Maria Montserrat Diaz Pedrosa

Sustained Liver Glucose Release in Response to Adrenaline Can Improve Hypoglycaemic Episodes in Rats under Food Restriction Subjected to Acute Exercise

Background. As the liver is important for blood glucose regulation, this study aimed at relating liver glucose release stimulated by glucagon and adrenaline to in vivo episodes of hypoglycaemia. Methods. The blood glucose profile during an episode of insulin-induced hypoglycaemia in exercised and nonexercised male Wistar control (GC) and food-restricted (GR, 50%) rats and liver glucose release stimulated by glucagon and adrenaline were investigated. Results. In the GR, the hypoglycaemic episodes showed severe decreases in blood glucose, persistent hypoglycaemia, and less complete glycaemic recovery. An exercise session prior to the episode of hypoglycaemia raised the basal blood glucose, reduced the magnitude of the hypoglycaemia, and improved the recovery of blood glucose. In fed animals of both groups, liver glucose release was activated by glucagon and adrenaline. In fasted GR rats, liver glycogenolysis activated by glucagon was impaired, despite a significant basal glycogenolysis, while an adrenaline-stimulated liver glucose release was recorded. Conclusions. The lack of liver response to glucagon in the GR rats could be partially responsible for the more severe episodes of hypoglycaemia observed in vivo in nonexercised animals. The preserved liver response to adrenaline can partially account for the less severe hypoglycaemia in the food-restricted animals after acute exercise.

Supplementation with L-Glutamine and L-Alanyl-L-Glutamine Changes Biochemical Parameters and Jejunum Morphophysiology in Type 1 Diabetic Wistar Rats.

We evaluated the effects of the supplementation with L-glutamine and glutamine dipeptide (GDP) on biochemical and morphophysiological parameters in streptozotocin-diabetic rats. For this purpose, thirty animals were distributed into six groups treated orally (gavage) during thirty days: non diabetic rats (Control) + saline, diabetic + saline; Control + L-glutamine (248 mg/kg), Diabetic + L-glutamine (248 mg/kg), Control + GDP (400 mg/kg), Diabetic + GDP (400 mg/kg). Diabetes was induced by an intravenous injection of streptozotocin (60 mg/kg) and confirmed by fasting glucose ≥ 200 mg/dL. Physiological parameters, i.e., body mass, food intake, blood glucose, water intake, urine and faeces were evaluated during supplementation. After the period of supplementation, the animals were euthanized. The blood was collected for biochemical assays (fructosamine, transaminases, lipid profile, total protein, urea, ammonia). Moreover, the jejunum was excised and stored for morphophysiological assays (intestinal enzyme activity, intestinal wall morphology, crypt proliferative index, number of serotoninergic cells from the mucosa, and vipergic neurons from the submucosal tunica). The physiological parameters, protein metabolism and intestinal enzyme activity did not change with the supplementation with L-glutamine or GDP. In diabetic animals, transaminases and fructosamine improved with L-glutamine and GDP supplementations, while the lipid profile improved with L-glutamine. Furthermore, both forms of supplementation promoted changes in jejunal tunicas and wall morphometry of control and diabetic groups, but only L-glutamine promoted maintenance of serotoninergic cells and vipergic neurons populations. On the other hand, control animals showed changes that may indicate negative effects of L-glutamine. Thus, the supplementation with L-glutamine was more efficient for maintaining intestinal morphophysiology and the supplementation with GDP was more efficient to the organism as a whole. Thus, we can conclude that local differences in absorption and metabolism could explain the differences between the supplementation with L-glutamine or GDP.

Immediate and residual effects of low-dose nandrolone decanoate and treadmill training on adipose and reproductive tissues of male Wistar rats

Abstract Context: Residual effects after nandrolone decanoate (ND) treatment are not reported. Objective: Immediate and residual effects of low-dose ND and treadmill training were investigated. Materials and methods: Male rats were trained and/or ND-treated for four weeks and the assessments were made after this period or four weeks later. Results: The groups did not differ in final plasma glucose or AUC of the ivGTT, but hyperinsulinemia was noticed in some trained/treated groups. Training with ND increased muscle mass and ND decreased the reproductive structures. Decreased fat with training was reversed by detraining. Discussion: The anabolic action of ND on skeletal muscle was enhanced by training. Fat and lipid changes were more linked to training/detraining, but the effects of ND on the reproductive structures persisted after treatment. Conclusions: The effects of training on fat and muscle were not maintained after detraining, but low-dose ND had persistent effects on the reproductive structures.

Food restriction promotes damage reduction in rat models of type 2 diabetes mellitus

There are several animal models of type 2 diabetes mellitus induction but the comparison between models is scarce. Food restriction generates benefits, such as reducing oxidative stress, but there are few studies on its effects on diabetes. The objective of this study is to evaluate the differences in physiological and biochemical parameters between diabetes models and their responses to food restriction. For this, 30 male Wistar rats were distributed in 3 groups (n = 10/group): control (C); diabetes with streptozotocin and cafeteria-style diet (DE); and diabetes with streptozotocin and nicotinamide (DN), all treated for two months (pre-food restriction period). Then, the 3 groups were subdivided into 6, generating the groups CC (control), CCR (control+food restriction), DEC (diabetic+standard diet), DER (diabetic+food restriction), DNC (diabetic+standard diet) and DNR (diabetic+food restriction), treated for an additional two months (food restriction period). The food restriction (FR) used was 50% of the average daily dietary intake of group C. Throughout the treatment, physiological and biochemical parameters were evaluated. At the end of the treatment, serum biochemical parameters, oxidative stress and insulin were evaluated. Both diabetic models produced hyperglycemia, polyphagia, polydipsia, insulin resistance, high fructosamine, hepatic damage and reduced insulin, although only DE presented human diabetes-like alterations, such as dyslipidemia and neuropathy symptoms. Both DEC and DNC diabetic groups presented higher levels of protein carbonyl groups associated to lower antioxidant capacity in the plasma. FR promoted improvement of glycemia in DNR, lipid profile in DER, and insulin resistance and hepatic damage in both diabetes models. FR also reduced the protein carbonyl groups of both DER and DNR diabetic groups, but the antioxidant capacity was improved only in the plasma of DER group. It is concluded that FR is beneficial for diabetes but should be used in conjunction with other therapies.

Changes of Liver Glucose Metabolism in C57BL/6 Mice Transgenic for Human Apolipoprotein ApoCIII

Mice overexpressing the human apolipoprotein apo CIII are a model of dyslipidemia. They become hypertriglyceridemic, hypercholesterolemic and have high blood levels of free fatty acids. Blood glucose is normal, but as the liver integrates lipid and carbohydrate metabolism, conditions of high inter-tissue circulation of energy substrates, such as fasting, may reveal hepatic alterations of glucose metabolism in these (CIII) mice. This hypothesis was explored by in situ liver perfusion in this investigation. The NTG (non-transgenic) animals showed liver and muscle glycogen content changes compatible with the fed or fasted state. In contrast, glycogen in group CIII was much lower in the fed state. The liver glucose release in group CIII after overnight fasting and adrenaline-stimulated was lower than in group NTG. Total glucose production under gluconeogenic conditions was not different between groups NTG and CIII, but glucose production from alanine was decreased in group CIII. Therefore, dyslipidemia caused by overexpression of apoCIII in mice alters the liver glucose metabolism, particularly compromising glycogen synthesis and degradation. This profile might have adverse outcomes during metabolic challenges that are more severe than fasting.

Responses of the Adult Rat Glucose Metabolism to Early Life Feeding, Caloric Restriction and Refeeding

Early life overfeeding in the rat can be experimentally induced by reducing litter size. This investigation assessed the consequences of this manipulation on glucose metabolism in vivo and in isolated hepatocytes in 150-day old rats. Additionally, after body growth, the effects of caloric restriction and refeeding were tested. Adult rats from control (G9) and reduced litters (G3L) did not differ in body and fat weights, glucose tolerance or insulin resistance (insulin-induced hypoglycemia), or hepatocyte glucose release under basal or gluconeogenic conditions. Caloric restriction (G3R) reduced body and fat weights, decreased glucose decay after insulin injection and decreased hepatocyte gluconeogenic glucose release. Refeeding after caloric restriction reversed these parameters to those of the freely-fed groups (G9 and G3L). Taken together, these results suggest that the liver glucose metabolism is not programmed by lactational overfeeding, but rather is responsive to the current nutritional condition of the animal.

Refeeding after caloric restriction reverses altered liver glucose release

Abstract Context: Caloric restriction increases liver glucose release (LGR), but it is not known if this is a permanent condition. Objective: To investigate if refeeding after caloric restriction reverses the high LGR. Materials and methods: Rats were organised in six-pups litters (GC); 12-pups litters with either 50% caloric restriction from 21 to 80 days of age (GR) or fed at will from 50 to 80 days of age (GRL). Liver perfusion was made at the age of 80 days. Results: LGR was higher in the GR both during basal and adrenaline-stimulated conditions. Refeeding after caloric restriction decreased it to values close to those of GC rats. Discussion: The altered LGR of GR rats was reversed by refeeding (group GRL). The influence of hypothalamic neuropetides on these hepatic changes is suggested. Conclusions: Enhanced LGR under caloric restriction is not programmed by early feeding; instead, it is determined by the current nutritional conditions.

Rat Hepatocyte Glucose Metabolism Is Affected by Caloric Restriction but not by Litter Size Reduction

This work aimed at investigating whether the liver glucose metabolism could have a role in any change of glucose homeostasis that might exist in the reduced-litter rat at the age of 60 days. Additionally, post-weaning caloric restriction and its hepatic effects were explored, as this intervention is reported as a useful measure against obesity and its related disturbances. The animals were raised in litters of nine (control, CG) or three pups during lactation. These small-litter pups were FG (fed freely) or subjected to 30% RG (caloric restriction) after weaning until 60 days of age. The increased adiposity induced by lactational overfeeding was not reversed by caloric restriction. Hepatocyte glucose metabolism and glucose tolerance test were not affected by litter size, but caloric restriction increased liver basal glucose release, diminished gluconeogenesis and retarded the glycemic decay during the insulin tolerance test. Liver glucose metabolism of young adult rats was not affected by lactational overfeeding. Up to this age, however, moderate caloric restriction had a potent influence that might compromise whole-body glucose homeostasis and prompt to insulin resistance.

Glutamine dipeptide and cortisol change the liver glucose metabolism and reduce the severity of insulin-induced hypoglycaemia in untreated T1DM Swiss mice

Abstract Context: Glutamine is conditionally essential in type 1 diabetes mellitus, and might be useful to counteract hypoglycaemia. Objective: To investigate the systemic and hepatic effects of counter-regulatory hormones and glutamine dipeptide (GDP) during hypoglycemic episodes. Materials and methods: Diabetic Swiss mice made hypoglycaemic by insulin injection (1 U/kg) were given counter-regulatory hormones and/or GDP. Sixty minutes later, liver histology, liver glucose metabolism and plasma were assessed. Results: Combined, cortisol and GDP improved the hypoglycemic profile. During liver perfusion, gluconeogenesis was possibly the major pathway leading to glucose release. Perfusion with gluconeogenic precursors after glycogen depletion by adrenaline increased liver glucose and urea release. Discussion: The less severe hypoglycaemia could result from cortisol stimulating periportal gluconeogenesis and GDP inhibiting pericentral glycogenolysis, both favouring liver glucose release. Conclusions: At least some benefits of GDP and cortisol during hypoglycaemia came from their hepatic actions, and their use in diabetic patients should be explored.

Early-onset obesity and food restriction alter hepatocyte metabolism in adult Wistar rats

Abstract Context: Caloric restriction (CR) is suggested for overweight control. Objective: Systemic and liver glucose metabolism in the reduced-litter (RL) rat model under 30% CR was investigated. Materials and methods: Newborn litters were organised in control (G9); RL with free diet (G3L); and RL with CR (G3R). Assessments were made at the age of 90 d. Results: Higher liver glycogen content and changes in systemic glucose handling were found in the RL groups. Hepatocyte glucose metabolism was similar in groups G9 and G3L, but basal glucose production and glycogenolysis were higher, while gluconeogenesis and basal glycolysis were lower in the G3R. Urea production was lower in the RL groups. Discussion: The altered glucose handling of the RL adult rats was not reversed by moderate (30%) CR. Hepatocyte glucose and nitrogen metabolism were changed by both early overfeeding and current feeding conditions. Conclusions: RL and CR alter systemic and liver glucose metabolism.