Reduced Skeletal Muscle Uncoupling Protein-3 Content in Prediabetic Subjects and Type 2 Diabetic Patients: Restoration by Rosiglitazone Treatment

Schrauwen, Patrick; Mensink, Marco; Schaart, Gert; Moonen‐Kornips, Esther; Sels, J. P. J. E.; Blaak, Ellen E.; Russell, Aaron P.; Hesselink, Matthijs K. C.

doi:10.1210/jc.2005-1572

Cited by 64 publications

(61 citation statements)

References 33 publications

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“…This increase, however, was significantly blunted in the model of progressive insulin resistance in fa/fa rats, resulting in significantly lower levels of UCP3 at week 19 in diabetic rats compared to control rats. This is consistent with our previous observation that UCP3 protein content is reduced by 50% in type 2 diabetic patients compared to BMI-matched controls (24). Despite this consistency, both the origin as the consequence of the blunted increase in UCP3 in fa/fa rats remains to be established and the differences in UCP3 protein expression were not reflected in differences in the expression of carbonylated proteins, an indirect marker of superoxide production.…”

Section: Articles Integrative Physiologysupporting

confidence: 92%

“…Here we show that in fa/fa rats, during the transition of the prediabetic state toward full-blown type 2 diabetes, marker proteins of mitochondrial density were unaltered and comparable to normoglycemic and normoinsulinemic control rats. This is in line with data in human prediabetic and type 2 diabetic subjects compared to age and BMI-matched normoglycemic controls, who also show no differences in the muscular protein content of complex I-V or cytochrome C (24). In these studies mitochondrial mass was examined by marker proteins of mitochondrial density or classical enzymatic assays supposed to reflect mitochondrial mass.…”

Section: Articles Integrative Physiologysupporting

confidence: 87%

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Adaptations in Mitochondrial Function Parallel, but Fail to Rescue, the Transition to Severe Hyperglycemia and Hyperinsulinemia: A Study in Zucker Diabetic Fatty Rats

Lenaers

Feyter

Hoeks

et al. 2010

Obesity

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Cross‐sectional human studies have associated mitochondrial dysfunction to type 2 diabetes. We chose Zucker diabetic fatty (ZDF) rats as a model of progressive insulin resistance to examine whether intrinsic mitochondrial defects are required for development of type 2 diabetes. Muscle mitochondrial function was examined in 6‐, 12‐, and 19‐week‐old ZDF (fa/fa) and fa/+ control rats (n = 8–10 per group) using respirometry with pyruvate, glutamate, and palmitoyl‐CoA as substrates. Six‐week‐old normoglycemic–hyperinsulinemic fa/fa rats had reduced mitochondrial fat oxidative capacity. Adenosine diphosphate (ADP)‐driven state 3 and carbonyl cyanide p‐trifluoromethoxyphenylhydrazone (FCCP)‐stimulated state uncoupled (state u) respiration on palmitoyl‐CoA were lower compared to controls (62.3 ± 9.5 vs. 119.1 ± 13.8 and 87.8 ± 13.3 vs. 141.9 ± 14.3 nmol O2/mg/min.). Pyruvate oxidation in 6‐week‐old fa/fa rats was similar to controls. Remarkably, reduced fat oxidative capacity in 6‐week‐old fa/fa rats was compensated for by an adaptive increase in intrinsic mitochondrial function at week 12, which could not be maintained toward week 19 (140.9 ± 11.2 and 57.7 ± 9.8 nmol O2/mg/min, weeks 12 and 19, respectively), whereas hyperglycemia had developed (13.5 ± 0.6 and 16.1 ± 0.3 mmol/l, weeks 12 and 19, respectively). This mitochondrial adaptation failed to rescue the progressive development of insulin resistance in fa/fa rats. The transition of prediabetes state toward advanced hyperglycemia and hyperinsulinemia was accompanied by a blunted increase in uncoupling protein‐3 (UCP3). Thus, in ZDF rats insulin resistance develops progressively in the absence of mitochondrial dysfunction. In fact, improved mitochondrial capacity in hyperinsulinemic hyperglycemic rats does not rescue the progression toward advanced stages of insulin resistance.

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Section: Articles Integrative Physiologysupporting

confidence: 92%

Section: Articles Integrative Physiologysupporting

confidence: 87%

Adaptations in Mitochondrial Function Parallel, but Fail to Rescue, the Transition to Severe Hyperglycemia and Hyperinsulinemia: A Study in Zucker Diabetic Fatty Rats

Lenaers

Feyter

Hoeks

et al. 2010

Obesity

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show abstract

“…UCP3 protein content was also found to be inversely correlated with plasma glucose and insulin levels (36). Thus, high levels of UCP3 may protect against the development of type 2 diabetes (36,37). This hypothesis is in accordance with the observation that mice overexpressing UCP3 were resistant to development of diet-induced diabetes (38).…”

Section: Ucp2-ucp3 Variants and Diabetessupporting

confidence: 72%

Genetic Variants in the UCP2-UCP3 Gene Cluster and Risk of Diabetes in the Women's Health Initiative Observational Study

et al. 2008

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OBJECTIVE-Mitochondrial uncoupling proteins (UCPs) are involved in body weight regulation and glucose homeostasis. Genetic variants in the UCP2-UCP3 gene cluster, located on chromosome 11q13, may play a significant role in the development of type 2 diabetes. RESEARCH DESIGN AND METHODS-We conducted a comprehensive assessment of common single nucleotide polymorphisms (SNPs) at the 70-kb UCP2-UCP3 gene cluster in relation to type 2 diabetes risk in a prospective, case-control study nested in the Women's Health Initiative Observational Study, an ethnically diverse cohort of postmenopausal women including Caucasian, African, Hispanic, and Asian American subjects. We genotyped 14 tag SNPs in 1,584 incident type 2 diabetes case and 2,198 control subjects matched by age, ethnicity, clinical center, time of blood draw, and length of follow-up. RESULTS-We identified a haplotype set (rs591758-rs668514-rs647126-rs1800006, spanning the UCP2-UCP3 intergenic and UCP3 regions) as significantly associated with greater type 2 diabetes risk (nominal P ϭ 0.0011, permutation P ϭ 0.046) in Caucasian women, especially among overweight Caucasians (BMI Ͼ25 kg/m 2 ) (nominal P ϭ 0.0006, permutation P ϭ 0.032). Compared with the most common haplotype (h1010 as the referent), haplotype h0001 (19.5% in control subjects) had odds ratios of 2.0 (95% CI 1.13-3.37) in in Caucasian overweight women. Similar haplotype-type 2 diabetes association was also observed among Hispanic women who were overweight. CONCLUSIONS-These findings suggest a role of UCP2-UCP3 gene cluster haplotypes in diabetes; in particular, the effects of the high-risk haplotypes were more apparent in overweight Caucasian women. These data warrant further confirmation in future prospective and experimental studies.

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“…But, UCP3 can also stimulate glucose uptake and recruitment of SLC2A4 to the cell surface (Huppertz et al 2001) and so its decline in programmed offspring may contribute to the observed accumulation of cytoplasmic SLC2A4. Interestingly, reduced skeletal muscle Ucp3 expression has also been observed in diabetic human subjects (Krook et al 1998, Schrauwen et al 2001, and a recent report indicates that this is already the case in prediabetic subjects with impaired glucose tolerance (Schrauwen et al 2006). Such a prediabetic state appears to characterize our programmed phenotype, since offspring of Dex-treated mothers were hyperinsulinemic, yet maintained euglycemia in the fasted state.…”

Section: Discussionmentioning

confidence: 74%

Developmental programming of adult hyperinsulinemia, increased proinflammatory cytokine production, and altered skeletal muscle expression of SLC2A4 (GLUT4) and uncoupling protein 3

Wyrwoll¹,

Mark²,

Mori³

et al. 2008

Journal of Endocrinology

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Fetal glucocorticoid excess programs detrimental effects in the adult phenotype including hyperleptinemia and aberrant glycemic control. In this study, we determined the interactive effects of maternal dexamethasone (Dex) treatment and postnatal dietary u-3 (n-3) fatty acids on adult proinflammatory cytokine production and skeletal muscle expression of genes central to glucose handling and fatty acid metabolism. Dex acetate was administered to pregnant rats (0 . 75 mg/ml drinking water) from day 13 to term. Offspring of treated and control mothers were cross-fostered to mothers on either a standard (Std) or high n-3 (Hn3) diet, and remained on these diets postweaning. Adult offspring exposed to Dex in utero exhibited fasting hyperinsulinemia when raised on the Std diet but not when raised on the Hn3 diet. Dex also programmed increased plasma tumour necrosis factora and interleukin 1b (IL-1b), but the increase in IL-1b was also prevented by the Hn3 diet. In skeletal muscle, expression of insulin regulated Slc2a4 (formerly known as GLUT4) was elevated (up to 15-fold) after Dex in utero, and this resulted in elevated intracellular, but not membrane-associated, SLC2A4 protein. Fetal glucocorticoid excess also reduced adult skeletal muscle Ucp3 expression in all offspring, whereas skeletal muscle expression of both Ppard and Ppargc1a were increased in females but not males. In conclusion, our data show that fetal glucocorticoid excess programs adult hyperinsulinemia and increased proinflammatory cytokine production. Related changes in the skeletal muscle Slc2a4, Ucp3, and Ppard indicate that fetal glucocorticoid excess disturbs adult glucose/fatty acid transport and metabolism.

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Reduced Skeletal Muscle Uncoupling Protein-3 Content in Prediabetic Subjects and Type 2 Diabetic Patients: Restoration by Rosiglitazone Treatment

Abstract: We show that UCP3 protein content is reduced in prediabetic subjects and type 2 diabetic patients. Eight weeks of rosiglitazone treatment restores skeletal muscle UCP3 protein in diabetic patients.

Cited by 64 publications

References 33 publications

Adaptations in Mitochondrial Function Parallel, but Fail to Rescue, the Transition to Severe Hyperglycemia and Hyperinsulinemia: A Study in Zucker Diabetic Fatty Rats

Adaptations in Mitochondrial Function Parallel, but Fail to Rescue, the Transition to Severe Hyperglycemia and Hyperinsulinemia: A Study in Zucker Diabetic Fatty Rats

Genetic Variants in the UCP2-UCP3 Gene Cluster and Risk of Diabetes in the Women's Health Initiative Observational Study

Developmental programming of adult hyperinsulinemia, increased proinflammatory cytokine production, and altered skeletal muscle expression of SLC2A4 (GLUT4) and uncoupling protein 3

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