Diabetic Goto-Kakizaki Rats Research Articles

The influence of massive jejunectomy on endocrine pancreas of diabetic Goto-Kakizaki.

Several bariatric surgeries have been related to the T2DM improvement in obese patients. Despite the different mechanism invoked for this improvement, many evidences showed that the pancreas cellularity is conditioned for the homeostatic physiological changes after these surgeries. Many authors reported the changes in beta-cell mass after some surgeries in healthy rats. We purpose to analyze the changes in β-cell cellularity and β-cell-mass after a severe malabsorptive surgical method. Thus, we studied several parameters of the islet morphometric composition after a massive jejunal resection. We employed Goto-Kakizaki diabetic non-obese rats, which underwent the 50% resection of middle portion of the jejunum versus a control group. After 3 months, rats were sacrificed and pancreas was immunohistochemicaly studied. The β-cell mass was analyzed and several parameters about the endocrine islet size distribution were studied. We report an increase of β-cell mass in massive resection surgical group versus controls. The islet distribution was significant different between both groups. Endocrine islets of surgical group were bigger with a different cellular distribution. According to the enteroendocrine changes related to surgeries in jejunum, as in other gastrointestinal portions, the cellularity of islets changes as an adaptive process to glycemic demands.

Contralesional angiotensin type 2 receptor activation contributes to recovery in experimental stroke

We and others have previously shown that angiotensin II receptor type 2 receptor (AT2R) is upregulated in the contralesional hemisphere after stroke in normoglycemic Wistar rats. In this study, we examined the expression of AT2R in type 2 diabetic Goto-Kakizaki (GK) rats and control Wistars after stroke. We also tested the contribution of the contralesional AT2R in recovery after stroke through a specific knockdown of the AT2R in this hemisphere only. Two experiments were conducted. In the first experiment, GK rats were subjected to middle cerebral artery occlusion (MCAO) and treated with the angiotensin II receptor type 1 receptor (AT1R) blocker candesartan or saline at reperfusion. Stroke outcomes, as well as AT2R expression, were examined and compared to control Wistars at 24 h. In the second experiment, localized AT2R knockdown was achieved through intrastriatal injection of short hairpin RNA (shRNA) lentiviral particles or non-targeting control into the left-brain hemisphere of Wistar rats. After 14 days, rats were subjected to right MCAO and treated with the AT2R agonist, Compound 21 (C21), or saline for 7 days. Behavioral outcomes were assessed for up to 10 days. In the first experiment, stroke reduced the expression of AT2R in GK rats. Candesartan treatment failed to improve the neurobehavioral outcomes, preserve vascular integrity or reduce oxidative/nitrative stress or apoptotic markers at 24 h post stroke in these animals. In the second experiment, contralesional AT2R knockdown reduced the C21-mediated functional recovery after stroke. In conclusion, contralesional AT2R upregulation after stroke is blunted in diabetic rats which show reduced sensitivity to post-stroke candesartan treatment. Contralesional AT2R could be involved in C21-mediated functional recovery after stroke.

Sodium-glucose co-transporter 1 (SGLT1) differentially regulates gluconeogenesis and GLP-1 receptor (GLP-1R) expression in different diabetic rats: a preliminary validation of the hypothesis of "SGLT1 bridge" as an indication for "surgical diabetes".

BackgroundSodium-glucose co-transporter 1 (SGLT1) may play a synergistic role in gluconeogenesis (GNG) and glucagon-like peptide-1 (GLP-1) expression. We proposed the hypothesis of a “SGLT1 bridge” as an indication for “surgical diabetes” that was preliminary validated in the present study.MethodsWe selected nonobese diabetic Goto-Kakizaki (GK) rats and Zuker diabetic fat (ZDF) rats to represent advanced and early diabetes, respectively. Based on glucose gavage with or without SGLT1 inhibitor phlorizin, the rats were divided into 4 groups: Gk-Glu, GK-P, ZDF-Glu, and ZDF-P. The expressions of SGLT1, GLP-1 receptor (GLP-1R), glucose-6 phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase-1 (Pck1) were determined by immunohistochemistry (IHC) or quantitative reverse transcription polymerase chain reaction (RT-qPCR), and the effects of phlorizin were analyzed.ResultsGlucose tolerance was worse in GK rats and the homeostasis model assessment-insulin resistance (HOMA-IR) was higher in ZDF rats, indicating different pathophysiological conditions between the different diabetic rats. GK rats showed higher activity of duodenal SGLT1 (P=0.022) and jejunal SGLT1 mRNA expression (P=0.000) and lower SGLT1 mRNA expression in the liver (P=0.000) and pancreas (P=0.000). Phlorizin effectively inhibited the activity of duodenal SGLT1 in both GK rats (P=0.000) and ZDF rats (P=0.000). In ZDF rats, the expression of GLP-1R mRNA was downregulated in the jejunum (P=0.001) and upregulated in the pancreas (P=0.021) by phlorizin, but there were no regulatory effects on GLP-1R mRNA in the jejunum and pancreas of GK rats. As for the regulatory effects on GNG, phlorizin upregulated Pck1 mRNA in the duodenum (P=0.000) and the jejunum (P=0.038), whereas it downregulated hepatic G6Pase mRNA in ZDF rats (P=0.005) and Pck1 mRNA expression in GK rats (P=0.001), suggesting that SGLT1 inhibitor may have upregulated intestinal GNG in ZDF rats and downregulated hepatic GNG in both ZDF and GK rats.ConclusionsSGLT1 showed synergistic regulatory effects on the entero-insular axis (EIA) and the gut-brain-liver axis (GBLA), preliminarily validating the hypothesis of a “SGLT1 bridge”. The distinct expression of SGLT1 and its differentially regulatory effects on diabetic rats with different pathophysiological conditions may provide probable potential indications involved in the “Surgical Diabetes” that is supposed as the inclusion for diabetic surgery.

Roles of Gastric Emptying and Gastrointestinal Transit Following Ileal Interposition in Alleviating Diabetes in Goto-Kakizaki Rats.

ObjectiveThis study aimed to determine the change of gastrointestinal (GI) emptying time after ileal interposition (IT) and elucidate the role of altered GI peristalsis in diabetic control.Materials and MethodsTwelve male Goto-Kakizaki rats were randomly divided into IT and sham groups. Body weight and food intake were recorded. Oral glucose tolerance test (OGTT), insulin tolerance test (ITT), plasma glucagon-like peptide-1 (GLP-1), and gastric emptying were measured at baseline and 4 and 8 weeks after operation. At 9 weeks postoperatively, the rats in the IT group were given atropine which can suppress the emptying of stomach and upper intestine, while sham rats were given metoclopramide (to expedite gastric emptying) for 1 week. At week 10 postoperatively, OGTT and GLP-1 were detected. The intestinal transit was tested at postoperative 12 weeks.ResultsNo differences were found between groups at baseline. After operation, the IT rats had lower body weight than sham rats. At 4 and 8 weeks postoperatively, the IT group showed better OGTT and ITT, with significantly elevated GLP-1 relative to sham. After administration of the GI motility drugs, however, the effect of diabetic control for the two groups became similar. The GI transit after IT was significantly slower than sham at all tested time points.ConclusionsAlthough IT inhibits the GI transit time, the earlier interaction between undigested nutrients and interpositioned ileum promotes gut hormone secretion and thus reduces body weight and alleviates hyperglycemia. A decrease of GI transit of IT rats exacerbates the antidiabetic effects.

Effects of Pharmacological Inhibitors of NADPH Oxidase on Myogenic Contractility and Evoked Vasoactive Responses in Rat Resistance Arteries.

Reactive oxygen species (ROS), such as superoxide anions and hydrogen peroxide, are reported to contribute to the dynamic regulation of contractility in various arterial preparations, however, the situation in pressurized, myogenically active resistance arteries is much less clear. In the present study, we have utilized established pharmacological inhibitors of NADPH oxidase activity to examine the potential contribution of ROS to intrinsic myogenic contractility in adult Sprague–Dawley rat resistance arteries and responses to vasoactive agents acting via the endothelium (i.e., acetylcholine, SKA-31) or smooth muscle (i.e., sodium nitroprusside, phenylephrine). In cannulated and pressurized cremaster skeletal muscle and middle cerebral arteries, the NOX inhibitors 2-acetylphenothiazine (2-APT) and VAS2870, selective for NOX1 and NOX2, respectively, evoked concentration-dependent inhibition of basal myogenic tone in a reversible and irreversible manner, respectively, whereas the non-selective inhibitor apocynin augmented myogenic contractility. The vasodilatory actions of 2-APT and VAS2870 occurred primarily via the vascular endothelium and smooth muscle, respectively. Functional responses to established endothelium-dependent and –independent vasoactive agents were largely unaltered in the presence of either 2-APT or apocynin. In cremaster arteries from Type 2 Diabetic (T2D) Goto-Kakizaki rats with endothelial dysfunction, treatment with either 2-APT or apocynin did not modify stimulus-evoked vasoactive responses, but did affect basal myogenic tone. These same NOX inhibitors produced robust inhibition of total NADPH oxidase activity in aortic tissue homogenates from control and T2D rats, and NOX isozymes 1, 2 and 4, along with superoxide dismutase 1, were detected by qPCR in cremaster arteries and aorta from both species. Based on the diverse effects that we observed for established, chemically distinct NOX inhibitors, the functional contribution of vascular NADPH oxidase activity to stimulus-evoked vasoactive signaling in myogenically active, small resistance arteries remains unclear.

Alterations in Energy Metabolism, Mitochondrial Function and Redox Homeostasis in GK Diabetic Rat Tissues Treated with Aspirin.

Our recent studies have demonstrated that aspirin treatment prevents inflammatory and oxidative stress-induced alterations in mitochondrial function, improves glucose tolerance and pancreatic endocrine function and preserves tissue-specific glutathione (GSH)-dependent redox homeostasis in Goto-Kakizaki (GK) diabetic rats. In the current study, we have investigated the mechanism of action of aspirin in maintaining mitochondrial bioenergetics and redox metabolism in the liver and kidneys of GK rats. Aspirin reduced the production of reactive oxygen species (ROS) and oxidative stress-induced changes in GSH metabolism. Aspirin treatment also improved mitochondrial respiratory function and energy metabolism, in addition to regulating the expression of cell signaling proteins that were altered in diabetic animals. Ultrastructural electron microscopy studies revealed decreased accumulation of glycogen in the liver of aspirin-treated diabetic rats. Hypertrophic podocytes with irregular fusion of foot processes in the renal glomerulus and detached microvilli, condensed nuclei and degenerated mitochondria observed in the proximal convoluted tubules of GK rats were partially restored by aspirin. These results provide additional evidence to support our previous observation of moderation of diabetic complications by aspirin treatment in GK rats and may have implications for cautious use of aspirin in the therapeutic management of diabetes.

Beneficial effects of combination therapy of canagliflozin and teneligliptin on diabetic polyneuropathy and β-cell volume density in spontaneously type 2 diabetic Goto-Kakizaki rats.

Beneficial effects of combination therapy of canagliflozin and teneligliptin on diabetic polyneuropathy and β-cell volume density in spontaneously type 2 diabetic Goto-Kakizaki rats.

Theabrownin-targeted regulation of intestinal microorganisms to improve glucose and lipid metabolism in Goto-Kakizaki rats.

Diabetes is a disease that is characterized by a disturbance of glucose metabolism. Theabrownin (TB) is one of the most active and abundant pigments in Pu-erh tea, and it is a brown pigment with multiple aromatic rings and attached residues of polysaccharides and proteins. TB has been shown to be hypolipidemic and displays fasting blood glucose (FBG)-lowering properties in rats fed a high-fat diet, but the underlying mechanism has not been elucidated. This study aimed to determine the effect of TB in treating diabetes and explore the underlying mechanism of action of intestinal microbes by using Goto-Kakizaki (GK) rats. Diabetic GK rats were treated up to 8 weeks with TB (GK-TB). Following treatment, the body weight, triglyceride (TG) content, fasting blood glucose (FBG) content, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were significantly lower in the GK-TB group than in the GK control group (P < 0.05). Meanwhile, the circulating adiponectin (ADPN), leptin, and glucokinase levels in the serum of the GK-TB group were significantly higher than those in the GK group, while there was little difference in hepatic lipase (HL) and hormone-sensitive triglyceride lipase (HSL) enzyme activities (P > 0.05). Furthermore, with the extension of treatment time, the number of unique intestinal microorganisms in GK rats greatly increased and an interaction among intestinal microorganisms was observed. The Firmicutes/Bacteroides ratio was decreased significantly, and the composition of Actinobacteria and Proteobacteria was increased. The use of multiple omics technologies showed that TB is involved in the targeted regulation of the core characteristic intestinal flora including Bacteroides thetaiotaomicron (BT), Lactobacillus murinus (LM), Parabacteroides distasonis (PD), and Bacteroides_acidifaciens (BA) which improved the glucose and lipid metabolism of GK rats via the AMP-activated protein kinase signaling pathway, insulin signaling pathway, bile secretion and glycerophospholipid metabolism. Intragastric administration of BT, LM, PD, or BA led to a significantly reduced HOMA-IR in GK rats. Furthermore, BT significantly reduced serum lipid TG and total cholesterol (TC) and BA significantly reduced the serum lipid TC and low-density lipoprotein (LDL). PD significantly reduced serum LDL, while the effect of LM was not significant. However, LM and PD significantly increased the content of ADPN in serum. Taken together, our results indicated that the effect of TB on diabetic rats mainly depends on the targeted regulation of intestinal microorganisms and that TB is a functional food component with great potential to treat or prevent diabetes.

A short review on the features of the non-obese diabetic Goto-Kakizaki rat intestine.

The Goto-Kakizaki (GK) rat is a non-obese experimental model of type 2 diabetes mellitus (T2DM) that allows researchers to monitor diabetes-induced changes without jeopardizing the effects of obesity. This rat strain exhibits notable gastrointestinal features associated with T2DM, such as marked alterations in intestinal morphology, reduced intestinal motility, slow transit, and modified microbiota compared to Wistar rats. The primary treatments for diabetic patients include administration of hypoglycemic agents and insulin, and lifestyle changes. Emerging procedures, including alternative therapies, metabolic surgeries, and modulation of the intestinal microbiota composition, have been shown to improve the diabetic state of GK rats. This review describes the morpho-physiological diabetic-associated features of the gastrointestinal tract (GIT) of GK rats. We also describe promising strategies, e.g., metabolic surgery and modulation of gut microbiota composition, used to target the GIT of this animal model to improve the diabetic state.

Reviewing physical exercise in non-obese diabetic Goto-Kakizaki rats.

There is a high incidence of non-obese type 2 diabetes mellitus (non-obese-T2DM) cases, particularly in Asian countries, for which the pathogenesis remains mainly unclear. Interestingly, Goto-Kakizaki (GK) rats spontaneously develop insulin resistance (IR) and non-obese-T2DM, making them a lean diabetes model. Physical exercise is a non-pharmacological therapeutic approach to reduce adipose tissue mass, improving peripheral IR, glycemic control, and quality of life in obese animals or humans with T2DM. In this narrative review, we selected and analyzed the published literature on the effects of physical exercise on the metabolic features associated with non-obese-T2DM. Only randomized controlled trials with regular physical exercise training, freely executed physical activity, or skeletal muscle stimulation protocols in GK rats published after 2008 were included. The results indicated that exercise reduces plasma insulin levels, increases skeletal muscle glycogen content, improves exercise tolerance, protects renal and myocardial function, and enhances blood oxygen flow in GK rats.

Luteolin Improves Perivascular Adipose Tissue Profile and Vascular Dysfunction in Goto-Kakizaki Rats.

We investigated the effects of luteolin on metabolism, vascular reactivity, and perivascular adipose tissue (PVAT) in nonobese type 2 diabetes mellitus animal model, Goto-Kakizaki (GK) rats. Methods: Wistar and GK rats were divided in two groups: (1) control groups treated with vehicle; (2) groups treated with luteolin (10 mg/kg/day, for 2 months). Several metabolic parameters such as adiposity index, lipid profile, fasting glucose levels, glucose and insulin tolerance tests were determined. Endothelial function and contraction studies were performed in aortas with (PVAT+) or without (PVAT−) periaortic adipose tissue. We also studied vascular oxidative stress, glycation and assessed CRP, CCL2, and nitrotyrosine levels in PVAT. Results: Endothelial function was impaired in diabetic GK rats (47% (GK − PVAT) and 65% (GK + PVAT) inhibition of maximal endothelial dependent relaxation) and significantly improved by luteolin treatment (29% (GK − PVAT) and 22% (GK + PVAT) inhibition of maximal endothelial dependent relaxation, p < 0.01). Vascular oxidative stress and advanced glycation end-products’ levels were increased in aortic rings (~2-fold, p < 0.05) of diabetic rats and significantly improved by luteolin treatment (to levels not significantly different from controls). Periaortic adipose tissue anti-contractile action was significantly rescued with luteolin administration (p < 0.001). In addition, luteolin treatment significantly recovered proinflammatory and pro-oxidant PVAT phenotype, and improved systemic and metabolic parameters in GK rats. Conclusions: Luteolin ameliorates endothelial dysfunction in type 2 diabetes and exhibits therapeutic potential for the treatment of vascular complications associated with type 2 diabetes.

Lifelong soya consumption in males does not increase lifespan but increases health span under a metabolic stress such as type 2 diabetes mellitus

Soya consumption can decrease oxidative stress in animal models. Moreover, phytoestrogens such as genistein, present in soya, can mimic some of the beneficial effects of estrogens and are devoid of significant side effects, such as cancer. In this study, we have performed a controlled lifelong study with male OF1 mice that consumed either a soya-free diet or a soya-rich diet. We show that, although we found an increase in the expression and activity of antioxidant enzymes in soya-consuming mice, it did not increase lifespan. We reasoned that the soya diet could not increase lifespan in a very healthy population, but perhaps it could extend health span in stressed animals such as type 2 diabetic Goto Kakizaki (GK) rats. Indeed, this was the case: we found that male GK rats consuming a soya-rich diet developed the disease at a lower rate and, therefore, lived longer than soya-free diet-consuming rats.

Functional Integration of Adult-Generated Neurons in Diabetic Goto-Kakizaki Rats.

Adult-born neurons in the dentate gyrus (DG) make important contributions to learning as they integrate into neuronal networks. Neurogenesis is dramatically reduced by a number of conditions associated with cognitive impairment, including type 2 diabetes mellitus (T2DM). Increasing neurogenesis may thus provide a therapeutic target for ameliorating diabetes-associated cognitive impairments, but only if new neurons remain capable of normal function. To address the capacity for adult-generated neurons to incorporate into functional circuits in the hyperglycemic DG, we measured Egr1 expression in granule cells (GCs), BrdU labeled four weeks prior, in Goto-Kakizaki (GK) rats, an established model of T2DM, and age-matched Wistars. The results indicate that while fewer GCs are generated in the DG of GK rats, GCs that survive readily express Egr1 in response to spatial information. These data demonstrate that adult-generated GCs in the hyperglycemic DG remain functionally competent and support neurogenesis as a viable therapeutic target.

Hepatic Glucose Regulations by Sago (Metroxylon sagu) Resistant Starch in Diabetic Goto Kakizaki Rat

Resistant starch (RS) Sago (Metroxylon sagu) intake has been linked with the improvement in postprandial hyperglycemia and diabetes management via several modes of action including delayed glucose absorption and inhibition of carbohydrate digestion in the gastrointestinal tract. However, to our knowledge, studies on local Malaysian sago RS associated with hepatic glucose production has not been reported elsewhere. Thus, this study was done to identify the underlying mechanisms of local Malaysian RS sago native and modified known as sago RS type 2 (sago RS2) and type 4 (sago RS4) respectively in glucose regulations by analyzing the targeted genes in hepatic glucose pathways. In this study, gene expression associated with Glucose and Glycogen Metabolism Pathways analysis in the liver of spontaneously type 2 diabetic rat, Goto kakizaki treated with water (control), Hi Maize (positive control), sago RS2 and RS4 was done using Rat Glucose Metabolism RT² Profiler PCR Array which consist of 84 genes. The results showed that several genes were significantly up- and down-regulated in the diabetic rats treated with Sago. Taldo1 was significantly upregulated whereas G6PC, Sdhb and Rplp1 genes were significantly downregulated in the rat liver treated with sago RS2. In the rat liver treated with sago RS4, Idh3g gene was significantly upregulated whereas G6pc, Pdk3, Eno3, Sdhb, Galm and Tkt genes were significantly downregulated. The gene expressions identified are associated in the blood glucose homeostasis involving the regulation and enzymatic pathways of glucose and glycogen metabolisms. In conclusion, the genes identified might be useful for therapeutic targets in glucose lowering effects by reducing hepatic glucose output indicating potential of our local sago in managing diabetes.

Effect of Aspirin on Mitochondrial Dysfunction and Stress in the Pancreas and Heart of Goto-Kakizaki Diabetic Rats.

Our previous study in Goto-Kakizaki (GK) type 2 diabetic rats provided significant evidence that aspirin treatment improves pancreatic β-cell function by reducing inflammatory responses and improving glucose tolerance. In the present study, we aimed to elucidate the mechanism of action of aspirin on the pathophysiology and progression of type 2 diabetic complications in the heart and pancreas of insulin-resistant GK rats. Aspirin treatment demonstrated a reduction in mitochondrial reactive oxygen species (ROS) production and lipid peroxidation, accompanied by improved redox homeostasis. Furthermore, the recovery of metabolic and mitochondrial functions, as well as cytochrome P450 enzyme activities, which were altered in the pancreas and heart of GK rats, were observed. Aspirin treatment brought the activity of CYP 2E1 to the control level in both tissues, whereas the CYP 3A4 level decreased only in the pancreas. This suggests the tissue-specific differential metabolism of substrates in these rats. The recovery of redox homeostasis could be the key target in the improvement of oxidative-stress-dependent alterations in mitochondrial functions which, in turn, facilitated improved energy metabolism in these tissues in the aspirin-treated GK rats. These results may have implications in determining the therapeutic use of aspirin, either alone or in combination with other clinically approved therapies, in insulin-resistant type 2 diabetes.

Involvement of P2Y signaling in the restoration of glucose-induced insulin exocytosis in pancreatic β cells exposed to glucotoxicity.

Purinergic P2Y receptors, by binding adenosine triphosphate (ATP), are known for enhancing glucose-stimulated insulin secretion (GSIS) in pancreatic β cells. However, the impact of these receptors in the actin dynamics and insulin granule exocytosis in these cells is not established, neither in normal nor in glucotoxic environment. In this study, we investigate the involvement of P2Y receptors on the behavior of insulin granules and the subcortical actin network dynamics in INS-1 832/13 β cells exposed to normal or glucotoxic environment and their role in GSIS. Our results show that the activation of P2Y purinergic receptors by ATP or its agonist increase the insulin granules exocytosis and the reorganization of the subcortical actin network and participate in the potentiation of GSIS. In addition, their activation in INS-1832/13 β-cells, with impaired insulin secretion following exposure to elevated glucose levels, restores GSIS competence through the distal steps of insulin exocytosis. These results are confirmed ex vivo by perifusion experiments on islets from type 2 diabetic (T2D) Goto-Kakizaki (GK) rats. Indeed, the P2Y receptor agonist restores the altered GSIS, which is normally lost in this T2D animal model. Moreover, we observed an improvement of the glucose tolerance, following the acute intraperitoneal injection of the P2Y agonist concomitantly with glucose, in diabetic GK rats. All these data provide new insights into the unprecedented therapeutic role of P2Y purinergic receptors in the pathophysiology of T2D.

Distinct Impact of Natural Sugars from Fruit Juices and Added Sugars on Caloric Intake, Body Weight, Glycaemia, Oxidative Stress and Glycation in Diabetic Rats.

Although fruit juices are a natural source of sugars, there is a controversy whether their sugar content has similar harmful effects as beverages’ added-sugars. We aimed to study the role of fruit juice sugars in inducing overweight, hyperglycaemia, glycation and oxidative stress in normal and diabetic animal models. In diabetic Goto-Kakizaki (GK) rats, we compared the effects of four different fruit juices (4-weeks) with sugary solutions having a similar sugar profile and concentration. In vitro, the sugary solutions were more susceptible to AGE formation than fruit juices, also causing higher postprandial glycaemia and lower erythrocytes’ antioxidant capacity in vivo (single intake). In GK rats, ad libitum fruit juice consumption (4-weeks) did not change body weight, glycaemia, oxidative stress nor glycation. Consumption of a matched volume of sugary solutions aggravated fasting glycaemia but had a moderate impact on caloric intake and oxidative stress/glycation markers in tissues of diabetic rats. Ad libitum availability of the same sugary solutions impaired energy balance regulation, leading to higher caloric intake than ad libitum fruit juices and controls, as well as weight gain, fasting hyperglycaemia, insulin intolerance and impaired oxidative stress/glycation markers in several tissues. We demonstrated the distinct role of sugars naturally present in fruit juices and added sugars in energy balance regulation, impairing oxidative stress, glycation and glucose metabolism in an animal model of type 2 diabetes.

Mineralocorticoid Receptor Pathway and Its Antagonism in a Model of Diabetic Retinopathy.

Diabetic retinopathy remains a major cause of vision loss worldwide. Mineralocorticoid receptor (MR) pathway activation contributes to diabetic nephropathy, but its role in retinopathy is unknown. In this study, we show that MR is overexpressed in the retina of type 2 diabetic Goto-Kakizaki (GK) rats and humans and that cortisol is the MR ligand in human eyes. Lipocalin 2 and galectin 3, two biomarkers of diabetes complications regulated by MR, are increased in GK and human retina. The sustained intraocular delivery of spironolactone, a steroidal mineralocorticoid antagonist, decreased the early and late pathogenic features of retinopathy in GK rats, such as retinal inflammation, vascular leakage, and retinal edema, through the upregulation of genes encoding proteins known to intervene in vascular permeability such as Hey1, Vldlr, Pten, Slc7a1, Tjp1, Dlg1, and Sesn2 but did not decrease VEGF. Spironolactone also normalized the distribution of ion and water channels in macroglial cells. These results indicate that MR is activated in GK and human diabetic retina and that local MR antagonism could be a novel therapeutic option for diabetic retinopathy.

Impaired brown adipose tissue is differentially modulated in insulin-resistant obese wistar and type 2 diabetic Goto-Kakizaki rats

Brown adipose tissue (BAT) is a potential target to treat obesity and diabetes, dissipating energy as heat. Type 2 diabetes (T2D) has been associated with obesogenic diets; however, T2D was also reported in lean individuals to be associated with genetic factors. We aimed to investigate the differences between obese and lean models of insulin resistance (IR) and elucidate the mechanism associated with BAT metabolism and dysfunction in different IR animal models: a genetic model (lean GK rats) and obese models (diet-induced obese Wistar rats) at 8 weeks of age fed a high-carbohydrate (HC), high-fat (HF) diet, or high-fat and high-sugar (HFHS) diet for 8 weeks. At 15 weeks of age, BAT glucose uptake was evaluated by 18F-FDG PET under basal (saline administration) or stimulated condition (CL316,243, a selective β3-AR agonist). After CL316, 243 administrations, GK animals showed decreased glucose uptake compared to HC animals. At 16 weeks of age, the animals were euthanized, and the interscapular BAT was dissected for analysis. Histological analyses showed lower cell density in GK rats and higher adipocyte area compared to all groups, followed by HFHS and HF compared to HC. HFHS showed a decreased batokine FGF21 protein level compared to all groups. However, GK animals showed increased expression of genes involved in fatty acid oxidation (CPT1 and CPT2), BAT metabolism (Sirt1 and Pgc1-α), and obesogenic genes (leptin and PAI-1) but decreased gene expression of glucose transporter 1 (GLUT-1) compared to other groups. Our data suggest impaired BAT function in obese Wistar and GK rats, with evidence of a whitening process in these animals

Injury-Induced HSP27 Expression in Peripheral Nervous Tissue Is Not Associated with Any Alteration in Axonal Outgrowth after Immediate or Delayed Nerve Repair

We investigated injury-induced heat shock protein 27 (HSP27) expression and its association to axonal outgrowth after injury and different nerve repair models in healthy Wistar and diabetic Goto-Kakizaki rats. By immunohistochemistry, expression of HSP27 in sciatic nerves and DRG and axonal outgrowth (neurofilaments) in sciatic nerves were analyzed after no, immediate, and delayed (7-day delay) nerve repairs (7- or 14-day follow-up). An increased HSP27 expression in nerves and in DRG at the uninjured side was associated with diabetes. HSP27 expression in nerves and in DRG increased substantially after the nerve injuries, being higher at the site where axons and Schwann cells interacted. Regression analysis indicated a positive influence of immediate nerve repair compared to an unrepaired injury, but a shortly delayed nerve repair had no impact on axonal outgrowth. Diabetes was associated with a decreased axonal outgrowth. The increased expression of HSP27 in sciatic nerve and DRG did not influence axonal outgrowth. Injured sciatic nerves should appropriately be repaired in healthy and diabetic rats, but a short delay does not influence axonal outgrowth. HSP27 expression in sciatic nerve or DRG, despite an increase after nerve injury with or without a repair, is not associated with any alteration in axonal outgrowth.