Non-insulin-dependent Diabetes Mellitus Model Research Articles

Development of the information quality scale for health information supply chain type 2 diabetes mellitus management using exploratory factor analysis.

Research on the quality scale of the healthcare supply chain is still limited. This study aimed to assess the information quality of the supply chain model with a focus on construct validity. Studies related to information quality measurement generally focus on measuring the dimensions of the completeness of medical records and consumer perspectives. We intended to assess the scale based on doctors needed as care coordinators on type 2 diabetes mellitus or the Non-Insulin-Dependent-Diabetes-Mellitus (NIDDM) program in primary healthcare. Sixty-four primary healthcare doctors with an age range of 24-51 years were involved in this research. The scale obtained was formed from the assessment of the point of view of a panel of experts through the content validity index (CVI). The exploratory factor analysis (EFA) method was used to explore the scale of information quality in the information supply chain model for the NIDDM chronic disease management program. The data analysis results indicated three main factors that affected the quality of the information supply chain model of NIDDM, namely accessibility, safety, and efficiency of information related to NIDDM. The results of the validity and reliability of the data showed that the scale used in this research was valid and reliable with a Cronbach alpha coefficient of 0.861. The scale developed in this research could be used to explore the quality of the information supply chain of NIDDM management in primary healthcare. Each item on the scale could explain the variables according to their respective groups.

Multimodal Imaging Analyses of Brain Hippocampal Formation Reveal Reduced Cu and Lipid Content and Increased Lactate Content in Non-Insulin-Dependent Diabetic Mice.

Non-insulin-dependent diabetes mellitus (NIDDM) is reported to increase the risk of cognitive impairment and dementia. However, the underlying mechanisms are not fully understood. While the brain homeostasis of metals and lipids is pivotal to maintaining energy metabolism and redox homeostasis for healthy brain function, no studies have reported hippocampal metal and biochemical changes in NIDDM. Therefore, we here utilized direct spectroscopic imaging to reveal the elemental distribution within the hippocampal subregions of an established murine model of NIDDM, db/db mice. In 26-week-old insulin resistant db/db mice, X-ray fluorescence microscopy revealed that the Cu content within the dentate gyrus and CA3 was significantly greater than that of the age-matched nondiabetic control mice. In addition, Fourier transform infrared (FTIR) spectroscopy analysis indicated a significant increase in the abundance of lactate within the corpus callosum (CC), dentate gyrus, CA1, and CA3 regions of diabetic db/db mice compared to that of the control, indicating altered energy metabolism. FTIR analysis also showed a significant decrease in the level of lipid methylene and ester within the CC of db/db mice. Furthermore, immunomicroscopy analyses demonstrated the increase in the level of glial fibrillary acidic protein expression and peri-vascular extravasation of IgG, indicating astrogliosis and blood-brain barrier dysfunction, respectively. These data suggest that astrogliosis-induced alterations in the supply of Cu, lipids, and energy substrates may be involved in the mechanisms of NIDDM-associated cognitive decline.

Neurolytic celiac plexus block enhances skeletal muscle insulin signaling and attenuates insulin resistance in GK rats.

Non-insulin-dependent diabetes mellitus (NIDDM) is associated with chronic inflammatory activity and disrupted insulin signaling, leading to insulin resistance (IR). The present study investigated the benefits of neurolytic celiac plexus block (NCPB) on IR in a rat NIDDM model. Goto-Kakizaki rats fed a high-fat, high-glucose diet to induce signs of NIDDM were randomly divided into NCPB and control groups; these received daily bilateral 0.5% lidocaine or 0.9% saline injections into the celiac plexus, respectively. Following 14 and 28 daily injections, rats were subject to oral glucose tolerance tests (OGTTs) or sacrificed for the analysis of serum free fatty acids (FFAs), serum inflammatory cytokines and skeletal muscle insulin signaling. Compared with controls, rats in the NCPB group demonstrated significantly (P<0.05) lower baseline, 60-min and 120-min OGTT values, lower 120-min serum insulin, lower IR [higher insulin sensitivity index (ISI1) and lower ISI2) and lower serum FFAs, tumor necrosis factor-α, interleukin (IL)-1β and IL-6. Conversely, NCPB rats exhibited higher basal and insulin-stimulated skeletal muscle glucose uptake and higher skeletal muscle insulin receptor substrate-1 (IRS-1) and glucose transporter type 4 expression. There were no differences between the groups in insulin receptor β (Rβ) or Akt expression; however Rβ-Y1162/Y1163 and Akt-S473 phosphorylation levels were higher and IRS-1-S307 phosphorylation were lower in NCPB rats than in the controls. These results indicate that NCPB improved insulin signaling and reduced IR, possibly by inhibiting inflammatory cytokine release.

Bioenergetics of Contractile Function in Heart Trabeculae from Diabetic Rats

Morbidity in non-insulin dependent diabetes mellitus (NIDDM) patients is commonly linked to cardiomyopathy, but the mechanisms involved in heart dysfunction are not well understood. In this study, the Zucker diabetic fatty (ZDF) rat was utilized as an animal model of NIDDM. Herein we present a comparative bioenergetic characterization of working heart trabeculae from ZDF and its lean control subjected to changes in workload through pacing frequency. We monitored in parallel the developed force and respiratory rate in the absence and presence of increasing levels of insulin.

Effect of N-benzoyl-d-phenylalanine on streptozotocin-induced changes in the lipid and lipoprotein profile in rats

The effect of N-benzoyl-D-phenylalanine (NBDP) and metformin combination treatment on circulatory lipids, lipoproteins and lipid peroxidation markers were studied in neonatal streptozotocin (nSTZ) non-insulin dependent diabetic rats. Non-insulin dependent diabetes mellitus (NIDDM) was induced by a single dose injection of streptozotocin (100 mg kg(-1), i. p.) to two-day-old rats. After 10-12 weeks, rats weighing above 150 g were selected for screening for the NIDDM model. The rats were checked for fasting blood glucose levels to confirm the status of NIDDM. NBDP (50,100 or 200 mg kg(-1) ) was administered orally for six weeks to the confirmed diabetic rats (to evaluate the effective dose). The levels of serum lipids and lipid peroxidation markers were significantly increased, whilst the activity of glucose-6-phosphate dehydrogenase was significantly decreased in nSTZ diabetic rats. NBDP and metformin were able to restore the altered serum lipids, lipoproteins, lipid peroxidation marker levels and glucose-6-phosphate dehydrogenase activity to almost control levels. The results showed the antihyperlipidaemic properties of NBDP and metformin in addition to its antidiabetic action. Combination treatment was more effective then either drug alone. The results indicated that the coadministration of NBDP with metformin to nSTZ diabetic rats normalized blood glucose and caused marked improvement in altered serum lipids, lipoproteins and lipid peroxidation markers during diabetes. The data indicated that NBDP represented an effective antihyperglycaemic and antihyperlipidaemic adjunct for the treatment of diabetes, and may be a potential source of new orally active agents for future therapy.

Insulin resistance associated with leptin deficiency in mice: a possible model for noninsulin-dependent diabetes mellitus.

Leptin deficiency, found in transgenic lipodystrophic mice and in obese (ob/ob) mice, was shown to cause increased lipogenesis in liver, through action of the sterol regulatory element-binding protein-1c, and increased liver gluconeogenesis, through a decline in the insulin receptor substrate-2. The resulting stimulation of insulin secretion by the pancreas owing to high blood glucose initiates a vicious cycle of insulin resistance.

Dietary Supplementation with Watermelon Pomace Juice Enhances Arginine Availability and Ameliorates the Metabolic Syndrome in Zucker Diabetic Fatty Rats ,

Watermelon is rich in L-citrulline, an effective precursor of L-arginine. This study was conducted to determine whether dietary supplementation with watermelon pomace juice could ameliorate the metabolic syndrome in the Zucker diabetic fatty (ZDF) rat, an animal model of noninsulin-dependent diabetes mellitus. Nine-week-old ZDF rats were assigned randomly to receive drinking water containing 0% (control) or 0.2% L-arginine (as 0.24% L-arginine-HCl), 63% watermelon pomace juice, 0.01% lycopene, or 0.05% citrus pectin (n = 6 per treatment). At the end of the 4-wk supplementation period, blood samples, aortic rings, and hearts were obtained for biochemical and physiological analyses. Feed or energy intakes did not differ among the 5 groups of rats. However, dietary supplementation with watermelon pomace juice or L-arginine increased serum concentrations of arginine; reduced fat accretion; lowered serum concentrations of glucose, free fatty acids, homocysteine, and dimethylarginines; enhanced GTP cyclohydrolase-I activity and tetrahydrobiopterin concentrations in the heart; and improved acetylcholine-induced vascular relaxation. Compared with the control, dietary supplementation with lycopene or citrus pectin did not affect any measured parameter. These results provide the first evidence to our knowledge for a beneficial effect of watermelon pomace juice as a functional food for increasing arginine availability, reducing serum concentrations of cardiovascular risk factors, improving glycemic control, and ameliorating vascular dysfunction in obese animals with type-II diabetes.

Effect of chronic administration of &lt;i&gt;Boerhaavia diffusa&lt;/i&gt; Linn. leaf extract on experimental diabetes in rats

Purpose: The root and aerial parts of Boerhaavia diffusa Linn. (Nyctaginaceae) were used in Ayurveda for the treatment of diabetes. The present study is aimed at evaluating the antidiabetic activity of chloroform extract of Boerhaavia diffusa leaves on chronic administration in streptozotocin-induced non-insulin-dependent diabetes mellitus (NIDDM) model diabetic rats. Methods: The blood glucose lowering activity of the leaf extract was studied in streptozotocininduced (65 mg/kg, i.v.) NIDDM model diabetic rats after oral administration of the extract at daily doses of 50, 100 and 200 mg/kg body weight for four weeks and compared with glibenclamide. Blood samples were collected from the tail vein before and also at weekly intervals for four weeks from the first dose of drug administration and blood glucose was analyzed by glucose-oxidase method using a visible spectrophotometer. Results: The leaf extract of B. diffusa produced dose-dependent reduction in blood glucose in streptozotocin-induced NIDDM rats comparable to that of glibenclamide. The results indicate that the reduction in blood glucose produced by the extract is probably through rejuvenation of pancreatic β-cells or through extrapancreatic action. Conclusion: The chloroform extract of Boerhaavia diffusa has significant antidiabetic activity and this supports the traditional usage of the plant by Ayurvedic physicians for the control of

Glycoprotein Changes in Non-Insulin Dependent Diabetic Rats: Effect of N-Benzoyl-D-Phenylalanine and Metformin

AbstractThe effect of N-benzoyl-D-phenylalanine (NBDP) and metformin on neonatal streptozotocin (nSTZ) induced diabetes has been studied on plasma and tissue glycoproteins. In some pathological conditions, such as cancer, rheumatoid arthritis and diabetes, there is an abnormal glycosylation of acute phase serum proteins. As most serum proteins are produced in the liver, we have examined glycoprotein metabolism in diabetic condition. To induce non-insulin-dependent diabetes mellitus (NIDDM) a single dose of streptozotocin (100 mg/kg body weight) was injected into two day old rats. After 1012 weeks, rats weighing above 150g were selected for NIDDM model. In these rat, blood glucose and plasma glycoproteins were significantly increased whereas plasma insulin was significantly decreased. There was a significant decrease in the level of sialic acid and elevated levels of hexose, hexosamine and fucose in tissues. Oral administration of NBDP and metformin to diabetic rats decreased blood glucose and plasma glycoproteins. Plasma insulin and tissue sialic acid were increased whereas tissue concentrations of hexose, hexosamine and fucose were near normal. Our study suggests that NBDP and metformin possess a significant beneficial effect on glycoproteins in addition to their antidiabetic effect.

Diabetic Complications in a New Animal Model (TSOD mouse) of Spontaneous NIDDM with Obesity

The TSOD mouse has been established as an inbred strain with spontaneous development of diabetes mellitus as the first clinical signs of diabetes. Polydipsia and polyuria are observed at about 2 months old only in male mice, after which hyperglycemia and hyperinsulinemia are detected. Following these symptoms obesity gradually develops until about 12 months old. In histopathological examination of the pancreas, severe hypertrophy of pancreatic islets was observed due to proliferation and swelling of B cells. In the kidney, thickening of the basement membrane in glomeruli and an increase of the mesangial area were observed at 18 months old. Motor neuropathy in TSOD mice began to appear at 14 months old and most male mice at 17 months old showed weakness of front and hind paws caused by neuron degeneration in the peripheral nerve. In sensory neuropathy, the threshold in the tail pressure test decreased significantly at 12 months old. Light microscopic and electron microscopic examination of sciatic nerves showed a decrease in the density of nerve fibers by the endoneural fibrosis and loss of these fibers. Degenerative changes of myelinated fibers, separation of myelin sheaths with intralamellar edema and remyelination were frequently observed. In the severely affected nerve fibers, the lamellar structure was completely destroyed and macrophages migrated around the myelin sheath or invaded the intramyelin space. Considering these findings similar to non-insulin dependent diabetes mellitus (NIDDM) in humans, the TSOD mouse should be a useful model for the pathogenic study of diabetic complications, especially of peripheral neuropathy.

Effect of N-benzoyl- d-phenylalanine and metformin on carbohydrate metabolic enzymes in neonatal streptozotocin diabetic rats

Background The effect of N-benzoyl- d-phenylalanine (NBDP) and metformin was studied on the activities of carbohydrate metabolic enzymes in neonatal streptozotocin (nSTZ) non-insulin-dependent diabetic rats. Methods To induce non-insulin-dependent diabetes mellitus (NIDDM), single dose injection of streptozotocin (STZ; 100 mg/kg body weight; i.p.) was given to 2-day old rats. After 10–12 weeks, rats weighing >150 g were selected for screening in NIDDM model, they were checked for fasting blood glucose concentrations to conform the status of NIDDM. NBDP (50,100 and 200 mg/kg body weight) was administered orally for 6 weeks into the confirmed diabetic rats. Results The activities of gluconeogenic enzymes were significantly increased, whereas the activities of hexokinase and glucose-6-phosphate dehydrogenase were significantly decreased in nSTZ diabetic rats. Both NBDP and metformin were able to restore the altered enzyme activities to almost control concentrations. Combination treatment was more effective than either drug alone. Conclusion The administration of NBDP along with metformin to nSTZ diabetic rats normalizes blood glucose and causes marked improvement of altered carbohydrate metabolic enzymes during diabetes.

Angiotensin-Converting enzyme inhibition and angiogenesis in myocardium of obese Zucker rats

Background Obesity, hypertension, and non-insulin-dependent diabetes mellitus (NIDDM) are associated with microvascular rarefaction in the myocardium and this contributes to increase cardiovascular morbidity and mortality. At present, controversial data exist in medical literature regarding the specific role of angiotensin-converting enzyme (ACE) inhibitors concerning angiogenesis in different tissues. The present study was designed to determine the possible beneficial effects of an ACE inhibitor perindopril on myocardial angiogenesis in an animal model of obesity, hypertension, and NIDDM, such as the obese Zucker rat (OZR) and control lean Zucker rats (LZR). Methods and results Ten-week-old male OZR ( fa/fa) and LZR (Fa/ fa) were used in this study: OZR group (G1, n = 10), OZR with perindopril group (G2, n = 10); LZR group (G3, n = 10). For 6 months, G2 received a daily dose of 3 mg/kg of perindopril, by gavage, and G1 and G3 received an equal volume of vehicle throughout the experiment. After 6 months of treatment, all rats were killed, hearts were harvested for pathology studies, including immunohistochemistry, using monoclonal antibodies against rat endothelial cell (RECA-1) and endothelial nitric oxide synthase. At the end of the study, OZR treated with perindopril presented: 1) lower blood pressure (BP) (127 ± 3.2 v 152.4 ± 3 mm Hg, P < .01) and 2) lower heart weight/100 g body weight (0.22 ± 0.02 v 0.36 ± 0.04 g, P < .01) than OZR untreated. Moreover, OZR that received perindopril showed higher: 1) myocyte density (2044 ± 67 v 847 ± 91 myocytes/mm 2, P < .01) and 2) capillary density (1348 ± 118 v 436 ± 78 capillaries/mm 2, P < .01); higher amount of: 1) vascular endothelial growth factor (VEGF) in the myocardium ( P < .01) and higher percentage of capillaries with positive immunostaining for eNOS ( P < .01), compared with untreated OZR. There was a correlation between both the amount of VEGF in myocardium and the number of capillaries ( r = 0.88; P < .01) and VEGF and eNOS expression in myocardial capillaries ( r = 0.93; P < .01) in OZR treated with perindopril. Finally, OZR that received P showed an improvement in insulin/glucose ratio ( P < .01) when compared with untreated OZR. Conclusions These results suggest that ACE inhibition by perindopril improves myocardial angiogenesis in this animal model of human metabolic syndrome. The pathway that involves bradykinin, eNOS, and VEGF could be involved in this effect; however, because no additional antihypertensive treatment group was included in our study, the BP-lowering effect cannot be excluded.

Cardiovascular protective role of a low-dose antihypertensive combination in obese Zucker rats.

Obesity, non-insulin-dependent diabetes mellitus (NIDDM) and hypertension are leading causes associated with increased cardiovascular morbidity and mortality. In modern times, the combined first line antihypertensive therapy with at least two drugs with a different mechanism of action to achieve a better blood pressure control, is increasing in acceptance worldwide. The aim of the present study was to determine possible beneficial effects of the low-dose combination (LDC) of an angiotensin-converting enzyme (ACE) inhibitor, perindopril (PER), and the diuretic indapamide (IND), regarding myocardial and vessels protection in an animal model of hypertension, obesity and NIDDM, such as the obese Zucker rat (OZR), and control lean Zucker rats (LZR). Ten-week-old male OZR (fa/fa) and LZR (Fa/fa) were used in this study. OZR group (G1, n=8), OZR with LDC group (G2, n=8); LZR group (G3, n=8) and LZR with LDC group (G4, n=8). During 6 months, G2 and G4 received a daily dose of 1 mg/kg combination of 0.76 mg/kg PER + 0.24 mg/kg IND, (ratio of doses 0.32), by gavage, and G1 and G3 received an equal volume of vehicle throughout the experiment. In order to evaluate cardiac dimensions and left ventricular mass (LVM) transthoracic echocardiograms were performed, at baseline and at the end of the experiment. Urine and blood samples for biochemical determination were obtained. After 6 months of treatment all rats were sacrificed, hearts were harvested for light microscopy (LM), high-resolution light microscopy (HRLM), immunohistochemistry including monoclonal antibodies against transforming growth factor beta (TGFbeta1) and anti-collagen type I (COL I) and type III (COL III) and electron microscopy (EM) studies. At the end of the study OZR treated with LDC presented: (1) lower blood pressure (128.9 +/- 4 versus 150.3 +/- 3.6 mmHg, P< 0.05); (2) smaller cardiac dimensions (P< 0.01); (3) lower LVM/100 g body weight (0.17 +/- 0.02 versus 0.30 +/- 0.05, P< 0.01); (4) higher fractional shortening (34.5 +/- 3.2 versus 23.3 +/- 5.9%, P< 0.01) than OZR untreated. Moreover, OZR that received LDC showed higher: (1) myocyte density (48 +/- 1.5 versus 20 +/- 2.5 myocytes/area, P< 0.01); (2) capillary density (30.5 +/- 3.1 versus 9.5 +/- 1.6 capillaries/area, P<0.01); (3) myofilament thickness (12.05 +/- 0.27 versus 9.83 +/- 0.39 nm, P<0.01); and lower amounts of: (1) TGFbeta1 in myocytes (P< 0.01), interstitium (P< 0.01) and vessel wall (P< 0.05); (2) COL I and COL III (P< 0.01), and COL I /COL III ratio (P< 0.01), compared with untreated OZR. Finally, OZR-treated with LDC showed not only unsubstantial modification in carbohydrate and lipid metabolism when compared with untreated OZR, but also an improvement in insulin/glucose ratio (P< 0.05). These results suggest that LDC of PER + IND can control cardiovascular damage in OZR providing an additional help in the metabolic scenario likewise.

Osteoporosis in the Cohen Diabetic Rat: Correlation Between Histomorphometric Changes in Bone and Microangiopathy

Osteoporosis is well documented in type I diabetes, but its occurrence is controversial in type II diabetes. Microangiopathy is a major complication of type I and type II diabetes. We studied bone and microvascular changes in the Cohen diabetic rat, a unique nonobese model of noninsulin-dependent diabetes mellitus. The aim of this study was to find whether there is a temporal correlation between the onset of these two complications. The diabetic rats were divided into three groups (A, B, and C) according to duration of diabetes (2 months, 3 months, and 7 to 8 months, respectively). Trabecular bone area was assessed by computerized image analysis and microangiopathy by means of renal function tests, histologic examination of the kidneys, and ultrastructural measurement of the width of capillary basement membranes. Bone density of the distal femur and vertebra was significantly reduced in the diabetic rats relative to the control rats in all three groups (Group A femur: 11.5 ± 1.6% versus 21.8 ± 3.0%, p < 0.02; Group A vertebra: 15.9 ± 1.6% versus 28.5 ± 2.0%, p < 0.02; Group C femur: 7.9 ± 1.1% versus 29.6 ± 3.5%, p < 0.001; Group C vertebra: 11.4 ± 0.7% versus 37.1 ± 1.9%, p < 0.002). Renal function tests were normal in the Group A diabetic rats and there was marked albuminuria in the Group C diabetic rats. Histologic changes in the kidneys were seen only in the Group C diabetic rats. Five of 15 Group C diabetic rats showed no albuminuria or histologic evidence of kidney damage. The bone density in this subgroup was reduced relative to controls to the same degree as that of the rats with renal damage. There was no evidence of capillary basement membrane thickening in the Group A diabetic rats. Our findings indicate that in the Cohen diabetic rat, osteoporosis precedes the onset of microangiopathy. Microangiopathy probably does not play an important role in the pathogenesis of osteoporosis in this animal model.

Role of ANG II in coronary capillary angiogenesis at the insulin-resistant stage of a NIDDM rat model.

With the use of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of human non-insulin-dependent diabetes mellitus (NIDDM), we assessed whether ANG II is involved in coronary capillary angiogenesis at the insulin-resistant stage of NIDDM (20 wk of age). In OLETF rats, ANG II labeling and angiotensin type 1 (AT(1)) receptor expression in coronary vessels were increased more than in nondiabetic controls. A marked increase in vascular expression of vascular endothelial growth factor (VEGF) at both mRNA and protein levels was found in OLETF rats. The increased expression level of VEGF was associated with accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) activated by increased advanced glycation end products (AGEs). Morphometric analysis showed a significantly increased total coronary capillary density, which was a result of arterialization of the venular capillary portion in OLETF rats. Treatment of OLETF rats with candesartan, an AT(1) receptor blocker, inhibited vascular expressions of VEGF, HIF-1alpha, and AGEs, and ameliorated the morphometric changes. These results suggest a key role of ANG II in the pathogenesis of the coronary capillary remodeling in this NIDDM model.

Identification of seven loci for static glucokinesis and dynamic glucokinesis in mice

Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by a breakdown of glucose homeostasis and is responsible for serious complications in various organs and vessels. Most of the genetic factors of NIDDM are yet unknown. Here, we identified two types of genetic factors that regulate homeostasis of blood glucose by measuring various pharmacokinetic parameters, some of which are used in the non-compartment analysis of drug metabolism in 340 F(2) progeny from the NIDDM model KK-A(y)/Ta Jcl mouse strain, and in non-diabetic PWK strain. We define "static glucokinesis" as the regulation of homeostasis that occurs during glucose deprivation, and "dynamic glucokinesis" as that during glucose stress; for instance, glucose tolerance test. Quantitative trait locus analysis revealed eight loci involved in the regulation of glucose homeostasis on chromosomes 7 ( Nidd1k), 2 ( Nidd2k), 1 ( Nidd3k, Nidd4k, and Nidd5k), 11 ( Nidd6k), 5 ( Nidd7k) (named Nidd1k through Nidd7k), and 4 ( Bwt1k). Nidd1k, Nidd4k, and Nidd7k were novel loci associated with NIDDM in mice. Nidd1k, Nidd2k, Nidd3k, and Nidd4k had linkage to factors characteristic of both static and dynamic glucokinesis. Nidd5k and Nidd6k showed linkage specific to markers of dynamic glucokinesis, and Nidd7k had linkage specific to static glucokinesis. Bwt1k was linked to obesity. Thus, the genetic factors for static glucokinesis and those for dynamic glucokinesis partially overlapped.

Norepinephrine transporter density as a causative factor in alterations in MIBG myocardial uptake in NIDDM model rats

Cardiac scintigraphic studies with iodine-123 labeled metaiodobenzylguanidine ([(123)I]MIBG) have demonstrated global and regionally pronounced decreases in myocardial accumulation of radioactivity in diabetes. The aim of this study was to investigate the cause of the regional differential decrease in accumulation. To this end, we investigated the global and regional myocardial distribution of [(125)I]MIBG in GK/Crj (GK) rats [a model of non-insulin-dependent diabetes mellitus (NIDDM)] and assessed the responsibility of regional myocardial blood flow, myocardial and plasma norepinephrine (NE) content, and norepinephrine transporter (NET) function for the regional variations in [(125)I]MIBG accumulation. To investigate the responsibility of myocardial blood flow for the alterations in MIBG accumulation, dual-isotope autoradiographic studies with [(125)I]MIBG and technetium-99m hexakis-2-methoxy-2-isobutylisonitrile (MIBI), a tracer for the measurement of myocardial blood flow, were carried out in GK rats and control rats. The results in respect of the uptake of radioactivity into various myocardial regions were expressed as distribution absorption ratios [DAR = (radioactivity of tissue/g of tissue) x (body weight/total injected dose)]. In control rats, uptake of [(125)I]MIBG was significantly higher in the inferior wall than in the anterior wall (anterior wall, 6.35 +/- 0.90; inferior wall, 8.12 +/- 1.27: P < 0.001). On the other hand, in GK rats, uptake of [(125)I]MIBG was similar between the anterior wall and the inferior wall (anterior wall, 4.91 +/- 0.71; inferior wall, 4.81 +/- 0.69). Compared with control rats, uptake of [(125)I]MIBG in GK rats was decreased in both the anterior wall and the inferior wall. Uptake of (99m)Tc-MIBI was not significantly different between the anterior and inferior walls in control (anterior wall, 17.9 +/- 4.42; inferior wall, 18.1 +/- 4.52) and GK rats (anterior wall, 16.6 +/-8.03; inferior wall, 16.7 +/- 7.90), indicating that myocardial blood flow did not change regionally in either control or GK rats, and that the blood flow was not responsible for the differential decrease in MIBG accumulation in GK rats. Cardiac and plasma NE levels were measured using an HPLC-electrochemical detection system. The cardiac and plasma NE concentrations were not significantly different between control (anterior wall, 347 +/- 56 ng/g; inferior wall, 354 +/- 31 ng/g; plasma 9.38 +/- 2.10 ng/ml) and GK rats (anterior wall, 323 +/- 62 ng/g; inferior wall, 344 +/- 35 ng/g; plasma, 9.41 +/- 2.39 ng/ml). The density and affinity of NET were investigated by studying the binding of [(3)H]desipramine to cardiac membranes. The B(max) (fmol/mg protein) in the inferior wall was significantly higher than that in the anterior wall in the control rats (anterior wall, 364 +/- 28; inferior wall, 459 +/- 36: P < 0.05). On the other hand, there was no significant difference in the B(max) value between the anterior and inferior walls in GK rats (anterior wall, 263 +/- 42; inferior wall, 251 +/- 27). In conclusion, myocardial MIBG uptake was differentially reduced in GK rats, and this decrease was associated with a decrease in NET density, but the regional myocardial blood flow and the NE concentration were not responsible for the alterations in MIBG uptake. Thus, NET density was identified as the factor responsible for decreases in MIBG accumulation.

Pathogenesis of obesity by food restriction in OLETF rats-increased intestinal monoacylglycerol acyltransferase activities may be a crucial factor

Obesity was considered to be one of the causes of non-insulin-dependent diabetes mellitus (NIDDM). However, the mechanism responsible for obesity has not yet been fully elucidated. In this study, we first examined the relationship between food intake amount and obesity in a NIDDM model animal, and then we focused on triacylglycerol (TG) synthetase activity, which play important roles in hypertriglyceridemia (HTG) associated with obesity. Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model of NIDDM, characterized by obesity, HTG and insulin resistance. In this study, OLETF rats were allocated to a food-satiated group (satiated) or food-restricted group (to eliminate the effects of hyperphagia on obesity, amount of daily food intake was the same as that in their control strain Long-Evans Tokushima Otsuka (LETO) rats). Changes in body weight, body fat, intraabdominal fat weight, and TG content in liver were measured and biochemical blood tests and activity assay of TG synthetase (monoacylglycerol acyltransferase (MGAT) and diacylglycerol acyltransferase (DGAT)) were performed. Results: (1) The body weight in the restricted OLETF rats was significantly decreased to 71.7% of that in the satiated OLETF rats, which was almost the same value as that in the LETO rats. However, body fat and intraabdominal fat weight were significantly increased in restricted OLETF rats and satiated OLETF rats compared with LETO rats. (2) Plasma TG, insulin, glucose, leptin and hepatic TG content were significantly higher in OLETF rats than the values in LETO rats. (3) MGAT activity in the small intestine from both satiated and restricted OLETF rats was significantly higher than that in LETO rats. DGAT activity in OLETF rats was not significantly different from that in LETO rats. In conclusion, the body fat weight and plasma TG were still significantly accelerated in OLETF rats at the same food intake as LETO rats. MGAT activity in the small intestine from OLETF rats was also significantly higher than those of LETO rats. Therefore, high MGAT activity in the small intestine may play an important role in HTG and obesity, subsequently hastening the development of NIDDM in OLETF rats.

Dehydrotrametenolic acid induces preadipocyte differentiation and sensitizes animal models of noninsulin-dependent diabetes mellitus to insulin.

We recently discovered that the triterpene acid compound dehydrotrametenolic acid promotes adipocyte differentiation in vitro and acts as an insulin sensitizer in vivo. This natural product has been isolated from dried sclerotia of Poria cocos WOLF (Polyporaceae), a well-known traditional Chinese medicinal plant. We examined the effects of dehydrotrametenolic acid on plasma glucose concentration in obese hyperglycemic db/db mice. Dehydrotrametenolic acid can reduce hyperglycemia in mouse models of noninsulin-dependent diabetes mellitus (NIDDM) and act as an insulin sensitizer as indicated by the results of the glucose tolerance test. These terpenoids and thiazolidine type of antidiabetic agents such as Ciglitazone, although structurally unrelated, share many biological activities: both induce adipose conversion, activate peroxisome proliferator-activated receptor gamma (PPAR gamma) in vitro, and reduce hyperglycemia in animal models of NIDDM. Dehydrotrametenolic acid is a promising candidate for a new type of insulin-sensitizing drug. This finding is very important for the development of insulin sensitizers that are not of the thiazolidine type.

Increased lymphatic lipid transport in genetically diabetic obese rats.

Otsuka Long-Evans Tokushima fatty (OLETF) rats are a model for noninsulin-dependent diabetes mellitus (NIDDM), which is first manifested at 18 wk of age. We assessed age-related changes in lymphatic lipid transport in the intestine of OLETF rats and compared them with those of control Long-Evans Tokushima Otsuka (LETO) rats. Olive oil was infused into the rats with a mesenteric lymph fistula, which was created under ethrane anesthesia. A significant increase in lymphatic triglyceride (TG) transport in OLETF rats was observed at 18-19 wk compared with under 17 wk, but no age-related change was observed in LETO rats. Food restriction, exercise training, or troglitazone treatment in OLETF rats prevented the age-related increase in lipid transport. Biliary phosphatidylcholine concentration was higher in OLETF rats than in LETO rats, but no difference was seen in bile acid concentrations or the activity of microsomal TG transfer protein between the two strains. This study shows that increased lipid transport in the intestine may occur in NIDDM.