DM Rats Research Articles

Electrical Responses from the Inner Retina of Rats with Streptozotocin-induced Early Diabetes Mellitus

Purpose: To evaluate behavior of the scotopic threshold response (STR) and the oscillatory potential (OP) in the electroretinogram (ERG) in streptozotocin (STZ)-induced diabetic rats (DM rats). Methods: The amplitude of the STR and the OP 3, the implicit time of the STR, and the peak latency of the OP 3 of the DM rats were measured. Results: No significant differences were observed in the mean amplitude or the mean implicit time of the STR between the control and the DM rats. On the other hand, the mean peak latency of OP 3 of the DM rats was significantly prolonged up to 125% of the control rats ( P<0.01), although there were no significant differences between the two groups in the mean OP 3 amplitude. Conclusions: Although both STR and OP were of inner retinal origin, their behavior was different in DM rats. This result supported some reports describing how dopaminergic amacrine cells generate OP and glycinergic or GABAergic amacrine cells generate STR. In the early stage of diabetic retinopathy, there may be not only minor ischemia but also disorder of neurotransmission of the amacrine cells in the inner retinal layers.

T-Type calcium channel blockage ameliorates proteinuria and renal extracellular matrix accumulation in experimental diabetic rats

Calcium channels have been shown to play an important role in the pathogenesis of diabetic nephropathy. The purpose of this study is to investigate the effect of T-type calcium channel blockers in uninephrectomized diabetic rats. Two weeks after uninephrectomy, streptozotocin (65 mg/kg) was given to male Sprague-Dawley rats to induce diabetes mellitus. In the succeeding days, four groups of animals were randomized to receive 30 mg/kg mibefradil (Mib, T-type calcium channel blocker), 30 mg/kg amlodipine (Aml, L-type calcium channel blocker), 10 mg/kg cilazapril (Cil, angiotensin converting enzyme inhibitor) or 25 mg/kg Mib + 8 mg/kg Cil (M+C), which were delivered daily by gavage (n = 6-8 for each group). At the fourth week, 24-hour urine, blood and kidney samples were collected for examinations. Renal morphometric analyses and assay for type IV collagen and laminin were performed. Untreated diabetic rats (DM) exhibited overt hyperglycemia, proteinuria and albuminuria when compared with uninephrectomized (UNx) control (17.67 ±4.9 vs 2.97 ±0.72 μg/24 hours, p < 0.05), while Cil and M+C treated rats had significantly reduced urinary protein excretion (Cil: 5.53 ±1.45, M+C: 3.87 ±0.88 vs DM: 17.67 ±4.9 μg/24 hours; p < 0.05, respectively). Mibefradil alone also ameliorated albuminuria in DM rats (7.69 ±1.87 vs 17.67 ±4.9 μg/24 hours, p < 0.05). Histopathological study revealed significantly less glomerular matrix, laminin, type IV collagen and proximal tubule cells (PTC) hypertrophy in the Cil and M+C groups when compared with the DM group (Collagen IV: DM 7.3 ±0.65 vs Mib 4.82 ±0.78, Cil 4.11 ±0.74, M+C 2. 64 ±0.66, UNx 3.71 ±0.99, p < 0.05). Albuminuria, glomerular matrix accumulation and collagen IV deposition were not changed in the Aml treated group. There was, however, significantly lower creatinine clearance and laminin volume in the Aml group. In conclusion, our study demonstrated that T-type calcium channel blockage reduced albuminuria and renal extracellular matrix accumulation in experimental diabetic rats, suggesting an important role for T-type calcium channel in the progression of diabetic nephropathy. Additional benefit can be achieved by combination with an angiotensin converting enzyme inhibitor. The mechanism of action, however, requires further investigation.

Alteration of antioxidants during the progression of heart disease in streptozotocin-induced diabetic rats

Involvement of oxidative stress is implicated in the progression of complication of diabetes mellitus. With respect to heart diseases, we have studied role of oxidative stress/antioxidants using rats treated with streptozotocin to induce diabetes (DM). Hemodynamic and echocardiographic measurements showed thickening of the wall and an increase in the internal dimension of the left ventricle (LV) in DM rats at 8th week. Decrease in diastolic posterior wall velocity and rate of LV pressure change, and increase in LV end diastolic pressures also proved cardiac dysfunction. These changes were further developed in DM rats after 12 weeks. Utilizing rat hearts at 8th and 12th weeks, the following estimations were performed. There was a decrease in the activity of Mn-superoxide dismutase (SOD), suggesting abnormal mitochondrial metabolism of reactive oxygen species. The level of glutathione (GSH) decreased concomitant with a decrease in the expression of γ-glutamylcysteine synthetase (γ-GCS). The expression of transforming growth factor-β1 (TGF-β1), known as a growth factor and a suppressor of GSH synthesis, elevated in DM rat hearts. Immunohistochemical estimation showed an increase in type IV collagen in DM hearts. Collectively, it was suggested a linkage between mitochondrial damage to generate reactive oxygen species and inactivation of Mn-SOD and elevation of the expression of TGF-β1 to lead suppression of GSH synthesis and induction of fibrous change for the consequent cardiac dysfunction in DM.

Scavenging effect of nicorandil on free radicals and lipid peroxide in streptozotocin-induced diabetic rats

Free radicals and lipid peroxide (LPO), easily formed in the diabetic state, play an important role in the development of diabetic complications. Potentially, nicorandil may reduce the production of free radicals and LPO in various organs. In fact, increased LPO levels in the serum, kidney, and cardiac muscle of diabetic (DM) rats were reduced by nicorandil treatment (N treatment). Xanthine oxidase (XOD), which produces free radicals, was decreased in the liver and increased in the kidney of DM rats compared with control rats, and these changes were prevented by N treatment. The concentration of Cu, Zn-superoxide dismutase (SOD) decreased in the cardiac muscle and increased in the kidney of DM rats, and these changes returned to normal after N treatment. The decreased concentration of Mn-SOD in the liver, kidney, and cardiac muscle from DM rats was also reversed by N treatment. The changes in catalase and glutathione peroxidase (GSH-PX) activities in DM rats were not improved effectively by N treatment. Another K-adenosine triphosphate (K-ATP) channel opener, tilisolol hydrochloride, had an effect similar to that of nicorandil. The effects of nicorandil and tilisolol were studied only in DM rats. These data imply that N treatment, as an antioxidative therapy, may be beneficial in preventing diabetic complications due to lipoperoxidation and free radicals in DM rats.

Renal afferent signaling diuretic response is impaired in streptozotocin-induced diabetic rats

Renal afferent signaling diuretic response is impaired in streptozotocin-induced diabetic rats. Renal insufficiency develops in diabetes and shows structural and functional abnormalities. Renal afferents, including chemoreceptors and mechanoreceptors located in the vascular and ureteropelvic portions of the kidney, may reflect changes in the environment and trigger an afferent nerve-mediated regulatory function that is known as the renorenal reflex. In this study, the involvement of these renal sensory receptors during the early diabetic state is defined. Diabetes was induced in rats after a tail vein injection of streptozotocin (STZ; 60 mg/kg intravenously). Four groups of rats, control (C), diabetic (DM), diabetic with acute insulin treatment (DMAI, 9 U/rat, subcutaneously, on the experimental day), and chronic insulin treatment (DMCI, 9 U/rat, subcutaneously, daily) were studied. Spontaneous firing type 2-renal chemoreceptor (CR2), arterial mechanoreceptor (MRa), ureteropelvic mechanoreceptor (MRu), and venous mechanoreceptor (MRv) were identified by single-unit analysis of renal afferent nervous activity. The receptor activities were confirmed by their response patterns to stimuli elicited by renal arterial occlusion (RAO), backflow of urine, increasing arterial pressure, increasing ureteropelvic pressure (UP), or renal venous occlusion (RVO). The response of these afferent receptors to a challenge of volume expansion and their functional activities on renorenal reflexes were also examined. Immunostaining with PGP 9.5 was applied for examination of the nerve distribution in the diabetic kidney. The tissue level of histamine in the renal pelvis was determined. We explored the effect of histamine on renal receptor activity in these animals to address the possible role of histamine in MRu receptor activity. In early diabetics, signaling activities in MRa and MRv were maintained; however, activity in CR2 and MRu was depressed. For CR2, the reduced basal discharge and the repressed responses to RAO, backflow of urine, and volume expansion found in DM rats were recovered by acute insulin treatment to restore glucose levels to near normal. For MRu, the depressed response to increasing UP and volume expansion was not restored by acute correction of hyperglycemia in DMAI rats. However, antihistamine treatment or chronic insulin treatment recovered the MRu response to mechanical stimuli in DM rats. Because of the desensitized CR2 and MRu activity, renorenal reflexes elicited by backflow of urine and increasing UP were depressed in DM rats. Despite a lack of structural changes, the operating system, signaling ability, and renorenal reflex regulatory function of two renal afferent nerve receptors, CR2 and MRu, are altered in the early diabetic state.

Alterations in contractile properties and Ca2+ handling in streptozotocin-induced diabetic rat myocardium.

The mechanisms of the slower time courses of Ca2+ transients (CaT) and contraction in diabetic (diabetes mellitus, DM) myocardium were studied. The aequorin method was applied to papillary muscles of streptozotocin-induced DM and control rats. The time courses of CaT and tension of twitch in DM were slower than those in control, although the magnitudes of the CaT and contraction were identical. The dependence of CaT decay time and relaxation time on developed tension in DM and control rats differed. The length-tension relation in twitch and the pCa-tension relation in tetanus were identical in the two groups. The magnitude of extra Ca2+ (transient increase in intracellular Ca2+ concentration induced by a quick release in tetanus) was identical in both groups. pCa-tension relations of skinned trabeculae at different sarcomere lengths were nearly identical. The cross-bridge cycling rate (CCR) in DM was slower than that in control. These results indicate that the tension-dependent change in the Ca2+ affinity of troponin C in DM myocardium functions as in control myocardium. The slower time courses of CaT and tension in DM myocardium are caused by slower Ca2+ uptake by the sarcoplasmic reticulum and the slower CCR.

Effects of thyroid hormone on the sorbitol pathway in streptozotocin-induced diabetic rats

Sorbitol accumulation plays an important role in diabetic complications involving the kidney, nerves, retina, lens and cardiac muscle. To investigate the influence of thyroid hormone on the sorbitol pathway, we studied the effects of thyroid hormone on polyol metabolism in normal and diabetic rats. Rats were divided into three groups: controls, streptozotocin (STZ)-induced diabetic euthyroid rats (DM) and STZ-induced diabetic hyperthyroid (thyroxine-injected) rats (DM+HT). The sorbitol (Sor) concentrations in the kidney, liver and sciatic nerve (2.53±0.74, 0.97±0.16 and 24.0±5.1 nmol/mg protein, respectively) of the DM rats were significantly higher than those (1.48±0.31, 0.58±0.13 and 3.1±0.6 nmol/mg protein) of the control rats. The Sor concentrations in the kidney and sciatic nerve of the DM+HT rats (1.26±0.29 and 9.40±1.2 nmol/mg protein) were significantly lower than those in the DM rats. These values were reduced in the liver, unchanged in the kidney, and increased in the sciatic nerve from the hyperthyroid rats without diabetes. Thyroid hormone reduced the aldose reductase (AR) activities in the kidney, liver and sciatic nerve of the DM rats, and similarly reduced AR in the kidney and liver, but not in the sciatic nerve, of the non-diabetic rats. The sorbitol dehydrogenase (SDH) activities were decreased by thyroid hormone in the kidney and liver but not the sciatic nerve of DM rats. In the non-diabetic rats, this enzyme activity was decreased in liver, but not in kidney or sciatic nerve. A positive correlation between the Sor concentration and AR activity was observed in the kidney and liver but not in the sciatic nerve from control, DM and DM+HT rats. A negative correlation was observed between the Sor concentration and SDH activities in the same organs. These data suggest that thyroid hormone affects the sorbitol pathway, but the detailed mechanism whereby this hormone reduces the sorbitol content (especially in diabetic rats) remains to be clarified.

Glycoxidation in aortic collagen from STZ-induced diabetic rats and its relevance to vascular damage

Glycoxidation reactions lead to the formation of permanent, irreversible chemical modifications and cross-links in protein, such as the glycoxidation products carboxymethyllysine (CML) and pentosidine. It has been implicated that CML as well as Amadori products play a role in the formation of superoxidative products, such as H 2O 2 and advanced glycosylation endproducts in trapping LDL. Therefore, a possible relationship between glycoxidation and lipoperoxidation might exist because oxidized lipoprotein, which has been directly linked to atheroma formation, could be produced by the superoxidative products released from the pathway of CML formation. Using a CML-specific monoclonal antibody (6D12) and a specific antiserum against hexitol-lysine (HL), an Amadori product, we studied the relationship between glycoxidation and lipoperoxidation by determining the aortic CML contents with ELISA and the fluorescence levels of lipoperoxidation side products, malondialdehyde (MDA) and hydroxynonenal (HNE) from STZ-induced diabetic rats and age-matched control rats. The immunohistochemical and ultrastructural changes relevant to glycoxidation and lipoperoxidation were also studied. The CML content measured by ELISA in DM rats was significantly higher than that in the control rats at 28 weeks ( n=11, P<0.01). The levels of MDA-linked and HNE-linked fluorescence in the DM rats increased in a similar way and were significantly higher than the levels in control rats at 28 weeks ( n=11, both P<0.01 at 28 weeks). The CML contents correlated with the fluorescence levels of both MDA-linked ( n=19, r=0.638, P<0.01) and HNE-linked fluorescence ( n=19, r=0.629, P<0.01) only in the DM rats, but not in the control rats. Our immunohistochemical study thus demonstrated that CML was initially formed in the aortic media of diabetic rats in the 16th week of diabetes, localized primarily in the extracellular matrix surrounding the aortic smooth muscle cells after HL occurred early in the 2nd week of diabetes. Consequently, a significant increase in the extracellular matrix and decrease in the area of the SMCs were observed in the aortic media in the DM rats by a morphometrical study. The in vivo results of this study provided the first evidence that CML correlated with fluorescence levels of MDA and HNE, and thus suggested the existence of a close relationship between glycoxidation and lipoperoxidation in vivo. This information is thus considered to shed some new light on the etiology of atherogenesis in diabetes.

Effects of Regular Treadmill Running on GLUT4 Protein of Skeletal Muscle in STZ-diabetic Rats

The purpose of this study was to investigate the effects of regular treadmill running on GLUT4 protein of skeletal muscle in STZ-diabetic rats. I used 19 male Sprague-Dawley rats weighing 140 to 160 grams. Rats were randomly assigned into normal, diabetes(DM) and DE(DE) groups. The exercise was loaded with treadmill running for 5 days per week during 4 weeks. All experimental procedures were carried out following overnight fasting 48 hours after last exercise. Gain(gm) in body weight in DM rats(822.4) was lowered compared to normal rats(1092.8), and decreased by exercise. Plasma glucose concentration(mg/dl) in DM rats was 1433.1 which is higher than that of normal group of 1036.4. The concentration of DE group was lower than that of DM rats. Plasma insulin concentration() of DM and DE rats was significantly lowerd compared to normal rats. There was no difference of plasma concentrations of FFA and HDL cholesterol among noraml, DM and DE groups. Plasma triglyceride concentration(mg/dl) was significantly highered in DM group compared to those of DM group, the concentration of DE group was lower. Glycogen concentration(mg/gm wet weight) of the plantaris muscle in DM and DE groups was significantly reduced compared to normal group. Glucose transporter 4(GLUT4) protein of soleus was analyzed by Western blot. In DM group, the GLUT4 protein level was markdly decreased compared to normal group, but the level was recovered to the level of normal group by 4 weeks treadmill running. In conclusion, the insulin resistance induced by STZ administration was partially improved by 4 weeks physical training in rats.

Renal angiotensin-converting enzyme localization in diabetic rats and the effect of low protein diet.

Recent evidence suggests a role of angiotensin-converting enzyme (ACE) in diabetic nephropathy. The effect of diabetes and low protein diet on renal immunohistochemical ACE localization was studied in streptozotocin-induced DM rats. Immunohistochemical ACE localization was reduced in DM rats, and a low protein diet partially resolved this abnormality while inhibiting the progression of diabetic nephropathy.

Determinants of hydroperoxide detoxification in diabetic rat intestine: Effect of insulin and fasting on the glutathione redox cycle

The capacity for hydroperoxide detoxification in diabetic (DM) intestine was studied in streptozocin-induced DM rats by quantification of the intestinal glutathione (GSH) redox cycle, a key cellular pathway for peroxide elimination. A role for luminal glucose in regulation of redox cycle activity was examined in insulin-treated or 24-hour—fasted DM animals. Intestinal activities of the redox enzymes, GSH peroxidase, GSSG reductase, and glucose-6-phosphate dehydrogenase (G6PD), were significantly decreased by 17 hours' insulin treatment, whereas only G6PD was decreased by fasting. Mucosal GSH levels were also markedly decreased under these conditions. These results are consistent with an overall suppression of intestinal GSH redox cycle function by short-term administration of insulin. Insulin treatment for 7 consecutive days increased hepatic G6PD activity by fourfold but was without effect on intestinal G6PD, suggesting tissue specificity in insulin regulation of G6PD. The rate of metabolism of tert-butyl hydroperoxide ( tBH) in isolated enterocytes was low in the absence of substrates (0.51 ± 0.07 nmol/10 6 cells/min) but was increased fivefold by exogenous glucose (2.70 ± 0.11 nmol/10 6 cells/min), indicating that glucose availability is an important contributor to intestinal detoxification of toxic hydroperoxides. Collectively, the current results show that GSH redox cycle enzymes in DM intestine are under coordinate insulin control, and that this control appears to be downregulated by short-term insulin treatment.

Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations

Recent evidence indicates a role for the renin-angiotensin system (RAS) in the pathogenesis of glomerular injury in diabetes. To further explore the RAS in diabetes, studies were conducted in nondiabetic control rats and in moderately hyperglycemic diabetic (DM) rats. In DM rats, both acute and chronic therapy with the specific angiotensin II (ANG II) receptor antagonist losartan did not affect glomerular hyperfiltration or hyperperfusion but selectively normalized the glomerular capillary hydraulic pressure and ultrafiltration coefficient. To determine the basis of intrarenal hemodynamic responsiveness to RAS inhibition, we conducted biochemical, molecular biological, and immunohistochemical studies to assess endogenous RAS activity. Values for plasma renin concentration and serum angiotensin-converting enzyme (ACE) activity in DM rats were normal. In contrast, intrarenal renin protein content, and renin and angiotensinogen mRNAs, were increased in DM rats, suggesting disproportionate activation of the intrarenal RAS. Total renal ACE activity was significantly reduced in DM rats, but immunohistochemical studies indicated redistribution of ACE in the diabetic kidney. Proximal tubule ACE activity was reduced, but ACE immunostaining intensity was enhanced in glomeruli and renal vasculature. Together, these observations indicate increased RAS activity in those sites (glomeruli and vasculature) most likely to regulate hemodynamic function, potentially explaining the prominent responses to pharmacological blockade of ANG II formation and/or action.

Insulin therapy normalizes GLUT1 glucose transporter mRNA but not immunoreactive transporter protein in streptozocin-diabetic rats

Previous studies have shown that the principal glucose transporter isoform within the blood-brain barrier (BBB) is GLUT1, and that GLUT1 mRNA is upregulated and immunoreactive GLUT1 protein is downregulated in rats with streptozocin (STZ)-induced experimental diabetes. The present studies investigate effects of insulin therapy on both GLUT1 mRNA and immunoreactive GLUT1 protein in brain capillaries isolated from control (CO), diabetic (DM), and insulin-treated diabetic (IR x) rats. The following variables were measured: serum glucose levels, rat brain capillary immunoreactive GLUT1 level by quantitative Western blotting, and rat brain capillary GLUT1 and actin mRNA levels by quantitative Northern blotting. Serum glucose levels were 6.4 ± 1.2, 30.3 ± 3.2, and 3.7 ± 1.7 mmol/L in CO, DM, and IR x rats, respectively. Brain capillary immunoreactive GLUT1 transporter protein level was 53% ± 13% of CO values in DM rats, and this value was unchanged with insulin treatment. GLUT1 mRNA level in rat brain was increased to 131% ± 8% of CO values in DM rats and was 80% ± 5% of CO values in IR x rats. In conclusion, short-term insulin therapy in rats with STZ-induced diabetes normalizes BBB GLUT1 mRNA level, but does not normalize depressed immunoreactive GLUT1 protein level.

Differential changes of adrenoceptor- and muscarinic receptor-linked prostacyclin synthesis by the aorta and urinary bladder of the diabetic rat.

1. The effect of experimental diabetes mellitus (DM; hyperglycaemic, non-ketototic; 2 months duration) in the rat on receptor-linked prostacyclin (PGI2) synthesis (measured as 6-oxo-PGF1 alpha by radioimmunoassay) was studied in the aorta and urinary bladder using adrenaline, angiotensin II (AII) and acetylcholine (ACh). Signal transduction systems were studied via stimulation of PGI2 synthesis with phorbol ester dibutyrate (PDBU; a protein kinase C activator [PKC]), Ca2+ ionophore A23187 (A23187) and thapsigargin (both elevate intracellular Ca2+, activating phospholipase A2 [PLA2]) and arachidonate (AA; substrate for PGI2 synthesis). 2. In response to adrenaline, AII and phorbol ester, aortic PGI2 release was markedly reduced (all > 75%) in diabetic rats compared to controls. EC50s of the dose-response curves for adrenaline, AII and PDBU were also markedly increased in aortae from DM rats compared to controls. Although there was decreased output of PGI2 in response to A23187 by aortae from diabetic rats compared to controls, there was no difference in the EC50s (mean +/- s.e. mean: diabetic, 2.7 +/- 0.2 x 10(-6) M; controls 2 +/- 0.18 x 10(-6) M). There were no differences in PGI2 release (or in the EC50s) in response to thapsigargin or AA between aortae from diabetic and control rats. 3. In the urinary bladder, there was a marked increase in PGI2 output in response to ACh and a marked decrease in EC50s for the ACh-PGI2 dose-response curves in diabetic rats (EC50 = 5.8 +/- 0.32 x 10(-7) M) compared to controls (EC50 = 2.2 +/- 0.15 x 10(-6) M). Although there was an increase in PGI2 output in the urinary bladders from diabetic rats in response to A23187, there were no differences in the EC50s (control, 1.8 +/- 0.2 x 10-6 M; diabetic, 1.1 +/- 0.15 X 10-6 M). In the urinary bladders, there were no differences in PGI2 output (or the EC50s) in response to PDBU, thapsigargin or AA between diabetic or control rats.4. These data indicate that: (i) reduced PGI2 synthesis coupled to adrenoceptors and AII receptors in the aortae of diabetic rats may be due to diminished PKC activity and not to changes in receptor density and/or affinity, Ca2+ stores, PLA2, cyclo-oxygenase or PGI2 synthase; (ii) the diametrically opposite effect of DM on ACh-stimulated PGI2 synthesis is not due to an increase in PKC activity, but possibly to an increase in muscarine receptor number and/or affinity; (iii) changes in receptor-linked PGI2 synthesis are not ubiquitous in experimental DM and may be organ-specific.

Effect of long-term administration of somatostatin analogue on renal enlargement in uninephrectomized-diabetic rats.

Recent study has demonstrated that the long-acting somatostatin analogue administration effectively prevented initial renal growth in diabetic and uninephrectomized rats. In the present study we examined long-term effect of somatostatin analogue (Sandostatin) on renal enlargement in uninephrectomized-diabetic rat5. Animals were divided into 4 groups: (1) normal control rats (C) (n = 7), (2) uninephrectomized rats (NPX) (n = 7), (3) uninephrectomized-diabetic rats (NPX + DM) (n = 7) and (4) NPX + DM rats treated with Sandostatin (NPX + DM + Tx) (n = 9). All animals had free access to diet (50% protein) and water during the experimental period. To the NPX + DM + Tx rats, 2.5 micrograms of Sandostatin was given subcutaneously twice a day for 8 weeks. Periodic observations were done at 0, 4 and 8 weeks. After 8 weeks. NPX rats (0.540 +/- 0.017 (SEM)) had higher fractional kidney weights (FKW) (wet kidney wt/body wt) compared to C rats (0.410 +/- 0.014) (p < 0.0005), and both NPX + DM rats (0.983 +/- 0.098) and NPX + DM + Tx rats (1.091 +/- 0.042) had higher FKW compared to C rats (p < 0.0001) and NPX rats (p < 0.005), respectively. But no significant change of FKW was observed between NPX + DM rats and NPX + DM + Tx rats. Systolic blood pressure, BUN, serum creatinine, glomerular filtration rate and 24 hour urine protein excretion in NPX + DM rats were not different from those in NPX + DM + Tx rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Diminished glomerular capillary hydraulic conductivity precedes morphologic changes in experimental diabetes mellitus in the rat.

Glomerular ultrafiltration coefficient, Kf, is diminished in established diabetic nephropathy. To determine whether Kf is decreased because of a decrease in capillary area, A, and or in hydraulic conductivity, Lp, glomerular Kf and morphometric parameters were measured, and Lp was calculated in glomeruli of young rats with STZ-induced DM and in control rats. STZ was administered to Fischer 344 rats that weighted 50-75 g; glomeruli were examined after 3 or 5 mo of DM, and their structure and function was compared with that of control rats. The effects of insulin or of an ACEI, enalapril, also were assessed after 3 or 5 mo. Growth of DM rats was markedly impaired, and their ratio of kidney weight to body weight was increased. Ccr was proportional to rat weight, and the ratio of Ccr to body weight was not different in DM and control rats. At 3 mo, average volume of glomeruli isolated from DM rats was less than that of glomeruli from control rats. In contrast, glomerular volume after 5 mo was equal in DM and control rats. No increase in GBM thickness or mesangial volume was observed, nor was any decrease seen in GBM area in DM rats at 5 mo. Kf was lower in DM rats than controls after 3 mo, but not after 5 mo. The Lp of DM and control glomeruli did not differ at 3 mo, but was lower in DM at 5 mo. Insulin therapy improved somatic growth and increased kidney and glomerular size in DM rats; the kidney weight/body weight ratio remained elevated.(ABSTRACT TRUNCATED AT 250 WORDS)

Nifedipine versus fosinopril in uninephrectomized diabetic rats

Antihypertensive agents have been shown to exert inequivalent effects on glomerular injury in experimental renal disease models. To compare the consequences of dissimilar antihypertensive regimens on the development of diabetic glomerulopathy, studies were performed in three groups of uninephrectomized moderately hyperglycemic diabetic rats. One group (DM) received no therapy except insulin. The remaining groups received insulin and either the angiotensin I converting enzyme inhibitor, fosinopril (FOS), or the calcium channel blocker, nifedipine (NIF). Both drugs lowered blood pressure comparably. At four to eight weeks, DM rats exhibited elevation of the single nephron glomerular filtration rate (SNGFR), due to elevations of the glomerular capillary plasma flow rate (QA) and the glomerular capillary hydraulic pressure (PGC). Neither NIF nor FOS affected values for SNGFR or QA. However, while FOS lowered PGC and increased Kf, NIF did not affect these parameters. In longer term (8 month) studies, DM rats exhibited progressive albuminuria and glomerular sclerosis. FOS markedly limited development of albuminuria and glomerular injury, but NIF was ineffective in limiting either parameter of glomerular injury. Thus, in contrast to the beneficial effects of converting enzyme inhibitors, chronic calcium channel blockade with nifedipine fails to limit PGC or glomerular injury in diabetic rats. These findings lend further support to the concept that different classes of antihypertensive agents are not equally effective in protecting against diabetic glomerulopathy.

Effects of Streptozocin-Induced Diabetes and Food Restriction on Quantities and Source of T4 and T3 in Rat Tissues

Diabetes mellitus and fasting are both associated with low plasma thyroid hormone concentrations and loss of body weight. To discriminate between the separate effects of energy shortage and insulin, we studied control rats, diabetic rats (DM), DM rats treated with insulin (DMI), and rats after modified fasting (MF1 and MF2; 70 and 30% of normal daily food intake, respectively). In double-isotopic equilibrium experiments, we determined the tissue thyroxine (T4) and triiodothyronine (T3) concentrations and the contribution of local T4-to-T3 conversion to total T3 in rat tissues; thyroidal T4 and T3 secretion and extrathyroidal T3 production were calculated. In DM and DMI rats, plasma T4 and T3 decreased; in MF1 and MF2 rats, only plasma T4 decreased. Thyroidal T4 secretion decreased, whereas that of T3 remained normal. The decrease in tissue T4 in MF and DM rats paralleled the decrease in plasma T4. Although plasma T3 did not differ in DM and DMI rats, total T3 concentrations in all tissues were not the same due to changed uptake of T3 from plasma and local T4-to-T3 conversion; these changes were not found in several tissues of MF1 and MF2 rats. Our results suggest that the decrease in tissue T4 during diabetes mellitus is due to the decrease in plasma T4 caused by the decreased thyroidal secretion, possibly due to intracellular energy shortage. The changes in tissue T3 during diabetes mellitus are only partly attributable to the same phenomenon; in several tissues, the decrease in T3 seems more related to the lack of insulin.

Short and long term effects of antihypertensive therapy in the diabetic rat

To compare the impact of differing antihypertensive regimens on the development of renal injury, studies were performed in three groups of moderately hyperglycemic diabetic rats, and one group of non-diabetic control (C) rats. One diabetic group (DM) received no therapy except insulin. The remaining diabetic groups received insulin and either the angiotensin I converting enzyme inhibitor captopril (CAP), or triple therapy (TRX) with reserpine, hydralazine and hydrochlorothiazide. CAP and TRX modestly and comparably lowered blood pressure. At 6 to 10 weeks, DM rats exhibited elevation of the single nephron glomerular filtration rate (SNGFR), due to elevations of the glomerular capillary plasma flow rate (QA) and the glomerular capillary hydraulic pressure (PGC). In both DM/CAP and DM/TRX rats, blood pressure reduction was associated with selective normalization of PGC, without change in SNGFR or QA. In long-term (70 weeks) studies, DM rats exhibited progressive albuminuria and marked glomerular sclerosis. CAP limited albuminuria and injury to values even lower than those in C rats, whereas TRX served only to delay, but not to prevent, the increase in albuminuria. TRX reduced glomerular sclerosis, but was less effective than CAP. At 70 weeks, CAP and TRX still reduced systemic blood pressure; PGC remained at normal levels with CAP but was no longer controlled with TRX. These results confirm the clinical observation that antihypertensive therapy slows diabetic glomerulopathy, but also suggest that CAP affords superior long-term protection as compared to the other antihypertensive drug regimen studied.

Effect of Insulin Administration Time on Feeding Behavior in Streptozotocin-induced DM Rats

Effect of Insulin Administration Time on Feeding Behavior in Streptozotocin-induced DM Rats