiac DNA laddering (indicating apoptotic inter-nucleosomal DNA fragment), and lipid peroxide levels of cardiac tissues of rats. Further, mean arterial blood pressure, heart rate, serum leptin, insulin, LDH, LDL-C, total cholesterol, triglycerides, and apolipoprotein-B levels were enhanced significantly, whereas serum HDL-C, apoliporotein-A1 levels, and cardiac Na⁺ K⁺ ATPase, antioxidant enzymes levels were significantly decreased. Furthermore, treatment with standardized ethanolic GSE (200 m/kg/p.o.) for a period of 28 days resulted in significant reversal of above mentioned changes in the obese Wistar rats.

Conclusion:

The present study has demonstrated the significant antiobesity potential of GSE in murine model of obesity.KEY WORDS: Cardiomyocyte apoptosis, Gymnema sylvestre, insulin, leptin, obesity     

PPARδ agonists have opposing effects on insulin resistance in high fat-fed rats and mice due to different metabolic responses in muscle

BACKGROUND AND PURPOSE

The peroxisome proliferator-activated receptor (PPAR)δ has been considered a therapeutic target for diabetes and obesity through enhancement of fatty acid oxidation. The present study aimed to characterize the effects of PPARδ agonists during insulin resistance of the whole body, muscle and liver.

EXPERIMENTAL APPROACH

Wistar rats and C57BL/J6 mice were fed a high fat diet (HF) and then treated with PPARδ agonists NNC61-5920 and GW501516. The effects on insulin resistance were evaluated by hyperinsulinaemic clamp or glucose tolerance tests combined with glucose tracers.

KEY RESULTS

In HF rats, 3 weeks of treatment with NNC61-5920 reduced the glucose infusion rate (by 14%, P < 0.05) and glucose disposal into muscle (by 20–30%, P < 0.01) during hyperinsulinaemic clamp. Despite increased mRNA expression of carnitine palmitoyltransferase-1, pyruvate dehydrogenase kinase 4 and uncoupling protein 3 in muscle, plasma and muscle triglyceride levels were raised (P < 0.01). Similar metabolic effects were observed after extended treatment with NNC61-5920 and GW501516 to 6 weeks. However, HF mice treated with NNC61-5920 improved their plasma lipid profile, glucose tolerance and insulin action in muscle. In both HF rats and mice, NNC61-5920 treatment attenuated hepatic insulin resistance and decreased expression of stearoyl-CoA desaturase 1, fatty acid translocase protein CD36 and lipoprotein lipase in liver.

CONCLUSIONS AND IMPLICATIONS

PPARδ agonists exacerbated insulin resistance in HF rats in contrast to their beneficial effects on metabolic syndrome in HF mice. These opposing metabolic consequences result from their different effects on lipid metabolism and insulin sensitivity in skeletal muscle of these two species.     

Effects of liraglutide and sibutramine on food intake,palatability, body weight and glucose tolerance in the gubra DIO-rats

Aim:

To validate the gubra DIO-rats as a useful animal model of human obesity.

Methods:

The gubra diet-induced obesity (DIO) rat model was based on male Sprague-Dawley rats with ad libitum access to regular chow and a palatable diet rich in fat and sugar. To evaluate the versatility of the gubra DIO-rats as a valid model of human obesity syndrome, the efficacy of 2 weight loss compounds liraglutide and sibutramine with different mechanisms of action were examined in 7-month-old gubra DIO-rats. Liraglutide (200 μg/kg, sc) was administered bi-daily, and sibutramine (5 mg/kg, po) was administered once daily for 23 d.

Results:

Both the compounds effectively reduced the food intake, body weight and total fat mass as measured by nuclear magnetic resonance. Whereas the 5-HT reuptake inhibitor/5-HT receptor agonist sibutramine reduced the intake of both chow and the gubra-diet, the GLP-1 analogue liraglutide predominantly reduced the intake of the highly palatable diet, indicating a shift in food preference. Sibutramine lowered the insulin sensitivity index, primarily via reductions in glucose-stimulated insulin secretion.

Conclusion:

This animal model responds well to 2 weight loss compounds with different mechanisms of action. Moreover, the gubra DIO-rat can be particularly useful for the testing of compounds with potential effects on diet preference.     

Body weight reduction in rats by oral treatment with zinc plus cyclo-(His-Pro)

Background and purpose:

We have previously shown that treatment with zinc plus cyclo-(His-Pro) (CHP) significantly stimulated synthesis of the insulin degrading enzyme and lowered plasma insulin and blood glucose levels, alongside improving oral glucose tolerance in genetically type 2 diabetic Goto-Kakizaki (G-K) rats and in aged obese Sprague-Dawley (S-D) rats. Thus, we postulated that zinc plus CHP (ZC) treatment might also improve body weight control in these rats. We therefore determined the effects of ZC treatment on body weights in both genetically diabetic, mature G-K rats and non-diabetic, obese S-D rats.

Experimental approach:

G-K rats aged 1.5–10 months and non-diabetic overweight or obese S-D rats aged 6–18 months were treated with 0–6 mg CHP plus 0–10 mg zinc·L⁻¹ drinking water for 2–4 weeks, and changes in weight, serum leptin and adiponectin levels, food and water intakes were measured.

Key results:

The optimal dose of CHP (in combination with zinc) to reduce weight and plasma leptin levels and to increase plasma adiponectin levels was close to 0.1 mg·kg⁻¹·day⁻¹, in either mature G-K rats and aged overweight or obese S-D rats. Food and water intake significantly decreased in ZC treated rats in both aged S-D rats and mature G-K rats, but not in young S-D and G-K rats.

Conclusions and implications:

ZC treatment improved weight control and may be a possible treatment for overweight and obesity.     

Oral salmon calcitonin attenuates hyperglycaemia and preserves pancreatic beta-cell area and function in Zucker diabetic fatty rats

BACKGROUND AND PURPOSE

Oral salmon calcitonin (sCT), a dual-action amylin and calcitonin receptor agonist, improved glucose homeostasis in diet-induced obese rats. Here, we have evaluated the anti-diabetic efficacy of oral sCT using parameters of glycaemic control and beta-cell morphology in male Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes.

EXPERIMENTAL APPROACH

Male ZDF rats were treated with oral sCT (0.5, 1.0 or 2 mg·kg⁻¹) or oral vehicle twice daily from age 8 to 18 weeks. Zucker lean rats served as control group. Fasting and non-fasted blood glucose, glycosylated haemoglobin (HbA1c) and levels of pancreas and incretin hormones were determined. Oral glucose tolerance test and i.p. glucose tolerance test were compared, and beta-cell area and function were evaluated.

KEY RESULTS

Oral sCT treatment dose-dependently attenuated fasting and non-fasted hyperglycaemia during the intervention period. At the end of the study period, oral sCT treatment by dose decreased diabetic hyperglycaemia by ∼9 mM and reduced HbA1c levels by 1.7%. Furthermore, a pronounced reduction in glucose excursions was dose-dependently observed for oral sCT treatment during oral glucose tolerance test. In addition, oral sCT treatment sustained hyperinsulinaemia and attenuated hyperglucagonaemia and hypersecretion of total glucagon-like peptide-1 predominantly in the basal state. Lastly, oral sCT treatment dose-dependently improved pancreatic beta-cell function and beta-cell area at study end.

CONCLUSIONS AND IMPLICATIONS

Oral sCT attenuated diabetic hyperglycaemia in male ZDF rats by improving postprandial glycaemic control, exerting an insulinotropic and glucagonostatic action in the basal state and by preserving pancreatic beta-cell function and beta-cell area.     

The study of aqueous extract of Pterocarpus marsupium Roxb. on cytokine TNF-α in type 2 diabetic rats

Objective:

This study was designed to investigate the effect of aqueous extract of Pterocarpus marsupium Roxb. on elevated inflammatory cytokine, tumor necrosis factor (TNF)-α in type 2 diabetic rats.

Materials and Methods:

Type 2 diabetes was induced by administering streptozotocin (90 mg/kg, i.p.) in a neonatal rat model. Aqueous extract of P. marsupium at a dose of 100 and 200 mg/kg was given orally to desired group of animals for a period of 4 weeks. After 4 weeks of drug treatment, parameters such as fasting blood glucose, postprandial blood glucose, and TNF-α in serum were analyzed.

Results:

Aqueous extract of P. marsupium at both doses, i.e., 100 and 200 mg/kg, decreased the fasting and postprandial blood glucose in type 2 diabetic rats. The 200 mg/kg had more pronounced effect on postprandial hyperglycemia. The drug also improved the body weight of diabetic animals. Cytokine TNF-α was found to be elevated in untreated diabetic rats due to chronic systemic inflammation. The aqueous extract at both doses significantly (P < 0.001) decreased the elevated TNF-α level in type 2 diabetic rats.

Conclusion:

Modulation of cytokine TNF-α by the rasayana drug P. marsupium is related with its potential anti-diabetic activity.     

Metabolic syndrome among patients receiving clozapine: A preliminary estimate

Objective:

To study the prevalence of metabolic syndrome in patients receiving clozapine.

Materials and Methods:

For this study, 100 patients attending the psychiatry outpatient clinic of a tertiary care hospital who were receiving clozapine for more than three months were evaluated for the presence of metabolic syndrome using the International Diabetes Federation (IDF) and modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III) criteria.

Results:

Forty-six patients fulfilled IDF criteria and 47 met modified NCEP ATP-III criteria of metabolic syndrome. There was significant correlation between these two sets of criteria used to define the metabolic syndrome (Kappa value –0.821, P < 0.001). Among the individual parameters studied, increased waist circumference was the most common abnormality, followed by abnormal blood glucose levels and elevated triglyceride levels. All these abnormalities were seen in more than half (52-61%) of the patients. When the sample was divided into two groups, i.e., those with and without metabolic syndrome, patients with metabolic syndrome had significantly higher body mass index and had spent more time in school. Logistic regression analysis revealed that these two variables together explained about 19% of the variance in metabolic syndrome (adjusted r² = 0193; F = 12.8; P < 0.001).

Conclusion:

The findings of the present study suggest that metabolic syndrome is highly prevalent in subjects receiving clozapine.     

Obesity enhances eosinophilic inflammation in a murine model of allergic asthma

Background and purpose:

Obesity is associated with deterioration in asthma outcomes. Although airways eosinophil accumulation is characteristic of lung allergic diseases, little is known about the influence of obesity on the allergic eosinophil trafficking from bone marrow to lung tissues, and recruitment to airways lumen. Here, we have assessed the effects of diet-induced obesity on allergic eosinophilic inflammation in mice, examining eosinophil trafficking from bone marrow to airways, and production of T_H1/T_H2 cytokines.

Experimental approach:

C57BL/6 mice fed for 10 weeks with standard chow or high-fat diet were sensitized and challenged with ovalbumin. At 24–96 h post-ovalbumin challenge, bronchoalveolar lavage (BAL) fluid, lung tissue and bone marrow were examined.

Key results:

The high-fat-fed mice exhibited increased body weight and epididymal fat, glucose intolerance and alterations in lipid profile compared with the lean mice. Obesity markedly elevated serum leptin and lowered adiponectin levels. Ovalbumin challenge in obese mice promoted a markedly higher eosinophil accumulation in bone marrow and connective tissue surrounding the bronchial and bronchiolar segments. Eosinophil number in BAL fluid of obese mice was lower at 24 and 48 h. Levels of interleukin (IL)-5, eotaxin, tumour necrosis factor-α and IL-10 in BAL fluid of obese mice were significantly higher than in lean mice.

Conclusions and implications:

Diet-induced obesity enhanced eosinophil trafficking from bone marrow to lung tissues, and delayed their transit through the airway epithelium into the airway lumen. Consequently, eosinophils remain longer in lung peribronchiolar segments due to overproduction of T_H1/T_H2 cytokines and chemokines.