Teresa Louro

Metformin restores endothelial function in aorta of diabetic rats

The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been fully elucidated. This study was designed to assess the effect of metformin on impaired endothelial function, oxidative stress, inflammation and advanced glycation end products formation in type 2 diabetes mellitus.

Effects of α‐lipoic acid on endothelial function in aged diabetic and high‐fat fed rats

This study was conducted to investigate the effects of α‐lipoic acid (α‐LA) on endothelial function in diabetic and high‐fat fed animal models and elucidate the potential mechanism underlying the benefits of α‐LA.

Metformin and atorvastatin combination further protect the liver in type 2 diabetes with hyperlipidaemia

Non‐alcoholic fatty liver disease (NAFLD) and type 2 diabetes are associated with dyslipidaemia, inflammation and oxidative stress. However, the pathophysiology of NAFLD in type 2 diabetes with hyperlipidaemia is not fully known, as well as the utility of the commonly prescribed anti‐diabetic and lipid‐lowering drugs in ameliorating liver injury markers.

Insulin and metformin may prevent renal injury in young type 2 diabetic Goto-Kakizaki rats.

Type 2 diabetes is increasing at epidemic proportions throughout the world, and diabetic nephropathy is the principal cause of end stage renal failure. Approximately 40% of patients with type 2 diabetes may progress to nephropathy and a good metabolic control can prevent the development of diabetic renal injury. The aim of our study was to evaluate, in young type 2 diabetic Goto-Kakizaki (GK) rats fed with atherogenic diet, the effects of the anti-diabetic compounds insulin, metformin and gliclazide on renal damage. GK rats fed with atherogenic diet showed increased body weight and fasting blood glucose, total cholesterol, triglycerides, C-reactive protein and protein carbonyl levels and lower HDL-cholesterol concentration; renal markers of inflammation and fibrosis were also elevated. All the anti-diabetic agents ameliorated fasting glycaemia and insulin resistance but only insulin and metformin were able to improve glycoxidation, fibrosis and inflammation kidney parameters. Our data suggest that insulin and metformin treatments, improving glicoxidative, inflammatory and fibrotic renal damage markers, play a key role in the prevention of diabetic nephropathy.

Soybean oil treatment impairs glucose-stimulated insulin secretion and changes fatty acid composition of normal and diabetic islets

We investigated the effect of sub-chronic soybean oil (SO) treatment on the insulin secretion and fatty acid composition of islets of Langerhans obtained from Goto-Kakizaki (GK), a model of type 2 diabetes, and normal Wistar rats. We observed that soybean-treated Wistar rats present insulin resistance and defective islet insulin secretion when compared with untreated Wistar rats. The decrease in insulin secretion occurred at all concentrations of glucose and arginine tested. Furthermore we observed that soybean-treated normal islets present a significant decrease in two saturated fatty acids, myristic and heneicosanoic acids, and one monounsaturated eicosenoic acid, and the appearance of the monounsaturated erucic acid. Concerning diabetic animals, we observed that soybean-treated diabetic rats, when compared with untreated GK rats, present an increase in plasma non-fasting free fatty acids, an exacerbation of islet insulin secretion impairment in all conditions tested and a significant decrease in the monounsaturated palmitoleic acid. Altogether our results show that SO treatment results in a decrease of insulin secretion and alterations on fatty acid composition in normal and diabetic islets. Furthermore, the impairment of insulin secretion, islet erucic acid and fasting plasma insulin levels are similar in treated normal and untreated diabetic rats, suggesting that SO could have a deleterious effect on β-cell function and insulin sensitivity.

A role for atorvastatin and insulin combination in protecting from liver injury in a model of type 2 diabetes with hyperlipidemia

Non-alcoholic fatty liver disease (NAFLD) is a major complication linked with the metabolic syndrome associated with dyslipidemia, inflammation, and oxidative stress. Impact of type 2 diabetes with hyperlipidemia in NAFLD has to be established, as well as the utility of commonly prescribed anti-diabetic and lipid-lowering agents in improving liver injury markers. Genetic type 2 diabetic Goto–Kakizaki rats were fed with a high-fat diet to test hepatic effects of type 2 diabetes with hyperlipidemia and the effect of atorvastatin and insulin, individually and in combination, in systemic and hepatic inflammatory and oxidative stress markers. High-fat diet aggravated fasting glycemia, systemic and liver lipids, and inflammatory and oxidative stress markers. Individual treatments improved glycemic and lipid profiles, but failed to improve inflammatory markers, whereas insulin was able to reduce liver oxidative stress parameters. Combination of insulin and atorvastatin further improved glycemic and lipid profiles and decreased circulating C-reactive protein levels and liver inflammatory and oxidative stress markers. Insulin and atorvastatin combination leads to better glycaemic and lipid profiles and to better protection against liver inflammation and oxidative stress, giving a superior level of liver protection in type 2 diabetic with hyperlipidemia.

Beneficial effects of dietary restriction in type 2 diabetic rats: the role of adipokines on inflammation and insulin resistance.

Inflammation plays an important role in diabetes mellitus and its complications. In this context, the negative cross-talk between adipose tissue and skeletal muscle leads to disturbances in muscle cell insulin signalling and induces insulin resistance. Because several studies have shown that energy restriction brings some benefits to diabetes, the aim of the present study was to evaluate the effects of dietary restriction on systemic and skeletal muscle inflammatory biomarkers, such C-reactive protein, adipokines and cytokines, and in insulin resistance in Goto-Kakizaki rats. This is an animal model of spontaneous non-obese type 2 diabetes with strongly insulin resistance and without dyslipidaemia. Animals were maintained during 2 months of dietary restriction (50 %) and were killed at 6 months of age. Some biochemical determinations were done using ELISA and Western blot. Data from the present study demonstrate that in Goto-Kakizaki rats the dietary restriction improved insulin resistance, NEFA levels and adipokine profile and ameliorated inflammatory cytokines in skeletal muscle. These results indicate that dietary restriction in type 2 diabetes enhances adipose tissue metabolism leading to an improved skeletal muscle insulin sensitivity.

Food Deprivation Promotes Oxidative Imbalance in Rat Brain

The present study was aimed to evaluate the effect of food deprivation in brain oxidative status of Wistar and Goto-Kakizaki (GK) rats. For this purpose, we evaluated several oxidative stress parameters: lipid peroxidation (thiobarbituric acid reactive substances [TBARS]) and protein oxidation markers, hydrogen peroxide (H(2)O(2)) levels, nonenzymatic (reduced [GSH] and oxidized glutathione [GSSG] and vitamin E) and enzymatic (glutathione peroxidase [GPx], glutathione reductase [GRed], and manganese superoxide dismutase [MnSOD]) antioxidant defenses. Four-mo-old Wistar and GK rats were divided into 2 groups. One group of each rat strain was maintained under normal diet and the other groups were maintained under 50% food deprivation during 2 mo. GK rats under normal diet presented lower levels of vitamin E and higher GRed activity and GSH/GSSG ratio when compared with Wistar control rats. In Wistar rats, food deprivation induced a significant decrease in vitamin E levels and a significant increase in GPx activity, H(2)O(2) production, and TBARS formation in the presence of the prooxidant pair ADP/Fe(2+). However, GK rats under food deprivation presented a significant decrease in vitamin E levels and GRed activity and a significant increase in H(2)O(2) production when compared with GK under normal diet. In summary, our results indicate that food deprivation affects brain oxidative status, which could predispose brain cells to degeneration and death.

Therapeutic association of atorvastatin and insulin in cardiac ischemia: Study in a model of type 2 diabetes with hyperlipidemia

UNLABELLED Combination therapy recently emerged as a potential therapeutic option in order to improve cardiovascular risk in diabetics, since therapies commonly used in monotherapy failed in significantly optimizing this risk. METHODS A type 2 diabetes animal model was used to test the effects of a high-fat diet, atorvastatin and insulin (isolated or in association), in glycemic, lipid and inflammatory profiles, oxidative stress markers and cardiac mitochondrial function in ischemia-reperfusion conditions. RESULTS High-fat diets significantly worsened fasting glycemia and lipid profile; it also increased C-reactive protein (CRP) and oxidative stress and compromised mitochondrial response to ischemia. Insulin decreased fasting glucose and free fatty acid levels and insulin resistance, while increasing HDL-cholesterol, but had no effect in inflammatory markers. Atorvastatin decreased circulating adiponectin levels and did not improve inflammatory markers, although it improved fasting glycemia, glucose tolerance, free fatty acids and HDL-cholesterol. The combined use of atorvastatin and insulin improved several parameters, as did each of the treatments separately. However, treatment association went beyond these results, by decreasing atherogenicity index and circulating CRP levels. Insulin and its association with atorvastatin significantly prevented mitochondrial dysfunction observed in the high-fat diet group, while atorvastatin showed some beneficial effects but in much less extent. CONCLUSIONS Altogether, these results show that administration of an high-fat diet in a model of type 2 diabetes increases cardiovascular risk and combined use of atorvastatin and insulin provides a superior control of cardiovascular risk markers in diabetic and hyperlipidemic subjects.

Glucagon secretion after metabolic surgery in diabetic rodents

Excessive or inadequate glucagon secretion promoting hepatic gluconeogenesis and glycogenolysis is believed to contribute to hyperglycemia in patients with type 2 diabetes. Currently, metabolic surgery is an accepted treatment for obese patients with type 2 diabetes and has been shown to improve glycemic control in Goto-Kakizaki (GK) rats, a lean animal model for type 2 diabetes. However, the effects of surgery on glucagon secretion are not yet well established. In this study, we randomly assigned forty 12- to 14-week-old GK rats to four groups: control group (GKC), sham surgery (GKSS), sleeve gastrectomy (GKSG), and gastric bypass (GKGB). Ten age-matched Wistar rats served as a non-diabetic control group (WIC). Glycemic control was assessed before and 4 weeks after surgery. Fasting- and mixed-meal-induced plasma levels of insulin and glucagon were measured. Overall glycemic control improved in GKSG and GKGB rats. Fasting insulin levels in WIC rats were similar to those for GKC or GKSS rats. Fasting glucagon levels were highest in GKGB rats. Whereas WIC, GKC, and GKSS rats showed similar glucagon levels, without any significant meal-induced variation, a significant rise occurred in GKSG and GKGB rats, 30 min after a mixed meal, which was maintained at 60 min. Both GKSG and GKGB rats showed an elevated glucagon:insulin ratio at 60 min in comparison with all other groups. Surprisingly, the augmented post-procedural glucagon secretion was accompanied by an improved overall glucose metabolism in GKSG and GKGB rats. Understanding the role of glucagon in the pathophysiology of type 2 diabetes requires further research.