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1.  Fibroblast Growth Factor 21 Predicts the Metabolic Syndrome and Type 2 Diabetes in Caucasians 
Diabetes Care  2012;36(1):145-149.
OBJECTIVE
The incidence of the metabolic syndrome and type 2 diabetes mellitus (T2DM) is rising worldwide. Liver-derived fibroblast growth factor (FGF)-21 affects glucose and lipid metabolism. The aim of this study was to analyze the predictive value of FGF-21 on the incidence of T2DM and the metabolic syndrome.
RESEARCH DESIGN AND METHODS
The Metabolic Syndrome Berlin Potsdam (MeSyBePo) recall study includes 440 individuals. Glucose metabolism was analyzed using an oral glucose tolerance test, including insulin measurements. FGF-21 was measured using enzyme-linked immunosorbent assay. Primary study outcome was diabetes and the metabolic syndrome incidence and change of glucose subtraits.
RESULTS
During a mean follow-up of 5.30 ± 0.1 years, 54 individuals developed the metabolic syndrome, 35 developed T2DM, and 69 with normal glucose tolerance at baseline progressed to impaired glucose metabolism, defined as impaired fasting glucose, impaired glucose tolerance, or T2DM. FGF-21 predicted incident metabolic syndrome (lnFGF-21 odds ratio [OR] 2.6 [95% CI 1.5 – 4.5]; P = 0.001), T2DM (2.4 [1.2–4.7]; P = 0.01), and progression to impaired glucose metabolism (2.2 [1.3 – 3.6]; P = 0.002) after adjustment for age, sex, BMI, and follow-up time. Additional adjustment for waist-to-hip ratio, systolic blood pressure, HDL cholesterol, triglycerides, and fasting glucose did not substantially modify the predictive value of FGF-21.
CONCLUSIONS
FGF-21 is an independent predictor of the metabolic syndrome and T2DM in apparently healthy Caucasians. These results may indicate FGF-21 resistance precedes the onset of the metabolic syndrome and T2DM.
doi:10.2337/dc12-0703
PMCID: PMC3526237  PMID: 22933429
2.  Glucose-Dependent Insulinotropic Polypeptide Reduces Fat-Specific Expression and Activity of 11β-Hydroxysteroid Dehydrogenase Type 1 and Inhibits Release of Free Fatty Acids 
Diabetes  2012;61(2):292-300.
Glucose-dependent insulinotropic polypeptide (GIP) has been suggested to have direct effects on nonislet tissues. GIP also reportedly increased glucose uptake and inhibition of lipolysis in adipocytes after inhibition of the intracellular cortisone-cortisol shuttle 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). We here analyzed whether GIP modifies lipid metabolism and further elucidated the relation between GIP, 11β-HSD1, and fatty acid metabolism. GIP reduced activity of 11β-HSD1 promoter constructs and the expression and activity of 11β-HSD1 in differentiated 3T3-L1 adipocytes in a time- and dose-dependent fashion. This was paralleled by a reduction of free fatty acid (FFA) release and a reduced expression of key enzymes regulating lipolysis in adipose tissue. Preinhibition of 11β-HSD1 completely abolished GIP-induced effects on FFA release. To investigate the acute effects of GIP in humans, a randomized clinical trial was performed. GIP lowered circulating FFAs compared with saline control and reduced expression and ex vivo activity of 11β-HSD1 and adipose triglyceride lipase expression in subcutaneous fat biopsies. Our data suggest that GIP reduces FFA release from adipose tissue by inhibition of lipolysis or by increased reesterification. This process appears to depend on a modification of 11β-HSD1 activity. In general, the presented data support that GIP has direct and insulin-independent effects on adipose tissue.
doi:10.2337/db10-0902
PMCID: PMC3266397  PMID: 22179810
3.  Histone Deacetylase 6 (HDAC6) Is an Essential Modifier of Glucocorticoid-Induced Hepatic Gluconeogenesis 
Diabetes  2012;61(2):513-523.
In the current study, we investigated the importance of histone deacetylase (HDAC)6 for glucocorticoid receptor–mediated effects on glucose metabolism and its potential as a therapeutic target for the prevention of glucocorticoid-induced diabetes. Dexamethasone-induced hepatic glucose output and glucocorticoid receptor translocation were analyzed in wild-type (wt) and HDAC6-deficient (HDAC6KO) mice. The effect of the specific HDAC6 inhibitor tubacin was analyzed in vitro. wt and HDAC6KO mice were subjected to 3 weeks’ dexamethasone treatment before analysis of glucose and insulin tolerance. HDAC6KO mice showed impaired dexamethasone-induced hepatic glucocorticoid receptor translocation. Accordingly, dexamethasone-induced expression of a large number of hepatic genes was significantly attenuated in mice lacking HDAC6 and by tubacin in vitro. Glucose output of primary hepatocytes from HDAC6KO mice was diminished. A significant improvement of dexamethasone-induced whole-body glucose intolerance as well as insulin resistance in HDAC6KO mice compared with wt littermates was observed. This study demonstrates that HDAC6 is an essential regulator of hepatic glucocorticoid-stimulated gluconeogenesis and impairment of whole-body glucose metabolism through modification of glucocorticoid receptor nuclear translocation. Selective pharmacological inhibition of HDAC6 may provide a future therapeutic option against the prodiabetogenic actions of glucocorticoids.
doi:10.2337/db11-0313
PMCID: PMC3266407  PMID: 22210316
4.  Attachment style contributes to the outcome of a multimodal lifestyle intervention 
Background & Aims
The long-term success of life-style interventions in the treatment of obesity is limited. Although psychological factors have been suggested to modify therapeutic effects, specifically the implications of attachment styles and the patient-therapist relationship have not been examined in detail yet.
Methods
This study included 44 obese patients who participated in a one-year multimodal weight-reduction program. Attachment style was analyzed by the Adult Attachment Prototype Rating (AAPR) inventory and its relation to a one-year weight reduction program was studied. The patient-therapist-relationship was assessed using the Helping Alliance Questionnaire.
Results
Attachment style was secure in 68% of participants and insecure (preoccupied and dismissing) in 32%. Interestingly a significantly higher weight-reduction was found in securely (SAI) compared to insecurely attached individuals (UAI; p < 0.05). This estimation correlated positively also to the quality of helping alliance (p = 0.004).
Conclusions
The frequency of insecure attachment in obese individuals was comparable to that of the normal population. Our data suggest a greater weight-reduction for SAI than for UAI, and the patient-therapist relationship was rated more positively. The conclusion can be drawn that a patient's attachment style plays a role in an interdisciplinary treatment program for obesity and has an influence on the effort to lose weight.
doi:10.1186/1751-0759-6-3
PMCID: PMC3296567  PMID: 22300715
attachment style; obesity; patient-therapist relationship; weight reduction
5.  Skeletal Muscle 11beta-HSD1 Controls Glucocorticoid-Induced Proteolysis and Expression of E3 Ubiquitin Ligases Atrogin-1 and MuRF-1 
PLoS ONE  2011;6(1):e16674.
Recent studies demonstrated expression and activity of the intracellular cortisone-cortisol shuttle 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in skeletal muscle and inhibition of 11beta-HSD1 in muscle cells improved insulin sensitivity. Glucocorticoids induce muscle atrophy via increased expression of the E3 ubiquitin ligases Atrogin-1 (Muscle Atrophy F-box (MAFbx)) and MuRF-1 (Muscle RING-Finger-1). We hypothesized that 11beta-HSD1 controls glucocorticoid-induced expression of atrophy E3 ubiquitin ligases in skeletal muscle. Primary human myoblasts were generated from healthy volunteers. 11beta-HSD1-dependent protein degradation was analyzed by [3H]-tyrosine release assay. RT-PCR was used to determine mRNA expression of E3 ubiquitin ligases and 11beta-HSD1 activity was measured by conversion of radioactively labeled [3H]-cortisone to [3H]-cortisol separated by thin-layer chromatography. We here demonstrate that 11beta-HSD1 is expressed and biologically active in interconverting cortisone to active cortisol in murine skeletal muscle cells (C2C12) as well as in primary human myotubes. 11beta-HSD1 expression increased during differentiation from myoblasts to mature myotubes (p<0.01), suggesting a role of 11beta-HSD1 in skeletal muscle growth and differentiation. Treatment with cortisone increased protein degradation by about 20% (p<0.001), which was paralleled by an elevation of Atrogin-1 and MuRF-1 mRNA expression (p<0.01, respectively). Notably, pre-treatment with the 11beta-HSD1 inhibitor carbenoxolone (Cbx) completely abolished the effect of cortisone on protein degradation as well as on Atrogin-1 and MuRF-1 expression. In summary, our data suggest that 11beta-HSD1 controls glucocorticoid-induced protein degradation in human and murine skeletal muscle via regulation of the E3 ubiquitin ligases Atrogin-1 and MuRF-1.
doi:10.1371/journal.pone.0016674
PMCID: PMC3031623  PMID: 21304964
6.  A1C Is Associated With Intima-Media Thickness in Individuals With Normal Glucose Tolerance 
Diabetes Care  2009;33(1):203-204.
OBJECTIVE
One-hour glucose during an oral glucose tolerance test (OGTT) was recently proposed as a valuable marker to identify individuals with normal glucose tolerance (NGT) and increased intima-media thickness (IMT). However, central markers of glycemic control were not considered. The aim of this study was to identify which marker of glycemic control is most informative with respect to the variation of IMT in individuals with NGT.
RESEARCH DESIGN AND METHODS
Cardiovascular risk factors, glucose metabolism (OGTT), and IMT were determined in 1,219 nondiabetic individuals (851 women, 368 men; 558 with NGT).
RESULTS
One-hour glucose and A1C levels were significantly correlated to carotid IMT in individuals with NGT, whereas fasting and 2-h glucose levels were not informative. Only A1C was associated with IMT independent of other confounders, whereas 1-h glucose was not informative. Comparable results were found in the total cohort, including individuals with IFG and IGT.
CONCLUSIONS
A1C was the most informative glycemic marker with respect to IMT in individuals with NGT.
doi:10.2337/dc09-1009
PMCID: PMC2797974  PMID: 19808917
7.  Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21 
Diabetes  2009;58(7):1532-1538.
OBJECTIVE
Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator–activator receptor (PPAR) α–dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPARα, might modify FGF-21 levels.
RESEARCH DESIGN AND METHODS
The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARγ activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks.
RESULTS
Oleate and linoleate increased FGF-21 expression and secretion in a PPARα-dependent fashion, as demonstrated by small-interfering RNA–induced PPARα knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect.
CONCLUSIONS
The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity.
doi:10.2337/db08-1775
PMCID: PMC2699854  PMID: 19401423

Results 1-7 (7)