Peripheral insulin resistance is early, progressive, and correlated with cachexia in Walker-256 tumor-bearing rats.

Insulin (INS) resistance is often found in cancer-bearing, but its correlation with cachexia development is not completely established. This study investigated the temporal sequence of the development of INS resistance and cachexia to establish the relationship between these factors in Walker-256 tumor-bearing rats (TB rats). INS hepatic sensitivity and INS resistance-inducing factors, such as free fatty acids (FFA) and tumor necrosis factor-α (TNF-α), were also evaluated. Studies were carried out on Days 2, 5, 8, and/or 12 after inoculation of tumor cells in rats. The peripheral INS sensitivity was assessed by the INS tolerance test and the INS hepatic sensitivity in in situ liver perfusion. TB rats with 5, 8, and 12 days of tumor, but not 2 days, showed decreased peripheral INS sensitivity (INS resistance), retroperitoneal fat, and body weight, compared to healthy rats, which were more pronounced on Day 12. Gastrocnemius muscle wasting was observed only on Day 12 of tumor. The peripheral INS resistance was significantly correlated (r = -.81) with weight loss. Liver INS sensitivity of TB rats with 2 and 5 days of tumor was unchanged, compared to healthy rats. TB rats with 12 days of tumor showed increased plasma FFA and increased TNF-α in retroperitoneal fat and liver, but not in the gastrocnemius, compared to healthy rats. In conclusion, peripheral INS resistance is early, starts along with fat and weight loss and before muscle wasting, progressive, and correlated with cachexia, suggesting that it may play an important role in the pathogenesis of the cachectic process in TB rats. Therefore, early correction of INS resistance may be a therapeutic approach to prevent and treat cancer cachexia.

A High-Fat Diet Induces Lower Systemic Inflammation than a High-Carbohydrate Diet in Mice.

Background: We previously established that male Swiss mice (Mus musculus) receiving a high-fat diet (HFD) during 8 weeks exhibit similar caloric ingestion and body weight (grams) compared with mice fed a high-carbohydrate diet (HCD). HFD mice exhibit a lower inflammatory state than an HCD in the liver, skeletal muscle, and brain. In addition, we demonstrated that HFD and HCD modulated fatty acids (FA) composition in these tissues. In this study, our objective was to compare HFD mice and HCD mice in terms of systemic inflammation. Methods: Saturated FA (SFA), monounsaturated FA, omega-6 polyunsaturated FA (n-6 PUFA), and n-3 PUFA were evaluated at the time points 0, 1, 7, 14, 28, and 56 days after starting the administration of the diets. We investigated n-6 PUFA:n-3 PUFA, SFA:n-3 PUFA, palmitic acid:α-linolenic acid (ALA), and myristic acid:docosahexaenoic acid (DHA) ratios as potential serum biomarkers of systemic inflammation. We also measured the serum levels of basic fibroblast growth factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), inducible protein 10 (IP-10), interferon gamma (IFN-γ), interleukin (IL)-1α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, macrophage inflammatory protein-1α (MIP-1-α), monocyte chemotactic protein 1 (MCP-1), monokine induced by IFN-γ (MIG), and tumor necrosis factor α (TNF-α). Results: The HFD group had lower (P < 0.05) n-6 PUFA:n-3 PUFA, palmitic acid:ALA, myristic acid:DHA ratios, and lower plasma levels of proinflammatory cytokines (IFN-γ, MIG, GM-CSF, and IL-6). Conclusion: The HFD mice showed lower systemic inflammation compared with a caloric ingestion-body weight-matched control HCD mice.

Effect of high-carbohydrate or high-monounsaturated fatty acid diets on blood pressure: a systematic review and meta-analysis of randomized controlled trials.

Context: Current dietary guidelines for cardiovascular disease risk management recommend restricting intake of saturated fatty acids (SFAs). However, the optimal macronutrient profile, in the context of a low-SFA diet, remains controversial. The blood-pressure effect of replacing SFAs in diets with monounsaturated fatty acids (MUFAs) compared with carbohydrate has not been quantified to date. Objective: To synthesize the evidence for the effect of substituting a high-carbohydrate (high-CHO) diet for a high-monounsaturated fatty acid (high-MUFA) diet on blood pressure, a systematic review and meta-analysis of randomized clinical trials in a population without health restrictions was conducted. Data Sources: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Clinical Trials were searched through June 7, 2017. Randomized controlled trials of > 3 weeks duration that assessed the effect of high-MUFA diets in isocaloric substitution for high-CHO diets on systolic blood pressure (SBP) and diastolic blood pressure (DBP) were included. Data Extraction: Data were pooled using the generic-inverse variance method with random effects models and expressed as mean differences (MDs) with 95% confidence intervals (CIs). Heterogeneity was assessed by Cochran Q statistic and quantified by the I2 statistic. The quality of the evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Results: Fourteen trials (n = 980 participants) were included in the analysis. Comparatively, the high-MUFA diets in isocaloric substitution for high-CHO diets did not demonstrate a greater reduction in blood pressure (SBP: MD, -0.08 mmHg [95%CI, -1.01 to 0.84], P = 0.86; DBP: MD = 0.01 mmHg [95%CI, -0.73 to 0.75], P = 0.98). The overall quality of the evidence was assessed as moderate. Conclusions: In the context of low SFAs, high-MUFA diets in isocaloric substitution for high-CHO diets did not affect blood pressure in individuals with and without hypertension. Large-scale trials achieving higher MUFA targets are required to support these findings. ClinicalTrials.gov ID: NCT02626325.

Thyroid hormone treatment decreases hepatic glucose production and renal reabsorption of glucose in alloxan-induced diabetic Wistar rats.

The thyroid hormone (TH) plays an important role in glucose metabolism. Recently, we showed that the TH improves glycemia control by decreasing cytokines expression in the adipose tissue and skeletal muscle of alloxan-induced diabetic rats, which were also shown to present primary hypothyroidism. In this context, this study aims to investigate whether the chronic treatment of diabetic rats with T3 could affect other tissues that are involved in the control of glucose homeostasis, as the liver and kidney. Adult Male Wistar rats were divided into nondiabetic, diabetic, and diabetic treated with T3 (1.5 µg/100 g BW for 4 weeks). Diabetes was induced by alloxan monohydrate (150 mg/kg, BW, i.p.). Animals showing fasting blood glucose levels greater than 250 mg/dL were selected for the study. After treatment, we measured the blood glucose, serum T3, T4, TSH, and insulin concentration, hepatic glucose production by liver perfusion, liver PEPCK, GAPDH, and pAKT expression, as well as urine glucose concentration and renal expression of SGLT2 and GLUT2. T3 reduced blood glucose, hepatic glucose production, liver PEPCK, GAPDH, and pAKT content and the renal expression of SGLT2 and increased glycosuria. Results suggest that the decreased hepatic glucose output and increased glucose excretion induced by T3 treatment are important mechanisms that contribute to reduce serum concentration of glucose, accounting for the improvement of glucose homeostasis control in diabetic rats.

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.

Insulin resistance in the liver: deficiency or excess of insulin?

In insulin-resistant states (obesity, pre-diabetes, and type 2 diabetes), hepatic production of glucose and lipid synthesis are heightened in concert, implying that insulin deficiency and insulin excess coexists in this setting. The fact that insulin may be inadequate or excessive at any one point in differing organs and tissues has many biologic ramifications. In this context the concept of metabolic compartmentalization in the liver is offered herein as one perspective of this paradox. In particular, we focus on the hypothesis that insulin resistance accentuates differences in periportal and perivenous hepatocytes, namely periportal glucose production and perivenous lipid synthesis. Subsequently, excessive production of glucose and accumulation of lipids could be expected in the livers of patients with obesity and insulin resistance. Overall, in this review, we provide our integrative perspective regarding how excessive production of glucose in periportal hepatocytes and accumulation of lipids in perivenous hepatocytes interact in insulin resistant states.

Pivotal role of cAMP in the activation of liver glycogen breakdown in high-fat diet fed mice.

AIMS: Liver glycogen catabolism was evaluated in male Swiss mice fed a high-fat diet rich in saturated fatty acids (HFD) or normal fat diet (NFD) during one week. MAIN METHODS: Liver glycogenolysis (LG) and liver glucose production (LGP) were measured either under basal or stimulated conditions (infusion of glycogenolytic agents). Thus, isolated perfused livers from HFD and NFD mice were infused with glycogenolytic agents, i.e., glucagon, epinephrine, phenylephrine, isoproterenol, adenosine-3'-5'-cyclic monophosphate (cAMP), N(6),2'-O-dibutyryl-cAMP (DB-cAMP), 8-bromoadenosine-cAMP (8-Br-cAMP) or N(6)-monobutyryl-cAMP (N6-MB-cAMP). Moreover, glycemia and liver glycogen content were measured. KEY FINDINGS: Glycemia, liver glycogen content and basal rate of LGP and LG were not influenced by the HFD. However, LGP and LG were lower (p<0.05) in HFD mice during the infusions of glucagon (1 nM), epinephrine (20 µM) or phenylephrine (20 µM). In contrast, the activation of LGP and LG during the infusion of isoproterenol (20 µM) was not different (HFD vs. NFD). Because glucagon showed the most prominent response, the effect of cAMP, its intracellular mediator, on LGP and LG was investigated. cAMP (150 µM) showed lower activation of LGP and LG in the HFD group. However, the activation of LGP and LG was not influenced by HFD whether DB-cAMP (3 µM), 8-Br-cAMP (3 µM) or N6-MB-cAMP (3 µM) were used. SIGNIFICANCE: The activation of LGP and LG depends on the intracellular availability of cAMP. It can be concluded that cAMP played a pivotal role on the activation of LG in high-fat diet fed mice.

Effect of linseed oil and macadamia oil on metabolic changes induced by high-fat diet in mice.

The effects of linseed oil (LO) and macadamia oil (MO) on the metabolic changes induced by a high-fat diet (HFD) rich in saturated fatty acid were investigated. For the purpose of this study, the vegetable oil present in the HFD, i.e. soybean oil (SO) was replaced with LO (HFD-LO) or MO (HFD-MO). For comparative purposes, a group was included, which received a normal fat diet (NFD). Male Swiss mice (6-week old) were used. After 14 days under the dietary conditions, the mice were fasted for 18 h, and experiments were then performed. The HFD-SO, HFD-LO and HFD-MO groups showed higher glycaemia (p < 0.05 versus NFD). However, no significant effect was observed on glycaemia, liver gluconeogenesis and liver ketogenesis when SO was replaced by either LO or MO. The body weight and the sum of epididymal, mesenteric, retroperitoneal and inguinal fat weights were higher (p < 0.05) in the HFD-SO and HFD-MO groups as compared with the NFD group. However, there was no significant difference in these parameters between the NFD and HFD-LO groups. Thus, the protective role of LO on lipid accumulation induced by an HFD rich in saturated fatty acid is potentially mediated by the high content of É·-3 polyunsaturated fatty acid in LO.

Effect of infliximab on metabolic disorders induced by Walker-256 tumor in rats.

BACKGROUND: The purpose of this study was to investigate the effect of infliximab, an anti-tumor necrosis factor α (TNFα) monoclonal antibody, on the progression of cachexia and several metabolic parameters affected by the Walker-256 tumor in rats. METHODS: Infliximab (0.5 mg/kg) was ip administered, twice a day, beginning at the day in which the Walker-256 tumor cells were inoculated. After 12 days of treatment, the tumor growth, some parameters of cachexia/anorexia, the blood levels of triacylglycerol, glucose, lactate and urea, the peripheral response to insulin and the hepatic glycolysis and gluconeogenesis were investigated. The peripheral response to insulin was evaluated by the insulin tolerance test and the glycolysis and gluconeogenesis in isolated perfused liver. RESULTS: The treatment with infliximab did not alter the growth of the Walker-256 tumor, but attenuated (p < 0.05) the reduction of body weight and prevented (p < 0.05) the loss of retroperitoneal adipose tissue induced by the tumor. Moreover, treatment with infliximab tended to minimize the loss of gastrocnemius muscle, the reduction in food intake, the peripheral response to insulin and the liver gluconeogenesis from alanine, as well as the increased blood triacylglycerol, caused by the tumor. In contrast, treatment with infliximab did not attenuate the reduction in hepatic glycolysis and glycemia, nor did it minimize the rise in blood levels of lactate and urea induced by the tumor. CONCLUSION: The treatment with infliximab ameliorated some changes associated with cachexia, such as the reduction of adipose tissue and body weight, suggesting that TNFα plays a significant role in mediating these changes induced by the tumor. In addition, infliximab tended to improve or had no effect on other metabolic parameters affected by the Walker-256 tumor, suggesting that other mediators or tumor-related events are involved in these disorders.

Effect of l-glutamine on myenteric neuron and of the mucous of the ileum of diabetic rats.

The objective of this work was to investigate the effect of the L-glutamine supplementation to prevent - diabetes induced changes in myenteric neurons and also to verify the effect on the mucosa of the ileum of Wistar rats. The animals were divided in five groups (n = 5): untreated normoglycaemic (UN), normoglycaemic treated with L-glutamine (NG), untreated diabetics (UD), diabetics treated with L-glutamine, starting on the 4th (DG4) or 45th day following diabetes induction (DG45). The amino acid was added to the diet at 1%. The density and size of neurons, the metaphasic index in the crypt, the height of the villus, the depth of the crypt and the number of globet cells were determined. There was no difference in the neuronal density and in the cellular body area of the myosin-stained myenteric neurons of groups DG4 and DG45 when compared to group D. The metaphase index and the number of goblet cells showed no significant differences when all groups were compared (P > 0.05). The villi height of groups DG4 and DG45 were 45.5% (P < 0.05) and 32.4% (P > 0.05) higher than those in group UD, respectively. The analyzed crypts showed similar depth for all studied groups.

Evaluation of liver glycogen catabolism during hypercortisolism induced by the administration of dexamethasone in rats.

BACKGROUND: The contribution of liver glycogen catabolism to hyperglycemia and glucose intolerance induced by pharmacological hypercortisolism were investigated. METHODS: For this purpose, adult male Wistar rats that received 1.0 mg/kg dexamethasone (DEX) ip at 8:00 a.m. (DEX group) or saline (CON group) once a day for 5 consecutive days were compared. RESULTS: Experimental hypercortisolism was confirmed by higher (p<0.05) glycemia, lower (p<0.05) body weight and glucose intolerance. In the fed state, the basal glycogen catabolism and the glucagon (1 nM) and epinephrine (2 µM) induced glycogen catabolism were similar between the groups. The activation of glycogen catabolism induced by phenylephrine (2 µM) and isoproterenol (20 µM) were increased (p<0.05) and decreased (p<0.05), respectively, in DEX rats. Furthermore, DEX rats exhibited higher (p<0.05) glycogen catabolism during the infusion of cAMP (3 µM). However, during the infusion of cAMP (15 µM), 6MB-cAMP (3 µM) or cyanide (0.5 mM), the intensification of glycogen breakdown was similar. Thus, in general, hypercortisolism does not influence the basal glycogen catabolism and the liver responsiveness to glycogenolytic agents in the fed state. In contrast with fed state, fasted rats (DEX group) showed a more intense (p<0.05) basal glycogen catabolism. CONCLUSION: The contribution of glycogen catabolism to hyperglycemia during hypercortisolism depends of the nutritional status, starting from a negligible participation in the fed state up to a significant contribution in the fasted state.

Time sequence of the intensification of the liver glucose production induced by high-fat diet in mice.

It is well established that the development of insulin resistance shows a temporal sequence in different organs and tissues. Moreover, considering that the main aspect of insulin resistance in liver is a process of glucose overproduction from gluconeogenesis, we investigated if this metabolic change also shows temporal sequence. For this purpose, a well-established experimental model of insulin resistance induced by high-fat diet (HFD) was used. The mice received HFD (HFD group) or standard diet (COG group) for 1, 7, 14 or 56 days. The HFD group showed increased (P < 0.05 versus COG) epididymal, retroperitoneal and inguinal fat weight from days 1 to 56. In agreement with these results, the HFD group also showed higher body weight (P < 0.05 versus COG) from days 7 to 56. Moreover, the changes induced by HFD on liver gluconeogenesis were progressive because the increment (P < 0.05 versus COG) in glucose production from l-lactate, glycerol, l-alanine and l-glutamine occurred 7, 14, 56 and 56 days after the introduction of the HFD schedule, respectively. Furthermore, glycaemia and cholesterolemia increased (P < 0.05 versus COG) 14 days after starting the HFD schedule. Taken together, the results suggest that the intensification of liver gluconeogenesis induced by an HFD is not a synchronous 'all-or-nothing process' but is specific for each gluconeogenic substrate and is integrated in a temporal manner with the progressive augmentation of fasting glycaemia.

Comparative effects of short-term and long-term insulin-induced hypoglycemia on glucose production in the perfused livers of weaned rats.

The liver glucose production (LGP) levels of 15-h overnight fasted weaned rats submitted to short-term insulin-induced hypoglycemia (ST-IIH) and long-term IIH (LT-IIH) were compared. Experiments to characterize ST-IIH or LT-IIH that followed an intraperitoneal (ip) injection (1.0 U/kg) of regular (ST-IIH) or insulin detemir (LT-IIH) were performed and glycemia were measured 0 (normoglycemic control), 0.5 h (ST-IIH), 4 h and 6 h (LT-IIH) later. The values of glycemia (mg/dl) were 77.8 ±l 7.2 (normoglycemic control), 26.2 ±l 6.1 (ST IIH 0.5 h), 21.2 ±l 7.6 (LT-IIH 4 h) and 35.3 ±l 14.5 (LT-IIH 6.0). The LGP levels were measured in the rats submitted to ST-IIH (0.5 h) and LT-IIH (4 h or 6 h). The rats that received ip saline were used as the normoglycemic control group (COG). The livers from the COG and IIH groups (ST-IIH or LT-IIH) were perfused in situ with infusion of L-alanine (5 mM), L-glutamine (10 mM), glutamine dipeptide (5 mM), L-lactate (2 mM) or glycerol (2 mM). The ST-IIH rats showed a higher LGP level than COG group following the L-glutamine infusion (p < 0.05), but the LGP levels that were measured following the L-lactate, L-alanine, glutamine dipeptide (5 mM), L-lactate (2 mM) or glycerol infusion remained unchanged. Moreover, if the period of IIH was expanded to 4 h following insulin injection, the LGP levels induced by L-alanine, glutamine dipeptide or glycerol infusion also increased (p < 0.05, LT-IIH vs. COG). However, the LGP from the L-lactate infusion remained unchanged until 6 h after insulin injection. In conclusion, these results suggest that the intensification of liver gluconeogenesis during ST-IIH and LT-IIH in weaned rats is not a synchronous "all or nothing" process; instead, this process integrated in a temporal manner and is specific for each gluconeogenic substrate.

Paradoxical increase in liver ketogenesis during long-term insulin-induced hypoglycemia in diabetic rats.

It is well established that insulin inhibits liver ketogenesis. However, during insulin-induced hypoglycemia (IIH) the release of counterregulatory hormones could overcome the insulin effect on ketogenesis. To clarify this question the ketogenic activity in livers from alloxan-diabetic rats submitted to long-term IIH was investigated. Moreover, liver glycogenolysis, gluconeogensis, ureagenesis and the production of L-lactate were measured, and its correlation with blood levels of ketone bodies (KB), L-lactate, glucose, urea and ammonia was investigated. For this purpose, overnight fasted alloxan-diabetic rats (DBT group) were compared with control non-diabetic rats (NDBT group). Long-term IIH was obtained with an intraperitoneal injection of Detemir insulin (1 U/kg), and KB, glucose, L-lactate, ammonia and urea were evaluated at 0, 2, 4, 6, 8 or 10 h after insulin injection. Because IIH was well established two hours after insulin injection this time was used for liver perfusion experiments. The administration of Detemir insulin decreased (P < 0.05) blood KB and glucose levels, but there was an increase in the blood L-lactate levels and a rebound increase in blood KB during the glucose recovery phase of IIH. In agreement with these results, the capacity to produce KB from octanoate was increased in the livers of DBT rats. Moreover, the elevated blood L-lactate levels in DBT rats could be attributed to the higher (P < 0.05) glycogenolysis when part of glucose from glycogenolysis enters glycolysis, producing L-lactate. In contrast, except glycerol, gluconeogenesis was negligible in the livers of DBT rats. Therefore, during long-term IIH the higher liver ketogenic capacity of DBT rats increased the risk of hyperketonemia. In addition, in spite of the fact that the insulin injection decreased blood KB, there was a risk of worsening lactic acidosis.

Amino acids and diabetes: implications for endocrine, metabolic and immune function.

Aberrant alterations in glucose and lipid concentrations and their pathways of metabolism are a hallmark of diabetes. However, much less is known about alterations in concentrations of amino acids and their pathways of metabolism in diabetes. In this review we have attempted to highlight, integrate and discuss common alterations in amino acid metabolism in a wide variety of cells and tissues and relate these changes to alterations in endocrine, physiologic and immune function in diabetes.

Insulin sensitivity and liver glucose production in the rat are influenced by lifetime food restriction.

In both humans and rats, food restriction leads to increased insulin sensitivity and predisposition to hypoglycemia. We hypothesized that metabolic responses to hypoglycemic episodes could be altered in food-restricted rats. To test our hypothesis, plasma glucose levels and liver glucose production during insulin-induced hypoglycemia were assessed. Rats either had free access to food (FF group) or were food restricted from birth (FR group). As adults, they were subjected to insulin-induced hypoglycemia after an overnight fast. Plasma glucose was measured before (time 0) the intraperitoneal injection of insulin (1 U/kg) and at regular intervals for 300 minutes. Some FF and FR rats received oral glucose (100 mg/kg) 15 minutes after insulin injection, and the same time intervals were investigated. The FR rats showed a larger decrease and slower recovery of plasma glucose than the FF group, and this was not influenced by oral glucose. Liver glucose production from glycogenolysis and gluconeogenesis (ie, before and during the infusion of L-alanine) was higher and lower, respectively, in the FR rats than in the FF rats, either with or without oral glucose before liver perfusion. Preference for glycogenolysis could be a metabolic adaptation for the maintenance of plasma glucose levels during fasting despite lower food availability in the FR rats. However, long-term FR increased the severity of hypoglycemia and impaired plasma glucose recovery. In addition, hypoglycemia could not be prevented by glucose administration. Therefore, food restriction in individuals with intensive insulin therapy should be more rigorously examined.

Investigation of glycemia recovery with oral administration of glycerol, pyruvate, and L-lactate during long-term, insulin-induced hypoglycemia.

AIM: The acute effect of oral administration of isolated or combined glycerol, pyruvate, and L-lactate on glycemia recovery (GR) during long-term, insulin-induced hypoglycemia (IIH) was compared. METHODS: Glycemia of 24 h-fasted rats that received intraperitoneal injection (1.0 U/kg) of regular insulin (IIH group) or saline (COG group) and, 15, 150, or 165 min later, oral saline (control IIH), glycerol (100 mg/kg), pyruvate (100 mg/kg), L-lactate (100 mg/kg), or combined glycerol+pyruvate+L-lactate (each 33.3 or 100 mg/kg) was compared. In addition, for comparative purposes, a group that received glucose (100 mg/kg) was included. Glycemia was measured 180 min after insulin or saline injection. To investigate the participation of the hepatic availability of gluconeogenic substrates to GR, livers from IIH and COG rats that received physiological or supraphysiological concentrations of isolated or combined glycerol, pyruvate, and L-lactate were compared. Liver experiments were done 180 min after insulin or saline injection. RESULTS: Oral glycerol, pyruvate, and L-lactate (isolated or combined) or glucose promoted GR. Moreover, the best GR was obtained with combined glycerol+pyruvate+L-lactate (100 mg/kg). In agreement, livers that received supraphysiological concentrations of glycerol, pyruvate, and L-lactate (isolated or combined) showed higher glucose release than livers that received physiological concentrations of these substances (isolated or combined). CONCLUSION: The best GR obtained with combined administration of glycerol, pyruvate, and L-lactate (100 mg/kg) during long-term IIH was a consequence of the higher liver availability of these substances associated with a maintained liver ability to produce glucose from gluconeogenic substrates.

Investigation of the acute effect of leptin on the inhibition of glycogen catabolism by insulin in rat liver perfused in situ.

Leptin, a cytokine secreted by adipose tissue, has been implicated in the insulin resistance associated with obesity. Here we examined the acute influence of leptin at physiological (10 ng/ml) and supraphysiological (50 ng/ml and 100 ng/ml) concentrations on the inhibition of glycogen catabolism promoted by insulin in rat liver perfusion experiments. Perfusion of the liver with insulin (20 microU/ml) decreased the activation of glucose production (p < 0.05) and glycogenolysis by cAMP (3 microM). However, the infusion of leptin, at concentrations similar to those found in non-obese (10 ng/ml), obese (50 ng/ml), and morbidly obese (100 ng/ml) individuals did not influence the acute inhibitory effect of insulin (20 microU/ml) on glucose production and glycogenolysis stimulated by cAMP (p > 0.05).We conclude that neither physiological nor supraphysiological concentrations of leptin directly influence the inhibition of glycogen catabolism promoted by insulin in rat liver perfused in situ.

Effect of experimental diabetes on the development and maintenance of vulvovaginal candidiasis in female rats.

OBJECTIVE: The purpose of this study was to develop an experimental model of diabetes in female rats and verify its influence on vulvovaginal candidiasis. STUDY DESIGN: The animals were divided into control and diabetic groups. Diabetes was induced with the use of an intravenous solution of alloxan (42 mg/kg bodyweight). One week after confirmation of hyperglycemia, the inoculation of Candida albicans yeast, previously standardized from a vaginal isolate, in concentrations of about 5 x 10(8), was performed. Infection control was made through vaginal culture, Papanicolaou cytology, and scanning electron microscopy (SCEM). RESULTS: The results pointed to different glycemias between the control (74.8 +/- 2.6) and experimental groups (543.1 +/- 12.1) and a significant bodyweight decrease (227.6 +/- 4.77 and 204 +/- 6.39, respectively). The positive infection was shown by culture, Papanicolaou test, and SCEM in the experimental group. CONCLUSION: Diabetes mellitus causes hyperglycemia, which was favorable to the vaginal colonization and infection by C albicans.

Hypoglycemic effect of the hydroalcoholic extract of leaves of Averrhoa carambola L. (Oxalidaceae) / Efeito hipoglicemiante do extrato hidroalcoólico de folhas de Averrhoa carambola L. (Oxalidaceae)

O efeito do tratamento via oral (20 mg/kg x day) com extrato hidroalcoólico de folhas de Averrhoa carambola L. (EHFC) sobre a glicemia de jejum (15 h) foi examinada ao compararmos ratos que receberam veículo (Grupo controle) ou EHFC (Grupo EHFC) durante 15 dias. O grupo EHFC apresentou menor glicemia de jejum (p<0,05). Em contraste, o grupo EHFC apresentou maior (p<0,05) produção hepática glicose a partir de L-alanina (5 mM). Este efeito foi mediado, pelo menos parcialmente, pela ativação do catabolismo da L-alanina, inferido pela maior produção hepática de uréia (p<0,05) e L-lactato (p<0,05). Diferente da L-alanina, a produção hepática de glicose a partir de L-glutamina (5 mM), L-lactato (2 mM) e glicerol (2 mM) no grupo EHFC foi similar ao grupo controle. Adicionalmente, o efeito do tratamento com EHFC sobre a captação de glicose no músculo soleus, inferida pela incorporação de [14C]-glicose em glicogênio (síntese de glicogênio) e produção de [14C]-lactato foi investigada, verificando-se resultados semelhantes nos dois grupos. Assim, concluiu-se que a redução da glicemia de jejum promovida pelo tratamento com EHFC não foi mediada por inibição da gliconeogenese hepática e/ou aumento da captação muscular de glicose.

The effect of the oral treatment (20 mg/kg x day) with the hydroalcoholic extract of leaves of Averrhoa carambola L. (HELAC) on fasting glycemia (15 h) was examined. For this purpose, rats that received vehicle (Control group) or HELAC (HELAC group) during 15 days were compared. HELAC group showed lower fasting glycemia (p<0.05). In contrast, livers from HELAC group showed higher (p<0.05) glucose production from L-alanine (5 mM). This effect was mediated, at least part of it, by an activation of the catabolism of L-alanine inferred by the increased hepatic urea (p<0.05) and L-lactate (p<0.05) production. Differently of L-alanine, the glucose production from L-glutamine (5 mM), L-lactate (2 mM) and glycerol (2 mM) was similar (Control group vs. HELAC group). In addition, the HELAC treatment did not change the glucose uptake in soleus muscles, inferred by the incorporation of [14C]-glucose to glycogen (glycogen synthesis) and [14C]-lactate production. Thus, we can conclude that the reduction of fasting glycemia promoted by the treatment with HELAC was not mediated by an inhibition of hepatic gluconeogenesis and/or an increased glucose uptake by muscles.