79 research outputs found
Quantifying the improvement of surrogate indices of hepatic insulin resistance using complex measurement techniques
We evaluated the ability of simple and complex surrogate-indices to identify individuals from an overweight/obese cohort with hepatic insulin-resistance (HEP-IR). Five indices, one previously defined and four newly generated through step-wise linear regression, were created against a single-cohort sample of 77 extensively characterised participants with the metabolic syndrome (age 55.6±1.0 years, BMI 31.5±0.4 kg/m2; 30 males). HEP-IR was defined by measuring endogenous-glucose-production (EGP) with [6–62H2] glucose during fasting and euglycemic-hyperinsulinemic clamps and expressed as EGP*fasting plasma insulin. Complex measures were incorporated into the model, including various non-standard biomarkers and the measurement of body-fat distribution and liver-fat, to further improve the predictive capability of the index. Validation was performed against a data set of the same subjects after an isoenergetic dietary intervention (4 arms, diets varying in protein and fiber content versus control). All five indices produced comparable prediction of HEP-IR, explaining 39–56% of the variance, depending on regression variable combination. The validation of the regression equations showed little variation between the different proposed indices (r2 = 27–32%) on a matched dataset. New complex indices encompassing advanced measurement techniques offered an improved correlation (r = 0.75, P<0.001). However, when validated against the alternative dataset all indices performed comparably with the standard homeostasis model assessment for insulin resistance (HOMA-IR) (r = 0.54, P<0.001). Thus, simple estimates of HEP-IR performed comparable to more complex indices and could be an efficient and cost effective approach in large epidemiological investigations
Genome Wide Meta-analysis Highlights the Role of Genetic Variation in RARRES2 in the Regulation of Circulating Serum Chemerin.
Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. Genetic factors determining chemerin release from adipose tissue are yet unknown. We conducted a meta-analysis of genome-wide association studies (GWAS) for serum chemerin in three independent cohorts from Europe: Sorbs and KORA from Germany and PPP-Botnia from Finland (total N = 2,791). In addition, we measured mRNA expression of genes within the associated loci in peripheral mononuclear cells by micro-arrays, and within adipose tissue by quantitative RT-PCR and performed mRNA expression quantitative trait and expression-chemerin association studies to functionally substantiate our loci. Heritability estimate of circulating chemerin levels was 16.2% in the Sorbs cohort. Thirty single nucleotide polymorphisms (SNPs) at chromosome 7 within the retinoic acid receptor responder 2 (RARRES2)/Leucine Rich Repeat Containing (LRRC61) locus reached genome-wide significance (p<5.0Ă—10?8) in the meta-analysis (the strongest evidence for association at rs7806429 with p = 7.8Ă—10?14, beta = ?0.067, explained variance 2.0%). All other SNPs within the cluster were in linkage disequilibrium with rs7806429 (minimum r2 = 0.43 in the Sorbs cohort). The results of the subgroup analyses of males and females were consistent with the results found in the total cohort. No significant SNP-sex interaction was observed. rs7806429 was associated with mRNA expression of RARRES2 in visceral adipose tissue in women (p<0.05 after adjusting for age and body mass index). In conclusion, the present meta-GWAS combined with mRNA expression studies highlights the role of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations
Defective Peripheral Nerve Development Is Linked to Abnormal Architecture and Metabolic Activity of Adipose Tissue in Nscl-2 Mutant Mice
BACKGROUND: In mammals the interplay between the peripheral nervous system (PNS) and adipose tissue is widely unexplored. We have employed mice, which develop an adult onset of obesity due to the lack the neuronal specific transcription factor Nscl-2 to investigate the interplay between the nervous system and white adipose tissue (WAT). METHODOLOGY: Changes in the architecture and innervation of WAT were compared between wildtype, Nscl2-/-, ob/ob and Nscl2-/-//ob/ob mice using morphological methods, immunohistochemistry and flow cytometry. Metabolic alterations in mutant mice and in isolated cells were investigated under basal and stimulated conditions. PRINCIPAL FINDINGS: We found that Nscl-2 mutant mice show a massive reduction of innervation of white epididymal and paired subcutaneous inguinal fat tissue including sensory and autonomic nerves as demonstrated by peripherin and neurofilament staining. Reduction of innervation went along with defects in the formation of the microvasculature, accumulation of cells of the macrophage/preadipocyte lineage, a bimodal distribution of the size of fat cells, and metabolic defects of isolated adipocytes. Despite a relative insulin resistance of white adipose tissue and isolated Nscl-2 mutant adipocytes the serum level of insulin in Nscl-2 mutant mice was only slightly increased. CONCLUSIONS: We conclude that the reduction of the innervation and vascularization of WAT in Nscl-2 mutant mice leads to the increase of preadipocyte/macrophage-like cells, a bimodal distribution of the size of adipocytes in WAT and an altered metabolic activity of adipocytes
Normalisierung histomorphometrischer und biomechanischer Parameter durch kontrollierte StoffwechselfĂĽhrung bei der Frakturheilung spontandiabetischer BB/OK-Ratten
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 wellcompensated
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
Einfluss des metabolischen Status diabetischer Ratten auf die Trommelfellwundheilung
Patienten mit Diabetes mellitus leiden häufiger unter Wundheilungsstörungen und chronischen Wunden der Haut, da die Störung des Stoffwechsels zu Mikro- und Makroangiopathie, verminderter Proliferationsrate von Fibrolasten sowie reduzierter Aktivität von Granulozyten führt. Da die Wundheilungsprozesse am Trommelfell ähnlich denen der Haut verlaufen, ist auch für das Trommelfell eine Beeinflussung der Wundheilung bei diabetischer Stoffwechsellage zu erwarten. Jedoch existieren keine Studien, die einen solchen Zusammenhang belegen. Ziel unserer verblindeten, randomisierten und kontrollierten Studie war es, einen möglichen Einfluss von diabetischer Stoffwechsellage auf die Qualität und den zeitlichen Verlauf der Trommelfellwundheilung zu untersuchen. Die Studien erfolgten an insgesamt 60 Ratten. Es wurden 3 Gruppen gebildet, die sich bezüglich ihres Blutzuckerspiegels unterschieden: 20 nicht diabetische BB.1K x BB.LL-Ratten (Kontrollgruppe), 17 BB/OK-Ratten mit gut eingestelltem Diabetes mellitus und 23 BB/OK-Ratten mit schlecht eingestelltem Diabetes mellitus. Nach Trommelfellperforationen im hinteren oberen Quadranten wurde der Verlauf der Trommelfellwundheilung otomikroskopisch für 3 Wochen kontrolliert. Zusätzlich erfolgten histologische Untersuchungen zu definierten Zeitpunkten. Die Ergebnisse dieser Studie sollen vorgestellt und diskutiert werden
Light rhythm and diet differently influence facets of the metabolic syndrome in WOKW rats
Delayed remodeling in the early period of fracture healing in spontaneously diabetic BB/OK rats depending on the diabetic metabolic state
Several clinical series, analyzing fracture
healing in patients with insulin-dependent type 1
diabetes (IDDM) demonstrated significant incidence of
delayed union, non-union, and pseudarthrosis. The
purpose of this study was to examine the detailed
histomorphometry and histology of bone formation and
remodeling during fracture 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 man.
A standardized fracture 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), 100
spontaneously diabetic BB/OK rats were divided into
groups with well-compensated (n=50, 167±77 mg%;
244±68 mg%; 1.8±1.9 IU/kg) or poorly compensated
(n=50, 380±89 mg%; 415±80 mg%; 6.0±1.0 IU/kg)
metabolic state. Fifty LEW.1A rats served as the
normoglycemic controls (97±15 mg%). Ten animals
from each group were killed 1, 2, 3, 4 and 6 weeks after
fracture and specimens were processed undecalcified for
quantitative histomorphometry and for qualitative light
microscopy.
In terms of bone histomorphometry, within the first
four weeks after fracture, severe mineralization disorders
occurred exclusively in the rats with poorly compensated
diabetic metabolic states with a significantly decrease of
all fluorochrome-based parameters of mineralization,
apposition, formation and timing of mineralization in
comparison to the spontaneously diabetic rats with wellcompensated
metabolic states and to the control rats.
This was confirmed histologically.
Early fracture healing in the spontaneously diabetic
BB/OK rats is delayed exclusively in poorly compensated diabetic metabolic states, and 6 weeks after
fracture, histomorphometrically significant deficits in the
measured and dynamically calculated parameters
remain. This study suggests that strictly controlled
insulin treatment resulting in well-compensated diabetic
metabolic states will ameliorate the impaired early
mineralization and cell differentiation disorders of
IDDM fracture healing
Histomorphometrische Untersuchungen zur verzögerten Knochendefektheilung bei spontandiabetischen BB/OK-Ratten
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