GK Rats Research Articles

Abstract 1944: Atorvastatin Reduces Intracerebral Hemorrhage after Experimental Stroke

Ischemic stroke is a leading cause of death and disability in the United States and diabetes mellitus is the fastest growing risk factor for stroke. In addition, hyperglycemia, which is usually associated with diabetes, tends to worsen ischemia/reperfusion injury and to induce more oxidative stress damage. Preliminary data from our laboratory showed that diabetic animals (Goto-Kakizaki rats (GKs) are more susceptible to vascular damage leading to intracerebral hemorrhage. Many studies have indicated that statins possess neuroprotective properties even when administered after the onset of ischemia. However, the acute vascular effects of statins after ischemic stroke have not been studied to date. Objective: to evaluate the efficacy and magnitude of vascular protection of acute statin therapy in both GKs and their normoglycemic controls after experimental ischemic stroke. Methods: Male Wistar (W) and GK rats (270–305 g) underwent 3 hours of middle cerebral artery occlusion (MCAO) followed by reperfusion for 21 hours. Animals were randomized to receive either atorvastatin (15mg/Kg) or methyl cellulose (0.5%), administered by oral gavage, the first dose 5 minutes after reperfusion and the second dose after 12 hours. Brain tissue was analyzed for infarct volume and hemoglobin content. In another set of Wistar rats (n=3), atorvastatin (15mg/Kg) was administered by oral gavage to compare its pharmacokinetic profile with that of humans Results: Atorvastatin-treated groups had significantly lower hemoglobin (p=0.0156) and infarct volume (p=0.0132) compared to their controls. Atorvastatin peak concentration (27–77 ng/ml) in rats’ plasma was found to be similar to that seen after 80mg/day of atorvastatin in humans. Conclusion: Atorvastatin can be a novel vascular protective agent after acute ischemic stroke especially in a high risk population like diabetics. The mechanisms through which these effects are mediated are currently being investigated.

Des-Aspartate-Angiotensin I Exerts Hypoglycemic Action via Glucose Transporter-4 Translocation in Type 2 Diabetic KKAy Mice and GK Rats

The present study investigated the hypoglycemic action of des-aspartate-angiotensin I (DAA-I), a metabolite of angiotensin I, in two animal models of type 2 diabetes. The rationale was based on our earlier studies demonstrating that DAA-I acts on the angiotensin AT(1) receptor and exerts responses opposing those of angiotensin II and on recent reports that curtailment of angiotensin II formation by angiotensin converting enzyme inhibitors and blockade of the AT(1) receptor attenuate hyperglycemia in type 2 diabetics and diabetic animals. Diabetic KKAy mice and GK rats were administered orally (by gavage) one of the following doses of DAA-I: 400, 600, or 800 nmol/kg.d for 4 and 6 wk, respectively. Control diabetic animals were similarly administered water. Blood glucose of each animal was determined fortnightly by oral glucose tolerance test and blood insulin on the last day of treatment. Animals were killed, and the levels of plasma membrane glucose transporter-4 and cytosolic tyrosine-phosphorylated insulin receptor substrate-1 in hind limb skeletal muscles were determined by Western blot in insulin-challenged and nonchallenged animals. Orally administered DAA-I had no effect on blood insulin level but exerted dose-dependent hypoglycemic action in KKAy mice and GK rats after 4 and 6 wk of treatment, respectively. At the maximal effective dose of 600 nmol/kg, insulin induced a significant increase in plasma membrane glucose transporter-4 and cytosolic tyrosine-phosphorylated insulin receptor substrate-1. These findings show that DAA-I is not an insulin secretagogue and exerts hypoglycemic action by attenuating insulin resistance, the first such demonstration indicating that the nonapeptide is involved in glycemic regulation.

Increased Number of Islet-Associated Macrophages in Type 2 Diabetes

Activation of the innate immune system in obesity is a risk factor for the development of type 2 diabetes. The aim of the current study was to investigate the notion that increased numbers of macrophages exist in the islets of type 2 diabetes patients and that this may be explained by a dysregulation of islet-derived inflammatory factors. Increased islet-associated immune cells were observed in human type 2 diabetic patients, high-fat-fed C57BL/6J mice, the GK rat, and the db/db mouse. When cultured islets were exposed to a type 2 diabetic milieu or when islets were isolated from high-fat-fed mice, increased islet-derived inflammatory factors were produced and released, including interleukin (IL)-6, IL-8, chemokine KC, granulocyte colony-stimulating factor, and macrophage inflammatory protein 1alpha. The specificity of this response was investigated by direct comparison to nonislet pancreatic tissue and beta-cell lines and was not mimicked by the induction of islet cell death. Further, this inflammatory response was found to be biologically functional, as conditioned medium from human islets exposed to a type 2 diabetic milieu could induce increased migration of monocytes and neutrophils. This migration was blocked by IL-8 neutralization, and IL-8 was localized to the human pancreatic alpha-cell. Therefore, islet-derived inflammatory factors are regulated by a type 2 diabetic milieu and may contribute to the macrophage infiltration of pancreatic islets that we observe in type 2 diabetes.

Exendin-4, but not dipeptidyl peptidase IV inhibition, increases small intestinal mass in GK rats

Long-term treatment with dipeptidyl peptidase IV inhibitors (DPPIV-I) or glucagon-like peptide (GLP)-1 analogs may potentially affect intestinal growth by down- or upregulating the intestinotrophic hormone GLP-2. This study compared the intestinotrophic effects of 12-wk administration of vehicle, exendin-4 (Ex-4; 5 nmol/kg bid sc), or DPPIV-I (NN-7201, 10 mg/kg qd orally) in GK rats. Some animals were observed additionally for 9 wk after the end of treatment. Both treatments lowered glycated hemoglobin A1c at wk 12 vs. control (Ex-4, -0.8%; DPPIV-I, -0.4%). Body weight was reduced by Ex-4 compared with control (361 +/- 4 vs. 399 +/- 5 g; P < 0.001) because of reduced food intake, whereas neither parameter was affected by DPPIV-I. Linear bone growth was unaffected by either treatment. After treatment end, food intake in Ex-4 animals increased, and, by wk 21, body weight was identical in all groups. The small intestine of Ex-4-treated animals was larger at wk 12 compared with control (length, 135.6 +/- 1.6 vs. 124.5 +/- 2.3 cm, P < 0.001; absolute weight, 8.4 +/- 0.2 vs. 6.4 +/- 0.4 g, P < 0.001), being most pronounced proximally, where the absolute cross-sectional area related to body weight increased by 24% because of increased mucosal thickness. These effects were reversible, and 9 wk after the end of treatment, no differences between Ex-4 and control were apparent. Plasma GLP-2 concentrations were unaltered by either treatment, and Ex-4 had no agonistic or antagonistic effects on the transfected GLP-2 receptor. DPPIV-I had no intestinal effects. In conclusion, the continued presence of Ex-4 is necessary to maintain weight loss in GK rats. Effective antihyperglycemic treatment with Ex-4 increases intestinal mass reversibly, whereas DPPIV-I lacks intestinal effects.

Glucose regulation of CDK7, a putative thiol related gene, in experimental diabetic nephropathy

We previously described the identification of the 3′end of an unknown gene CDK7 using differential display which appeared to be up-regulated in diabetic kidneys [R.A. Page, C.A. Morris, J.D. Williams, C.J. von Ruhland, A.N. Malik, Isolation of diabetes-associated kidney genes using differential display, Biochem. Biophys. Res. Commun. 232 (1997) 49–53]. Here we show that CDK7 is a putative thiol related gene which is regulated by glucose in human and rat renal cells. CDK7 mRNA increased by >threefold in cultured human mesangial cells grown in high glucose for 4 days. In the kidneys of the GK rat, a model of type II diabetes, CDK7 showed a steady age-related increase in mRNA, increasing to >sixfold in 40 week GK rats compared to normoglycemic age-matched Wistar rat kidneys, this increase correlates with progressive hyperglycemia. CDK7 mRNA is widely expressed, showing particularly high levels of expression in rat and human liver, and encodes a putative 338 amino acids highly conserved peptide with several conserved domains, including a cys-pro-arg-cys domain conserved in 15 diverse species which is similar to the catalytic centre of thioredoxin, suggesting a role in oxidative stress.

Expression of growth factor receptor and microRNAs in myocardium MVECS and their relation with angiogenesis

This study aimed to determine the changes of VEGF, Flk-1 and Flt-1 expression in myocardium microvascular endothelial cells (MMVECs) from Goto-Kakizaki diabetic rats (GK rats) by comparing with the age-matched normal Wistar rats, and the possible role of their microRNA in the diabetic impaired angiogenesis. The angiogenesis ability of GK rat MMVEC was studied by capillary-like tube formation assay and cell migration assay in vitro. The pattern of the angiogenesis-associated gene expression of MMVECs from GK and Wistar rats by specific angiogenesis gene microarray was observed. The most significantly up-regulated microRNAs were verified by real-time PCR. Tube formation and cell migration of GK MMVECs were significantly decreased (P<0.05). Using angiogenesis gene microarray, we found that mRNA expression of 11 angiogenic growth factor genes and 10 growth factor receptor genes was up-regulated in the GK MMVECs. Results demonstrated that their mRNA expression significantly increased (P<0.01). However, protein expressions of VEGF and Flk-1/Flt-1 markedly decreased. The results of microRNA array indicated that microRNAs were aberrantly expressed in GK MMVECs. More than 2-fold up-regulated expression of miR-370, miR-494, miR-503_MM1, and 3 non-denominated miRNAs was detected by microRNA array and confirmed by real-time PCR. The up-regulated microRNAs may play an important role in the down-regulation of growth factor receptors in diabetic impaired angiogenesis.

AKT as a mediator of the hypertrophic effect of increased NHE1 activity

Aims/hypothesis. Because several studies have suggested that the Na+/H+ exchanger (NHE1) is involved in molecular mechanisms of cardiac hypertrophy, we investigated its activity and its role in myocytes of GK rats (a model of type 2 diabetes) with left ventricular (LV) hypertrophy.

Effects of glucagon-like peptide-1-(7–36)-amide on pancreatic islet and intestinal blood perfusion in Wistar rats and diabetic GK rats

The aim of the present study was to evaluate the effects of GLP-1 [glucagon-like peptide-1-(7-36)-amide] on total pancreatic, islet and intestinal blood perfusion in spontaneously hyperglycaemic GK rats and normal Wistar rats using a microsphere technique. GK rats had hyperglycaemia and increased pancreatic and islet blood flow. Blood glucose concentrations were not affected when measured shortly (8 min) after GLP-1 administration in either GK or Wistar rats. GLP-1 had no effects on baseline pancreatic or islet blood flow in Wistar rats, but did prevent the blood flow increase normally seen following glucose administration to these animals. In GK rats, administration of GLP-1 decreased both pancreatic and islet blood flow. Glucose administration to the GK rats decreased pancreatic and islet blood flow. This decrease was not affected by pre-treatment with GLP-1. We conclude that administration of GLP-1 leads to a decrease in the augmented blood flow seen in islets of diabetic GK rats. The GLP-1-induced action on islet blood perfusion may modulate output of islet hormones and contribute to the antidiabetogenic effects of the drug in Type 2 diabetes (non-insulin-dependent diabetes).

Glucose regulation of β-defensin-1 mRNA in human renal cells

We previously showed that β-defensin-1 (BD-1), an anti-microbial peptide, is up-regulated during progressive hyperglycemia in the kidneys of the GK rat [R.A. Page, C.A. Morris, J.D. Williams, C.J. von Ruhland, A.N. Malik, Isolation of diabetes-associated kidney genes using differential display, Biochem. Biophys. Res. Commun. 232 (1997) 49–53, R.A. Page, A.N. Malik, Elevated levels of β-defensin-1 mRNA in diabetic kidneys of GK rats, Biochem. Biophys. Res. Commun. 310 (2003) 513–521]. In this paper, we show that human β-defensin-1 (hBD-1) mRNA is directly up-regulated by glucose in cultured human renal cells. hBD-1 mRNA levels increased by ∼7-fold and ∼4-fold in human embryonic kidney (HEK) cells and human mesangial cells (HMC) grown in 25 mM glucose for four days, as determined by quantitative real-time PCR. Immunofluorescence showed that the hBD1 protein is located in the cytoplasm of HEK cells and transfected HMCs. The highest levels of hBD-1 mRNA were found in the kidney compared with 21 other human tissues. The increased expression of hBD-1 mRNA in cultured HMCs in high glucose suggests a role for hBD-1 in the molecular pathways induced during hyperglycemia.

The effects of Danggui-Buxue-Tang on blood lipid and expression of genes related to foam cell formation in the early stage of atherosclerosis in diabetic GK rats

Danggui-Buxue-Tang (DBT) is a famous traditional Chinese formula. We determined the effects of DBT on blood lipid and expression of genes related to foam cell formation in the early stage of atherosclerosis in diabetic GK rats. DBT (3 or 6 g/kg/day for 4 weeks) was orally administrated to the diabetic atherosclerosis rats, which were induced by nitric oxide inhibition ( l-NAME in drinking water, 1 mg/ml) plus high-fat diet. The total cholesterol (TC), triglyeride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), and the mRNAs expression of monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1 and CD36 mRNA in aorta were determined. The results demonstrated that DBT could regulate blood lipid, inhibit the genes expression of MCP-1, ICAM-1 and CD36 in aorta.

Fatty acid content and pattern of epididymal and parametrial adipose tissue lipids in streptozotocin (type 1) and Goto-Kakizaki (type 2) diabetic rats

Attention was recently drawn to differences in the fatty acid pattern of liver phospholipids and triglycerides in animal models of type 1 and type 2 diabetes. The present study extends this knowledge to epididymal or parametrial adipose tissue lipids. The fatty acid pattern of such lipids was established in four fed female normal rats, four overnight fasted female normal rats, six fed female rats rendered diabetic by an injection of streptozotocin 3 days before sacrifice (STZ rats), and four female and four male Goto-Kakizaki rats (GK rats) also examined in the fed or fasted state. In addition to the fasting-induced and diabetes-related changes in plasma D-glucose and insulin concentrations, differences in either the weight percentage of fatty acids or the paired ratio between distinct fatty acids were often encountered. For instance, in the GK rats, gender differences were observed in the weight percentage of C18:2omega6, as well as C18:2omega6/C18:3omega6, C18:3omega6/C20:4omega6, C20:5omega3/C22:5omega3 and C22:5omega3/C22:6omega3 ratios. When compared to normal rats, the activity of Delta9-desaturase was markedly increased in GK rats and, to a lesser extent, in STZ rats. Starvation also increased to some extent the activity of Delta9-desaturase. The relative content of C22:6omega3 was also higher in diabetic than in normal rats. Further differences between GK and STZ rats concerned the generation of C18:3omega6 from C18:2omega6, C20:4omega6 from C18:3omega6, and C20:5omega3 from C18:3omega3. Several differences found in the adipose tissue of GK versus STZ rats were reminiscent of those recently identified in the liver triglycerides of these two types of diabetic animals, suggesting a common regulatory mechanism, possibly linked to the higher insulinemia of GK rats versus STZ rats.

Separately Inherited Defects in Insulin Exocytosis and β-Cell Glucose Metabolism Contribute to Type 2 Diabetes

The effects of genetic variation on molecular functions predisposing to type 2 diabetes are still largely unknown. Here, in a specifically designed diabetes model, we couple separate gene loci to mechanisms of beta-cell pathology. Niddm1i is a major glucose-controlling 16-Mb region in the diabetic GK rat that causes defective insulin secretion and corresponds to loci in humans and mice associated with type 2 diabetes. Generation of a series of congenic rat strains harboring different parts of GK-derived Niddm1i enabled fine mapping of this locus. Congenic strains carrying the GK genotype distally in Niddm1i displayed reduced insulin secretion in response to both glucose and high potassium, as well as decreased single-cell exocytosis. By contrast, a strain carrying the GK genotype proximally in Niddm1i exhibited both intact insulin release in response to high potassium and intact single-cell exocytosis, but insulin secretion was suppressed when stimulated by glucose. Islets from this strain also failed to respond to glucose by increasing the cellular ATP-to-ADP ratio. Changes in beta-cell mass did not contribute to the secretory defects. We conclude that the failure of insulin secretion in type 2 diabetes includes distinct functional defects in glucose metabolism and insulin exocytosis of the beta-cell and that their genetic fundaments are encoded by different loci within Niddm1i.

Post-translational modification regulates prostaglandin D 2 synthase apoptotic activity: Characterization by site-directed mutagenesis

Lipocalin-type prostaglandin D 2 synthase (L-PGDS) is a highly glycosylated protein found in several body fluids. Elevated L-PGDS levels have been observed in the serum of patients with renal impairment, diabetes mellitus, and hypertension. Recently, we demonstrated the ability of L-PGDS to induce apoptosis in a variety of cell types including epithelial cells, neuronal cells, and vascular smooth muscle cells (VSMCs). The aim of this study was to investigate the effect several site-directed mutations had on L-PGDS-induced apoptosis in order to identify potential sites of regulation. Point mutations created in a glycosylation site (Asn51), a protein kinase C phosphorylation site (Ser106), and the enzymatic active site (Cys65) all inhibited L-PGDS-induced apoptosis as determined by both terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) and caspase3 activity. We also compared the L-PGDS isoforms present in GK rat serum to WKY control serum using two-dimensional gel electrophoresis and observed distinct differences which vanished after PNGase F glycolytic digestion. We conclude that post-translational modification of L-PGDS, by either glycosylation or phosphorylation, enhances its apoptotic activity and inhibits VSMC hyperproliferation and postulate that this process is altered in type 2 diabetes.

High-Resolution Quantitative Trait Locus Analysis Reveals Multiple Diabetes Susceptibility Loci Mapped to Intervals &amp;lt;800 kb in the Species-ConservedNiddm1iof the GK Rat

AbstractNiddm1i, a 16-Mb locus within the major diabetes QTL in the diabetic GK rat, causes impaired glucose tolerance in the congenic NIDDM1I strain. Niddm1i is homologous to both human and mouse regions linked with type 2 diabetes susceptibility. We employed multiple QTL analyses of congenic F2 progeny selected for one recombination event within Niddm1i combined with characterization of subcongenic strains. Fine mapping located one hyperglycemia locus within 700 kb (Niddm1i4, P = 5 × 10−6). Two adjacent loci were also detected, and the GK allele at Niddm1i2 (500 kb) showed a glucose-raising effect, whereas it had a glucose-lowering effect at Niddm1i3 (400 kb). Most proximally, Niddm1i1 (800 kb) affecting body weight was identified. Experimental data from subcongenics supported the four loci. Sorcs1, one of the two known diabetes susceptibility genes in the region, resides within Niddm1i3, while Tcf7l2 maps outside all four loci. Multiple-marker QTL analysis incorporating the effect of cosegregating QTL as cofactors together with genetically selected progeny can remarkably enhance resolution of QTL. The data demonstrate that the species-conserved Niddm1i is a composite of at least four QTL affecting type 2 diabetes susceptibility and that two adjacent QTL (Niddm1i2GK and Niddm1i3GK) act in opposite directions.

The Mechanism of Diabetes Control After Gastrointestinal Bypass Surgery Reveals a Role of the Proximal Small Intestine in the Pathophysiology of Type 2 Diabetes

Most patients who undergo Roux-en-Y gastric bypass (RYGB) experience rapid resolution of type 2 diabetes. Prior studies indicate that this results from more than gastric restriction and weight loss, implicating the rearranged intestine as a primary mediator. It is unclear, however, if diabetes improves because of enhanced delivery of nutrients to the distal intestine and increased secretion of hindgut signals that improve glucose homeostasis, or because of altered signals from the excluded segment of proximal intestine. We sought to distinguish between these two mechanisms. Goto-Kakizaki (GK) type 2 diabetic rats underwent duodenal-jejunal bypass (DJB), a stomach-preserving RYGB that excludes the proximal intestine, or a gastrojejunostomy (GJ), which creates a shortcut for ingested nutrients without bypassing any intestine. Controls were pair-fed (PF) sham-operated and untreated GK rats. Rats that had undergone GJ were then reoperated to exclude the proximal intestine; and conversely, duodenal passage was restored in rats that had undergone DJB. Oral glucose tolerance (OGTT), food intake, body weight, and intestinal nutrient absorption were measured. There were no differences in food intake, body weight, or nutrient absorption among surgical groups. DJB-treated rats had markedly better oral glucose tolerance compared with all control groups as shown by lower peak and area-under-the-curve glucose values (P < 0.001 for both). GJ did not affect glucose homeostasis, but exclusion of duodenal nutrient passage in reoperated GJ rats significantly improved glucose tolerance. Conversely, restoration of duodenal passage in DJB rats reestablished impaired glucose tolerance. This study shows that bypassing a short segment of proximal intestine directly ameliorates type 2 diabetes, independently of effects on food intake, body weight, malabsorption, or nutrient delivery to the hindgut. These findings suggest that a proximal intestinal bypass could be considered for diabetes treatment and that potentially undiscovered factors from the proximal bowel might contribute to the pathophysiology of type 2 diabetes.

Brain phospholipid and triglyceride fatty acid content and pattern in Type 1 and Type 2 diabetic rats

The liver phospholipid and triglyceride content and/or fatty acid pattern differ(s) not solely in normal versus diabetic rats, but also in distinct rat models of diabetes mellitus. The present study reveals that a comparable situation prevails in the brain. Fed and overnight fasted female normal rats (N) and Goto-Kakizaki rats (GK), as well as fed rats rendered diabetic by a prior injection 3 days before sacrifice of streptozotocin (STZ) were examined. The brain phospholipid content, expressed as milligrams of fatty acids per gram wet weight, was comparable in all groups of rats, with an overall mean value of 31.2 ± 0.8 ( n = 22). The GK rats differed from N and STZ rats by lower C18:0/C18:1ω9 and C18:2ω6/C18:3ω6 ratios and a lower C20:5ω3 content of brain phospholipids. The total amount of fatty acids in triglycerides was 7–8 times higher in GK than N and STZ rats. The GK rats differed from N and STZ rats by lower C16:0/C16:1ω7, C18:0/C18:1ω9 and (C16:0 + C16:1ω7)/(C18:0 + C18:1ω9) ratios in triglycerides. These findings extend to the brain, the knowledge of alterations in phospholipid and triglyceride content and/or fatty acid pattern in GK rats, as compared to N or STZ rats. The former rats indeed displayed: (i) an apparently increased activity of Δ9- and Δ6-desaturases, as suggested by the phospholipid measurements, and a decreased C20:5ω3 content in such phospholipids; (ii) a dramatic increase in brain triglyceride content; and (iii) an increased activity of Δ9-desaturase, as well as elongase, as judged from the triglyceride data.

Effects of Type II diabetes on capillary hemodynamics in skeletal muscle

Microcirculatory red blood cell (RBC) hemodynamics are impaired within skeletal muscle of Type I diabetic rats (Kindig CA, Sexton WL, Fedde MR, and Poole DC. Respir Physiol 111: 163-175, 1998). Whether muscle microcirculatory dysfunction occurs in Type II diabetes, the more prevalent form of the disease, is unknown. We hypothesized that Type II diabetes would reduce the proportion of capillaries supporting continuous RBC flow and RBC hemodynamics within the spinotrapezius muscle of the Goto-Kakizaki Type II diabetic rat (GK). With the use of intravital microscopy, muscle capillary diameter (d(c)), capillary lineal density, capillary tube hematocrit (Hct(cap)), RBC flux (F(RBC)), and velocity (V(RBC)) were measured in healthy male Wistar (control: n = 5, blood glucose, 105 +/- 5 mg/dl) and male GK (n = 7, blood glucose, 263 +/- 34 mg/dl) rats under resting conditions. Mean arterial pressure did not differ between groups (P > 0.05). Sarcomere length was set to a physiological length ( approximately 2.7 mum) to ensure that muscle stretching did not alter capillary hemodynamics; d(c) was not different between control and GK rats (P > 0.05), but the percentage of RBC-perfused capillaries (control: 93 +/- 3; GK: 66 +/- 5 %), Hct(cap), V(RBC), F(RBC), and O(2) delivery per unit of muscle were all decreased in GK rats (P < 0.05). This study indicates that Type II diabetes reduces both convective O(2) delivery and diffusive O(2) transport properties within muscle microcirculation. If these microcirculatory deficits are present during exercise, it may provide a basis for the reduced O(2) exchange characteristic of Type II diabetic patients.

What are Arrhythmogenic Substrates in Diabetic Rat Atria?

Diabetes mellitus is one of the significant independent risk factors for the development of atrial fibrillation (AF). However, the pathophysiological mechanisms of the relationship have not been fully elucidated. The genetic type II diabetes (GK) rats and their original (Wistar) ones were subjected to electrophysiological (n = 8 per group) and histological (n = 7 per group) studies. At 40 weeks old, when GK rats had significantly (P < 0.01) more increased plasma glucose and HbA(1c) values than Wistar rats, atrial electrical stimuli in the isolated-perfused hearts induced significantly greater number of repetitive atrial responses in GK rats than in Wistar rats (47.9 +/- 17.5 vs 3.1 +/- 1.3 beats, respectively, P < 0.01). GK rats showed significantly longer intra-atrial activation time than Wistar rats (18.3 +/- 0.4 ms vs 15.9 +/- 0.5 ms, P < 0.01) without any significant difference in the atrial refractoriness. The histological examination revealed significantly increased diffuse fibrotic deposition in GK rats atria compared with Wistar ones (P < 0.01). The present diabetic GK rat showed increased atrial arrhythmogenicity with intra-atrial conduction disturbance, and thus indicated that the structural remodeling of atrium characterized by diffuse interstitial fibrosis would be a major substrate for diabetes-related AF.

Danggui–Buxue–Tang decoction has an anti-inflammatory effect in diabetic atherosclerosis rat model

Danggui–Buxue–Tang (DBT) is a famous traditional Chinese formula. We examined the anti-inflammatory effect of it in diabetic atherosclerosis rats. DBT (3 or 6 g/kg/day for 4 weeks) was orally administrated to the diabetic atherosclerosis rats, which were induced by nitric oxide inhibition ( l-NAME in drinking water, 1 mg/ml) plus high-fat diet. The concentrations of circulating inflammatory markers C-reactive protein (CRP) and tumour necrosis factor-α (TNF-α) and serum fructosamine were determined. The results showed that DBT had no direct effect in lowering serum fructosamine level, but can decrease the concentrations of CRP and TNF-α, produce a higher survival rate and less body weight loss, and decrease water intake in diabetic atherosclerosis in GK rats.

Periodontitis Deteriorates Metabolic Control in Type 2 Diabetic Goto‐Kakizaki Rats

Epidemiologic and clinical studies have indicated that periodontal disease (PD) may cause disturbances in general health and even affect diabetes. The aim of this study was to gain knowledge on the effect of PD on diabetes metabolic control in a new model for type 2 diabetes-associated PD (i.e., the Goto-Kakizaki [GK] rat). GK rats represented the type 2 diabetes group and were allocated into two groups: diabetes or diabetes+PD group; Wistar rats represented the non-diabetes group and were divided into non-diabetes+PD and non-diabetes groups. PD was induced by placing ligatures around second maxillary molars, and the animals were followed for 6 weeks. Serum insulin, glucose, and free fatty acid levels were evaluated; interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha were measured in adipose tissue supernatant; glucose tolerance and insulin resistance were calculated. Further, alveolar bone destruction was estimated morphometrically and radiographically. Rats with diabetes+PD became almost 30% more glucose intolerant (P<0.01) and presented a 25% increase in IL-1beta in adipose tissue (P<0.05) compared to rats from the diabetes group. Moreover, PD associated with diabetes resulted in more alveolar bone destruction in comparison to PD in the absence of diabetes (P<0.01). Our results indicated that PD deteriorates metabolic control in diabetes, which emphasizes that PD may play a significant role for the course of diabetes. The GK rat can represent a suitable model for further studies on the association between PD and diabetes.