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I Klöting

Publications and source records attributed to I Klöting.

At least 19 recordsLinked to original sources
PubMed2004

[Bone healing in drill hole defects in spontaneously diabetic BB/OK rats. A histomorphometric and biomechanical study].

The objective of this study was to examine changes in the histomorphometric and mechanical evaluation of the influence of the diabetic metabolic state on defect healing depending on the defect size in spontaneously diabetic BB/O(ttawa)K(arlsburg) rats. Based on blood glucose levels and postoperative insulin requirements, 120 spontaneously diabetic BB/OK rats were divided into groups with well-compensated or poorly compensated metabolic state. Sixty LEW.1A rats served as the normoglycemic controls. Bone defects of different sizes were created proximal to the knee joint space and then allowed to heal for 2, 4, and 6 weeks. Bone defect sizes > or =0.8 mm showed significant differences in the structural calculations and bone defect sizes > or =1.2 mm showed a significant decrease of all fluorochrome-based parameters of mineralization exclusively in the rats with poorly compensated diabetic metabolic state as well as significantly decreased values of biomechanical properties in comparison to the spontaneously diabetic rats with well-compensated metabolic states and to the control rats. Bone repair of minor bone defects is independent of the diabetic metabolic state in the spontaneously diabetic BB/OK rats. With controlled insulin therapy and resultant well-compensated diabetic metabolic state, severe mineralization and biomechanical disorders in healing of larger bone defects in the poorly compensated diabetic metabolic state of the experimental animal can be avoided.

Animals↗
PubMed2004

Improving metabolic control reverses the histomorphometric and biomechanical abnormalities of an experimentally induced bone defect in spontaneously diabetic rats.

Insulin-dependent type 1 diabetes mellitus (IDDM) has been shown to alter the properties of bone and to impair fracture-healing in both humans and animals. The objective of this study was to examine changes in the histomorphometric and mechanical parameters of bone and remodeling during bone-defect healing, depending on the diabetic metabolic state in spontaneously diabetic BB/O(ttawa)K(arlsburg) rats, a rat strain that represents a close homology to IDDM in humans. A standardized bone-defect model was chosen and based on blood-glucose values at the time of surgery (mg%), postoperative blood-glucose course (mg%), and postoperative insulin requirements (IU/kg). A total of 120 spontaneously diabetic BB/OK rats were divided into groups with a well-compensated (n = 60; 169 +/- 102 mg%; 230 +/- 126 mg%; and 2.2 +/- 1.1 IU/ kg) or poorly compensated (n = 60; 380 +/- 159 mg%; 359 +/- 89 mg%; and 5.4 +/- 1.1 IU/kg) metabolic state. Sixty LEW.1A rats served as the normoglycemic controls (93 +/- 19 mg%). Fifteen animals from each group were killed on postoperative days 7, 14, 24, and 42, and specimens were processed undecalcified for quantitative bone histomorphometry and for biomechanical testing. Our study showed in terms of bone histomorphometry, within the first 14 days, that severe mineralization disorders occurred exclusively in the rats with a poorly compensated diabetic metabolic state with a highly significant (P < 0.001) or significant (P < 0.01) decrease of all fluorochrome-based parameters of mineralization, apposition, formation and timing of mineralization, as well as significantly decreased values of biomechanical properties (P < 0.05) in comparison to the spontaneously diabetic rats with a well-compensated metabolic state and to the control rats. Bone-defect healing in spontaneously diabetic BB/ OK rats is retarded exclusively in a poorly compensated diabetic metabolic state. This study suggests that strictly controlled insulin treatment resulting in a well-compensated diabetic metabolic state will ameliorate the impaired early and late parameters of IDDM bone-defect healing.

Animals↗
PubMed2003

Scanning electron microscopic examinations on retarded bone defect healing in spontaneously diabetic BB/O(ttawa)K(arlsburg) rats.

To date, no detailed knowledge from animal experiments is available on the kind and extent of osseous and mineral metabolic disorders in genetically determined, insulin-dependent Type I diabetes. The purpose of this study was to examine the influence of the diabetic metabolic state in spontaneously diabetic BB/O(ttawa)K(arlsburg) rats on bone defect healing. Eighty spontaneously-diabetic BB/OK rats with a blood-glucose value of 391 +/- 106 mg% (mean +/- SD) at the time of manifestation were used in the study. Based on blood-glucose values at the time of surgery (mg%), postoperative blood-glucose course (mg%) and postoperative insulin requirements (IU/kg), the animals were divided into groups with well-compensated (n = 40, 170 +/- 101 mg%; 221 +/- 120 mg%; 2.1 +/- 1 IU/kg) or poorly compensated (n = 40; 371 +/- 158 mg%; 357 +/- 83 mg%; 5.2 +/- 1.4 IU/kg) metabolic state. Forty LEW.1A rats served as the normoglycemic controls (95 +/- 18 mg%). Using a 1-mm-diameter Kirschner wire, a hole of femoral bone ca. 1 cm proximal to the knee joint space was centrally drilled. Ten animals from each group were killed on postoperative days 7, 14, 24, and 42, and specimens were taken for analysis. Using SEM to measure regions of new bone semiautomatically and quantitatively, also determining the number, area, and circumference of regions not yet filled with new bone. Up to postoperative day 14, very significant differences (p < 0.0001) for all investigated characteristics were found between the spontaneously-diabetic BB/OK rats and the control animals--in favor of the controls--and up to postoperative day 24 within the group of spontaneously-diabetic BB/OK rats, where the well-compensated animals had significantly better results in terms of number and area of regions of bone not yet filled with new bone formations. Forty-two days postoperatively, SEM observations showed no differences between examination groups. The process of bone defect healing in spontaneously-diabetic rats was disturbed only in the early phase and exhibited retardation in its progression. After 42 days, bone defect healing was complete, regardless of the diabetic metabolic state; no differences were detected with the SEM between examination groups at this time point.

Animals↗
PubMed2002

Metabolic syndrome and aging in Wistar Ottawa Karlsburg W rats.

BACKGROUND AND OBJECTIVE: Comparative studies have shown that Wistar Ottawa Karlsburg W (RT1u) rats (WOKW) develop a nearly complete metabolic syndrome with obesity, moderate hypertension, dyslipidemia, hyperinsulinemia, and impaired glucose tolerance up to an age of 28 weeks. Because metabolic data thereafter are missing, WOKW and disease-resistant DA rats were studied for 12 months beginning at an age of 5 months. METHODS: Eighteen male inbred WOKW and DA rats were studied monthly from the 5th to the 17th month of life for traits of the metabolic syndrome such as body weight, body mass index (BMI), serum triglycerides, total cholesterol, leptin, insulin as well as glucose tolerance, 24 h excretion of urine total protein and creatinine including telemetric measurement of blood pressure in six males per each group. RESULTS: Except for serum total cholesterol, the measured values for most traits studied were significantly higher in WOKW than in DA rats at an age of 5 months. At an age of 17 months all traits were significantly elevated in WOKW compared with DA rats. WOKW rats were hypertensive, dyslipidemic, obese, glucose intolerant, hyperinsulinemic and proteinuric. CONCLUSION: Considering the phenotype of the WOKW rat described until now and the fact that the metabolic syndrome in this rat is polygenetically determined, the WOKW rat is the most suitable animal model to study the pathophysiology of the facets of the syndrome.

Aging↗
PubMed2001

Quantitative trait loci for body weight, blood pressure, blood glucose, and serum lipids: linkage analysis with wild rats (Rattus norvegicus).

To study polygenetically inherited human diseases like hypertension, inbred rat strains are usually the preferred models. Because many inbred generations under optimized environmental conditions may have led to the survival of "silent" disease genes, we used a cross between one wild rat and genetically hypertensive SHR rats to analyze quantitative trait loci (QTLs) of blood pressure and related traits. The (Wild x SHR)F1 hybrids were transferred into a pathogen-free environment by wet-hysterectomy and were backcrossed onto SHR to generate first backcross hybrids (BC1). Progeny from one F1 female (n = 72) were phenotypically and genetically characterized to map QTLs. Significant, subsignificant, and suggestive evidence was found for more sex-specific than common linkage of blood pressure and most blood-pressure-related traits. Male- and female-specific regions were determined on different chromosomes for blood pressures (Chrs. 2 and 7 vs 5 and 11), body weight (Chrs. 10 vs 18), and blood glucose (Chr. 17 vs 20). A linkage in both males and females was shown for serum triglycerides on chromosomes 6 and 17, respectively, and blood glucose on chromosome 15. For serum total cholesterol, a significant linkage was found on chromosome 14 only in males. Our findings not only indicate the complex character of quantitative traits per se but also show impressively their dependence on sex, age, and strains in cosegregation analysis.

Animals↗
PubMed2001

Sex-specific and sex-independent quantitative trait loci for facets of the metabolic syndrome in WOKW rats.

WOKW rats develop a complete metabolic syndrome closely resembling human disease. Since genetic studies using male (WOKW x DA)F2 progeny showed that several independent genetic factors were involved, a polygenic basis for the syndrome in WOKW was assumed. However, because the metabolic syndrome in human clearly demonstrates sex differences, we have extended our study to include both male and female (WOKW x DA)F2 progeny in a genome-wide scan. Male- or female-specific quantitative trait loci (QTLs) were mapped for body weight, body mass index, adiposity index and serum insulin on chromosomes 1 and 5, serum triglycerides on chromosomes 4, 7, 11, and 16, serum total and high density lipoprotein cholesterol on chromosomes 3, 4, 5, 10, and 17, and serum leptin on chromosomes 8 and 16 as well as blood glucose and glucose tolerance (AUC) on chromosomes 3, 4 and 17. QTLs for both, males and females were only found for body weight on chromosome 1 and for serum total cholesterol on chromosome 3 and 10. These findings clearly demonstrate that there are sex-specific and sex-independent QTLs for facets of the metabolic syndrome in WOKW rats.

Animals↗
PubMed2001

Genes of SHR rats protect spontaneously diabetic BB/OK rats from diabetes: lessons from congenic BB.SHR rat strains.

Diabetes in BB rats share many common features with human type 1 diabetes. One of them is the complex and polygenic nature of disease. Analysis of cross hybrids of diabetic BB/OK rats and rats of different diabetes-resistant strains has demonstrated that beside the MHC genes, Iddm1 and the lymphopenia, Iddm2, additional non-MHC genes are involved in diabetes development. To study the importance of the non-MHC genes, Iddm4 and Iddm3, two congenic BB.SHR rat strains were generated by recombining a segment of the SHR chromosome 6 (Iddm4; termed BB.6S; 15cM) or chromosome 18 (Iddm3; termed BB.18S; 24cM) into the BB/OK background by serial backcrossing and marker-aided selection. The characterization of both congenic strains demonstrates a drastic reduction of diabetes frequency in comparison to the BB/OK strain (86% vs 14% and 34%). It is supposed that diabetes protective genes of SHR must be located on both chromosomal segments and that these suppress the action of the essential and most important genes of diabetes development in the BB/OK rat, Iddm1, and Iddm2.

Animals↗
PubMed2001

Congenic BB.SHR rat provides evidence for effects of a chromosome 4 segment (D4Mit6-Npy approximately 1 cm) on total serum and lipoprotein lipid concentration and composition after feeding a high-fat, high-cholesterol diet.

Congenic BB.SHR (previously referred to as BB.LL) rats were generated by transferring the segment of chromosome 4 flanked by the D4Mit6 and Spr loci from the spontaneously hypertensive rat (SHR/Mol) onto the genetic background of the diabetes-prone BB/OK rat. In this study, the influence of the above-mentioned region of chromosome 4 on triglyceride, cholesterol, and phospholipid phenotypes after a high-fat, high-cholesterol diet was examined by comparison of BB.SHR congenic rats with BB/OK rats. BB/OK and BB.SHR had comparable concentrations of basal and postdietary serum insulin, as well as of basal total serum triglycerides and had an identical body weight and food intake at the beginning of the test period. However, after 4 weeks on the test diet, BB.SHR rats were significantly heavier than BB/OK rats and had significantly higher food intake and lower total serum triglyceride concentrations. The basal serum leptin level was significantly lower, but postdietary serum leptin concentration did not show a significant difference between the 2 strains. Furthermore, significantly higher basal total serum cholesterol and phospholipid levels were observed in BB.SHR rats, but this difference disappeared after feeding the high-fat, high-cholesterol diet. Postdietary high-density lipoprotein (HDL)(2) cholesterol and phospholipid levels were significantly elevated in BB.SHR rats when compared with BB/OK rats. The 2 strains also differed slightly, but significantly, with respect to the other HDL phospholipid concentrations. In addition to previously described differences between BB/OK and BB.SHR rats, the results of this study clearly show the impact of genes, lying within the transferred segment, on serum lipid phenotypes after high-fat, high-cholesterol diet.

Alleles↗
PubMed2001

Insulin treatment improves islet function in type 2 diabetic Chinese hamsters.

To study whether normalization of hyperglycemia improves islet function in long-standing type 2 diabetes, hyperglycemic CHIG/Han subline of the genetic type 2 diabetic Chinese hamster (>15 mmol/l: n=23) were either treated with insulin implants (liberating 1 U/day) or vehicle for two weeks. Islets were isolated and incubated for 3 h in the presence of 10 mmol/l glucose with or without 0.1 mmol/l 3-isobutyl-1-methylxanthine (IBMX). Specimens were also taken for immunocytochemical analysis of insulin cells. Glucose-stimulated insulin secretion was reduced by 83% in the vehicle-treated diabetic hamsters compared to non-diabetic controls (p<0.001). This impairment was not improved by the two-week insulin treatment. IBMX potentiated glucose-stimulated insulin secretion; this effect was markedly reduced in vehicle-treated diabetics compared to controls (p<0.001). In fact, the linear relation between IBMX-potentiated and glucose-stimulated insulin secretion in controls was absent in islets from diabetic animals. The two week insulin treatment normalized this relation, although still the total insulin secretory response to IBMX and glucose was lower than in controls. Furthermore, the islet insulin content was significantly increased by the 2 week normalization of glucose and, finally, the severe degranulation and lowering of insulin staining in islet beta cells in diabetic animals were markedly improved by insulin treatment. The results suggest that two-weeks of normalization of glycemia in long-standing type 2 diabetes in non-obese Chinese hamster improves beta cell signaling induced by the cyclic AMP pathway in conjunction with improved islet insulin content and beta cell morphology.

1-Methyl-3-isobutylxanthine↗
PubMed2001

Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB.

Activation of the transcription factor nuclear factor-kappaB (NF-kappaB) has been suggested to participate in chronic disorders, such as diabetes and its complications. In contrast to the short and transient activation of NF-kappaB in vitro, we observed a long-lasting sustained activation of NF-kappaB in the absence of decreased IkappaBalpha in mononuclear cells from patients with type 1 diabetes. This was associated with increased transcription of NF-kappaBp65. A comparable increase in NF-kappaBp65 antigen and mRNA was also observed in vascular endothelial cells of diabetic rats. As a mechanism, we propose that binding of ligands such as advanced glycosylation end products (AGEs), members of the S100 family, or amyloid-beta peptide (Abeta) to the transmembrane receptor for AGE (RAGE) results in protein synthesis-dependent sustained activation of NF-kappaB both in vitro and in vivo. Infusion of AGE-albumin into mice bearing a beta-globin reporter transgene under control of NF-kappaB also resulted in prolonged expression of the reporter transgene. In vitro studies showed that RAGE-expressing cells induced sustained translocation of NF-kappaB (p50/p65) from the cytoplasm into the nucleus for >1 week. Sustained NF-kappaB activation by ligands of RAGE was mediated by initial degradation of IkappaB proteins followed by new synthesis of NF-kappaBp65 mRNA and protein in the presence of newly synthesized IkappaBalpha and IkappaBbeta. These data demonstrate that ligands of RAGE can induce sustained activation of NF-kappaB as a result of increased levels of de novo synthesized NF-kappaBp65 overriding endogenous negative feedback mechanisms and thus might contribute to the persistent NF-kappaB activation observed in hyperglycemia and possibly other chronic diseases.

Adult↗
PubMed2000

Genetic dissection of the syndrome X in the rat.

In 1988, Reaven used the term syndrome X to describe a relation between several disorders including hypertension, dyslipidemia, impaired glucose tolerance, obesity, and coronary heart disease. Despite a number of studies dealing with syndrome X, its genetic basis remains poorly understood. Regarding the complexity of this syndrome, it is important to use animal models developing the traits of the disease. Here we show a genetic dissection of syndrome X in the WOKW rat, an animal model of genetically determined syndrome X. We found a major quantitative trait locus (QTL) for glucose metabolism on chromosome 3 and further QTLs influencing obesity and body weight on chromosomes 1 and 5. Genetic determinants of dyslipidemia were mapped to chromosomes 4 and 17. In addition, suggestive linkage for serum insulin was found on chromosome 1 to the region previously shown to be associated with type-1 diabetes mellitus. This is the first study demonstrating independent genetic factors influencing traits of the syndrome X in the rat as well as a possible genetic relationships between syndrome X and diabetes mellitus. Moreover, regarding the close similarities between WOKW rat and human syndrome X, the study could help in a search of genetic factors involved in this complex metabolic disorder in human.

Animals↗
PubMed2000

Metabolic features in disease-resistant as well as in spontaneously hypertensive rats and newly established obese Wistar Ottawa Karlsburg inbred rats.

OBJECTIVE: Studies, comparing several disease-prone and disease-resistant rat strains to elucidate the extent and severity of syndromes resembling human diseases are lacking. Therefore we studied the inbred rat strains BB/OK, BN/Crl, LEW/K and WKY/Crl in comparison with SHR/Mol and WOKW/K rats as models of metabolic syndrome. DESIGN: Body weight and body mass index (BMI) were measured in 12 males of each strain at 14 weeks. In addition blood glucose, serum triglycerides, cholesterol, insulin and leptin were determined at 12, 13 and 14 weeks of age. RESULTS: In contrast to SHR animals, WOKW rats develop a severe metabolic syndrome including obesity, hyperleptinemia, hyperinsulinemia and dyslipidemia. CONCLUSION: We conclude that; (i) the choice of disease-resistant inbred rat strains as 'healthy controls' for a disease-prone strain has to be carefully evaluated; (ii) in comparison with SHR, WOKW rats develop most if not all facets of the metabolic syndrome described in human and (iii) as with the human disease the syndrome in rats is polygenic.

Animals↗
PubMed2000

Metabolic variability among disease-resistant inbred rat strains and in comparison with wild rats (Rattus norvegicus).

1. Inbreeding and optimization of environmental conditions for laboratory rats may have led to the survival of mutants with metabolic aberrations but without evident disease phenotype. Therefore, in the present study, we compared metabolic traits between so-called disease-resistant inbred rat strains Dark Agouti (DA), Brown Norway (BN), Lewis (LEW), Wistar-Kyoto (WKY), Fischer 344 (F344) and wild rats (Rattus norvegicus). 2. Twelve males of each strain at 12, 13 and 14 weeks of age were studied for bodyweight, body mass index (BMI), blood glucose, serum triglycerides, total cholesterol, insulin and leptin. 3. In comparison with wild rats, the cholesterol values were significantly increased in all inbred rats studied. Except for DA rats, all rats were also significantly heavier than wild rats. 4. There were also significant differences between the different disease-resistant strains and WKY rats were the biggest animals with the highest bodyweight, BMI and cholesterol values. 5. The strains could be separated into groups with either very high (F344, LEW, WKY) or low values (DA, BN) of serum insulin and leptin levels. 6. Because all rats were studied under the same conditions, the findings suggest a substantial strain dependence in feeding behaviour and energy balance caused by the different genotypes.

Animals↗
PubMed2000

Features of the metabolic syndrome in the spontaneously hypertriglyceridemic Wistar Ottawa Karlsburg W (RT1u Haplotype) rat.

The aim of this study was to characterize the Wistar Ottawa Karlsburg W ([WOKW] RT1u haplotype) rat in a cross-sectional study (up to 14 weeks of age) for traits with pathophysiological relevance to the metabolic syndrome in comparison to the Dark Agouti (DA) rat, to determine the age at which the WOKW rat begins to manifest the characteristics of the metabolic syndrome. The findings indicate that the WOKW rat is dyslipidemic (high serum triglycerides and low high-density lipoprotein [HDL] cholesterol), hyperinsulinemic, and obese. The interval between 8 and 10 weeks appears to be the crucial age after which the most dramatic changes were observed in the measured phenotypic traits in the WOKW rat, as well as the most expressive differences between the WOKW and DA strains. Considering the phenotypic differences between WOKW and DA rats, the DA rat provides an appropriate control strain for crossing studies with the WOKW rat, which might contribute to the explanation of the genetic basis for traits of the metabolic syndrome in this model.

Aging↗
PubMed1999

Congenic diabetes-prone BB.Sa and BB.Xs rats differ from their progenitor strain BB/OK in frequency and severity of insulin-dependent diabetes mellitus.

Two newly established congenic diabetes-prone BB rat strains designated BB.Sa and BB.Xs carrying a region of chromosome 1 (Sa-Lsn-Secr-Igf2-Tnt, 16 cM) and a region of chromosome X (DXMgh3-Mycs/Pfkb1-Ar, 36 cM) of the SHR rats, respectively, were studied to determine whether the transferred chromosomal regions influence diabetes frequency, age at onset, and clinical picture. Therefore, 4 complete litters of BB/OK (n = 43), BB.Sa (n = 45), and BB.Xs (n = 41) were observed for diabetes occurrence up to the age of 30 weeks. From these litters 6 diabetic males of each strain manifesting in an interval of 1 week were chosen to study body weight, blood glucose, insulin requirement to survive, and several diabetes-related serum constituents at onset of diabetes and after a diabetes duration of 150 days. The diabetes frequency was significantly lower in BB.Xs than in rats of the parental strain BB/OK, whereas comparable frequencies were found between BB/OK and BB.Sa rats. Obvious differences were observed 150 days after diabetes onset between BB/OK and both BB.Sa and BB.Xs rats. BB/OK rats were significantly heavier and needed significantly more insulin/100 g body weight than BB.Sa and BB.Xs rats. Comparisons of the serum constituents as lipids, proteins, and minerals revealed significant differences between diabetic BB/OK rats and their diabetic congenic derivatives in several traits studied at onset and after 150 days of insulin treatment. These results not only show the power of congenic lines in diabetes research, but indicate for the first time that there are genetic factors on chromosomes 1 and X influencing frequency and severity of diabetes in the BB/OK rat.

Aging↗