ZDF Rats Research Articles

Diabetic cardiomyopathy in Zucker diabetic fatty rats: the forgotten right ventricle

BackgroundIn patients with myocardial infarction or heart failure, right ventricular (RV) dysfunction is associated with death, shock and arrhythmias. In patients with type 2 diabetes mellitus, structural and functional alterations of the left ventricle (LV) are highly prevalent, however, little is known about the impact of diabetes on RV characteristics. The purpose of the present study was to investigate whether LV changes are paralleled by RV alterations in a rat model of diabetes.MethodsZucker diabetic fatty (ZDF) and control (ZL) rats underwent echocardiography and positron emission tomography (PET) scanning using [18F]-2-fluoro-2-deoxy-D-glucose under hyperinsulinaemic euglycaemic clamp conditions. Glucose, insulin, triglycerides and fatty acids were assessed from trunk blood. Another group of rats received an insulin or saline injection to study RV insulin signaling.ResultsZDF rats developed hyperglycaemia, hyperinsulinaemia and dyslipidaemia (all p < 0.05). Echocardiography revealed depressed LV fractional shortening and tricuspid annular plane systolic excursion (TAPSE) in ZDF vs. ZL rats (both p < 0.05). A decrease in LV and RV insulin-mediated glucose utilisation was found in ZDF vs. ZL rats (both p < 0.05). LV associated with RV with respect to systolic function (r = 0.86, p < 0.05) and glucose utilisation (r = 0.74, p < 0.05). TAPSE associated with RV MRglu (r = 0.92, p < 0.05) and M-value (r = 0.91, p < 0.0001) and RV MRglu associated with M-value (r = 0.77, p < 0.05). Finally, reduced RV insulin-stimulated phosphorylation of Akt was found in ZDF vs. ZL (p < 0.05).ConclusionsLV changes were paralleled by RV alterations in insulin-stimulated glucose utilisation and RV systolic function in a rat model of diabetes, which may be attributed to ventricular interdependence as well as to the uniform effect of diabetes. Since diabetic patients are prone to develop diabetic cardiomyopathy and myocardial ischaemia, it might be suggested that RV dysfunction plays a central role in cardiac abnormalities in this population.

Curcumin Supplementation Causes PTEN Inhibition in Liver and Lowers Blood Glucose, Oxidative Stress and Markers of Endothelial Dysfunction and Vascular Inflammation in ZDF Rats

Curcumin Supplementation Causes PTEN Inhibition in Liver and Lowers Blood Glucose, Oxidative Stress and Markers of Endothelial Dysfunction and Vascular Inflammation in ZDF Rats

Treatment of Erectile Dysfunction in the Obese Type 2 Diabetic ZDF Rat with Adipose Tissue-Derived Stem Cells

Treatment of Erectile Dysfunction in the Obese Type 2 Diabetic ZDF Rat with Adipose Tissue-Derived Stem Cells

Dual-Action Lipophilic Iminosugar Improves Glycemic Control in Obese Rodents by Reduction of Visceral Glycosphingolipids and Buffering of Carbohydrate Assimilation

The lipophilic iminosugar N-[5-(adamantan-1-ylmethoxy)pentyl]-1-deoxynojirimycin (2, AMP-DNM) potently controls hyperglycemia in obese rodent models of insulin resistance. The reduction of visceral glycosphingolipids by 2 is thought to underlie its beneficial action. It cannot, however, be excluded that concomitant inhibition of intestinal glycosidases and associated buffering of carbohydrate assimilation add to this. To firmly establish the mode of action of 2, we developed a panel of lipophilic iminosugars varying in configuration at C-4/C-5 and N-substitution of the iminosugar. From these we identified the l-ido derivative of 2, l-ido-AMP-DNM (4), as a selective inhibitor of glycosphingolipid synthesis. Compound 4 lowered visceral glycosphingolipids in ob/ob mice and ZDF rats on a par with 2. In contrast to 2, 4 did not inhibit sucrase activity or sucrose assimilation. Treatment with 4 was significantly less effective in reducing blood glucose and HbA1c. We conclude that the combination of reduction of glycosphingolipids in tissue and buffering of carbohydrate assimilation by 2 produces a superior glucose homeostasis.

Exercise maintains euglycemia in association with decreased activation of c-Jun NH2-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats

Stress-activated systems and oxidative stress are involved in insulin resistance, which, along with beta-cell failure, contribute to the development of type 2 diabetes mellitus (T2DM). Exercise improves insulin resistance and glucose tolerance, and these adaptations may, in part, be related to reductions in inflammation and oxidative stress. We investigated circulating and tissue-specific markers of inflammation and oxidative stress and insulin-signaling pathways in a rodent model of T2DM, the Zucker diabetic fatty rat, with and without voluntary exercise. At 5 wk of age, Zucker diabetic fatty rats (n = 8-9/group) were divided into basal (B), voluntary exercise (E), and sedentary control (S) groups. B rats were euthanized at 6 wk of age, and S and E rats were euthanized 10 wk later. E rats ran approximately 5 km/day, which improved insulin sensitivity and maintained fed and fasted glucose levels and glucose tolerance. Ten weeks of exercise also decreased whole body markers of inflammation and oxidative stress in plasma and liver, including lowered circulating IL-6, haptoglobin, and malondialdehyde levels, hepatic protein oxidation, and phosphorylated JNK, the latter indicating decreased JNK activity. Hepatic phosphoenolpyruvate carboxykinase levels and Ser(307)-phosphorylated insulin receptor substrate-1 were also reduced in E compared with S rats. In summary, we show that, in a rodent model of T2DM, voluntary exercise decreases circulating markers of inflammation and oxidative stress and lowers hepatic JNK activation and Ser(307)-phosphorylated insulin receptor substrate-1. These changes in oxidative stress markers and inflammation are associated with decreased hyperglycemia and insulin resistance and reduced expression of the main gluconeogenic enzyme phosphoenolpyruvate carboxykinase.

Lipogenesis in arterial wall and vascular smooth muscular cells: regulation and abnormalities in insulin-resistance

BackgroundVascular smooth muscular cells (VSMC) express lipogenic genes. Therefore in situ lipogenesis could provide fatty acids for triglycerides synthesis and cholesterol esterification and contribute to lipid accumulation in arterial wall with aging and during atheroma.MethodsWe investigated expression of lipogenic genes in human and rat arterial walls, its regulation in cultured VSMC and determined if it is modified during insulin-resistance and diabetes, situations with increased risk for atheroma.ResultsZucker obese (ZO) and diabetic (ZDF) rats accumulated more triglycerides in their aortas than their respective control rats, and this triglycerides content increased with age in ZDF and control rats. However the expression in aortas of lipogenic genes, or of genes involved in fatty acids uptake, was not higher in ZDF and ZO rats and did not increase with age. Expression of lipogenesis-related genes was not increased in human arterial wall (carotid endarterectomy) of diabetic compared to non-diabetic patients. In vitro, glucose and adipogenic medium (ADM) stimulated moderately the expression and activity of lipogenesis in VSMC from control rats. LXR agonists, but not PXR agonist, stimulated also lipogenesis in VSMC but not in arterial wall in vivo. Lipogenic genes expression was lower in VSMC from ZO rats and not stimulated by glucose or ADM.ConclusionLipogenic genes are expressed in arterial wall and VSMC; this expression is stimulated (VSMC) by glucose, ADM and LXR agonists. During insulin-resistance and diabetes, this expression is not increased and resists to the actions of glucose and ADM. It is unlikely that this metabolic pathway contribute to lipid accumulation of arterial wall during insulin-resistance and diabetes and thus to the increased risk of atheroma observed in these situations.

Prevention of Hepatic Steatosis and Hepatic Insulin Resistance by Knockdown of cAMP Response Element-Binding Protein

In patients with poorly controlled type 2 diabetes mellitus (T2DM), hepatic insulin resistance and increased gluconeogenesis contribute to fasting and postprandial hyperglycemia. Since cAMP response element-binding protein (CREB) is a key regulator of gluconeogenic gene expression, we hypothesized that decreasing hepatic CREB expression would reduce fasting hyperglycemia in rodent models of T2DM. In order to test this hypothesis, we used a CREB-specific antisense oligonucleotide (ASO) to knock down CREB expression in liver. CREB ASO treatment dramatically reduced fasting plasma glucose concentrations in ZDF rats, ob/ob mice, and an STZ-treated, high-fat-fed rat model of T2DM. Surprisingly, CREB ASO treatment also decreased plasma cholesterol and triglyceride concentrations, as well as hepatic triglyceride content, due to decreases in hepatic lipogenesis. These results suggest that CREB is an attractive therapeutic target for correcting both hepatic insulin resistance and dyslipidemia associated with nonalcoholic fatty liver disease (NAFLD) and T2DM.

Lipase maturation factor 1: Its expression in Zucker diabetic rats, and effects of metformin and fenofibrate

Aim High triglyceride (TG) levels are a risk factor for cardiovascular diseases, and TG concentrations depend on the balance between its appearance in and clearance from plasma. TG clearance is controlled mainly by lipoprotein lipase (LPL), the maturation and activity of which are dependent on lipase maturation factor 1 (LMF1) protein. The present study aimed to investigate LMF1 expression in hypertriglyceridaemia and the regulation of its expression, as little is currently known of these processes. Methods We measured LMF1 expression (mRNA) in Zucker diabetic rats (ZDF) throughout the development of obesity, insulin resistance and diabetes, and compared it with that of control rats. We also determined whether fenofibrate and metformin, agents with TG-lowering activities, have an effect on LMF1 expression in ZDF rats. Results At 7 weeks, the ZDF rats were obese, insulin-resistant and hypertriglyceridaemic, and their LMF1 mRNA levels were – whichever tissue was investigated – comparable to those of the control rats. Diabetic ZDF rats (14 and 21-week-old) also had high TG levels, but the presence of diabetes had no effect on LMF1 expression; mRNA levels remained comparable to those in the controls. Although fenofibrate and metformin both decreased plasma TG levels, fenofibrate had no effect on LMF1 expression, whereas metformin increased LMF1 mRNA in heart tissue (14- and 21-week-old ZDF rats; P < 0.01), and induced a trend towards increases in adipose tissue (14-week-old ZDF rats) and muscle (14- and 21-week-old ZDF rats). Conclusion LMF1 expression was not altered in this experimental animal model of obesity, insulin resistance and diabetes in the presence of raised TG levels. However, metformin increased LMF1 expression in the heart, suggesting that stimulation of LMF1 may play a part in its TG-lowering action.

Noninvasive Quantification of Pancreatic Fat in Humans

To validate magnetic resonance spectroscopy (MRS) as a tool for non-invasive quantification of pancreatic triglyceride (TG) content and to measure the pancreatic TG content in a diverse human population with a wide range of body mass index (BMI) and glucose control. To validate the MRS method, we measured TG content in the pancreatic tissue of 12 lean and 12 fatty ZDF rats (ages 5-14 weeks) both by MRS and the gold standard biochemical assay. We used MRS to measure pancreatic TG content in vivo in 79 human volunteers. Additionally, to assess the reproducibility of the method, in 33 volunteers we obtained duplicate MRS measurements 1-2 weeks apart. MRS quantifies pancreatic TG content with high reproducibility and concordance to the biochemical measurement (Spearman's rank correlation coefficient = 0.91). In humans, median pancreatic TG content was as follows: (1) normal weight and normoglycemic group 0.46 f/w%, (2) overweight or obese but normoglycemic group 3.16 f/w%, (3) impaired fasting glucose or impaired glucose tolerance group (BMI matched with group 2) 5.64 f/w%, and (4) untreated type 2 diabetes group (BMI matched with group 2) 5.54 f/w% (Jonckheere-Terpstra trend test across groups p < 0.001). Human pancreatic steatosis, as measured by MRS, increases with BMI and with impaired glycemia. MRS is a quantitative and reproducible non-invasive clinical research tool which will enable systematic studies of the relationship between ectopic fat accumulation in the pancreas and development of type 2 diabetes.

In Vivo Metabolic Phenotyping of Myocardial Substrate Metabolism in Rodents

Background— Cardiovascular disease is the leading cause of death among diabetic patients, with alteration in myocardial substrate metabolism being a likely contributor. We aimed to assess noninvasively the efficacy of metformin and rosiglitazone monotherapy in normalizing myocardial substrate metabolism in an animal model of type 2 diabetes mellitus. Methods and Results— The study used 18 male ZDF rats (fa/fa) with 6 rats in each group: an untreated group; a group treated with metformin (16.6 mg/kg/d), and a group treated with rosiglitazone (4 mg/kg). Each rat was scanned at age 14 weeks (baseline) and subsequently at 19 weeks with small-animal positron emission tomography to estimate myocardial glucose utilization (MGU) and myocardial utilization (MFAU), oxidation (MFAO), and esterification (MFAE). Treatment lasted for 5 weeks after baseline imaging. At week 19, rats were euthanized and hearts were extracted for expression analysis of select genes encoding for GLUT transporters and fatty acid transport and oxidation genes. In addition, echocardiography measurements were obtained at weeks 13 and 18 to characterize cardiac function. Metformin had no significant effect on either MGU or MFAU and MFAO. In contrast, rosiglitazone tended to enhance MGU and significantly reduced MFAU and MFAO. Rosiglitazone-induced increase in glucose uptake correlated significantly with increased expression of GLUT4, whereas diminished MFAO correlated significantly with decreased expression of FATP-1 and MCAD. Finally, changes in fractional shortening as a measure of cardiac function were unchanged throughout the study. Conclusions— Treatment with rosiglitazone enhanced glucose utilization and diminished MFAO, thus reversing the metabolic phenotype of the diabetic heart.

Arterial stiffness and the autonomic nervous system during the development of Zucker diabetic fatty rats

Aim This study aimed to investigate the role played by sympathovagal balance in arterial stiffness, a common feature of insulin resistance and type 2 diabetes. Methods We investigated the relationship between autonomic nervous system activity and arterial stiffness in Zucker diabetic fatty rats (ZDF: Gmi- fa/fa) and their age-matched controls (lean: ?/fa). Using simultaneous catheterization of the proximal and distal aorta, we measured intra-arterial blood pressure (BP), heart rate (HR), their variability (spectral analysis) and aortic pulse wave velocity (PWV) in a series of at least six conscious rats aged 6, 12, 18 and 24 weeks. Results BP and PWV increased with age ( P < 0.001) in both strains with no differences between strains, despite the insulin resistance already present at 6 weeks in ZDF rats. HR was significantly lower ( P < 0.001) in ZDF than in lean rats. In ZDF compared with lean rats, the low-frequency (LF) component of the systolic BP variations and the LF/high-frequency (HF) component of the pulse interval (PI) variation ratio were reduced ( P < 0.01 and P < 0.05, respectively), while the HF component of the PI (HF-PI) variation was raised ( P < 0.05). PWV was negatively correlated with HF-PI ( r = −0.37, P < 0.01), but not with biochemical parameters. HF-PI was an independent variable explaining the variation in PWV. Conclusion During the development of disease of ZDF rats, sympathovagal balance might account for the lack of increase in PWV.

Altered myocardial substrate metabolism is associated with myocardial dysfunction in early diabetic cardiomyopathy in rats: studies using positron emission tomography

BackgroundIn vitro data suggest that changes in myocardial substrate metabolism may contribute to impaired myocardial function in diabetic cardiomyopathy (DCM). The purpose of the present study was to study in a rat model of early DCM, in vivo changes in myocardial substrate metabolism and their association with myocardial function.MethodsZucker diabetic fatty (ZDF) and Zucker lean (ZL) rats underwent echocardiography followed by [11C]palmitate positron emission tomography (PET) under fasting, and [18F]-2-fluoro-2-deoxy-D-glucose PET under hyperinsulinaemic euglycaemic clamp conditions. Isolated cardiomyocytes were used to determine isometric force development.ResultsPET data showed a 66% decrease in insulin-mediated myocardial glucose utilisation and a 41% increase in fatty acid (FA) oxidation in ZDF vs. ZL rats (both p < 0.05). Echocardiography showed diastolic and systolic dysfunction in ZDF vs. ZL rats, which was paralleled by a significantly decreased maximal force (68%) and maximal rate of force redevelopment (69%) of single cardiomyocytes. Myocardial functional changes were significantly associated with whole-body insulin sensitivity and decreased myocardial glucose utilisation. ZDF hearts showed a 68% decrease in glucose transporter-4 mRNA expression (p < 0.05), a 22% decrease in glucose transporter-4 protein expression (p = 0.10), unchanged levels of pyruvate dehydrogenase kinase-4 protein expression, a 57% decreased phosphorylation of AMP activated protein kinase α1/2 (p < 0.05) and a 2.4-fold increased abundance of the FA transporter CD36 to the sarcolemma (p < 0.01) vs. ZL hearts, which are compatible with changes in substrate metabolism. In ZDF vs. ZL hearts a 2.4-fold reduced insulin-mediated phosphorylation of Akt was found (p < 0.05).ConclusionUsing PET and echocardiography, we found increases in myocardial FA oxidation with a concomitant decrease of insulin-mediated myocardial glucose utilisation in early DCM. In addition, the latter was associated with impaired myocardial function. These in vivo data expand previous in vitro findings showing that early alterations in myocardial substrate metabolism contribute to myocardial dysfunction.

The mannose-binding lectin pathway is a significant contributor to reperfusion injury in the type 2 diabetic heart

The severity of ischaemic heart disease is markedly enhanced in type 2 diabetes. We recently reported that complement activation exacerbates I/R injury in the type 2 diabetic heart. The purpose of this study was to isolate and examine MBL pathway activation following I/R injury in the diabetic heart. ZLC and ZDF rats underwent 30 minutes of left coronary artery occlusion followed by 120 minutes of reperfusion. Two different groups of ZDF rats were treated with either FUT-175, a broad complement inhibitor, or P2D5, a monoclonal antibody raised against rat MBL-A. ZDF rats treated with FUT175 and P2D5 had significantly decreased myocardial infarct size, C3 deposition and neutrophil accumulation compared with untreated ZDF controls. Taken together, these findings indicate that the MBL pathway plays a key role in the severity of complement-mediated I/R injury in the type 2 diabetic heart.

Myocardial metabolism of triacylglycerol‐rich lipoproteins in type 2 diabetes

Cardiac utilisation of very-low-density lipoprotein (VLDL) and chylomicrons (CM) was investigated in the ZDF rat model of type 2 diabetes, in order to define the role of triacylglycerol (TAG) metabolism in the development of contractile dysfunction. Hearts from obese diabetic and lean littermate control rats were perfused with VLDL and CM from diabetic and control rats. Metabolic fate of the lipoprotein TAG and contractile function were examined. Myocardial utilisation of both VLDL- and CM-TAG was increased in the diabetic state. Diabetic hearts oxidised diabetic lipoprotein-TAG to a greater extent than control lipoproteins; glucose oxidation was decreased. There was no difference in lipoprotein-TAG assimilation into diabetic heart lipids; diabetic lipoproteins were, however, a poor substrate for control heart tissue lipid accumulation. Although the proportion of exogenous lipid incorporated into tissue TAG was increased in diabetic hearts perfused with control lipoproteins, this effect was not seen in diabetic hearts perfused with diabetic lipoproteins. Myocardial heparin-releasable lipoprotein lipase (LPL) activity was moderately increased in the diabetic state, and diabetic lipoproteins increased tissue-residual LPL activity. Cardiac hydraulic work was decreased only in diabetic hearts perfused with diabetic CM. Compositional analysis of diabetic variant lipoproteins indicated changes in size and apoprotein content. Alterations in cardiac TAG-rich lipoprotein metabolism in type 2 diabetes are due to changes in both the diabetic myocardium and the diabetic lipoprotein particle; decreased contractile function is not related to cardiac lipid accumulation from TAG-rich lipoproteins but may be associated with changes in TAG-fatty acid oxidation.

Novel application of surface plasmon resonance biosensor chips for measurement of advanced glycation end products in serum of Zucker diabetic fatty rats

Advanced glycation end products (AGEs) have been implicated in diabetic complications. To measure AGEs, especially N ɛ-(carboxymethyl)lysine (CML), in sera from Zucker diabetic fatty rats (ZDF) and Zucker lean rats (ZL), we used a novel method of protein chip and surface plasmon resonance imaging (SPRI). Serum samples were obtained from male ZDF and ZL rats at 20 weeks of age. Antibodies to AGEs or CML were immobilized on a gold surface, which was modified by cysteine-tagged, protein-G constructs. The gold chip upon which the serum was spotted was optically coupled with a prism coupler. The reflected images from the gold chip were obtained using a charge-coupled device (CCD) camera. The direct analysis of the glycated proteins and products using SPRI showed that AGEs and CML levels were elevated in ZDF serum, compared with ZL serum. The lowest detection limit of AGEs was 10 ng/ml, with a working range covering the physiological range. These results indicate that the protein chip and SPRI system is very suitable for the measurement of glycated proteins and end products in serum samples. This system offers high sensitivity without any fluorescent or other labeling of the components and saves a substantial amount of time, resources, and labor. Our results suggest that SPRI systems can be used as a tool to diagnose diabetic complications.

Vasopeptidase Inhibitor Improves Coronary Dysfunction in Zucker Obese but not Zucker Diabetic Fatty (ZDF) Rats

Previous studies have shown endothelial dysfunction in coronary and mesenteric near resistance arteries in Zucker obese and ZDF rats. Our hypothesis is that vascular dysfunction is due in part to upreglulation of neutral endopeptidase and treatment with a vasopeptidase inhibitor will improve vascular function. 20‐week‐old Zucker obese and 12‐week‐old ZDF rats were treated with the vasopeptidase inhibitor AVE7688 (500mg/kg) for 12 weeks. Afterwards, coronary and mesenteric function was evaluated using an isolated vessel preparation. Vessels (75 ‐ 175µm intraluminal diameter and ~1 mm in length) were studied under hydrostatic pressure (40mm Hg) and no flow, and internal diameter was measured. Dilator responses were evaluated for acetylcholine (Ach, 10−10‐10−4 M), and calcitonin gene‐related peptide (CGRP, 10−11‐10−9 M) after constriction with U46619.ResultsACh (10μM) responses were attenuated in arteries from untreated rats compared to responses from lean rats (coronary: Zucker obese = 49.4%, ZDF = 50.7% decrease and mesenteric: Zucker obese = 27.4%, ZDF = 33.5% decrease). ACh response was augmented in coronary vessels from AVE7688 treated Zucker obese but not ZDF rats when compared to vessels from untreated rats. Our data suggest that coronary artery endothelial dysfunction is improved when Zucker obese but not ZDF rats were treated with AVE7688. Supported by VA Merits to Dr. Oltman and Dr. Yorek.

Renal 25‐hydroxycholecalciferol reabsorption is modulated in a type II diabetic rat model.

Alterations of serum levels of the major circulating form of vitamin D (25‐hydroxycholecalciferol, 25D3) and its active hormone derivative (1,25‐dihydroxycholecalciferol, 1,25D3) have long been associated with type II diabetes, although a mechanistic basis for this occurrence has not been fully elucidated. Renal reabsorption of vitamin D occurs by receptor‐mediated endocytosis of the 25D3‐vitamin D binding protein (DBP) complex via megalin‐, cubilin‐, and disabled‐2 (Dab2)‐mediated endocytosis. Because renal dysfunction can lead to decreased expression of megalin and proteinuria , changes in serum vitamin D status in the uncontrolled diabetic may be due to increased urinary excretion of protein‐complexed 25D3. In the present study, we used a type II diabetic rat model [Zucker Diabetic Fatty Rats (ZDF)] to characterize the relationship between renal reuptake of 25D3‐DBP and vitamin D homeostasis. Using immunoblotting and real‐time PCR, we analyzed transcript and protein levels of renal megalin, cubilin, and Dab2 and serum and urinary 25D3,1,25D3 and DBP levels in 16 wk old ZDF rats. Our preliminary data suggest that renal megalin and cubilin mRNA and protein expression is reduced in diabetic animals when compared to their lean non‐diabetic controls. In addition, preliminary results indicate that urinary excretion of DBP is markedly elevated in diabetic rats. Taken together, these data suggest that vitamin D status is compromised in diabetics due to poor vitamin D reabsorption in the kidney. Supported by USDA (Iowa State University Nutrition and Wellness Center SRPG to MR) and the Iowa State University Experiment Station.

Efectos de la transposición ileal, el bypass gastroyeyunal y la gastroplastia vertical en la regulación de la ingesta en un modelo experimental de obesidad relacionada con diabetes mellitus tipo 2

Aim The continual advances in our knowledge of the pathogenesis and hormonal disorders of morbid obesity lead to new studies in experimental animals and the development of new technical options. The aim is to asses whether ileal transposition can be a good treatment of morbid obesity associated with diabetes mellitus due to the action of intestinal peptide Glp-1 (enteroglucagon) compared to gastric bypass and vertical gastroplasty (VGB). Material and methods Trial enviroment: experimental animals ZDF rats (Zucker Diabetic Fatty rats). Subjects of the study: three groups of 10 animals each one divided as: a) ileal tranposition; b) gastro-jejunal bypass; c) vertical gastroplasty. Parameters to determine: weight loss, levels of glycaemia, enteroglucagon, insulin and ghrelin in blood, one week before the operation as a baseline control, and 15 days after the surgical procedure. Results Gastrojejunal bypass produces the most significant weight loss. There is a significant decrease in intake in all groups. Hyperinsulinaemia and hyperglycaemia tend to decrease after surgery in all groups, but in ileal transposition there is better control of ketosis. After gastrojejunal bypass and ileal transposition, we observed an increase in GLP-1 levels but were only significant in ileal transposition. Conclusions Ileal transposition produces a decrease in plasma glucose and better control of diabetes mellitus, which could benefit patients affected by morbid obesity and poor metabolic control. More studies are needed on other models of obesity. A model of exogenous and reversible obesity could be a good option to study the real benefits of the interventions.

Diabetic cardiomyopathy: effects of fenofibrate and metformin in an experimental model – the Zucker diabetic rat

BackgroundDiabetic cardiomyopathy (DCM) contributes to cardiac failure in diabetic patients. It is characterized by excessive lipids accumulation, with increased triacylglycerol (TAG) stores, and fibrosis in left ventricle (LV). The mechanisms responsible are incompletely known and no specific treatment is presently defined. We evaluated the possible usefulness of two molecules promoting lipid oxidation, fenofibrate and metformin, in an experimental model of DCM, the Zucker diabetic rat (ZDF).MethodsZDF and controls (C) rats were studied at 7, 14 and 21 weeks. After an initial study at 7 weeks, ZDF rats received no treatment, metformin or fenofibrate until final studies (at 14 or 21 weeks). C rats received no treatment. Each study comprised measurements of metabolic parameters (plasma glucose, TAG, insulin levels) and sampling of heart for histology and measurements of TAG content and relevant mRNA concentration.ResultsZDF rats were insulin-resistant at 7 weeks, type 2 diabetic at 14 weeks and diabetic with insulin deficiency at 21 weeks. Their plasma TAG levels were increased. ZDF rats had at 7 weeks an increased LV TAG content with some fibrosis. LV TAG content increased in untreated ZDF rats at 14 and 21 weeks and was always higher than in C. Fibrosis increased also moderately in untreated ZDF rats. Metformin and fenofibrate decreased plasma TAG concentrations. LV TAG content was decreased by metformin (14 and 21 weeks) and by fenofibrate (14 weeks). Fibrosis was reduced by fenofibrate only and was increased by metformin. Among the mRNA measured, fenofibrate increased Acyl-CoA Oxidase mRNA level, metformin decreased Acyl-CoA Synthase and increased AdipoR1 and pro-inflammatory mRNA levels.ConclusionFenofibrate had favourable actions on DCM. Metformin had beneficial effect on TAG content but not on fibrosis. PPARα agonists could be useful for the prevention and treatment of DCM.

Glucose-stimulated insulin secretion is increased and diabetes prevented in ZDF rats following voluntary running exercise training

Glucose-stimulated insulin secretion is increased and diabetes prevented in ZDF rats following voluntary running exercise training