Goto-Kakisaki Rats Research Articles

Single-Anastomosis Duodenal Jejunal Bypass Improve Glucose Metabolism by Regulating Gut Microbiota and Short-Chain Fatty Acids in Goto-Kakisaki Rats.

In recent years, bariatric surgery has emerged as a promising treatment for type 2 diabetes. Bariatric surgery is known to cause alterations in the relative abundance and composition of gut microbiota, which may lead to alterations in the levels of Short-Chain Fatty Acids (SCFAs) that are produced during fermentation by gut microbes. However, little is known about the mechanism of improved glucose metabolism mediated by gut microbiota following bariatric surgery. The aim of our study was to explore whether changes in gut microbiota and in fecal SCFA could be detected following single-anastomosis duodenal jejunal bypass (DJB-sa) surgery, a type of bariatric surgery, and whether these alterations might be related to the improvement of glucose metabolism. To this end, we performed DJB-sa or SHAM surgery on Goto-Kakisaki (GK) rats. We then compared the glucose metabolism as well as changes in gut microbiota and SCFAs levels between both groups. Our results showed that DJB-sa surgery was associated with a significant decrease in fasting blood glucose (FBG), intraperitoneal glucose tolerance test (IPGTT), and fasting serum insulin (FSI). And, DJB-sa led to a change in the composition of gut microbiota including an increase in the relative abundance of SCFA-producing bacteria (Bifidobacterium and Subdoligranulum). Moreover, the levels of six SCFAs in feces, as well as the intestinal expression of SCFA receptors including G-protein-coupled receptor 41 (GPR41), G-protein-coupled receptor 43 (GPR43), and G-protein-coupled receptor 109A (GPR109A), and the expression of Glucagon-like peptide-1 (GLP-1) displayed a significant increase following DJB-sa compared with the Sham group. Thus, the gut microbiota may contribute to the improvement of glucose metabolism in type 2 diabetes following DJB-sa. In conclusion, our study shows that DJB-sa improves glucose metabolism by modulating gut microbiota and by increasing short-chain fatty acid production.

Duodenojejunal Bypass Plus Sleeve Gastrectomy Reduces Infiltration of Macrophages and Secretion of TNF-α in the Visceral White Adipose Tissue of Goto-Kakizaki Rats.

Current studies indicate that inflammation of white adipose tissue (WAT) is a pathogenic characteristic of insulin resistance. However, the significance of visceral WAT inflammation after bariatric surgery remains unclear. Duodenojejunal bypass plus sleeve gastrectomy (DJB-SG) was performed on Goto-Kakisaki rats. Weight, fasting blood glucose (FBG), and homeostatic model assessment of insulin resistance (HOMA-IR) in the DJB-SG group were compared to those in a sham surgery (SHAM) group every 2weeks. The results of an oral glucose tolerance test (OGTT) and the volume of visceral adipose tissue (Visc.Fat) were compared before and 8weeks postsurgery. Eight weeks after surgery, the rats were sacrificed and visceral WAT collected from the greater omentum. Tumor necrosis factor-α (TNF-α) and cluster of differentiation 68 (CD68) expression in the WAT were evaluated in paraffin-embedded sections by immunohistochemistry. Compared with the SHAM group, the DJB-SG group demonstrated a significant reduction in weight, FBG, and HOMA-IR (P < 0.05), with elevation of insulin levels (P < 0.05) from 4weeks after surgery. OGTT and the quantity of Visc.Fat were significantly reduced (P < 0.05) 8weeks after surgery. Moreover, the expression of TNF-α and CD68 in the visceral white adipose tissue was significantly lower 8weeks after surgery (P < 0.05). The DJB-SG model established in Goto-Kakisaki rats achieved anticipated efficacy. Reduced TNF-α-related inflammation in visceral WAT may result in improved insulin resistance.

Fermentation Products of Paenibacillus bovis sp. nov. BD3526 Alleviates the Symptoms of Type 2 Diabetes Mellitus in GK Rats.

Gut microbiota is closely related to type 2 diabetes mellitus (T2DM). The gut microbiota of patients with T2DM is significantly different from that of healthy subjects in terms of bacterial composition and diversity. Here, we used the fermentation products of Paenibacillus bovis sp. nov. BD3526 to study the disease progression of T2DM in Goto-kakisaki (GK) rats. We found that the symptoms in GK rats fed the fermentation products of BD3526 were significantly improved. The 16S rRNA sequencing showed that the fermentation products of BD3526 had strong effects on the gut microbiota by increasing the content of Akkermansia. In addition, the interaction of the genus in the gut of the BD3526 group also significantly changed. Additional cytokine detection revealed that the fermentation products of BD3526 can reduce the inflammatory factors in the intestinal mucus of GK rats and thereby inhibit the inflammatory response and ameliorate the symptoms of T2DM.

Role of hepatic neuregulin 4 in the regulation of gluconeogenesis in mice

AimsEnhanced hepatic gluconeogenesis is an important cause of hyperglycemia in type 2 diabetes. However, the regulatory mechanisms underlying disordered hepatic gluconeogenesis remains largely unclear. In the present study, we investigated the potential role of hepatic neuregulin 4 (Nrg4) in the regulation of gluconeogenesis in mice. Main methodsMicroarray analysis was performed in primary mouse hepatocytes treated with or without 8-Br-cAMP. Primary mouse hepatocytes transfected with Nrg4 overexpressing or shRNA adenovirus were used to detect the expressions of the key gluconeogenic genes and glucose output. Hepatic Nrg4 expression levels were measured in fasted C57/BL6 mice, obese ob/ob mice, diabetic db/db mice and Goto-Kakisaki (GK) rats. Pyruvate tolerance test was performed and gluconeogenic gene expressions were detected 7 days after Nrg4 shRNA adenovirus was injected into male C57BL/6 and db/db mice. Key findingsMicroarray analysis revealed that Nrg4 expression was significantly induced by 8-Br-cAMP in primary mouse hepatocytes, along with the upregulation of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Adenovirus-mediated overexpression or knockdown of Nrg4 in primary mouse hepatocytes increased or decreased PEPCK and G6Pase expressions as well as hepatic glucose production. Hepatic Nrg4 expression was induced by fasting in normal C57/BL6 mice, and markedly upregulated in obese ob/ob mice, diabetic db/db mice and GK rats. Hepatic Nrg4 knockdown in C57BL/6 and db/db mice improved pyruvate tolerance, with the downregulation of PEPCK, G6Pase, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). SignificanceHepatic Nrg4 plays a crucial role in the regulation of gluconeogenesis and may be a therapeutic target of type 2 diabetes.

Apocynin decreases AGEs-induced stimulation of NF-κB protein expression in vascular smooth muscle cells from GK rats

Context: Elevated oxidative stress plays a key role in diabetes-associated vascular disease. Excessive production of reactive oxygen species via advanced glycation end products (AGEs) activates peroxisome proliferator-activated receptor gamma (PPARγ) and the transcription factor nuclear factor-kB (NF-κB) in aortic vascular smooth muscle cells (VSMCs). Apocynin, a drug with an antioxidant effect, has also been proposed as a therapeutic agent for atherosclerotic disease.Objectives: This work investigates the effects of apocynin on the PPARγ and NF-κB protein expression evoked by AGEs in cultured VSMCs from Goto–Kakisaki (GK) rats, a non-obese insulin model of both insulin resistance and type 2 diabetes.Materials and methods: VSMCs, isolated from aortas of GK and non-diabetic rats, were cultured. The expression of proteins was evaluated by Western blot. The blood glucose concentration was measured with a blood glucose test meter. The diabetes of GK rats was controlled by blood glucose and insulin determinations (non-fasting values). The serum insulin concentration was determined by radioimmunoassay.Results: In VSMCs from non-diabetic and GK rats, apocynin (1 and 10 µM) abolished the protein overexpression of NF-κB induced by glycated bovine serum albumin (AGEs-BSA) incubation. However, apocynin (1 and 10 µM) enhanced the expression of PPARγ protein in the presence of AGEs-BSA (100 μg/mL) in VSMCs from non-diabetic, but not from GK rats.Conclusion: These findings suggest that apocynin decreases the incidence of alterations in VSMCs induced by AGEs through the reduction of NF-κB and may represent an attractive therapeutic approach to treat diabetes mellitus.

A Prescribed Chinese Herbal Medicine Improves Glucose Profile and Ameliorates Oxidative Stress in Goto-Kakisaki Rats Fed with High Fat Diet

Oxidative stress (OS) plays a role in hyperglycemia induced islet β cell dysfunction, however, studies on classic anti-oxidants didn’t show positive results in treating diabetes. We previously demonstrated that the prescribed Chinese herbal medicine preparation “Qing Huo Yi Hao” (QHYH) improved endothelial function in type 2 diabetic patients. QHYH protected endothelial cells from high glucose-induced damages by scavenging superoxide anion and reducing production of reactive oxygen species. Its active component protected C2C12 myotubes against palmitate-induced oxidative damage and mitochondrial dysfunction. In the present study, we investigated whether QHYH protected islet β cell function exacerbated by high fat diet (HFD) in hyperglycemic GK rats. 4-week-old male rats were randomly divided into high HFD feeding group (n = 20) and chow diet feeding group (n = 10). Each gram of HFD contained 4.8 kcal of energy, 52% of which from fat. Rats on HFD were further divided into 2 groups given either QHYH (3 ml/Kg/d) or saline through gastric tube. After intervention, serum glucose concentrations were monitored; IPGTTs were performed without anesthesia on 5 fasting rats randomly chosen from each group on week 4 and 16. Serum malondialdehyde (MDA) concentrations and activities of serum antioxidant enzymes were measured on week 4 and 16. Islet β cell mass and OS marker staining was done by immunohistochemistry on week 16. QHYH prevented the exacerbation of hyperglycemia in HFD feeding GK rats for 12 weeks. On week 16, it improved the exacerbated glucose tolerance and prevented the further loss of islet β cell mass induced by HFD. QHYH markedly decreased serum MDA concentration, increased serum catalase (CAT) and SOD activities on week 4. However, no differences of serum glucose concentration or OS were observed on week 16. We concluded that QHYH decreased hyperglycemia exacerbated by HFD in GK rats by improving β cell function partly via its antioxidant effect.

The Protective Effects of α-Lipoic Acid on Kidneys in Type 2 Diabetic Goto-Kakisaki Rats via Reducing Oxidative Stress

To evaluate the protective effects of α-lipoic acid on the kidneys of Goto-Kakisaki (GK) diabetic rats, ten GK diabetic rats were randomly divided into a diabetic control group and a lipoic acid-treated diabetic group with α-lipoic acid 35 mg·Kg−1 intraperitoneal injections. Four healthy Wistar rats served as normal controls. Malonaldehyde (MDA), ascorbic acid (vitamin C), vitamin E, glutathione (GSH) and superoxide dismutase (SOD) levels in renal homogenate, and urine protein excretion were measured. The expression of mRNA for NF-κB, NADPH oxidase subunits p22phox and p47phox in renal tissue was examined by realtime PCR. Pathological changes in renal tissue were evaluated by light and electron microscopy. There were significant increases in urine protein excretion, MDA levels and the expression of mRNA of NF-κB, p22phox and p47phox, and significant decreases in GSH, SOD, vitamin C and vitamin E levels in the diabetic control group compared with the normal control group. Pathological changes of renal tissue were more progressive in the diabetic control group than in the normal control group. All the parameters above were improved in the α-lipoic acid-treated diabetic group. Oxidative stress is increased in the kidney of type 2 diabetic GK rats. It is associated with the progression of diabetic nephropathy. α-lipoic acid can protect renal function in diabetic rats via its antioxidant activity.

Multiple Statistical Methods for Assessing Differential Gene Expression in Microarray Data of Diabetic Model Rats to Predict the Molecular Mechanism of Atorvastatin on Anti-Atherogenesis

Many evidences indicate that statins have pleiotropic effects that are lipid-lowering independent. These effects could suggest attenuation of many of the stages critical to atherosclerosis. However, the specific molecular mechanisms of statins on atherogenesis are still unknown. The goal is to detect and analyze the altered gene expression of the artery after atorvastatin treatment in streptozocin (STZ)-induced diabetic rats, and to predict the possible cholesterol-independent effects of atorvastatin on anti-atherogenesis. A total of 33 Sprague Dawley (SD) rats were randomly divided into 3 groups: control group, diabetic group, and diabetic group with atorvastatin treatment (receiving 50 mg/kg qd atorvastatin). Rats were sacrificed at the end of 4 weeks, and the aortas were obtained. The pathological changes were observed by Hematoxylin and eosin (HE) staining. A cDNA microarray analysis was carried out, and the results were analyzed by the random variance model (RVM) t-test, Stc analysis, Stc-Gene Ontology (GO) analysis, Stc-pathway analysis, and GeneFunNet analysis. Then reverse transcription polymerase chain reaction (RT-PCR) was used to evaluate the mRNA expression of Cathepsin S (Cat S),Which was one of the significant genes obtained by statistical analysis, in the aortas of rats in control group (Wistar rats), DM group (Goto Kakisaki rats) and atorvastatin treated DM group (Goto Kakisaki rats with 50 mg/kg qd atorvastatin) for 12 weeks. A total of 1 073 differential expression genes were found in the 3 groups. 2 tendency profiles of gene expression, which represented the medicine effect, were picked out by Stc analysis of gene expression. The main functions of genes and the significant pathways in the 2 profiles were figured out by Stc-go analysis and Stc-pathway analysis. The core regulatory factors in the co-expression network were shown by GeneFunNet analysis. Among these significant genes, Cat S was chosen to be further evaluated as a target gene. Expression of Cat S was upregulated in the aortas of the diabetic rats and downregulated with statistical significance by atorvastatin treatment. Atorvastatin can influence the expression of many genes and signal pathways, some may be significant and produce their marked effects on all of the processes of atherogenesis. Cat S is one of them. These data thus predict the possible molecular mechanism of pleiotropic effects of atorvastatin, which is useful for further experimental design.

Whole grain consumption has a modest effect on the development of diabetes in the Goto–Kakisaki rat

Epidemiological evidence suggests that whole grain intake is associated with reduced risk of type 2 diabetes. However, studies of individual whole grains on the prevention of type 2 diabetes are lacking. The objective of the present study was to examine the effect of different whole grains on type 2 diabetes in an animal model of type 2 diabetes, the Goto-Kakisaki (GK) rat. GK rats were fed either a basal diet or a whole grain-containing diet for 5 months. Whole grain diets contained 65% whole grain flours of wheat, barley, oats or maize. After 2 months of feeding, fasting plasma glucose concentrations were lower in the wheat, barley and oats groups, compared with the basal group, whereas glycated Hb was significantly greater in the wheat group compared with other groups. Feeding of whole barley and maize increased plasma C-peptide concentrations compared with whole wheat at 2 months. There was a trend in the improvement of insulin resistance with a consumption of barley and oats diets at 2 months (P=0·06) compared with the basal diet. Oxidative stress markers, urinary thiobarbituric acid-reactive substances and 8-isoprostane, did not improve with whole grain intake at 2 months. At 5 months, whole grain diets did not differ from the basal diet in glycaemic control, insulin secretion, oxidative stress and preservation of pancreatic β-cell mass. These results suggest that the consumption of whole grains may offer modest benefit early in the development of type 2 diabetes, but this benefit is lost with further development of the disease.

Atorvastatin exerts its anti-atherosclerotic effects by targeting the receptor for advanced glycation end products

Recent studies demonstrated the beneficial role of atorvastatin in reducing the risk of cardiovascular morbidity and mortality in patients with diabetes mellitus and/or metabolic syndrome. To investigate the mechanisms underlying the anti-atheroscleroic action of atorvastatin, we examined the expression of the receptor for advanced glycation end products (RAGE) and its downstream target gene, monocyte chemoattractant protein-1 (MCP-1) using real-time PCR. In in vitro studies, exposure to high glucose or AGE induced oxidative stress and activation of the AGE/RAGE system in human umbilical vein endothelial cells. Treatment of the cells with atorvastatin significantly released the oxidative stress by restoring the levels of glutathione and inhibited the RAGE upregulation. In diabetic Goto Kakisaki (GK) rats fed with a high-fat diet for 12 weeks, RAGE and MCP-1 were upregulated in the aortas, and there was a significant correlation between RAGE and MCP-1 mRNA abundance ( r = 0.482, P = 0.031). Treatment with atorvastatin (20 mg/kg qd) significantly downregulated the expression of RAGE and MCP-1. These data thus demonstrate a novel “pleiotropic” activity of atorvastatin in reducing the risk of cardiovascular diseases by targeting RAGE expression.

Whole grain consumption does not slow diabetic progression in GK rats

Whole grain consumption is inversely associated with risk of type II diabetes epidemiologically. The aim of this study was to study the effect of whole grain consumption on diabetic control and progression in an animal model of type II diabetes, the Goto‐Kakisaki (GK) rat. GK rats were fed either a whole grain‐free control diet or a whole grain‐containing diet for 5 months. Whole grain diets contained 65% whole grain flours of either wheat, barley, oat, or corn. After two months, fasting plasma glucose concentration was significantly lower with the wheat, barley, or oat diets compared to the control diet. However, glycated hemoglobin was significantly greater in the wheat group compared to other groups. At 5 months, whole grain diets did not improve glycemic control. Fasting plasma insulin and C‐Peptide levels were decreased from month 2 to month 5 indicating diabetic progression. Insulin resistance, determined by the homeostasis model assessment, was not significantly different among groups at either 2 or 5 months. However, there was a trend for improvement of insulin resistance with the barley and oat diets at 2 months (P=0.06). There were no significant differences in the total pancreatic β‐cell mass among groups. These results offer little support for improvement of diabetic control and delayed progression with consumption of whole grains. (Supported by the General Mills Bell Inst. of Health and Nutrition)Grant Funding SourceGeneral Mills Bell Inst. of Health and Nutrition

Anatomical versus functional β‐cell mass in experimental diabetes

The ability of pancreatic beta-cell mass to vary according to insulin requirements is an important component of optimal long-term control of glucose homeostasis. It is generally assumed that alteration of this property largely contributes to the impairment of insulin secretion in type 2 diabetes. However, data in humans are scarce and it is impossible to correlate beta-cell mass and function with the various stages of the disease. Thus, the importance of animal models is obvious. In rodents, increased beta-cell mass associated with an increase in the function of individual beta-cells contributes to the adaptation of the insulin response to insulin resistance in late pregnancy and in obesity. A reduction in beta-cell mass always corresponds to an alteration in insulin secretory capacity of islet tissue (Zucker diabetic fatty and Goto-Kakisaki rats, db/db mice). During regenerative processes following experimental reduction of beta-cell mass [partial pancreatectomy, streptozocin (STZ) injection], beta-cell mass increase is not associated with a corresponding improvement of beta-cell function, thus indicating that regenerative beta-cells did not achieve functional maturity. The main lesson from experimental diabetes is therefore that beta-cell mass cannot always predict functional capacity of the beta-cell tissue and that the functional beta-cell mass rather than the anatomical beta-cell mass must be taken into account at all times.

Of mighty mice and diabetic men: animal models of islet dysfunction

Of mighty mice and diabetic men: animal models of islet dysfunction

Modulation of CD36 protein expression by AGEs and insulin in aortic VSMCs from diabetic and non-diabetic rats

Background and aim In type 2 diabetes, the interplay between cells and inflammatory mediators up-regulates CD36 expression in macrophages. The aim of this work was to investigate advanced glycation end products (AGE)-induced CD36 expression and its regulation by insulin in aortic vascular smooth muscle cells (VSMCs) from Goto–Kakisaki (GK) rats, a non-obese insulin model of both insulin resistance and type 2 diabetes. The context of overexpression of CD36 in aortas was also evaluated. Methods and results VSMCs were isolated and cultured from the aortas of GK rats and non-diabetic rats. The expression of proteins was evaluated by Western blot. The aortic production of superoxide anion (O 2 ·−) was measured by luminescence on isolated tissue. AGEs and advanced oxidation protein products (AOPPs) were determined in plasma by fluorescence spectroscopy and spectrophotometry, respectively. AGE receptor (RAGE), NF-κB, and CD36 protein expression as well as O 2 ·− production were higher in GK aortas than in control aortas, and AGEs and AOPPs were higher in GK plasma. In VSMCs from non-diabetic rats, insulin was able to reduce (10 nM) or suppress (100 nM) the protein overexpression of CD36 induced by AGEs–BSA. In contrast, in VSMCs from GK rats, insulin was unable to reduce AGEs–BSA-induced CD36 overexpression. Conclusions The results suggest an overexpression of CD36 in VSMCs from GK rats and impaired control by insulin. In the context of increased plasma AGEs, aortic RAGE overexpression and increased oxidative stress markers, the data are compatible with an AGEs induced CD36 overexpression in diabetes.

Natural vanadium-containing Mt. Fuji ground water improves hypo-activity of liver insulin receptor in Goto-Kakisaki rats

After daily treatments with Mt. Fuji ground water containing natural vanadium (approximately 65 microg/l) at doses of 0.53 microg/kg/day for 12 weeks, blood glucose (BG), serum hemoglobin A1C (HbA1C) levels and insulin secretion from the pancreas of Goto-Kakisaki (GK) rats, a genetic model of Type 2 diabetes, were improved. In GK rat liver insulin receptors, the binding properties of [125I] insulin, and the activities of insulin receptor beta subunit and primary insulin-like growth factor-1beta all recovered to normal levels of those found in Wistar rats. These results suggest that daily treatment with small concentrations of natural vanadium improves hyperglycemia by ameliorating liver insulin receptor activity.

Effect of early dietary restriction on insulin action and secretion in the GK rat, a spontaneous model of NIDDM.

The availability of the Goto-Kakisaki (GK) rat model of non-insulin-dependent diabetes mellitus prompted us to test the effect of a limited period of undernutrition in previously diabetic young rats on their insulin secretion and insulin action during adult age. Four-week-old female GK rats were either food restricted (35% restriction, 15% protein diet) or protein and energy restricted (35% restriction, 5% protein diet) for 4 wk. Food restriction in the young GK rat lowered weight gain but did not aggravate basal hyperglycemia or glucose intolerance, despite a decrease in basal plasma insulin level. Furthermore, the insulin-mediated glucose uptake by peripheral tissues in the GK rat was clearly improved. We also found that food restriction, when it is coupled to overt protein deficiency in the young GK rat, altered weight gain more severely and slightly decreased basal hyperglycemia but conversely aggravated glucose tolerance. Improvement of basal hyperglycemia was related to repression of basal hepatic glucose hyperproduction, despite profound attenuation of basal plasma insulin level. Deterioration of tolerance to glucose was related to severe blunting of the residual glucose-induced insulin secretion. It is, however, likely that the important enhancement of the insulin-mediated glucose uptake helped to limit the deterioration of glucose tolerance.

Beta-cell growth in the neonatal Goto-Kakisaki rat and regeneration after treatment with streptozotocin at birth

In the Goto-Kakisaki rat, a genetic model of non-insulin dependent diabetes, we have recently reported that as early as fetal age, there is a restriction of the beta-cell mass which is maintained in the adult animal and is detectable before the onset of hyperglycaemia. It is therefore important to investigate the beta-cell growth potential in young Goto-Kakisaki rats. We have studied in 4 and 7-day-old Goto-Kakisaki neonates: 1. the in vivo replication rate of the beta cell; 2. the occurrence of beta-cell apoptosis; 3. the effectiveness of beta-cell regeneration after damage caused by neonatal treatment with streptozotocin. The replication rate in vivo of beta cells and the beta-cell apoptosis were similar in untreated Wistar and Goto-Kakisaki neonates on days 4 and 7 whereas the total beta-cell masses were reduced to 50 % in the Goto-Kakisaki groups. Treatment with streptozotocin reduced the total beta-cell mass to the same extent in both Wistar and Goto-Kakisaki rats on day 4 compared with the corresponding normal values in Wistar and Goto-Kakisaki neonates. From day 4 to day 7, spontaneous beta-cell regeneration was manifest in both groups. Compared with the Wistar streptozotocin group, the net value of the beta-cell mass added during this period was more limited in the Goto-Kakisaki streptozotocin group, despite the replication activity of the residual beta cells being increased in this group to the same extent as in the Wistar streptozotocin group. We therefore suggest: 1. that the reduced beta-cell mass in the untreated neonatal Goto-Kakisaki rat does not appear to reflect a reduction in the rate of beta-cell replication or an increased beta-cell death by apoptosis but is potentially due to an impaired rate of beta-cell neogenesis, and 2. that beta-cell regeneration can be reactivated after streptozotocin insult in the neonatal Goto-Kakisaki rat, although to a lesser extent compared with that in streptozotocin-treated Wistar neonates.

Effect of gliclazide treatment on insulin secretion and β-cell mass in non-insulin dependent diabetic Goto–Kakisaki rats

The Goto–Kakisaki rat is a genetic non-overweight model of non-insulin-dependent diabetes mellitus. Adult Goto–Kakisaki rats exhibit a mild basal hyperglycaemia (11 mmol/l) with impaired glucose tolerance, elevated basal plasma insulin level, a failure of insulin release in response to glucose together with a 50% depletion of the total pancreatic β-cell mass and insulin stores. We have examined the effects of long-term (4 weeks) gliclazide treatment on the severity of diabetes in adult male Goto–Kakisaki rats (10–12 weeks of age). Gliclazide was administered orally (10 mg/kg per day). Gliclazide-treated Goto–Kakisaki rats were evaluated against Wistar and untreated Goto–Kakisaki rats. In the gliclazide-treated Goto–Kakisaki rats, basal plasma glucose levels declined progressively reaching 8 mmol/l as a mean at the end of treatment, and their basal insulin levels decreased to values similar to those in non-diabetic Wistar rats. Despite their total pancreatic β-cell remaining unaffected, their pancreatic insulin stores were twice increased, with a similar improvement of the insulin content per individual β-cell. Furthermore, the glucose-stimulated insulin release as evaluated in vivo during an intravenous glucose tolerance-test was significantly improved (twice increased) in the gliclazide-treated Goto–Kakisaki rats. This was correlated with a modest but significant enhancement of the early phase of insulin release in vitro (isolated perfused pancreas), in response to glucose. However, the overall insulin response in vitro remained clearly defective with no reappearance of the late phase of insulin release. The in vitro response to arginine (which was basically amplified in the Goto–Kakisaki model) or to gliclazide were kept unchanged after the gliclazide treatment. In conclusion, chronic gliclazide does not exert any β-cytotrophic effect, but improves β-cell function in the adult Goto–Kakisaki rat as far as it lowers basal insulin release, increases β-cell insulin stores, and increases the glucose-induced insulin release.

Lack of deterioration of insulin action with aging in the GK rat: A contrasted adaptation as compared with nondiabetic rats

One of the main characteristics of non—insulin-dependent diabetes mellitus (NIDDM) is an alteration of tissue insulin sensitivity, which is also observed during the aging process in the nondiabetic, in this study, we evaluated the influence of age on insulin resistance in a genetic lean model of NIDDM, the Goto-Kakisaki (GK) rat, using the euglycemic-hyper insulinemic clamp technique at 2, 12, and 18 months of age. In GK rats, basal hyperglycemia (11 mmol/L) and insulinemia, glucose intolerance, and the specific failure of the insulin response to glucose apparent at 2 months of age remained stable until 18 months. Whatever the age, the insulin-suppressive effect on glucose production was significantly less in GK rats than in Wistar rats. The insulin effect on whole-body glucose utilization was decreased at 2 months (15.8 ± 1.0 mg/min/kg v 23 5 ± 2.0, P < .001) and was only mildly aggravated between 2 and 18 months (10.3 ± 0.9 mg/min/kg, P < .05). By contrast, in Wistar control rats, basal insulinemia and the insulin response to glucose markedly increased between 2 and 18 months (2-month ΔI v 18-month ΔI, 1.4 ± 0.1 mU/ml · min v 2.9 ± 0.3, P < .001) and glucose tolerance remained normal. In 18-month-old Wistar rats, the insulin-stimulated glucose utilization rate (GUR) was found to be marked y decreased compared with that of 2-month-old Wistar rats (9.9 ± 0.8 mg/min/kg v 23.5 ± 2.0, P < .001), thus demonstrating an age-related decrease of insulin action. In conclusion, we find that there is no major alteration of insulin action due to aging in the GK rat, at variance with the pattern in nondiabetic rodents. It is speculated that such an adaptation in this lean model of NIDDM could be related to the limited capacity of these rats to expand their body weight with age, since it is recognized that body weight gain is largely responsible for the age-related impairment in peripheral insulin action in nondiabetic humans and nondiabetic animal models.