scholarly journals Alterations in glomerular proteoglycan metabolism in experimental non-insulin dependent diabetes mellitus.

1993 ◽  
Vol 3 (10) ◽  
pp. 1694-1704
Author(s):  
P Fioretto ◽  
W F Keane ◽  
B L Kasiske ◽  
M P O'Donnell ◽  
D J Klein
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Dependent Diabetes Mellitus ◽  
Insulin Dependent Diabetes ◽  
Zucker Rats ◽  
Dependent Diabetes Mellitus ◽  
Zucker Rat ◽  
Obese Zucker Rat ◽  
Obese Rats ◽  
Insulin Dependent ◽  
Obese Zucker Rats

Glomerular proteoglycans (PG) are important in modulating extracellular matrix assembly and glomerular permselectivity. In the obese Zucker rat, an experimental model of non-insulin dependent diabetes mellitus, expansion of the mesangial matrix, and microalbuminuria occur before the development of overt renal disease. The in vivo incorporation of (35S)sulfate into glomerular PG in 12-wk-old obese Zucker rats at the onset of microalbuminuria was compared with that of 12-wk-old lean Zucker rats. Specific (35S)sulfate incorporation into glomerular PG over 8 h was increased by 57% in obese rats compared with lean rats, suggesting increased PG synthesis. However, at variance with the observation in experimental models of insulin-dependent diabetes mellitus, the proportion of total glomerular (35S)PG released by heparin treatment was unchanged. Heparan sulfate (HS)-PG constituted over 60% of radiolabeled de novo synthesized glomerular PG. Similar proportions of HS-PG were extracted from the glomeruli of obese and lean rats. Isolated glomeruli spontaneously released two HS-PG, which constituted approximately 30% of total glomerular (35S)PG. On the basis of their chromatographic and electrophoretic patterns, these PG were similar in obese and lean rats. Heparin treatment of isolated glomeruli released an additional HS-PG, which appeared to be derived primarily from the glomerular extracellular matrix compartment and not from the detergent soluble cell fraction. Heparin-releasable HS-PG from both the lean and obese Zucker rats eluted at a KAV of 0.31 from Sepharose CL-6B chromatographic columns, indicating a hydrodynamic size similar to that reported for glomerular basement membrane HS-PG. However, gel electrophoresis demonstrated faster migration of the HS-PG released by heparin from the glomeruli of obese Zucker rats, suggesting increased electronegativity. Thus, early in the course of nephropathy in the obese Zucker rat, there is increased glomerular PG synthesis with no change in the proportions of the constitutively releasable and heparin-releasable HS-PG. Whether electrophoretic abnormalities of the heparin-releasable HS-PG observed in the obese rats contribute to the development of albuminuria and/or mesangial matrix expansion remains to be established.

Elevated Renal Endothelin-1 Clearance and mRNA Levels Associated with Albuminuria and Nephropathy in Non-Insulin-Dependent Diabetes Mellitus: Studies in Obese fa/fa Zucker Rats

1997 ◽  
Vol 93 (6) ◽  
pp. 565-571 ◽  
Author(s):  
N. C. Turner ◽  
P. J. Morgan ◽  
A. C. Haynes ◽  
M. Vidgeon-Hart ◽  
N. Toseland ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Urinary Excretion ◽  
Cyclic Gmp ◽  
Insulin Dependent Diabetes Mellitus ◽  
Insulin Dependent Diabetes ◽  
Zucker Rats ◽  
Dependent Diabetes Mellitus ◽  
Mrna Levels ◽  
Zucker Rat ◽  
Insulin Dependent

1. The obese fa/fa Zucker rat is a genetic model of obesity and insulin resistance which develops a number of metabolic and endocrine features of non-insulin-dependent diabetes, including hypertension, proteinuria and glomerular sclerosis. 2. We have investigated the urinary excretion of the metabolites of thromboxane (thromboxane B2) and prostacyclin (6-keto prostaglandin F1α), and of endothelin and cyclic GMP as markers for changes in the balance of renal haemodynamic factors in the obese Zucker rat. 3. Obese fa/fa Zucker rats were hypertensive compared with their lean counterparts (161 ± 3 and 138 ± 3 mmHg respectively, P < 0.01); obese animals were also markedly proteinuric (16.7 ± 6.7 versus 1.1 ± 0.1 mg/ml) and albuminuric (8.3 ± 2.9 versus 0.4 ± 0.25 mg/ml) and excreted less creatinine than lean animals (all P < 0.01). Urinary excretion of endothelin was greater in obese rats (123 ± 24 versus 62 ± 10 pg/15 h, P < 0.05) as was the level of pre-proendothelin mRNA, but excretion of cyclic GMP was depressed (12.5 ± 1.6 versus 27.2 ± 3.1 nmol/ 15 h, P < 0.01). Histological examination of kidneys from obese animals showed evidence of focal glomerulosclerosis and cortical tubular damage. 4. These results show that increased urinary endothelin is associated with proteinuria and early stage nephropathy in this animal model of non-insulin-dependent diabetes mellitus. This finding, coupled with a decreased excretion of cyclic GMP, suggests that these increased renal vasoconstrictor/vasodilator forces might contribute to the renal functional changes in non-insulin-dependent diabetes mellitus.

The VMH-dietary obese rat: a new model of non-insulin-dependent diabetes mellitus

1994 ◽  
Vol 266 (3) ◽  
pp. R921-R928
Author(s):  
K. V. Axen ◽  
X. Li ◽  
K. Fung ◽  
A. Sclafani
Keyword(s):  
Diabetes Mellitus ◽  
Glucose Concentration ◽  
Insulin Dependent Diabetes Mellitus ◽  
Ventromedial Hypothalamus ◽  
Insulin Dependent Diabetes ◽  
Dependent Diabetes Mellitus ◽  
Adult Rats ◽  
Obese Rats ◽  
Electrolytic Lesions ◽  
Insulin Dependent

A model of non-insulin-dependent diabetes mellitus (NIDDM) has been developed in adult rats by combining bilateral electrolytic lesions of the ventromedial hypothalamus (VMH) and high fat-high sucrose diets. VMH-dietary obese rats showed fasting hyperinsulinemia (> or = 540 pM) and hypertriglyceridemia (> or = 180 mg/dl) generally within 3 wk on the protocol. Fasting hyperglycemia (> or = 10 mM) was observed in the majority of animals in seven consecutive experiments. Hyperglycemic animals showed impaired glucose tolerance despite high prevailing insulin levels. Pancreatic islets isolated from VMH-dietary obese rats showed a loss of insulin secretory response to glucose by week 5, before the onset of hyperglycemia. Islets from hyperglycemic rats no longer responded to an increase in glucose concentration and failed to suppress insulin release normally in response to 15 nM norepinephrine or to a decrease in glucose concentration. This model mimics the major characteristics of obesity-associated human NIDDM as well as several stages of its progression, rendering it useful for studying the etiology of the metabolic and secretory defects in the syndrome.

scholarly journals Experimental rat models to study the metabolic syndrome

2009 ◽  
Vol 102 (9) ◽  
pp. 1246-1253 ◽  
Author(s):  
Amaya Aleixandre de Artiñano ◽  
Marta Miguel Castro
Keyword(s):  
Diabetes Mellitus ◽  
Metabolic Syndrome ◽  
Experimental Model ◽  
Insulin Dependent Diabetes Mellitus ◽  
Experimental Models ◽  
Zucker Rats ◽  
Dependent Diabetes Mellitus ◽  
The Metabolic Syndrome ◽  
Insulin Dependent ◽  
Obese Zucker Rats

Being the metabolic syndrome a multifactorial condition, it is difficult to find adequate experimental models to study this pathology. The obese Zucker rats, which are homozygous for the fa allele, present abnormalities similar to those seen in human metabolic syndrome and are a widely extended model of insulin resistance. The usefulness of these rats as a model of non-insulin-dependent diabetes mellitus is nevertheless questionable, and they neither can be considered a clear experimental model of hypertension. Some experimental models different from the obese Zucker rats have also been used to study the metabolic syndrome. Some derive from the spontaneously hypertensive rats (SHR). In this context, the most important are the obese SHR, usually named Koletsky rats. Hyperinsulinism, associated with either normal or slightly elevated levels of blood glucose, is present in these animals, but SHR/N-corpulent rats are a more appropriated model of non-insulin-dependent diabetes mellitus. The SHR/NDmc corpulent rats, a subline of SHR/N-corpulent rats, also exhibit metabolic and histopathologic characteristics associated with human metabolic disorders. A new animal model of the metabolic syndrome, stroke-prone–SHR (SHRSP) fatty rats, was obtained by introducing a segment of the mutant leptin receptor gene from the Zucker line heterozygous for the fa gene mutation into the genetic background of the SHRSP. Very recently, it has been developed as a non-obese rat model with hypertension, fatty liver and characteristics of the metabolic syndrome by transgenic overexpression of a sterol-regulatory element-binding protein in the SHR rats. The Wistar Ottawa Karlsburg W rats are also a new strain that develops a nearly complete metabolic syndrome. Moreover, a new experimental model of low-capacity runner rats has also been developed with elevated blood pressure levels together with the other hallmarks of the metabolic syndrome.

Potential role ofN-myristoyltransferase in pathogenic conditions

2004 ◽  
Vol 82 (10) ◽  
pp. 849-859 ◽  
Author(s):  
Rajendra K Sharma
Keyword(s):  
Diabetes Mellitus ◽  
Animal Model ◽  
Rat Liver ◽  
Potential Role ◽  
Ischemia Reperfusion ◽  
Insulin Dependent Diabetes Mellitus ◽  
Insulin Dependent Diabetes ◽  
Zucker Rats ◽  
Dependent Diabetes Mellitus ◽  
Insulin Dependent

N-Myristoyltransferase (NMT) is the enzyme that catalyzes the covalent transfer of myristic acid to the N-terminal glycine residue of a protein substrate. In this review article, I summarize that NMT may have a potential role in cardiac muscle in the experimentally induced ischemia–reperfusion rat model and also in the streptozotoein-induced diabetic rat. Both the expression and activity of NMT were increased by ischemia–reperfusion. Immunohistochemical studies showed cytosolic localization of NMT in normal rat heart and predominant nuclear localization after ischemia followed by reperfusion. However, the localization of NMT is reversed by treatment with a calpain inhibitor (ALLM N-Ac-Leu-Leu-methioninal). During ischemia–reperfusion, the degradation of c-Src, which is a substrate of NMT, was observed. These findings suggested that the Src signaling may be impaired in ischemia–reperfusion owing to the altered localization of NMT from cytoplasm to nucleus. Streptozotocin-induced diabetes (an animal model for insulin-dependent diabetes mellitus) resulted in a 2.0-fold increase in rat liver NMT activity as compared with control animals. In obese (fa/fa) Zucker rats (an animal model for non-insulin-dependent diabetes mellitus), there was an ~4.7-fold lower liver particulate NMT activity as compared with control lean rat livers. Administration of sodium orthovanadate to the diabetic rats normalized liver NMT activity. These results would indicate that rat liver particulate NMT activity appears to be inversely proportional to the level of plasma insulin, implicating insulin in the control of N-myristoylation. These are the first studies demonstrating the role of NMT in the pathogenesis of ischemia–reperfusion and diabetes mellitus. These conditions remain an important area of investigation.Key words: N-myristoyltransferase, ischemic heart, calpains, diabetes, vanadate.

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