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1.  Mechanisms Underlying the Onset of Oral Lipid–Induced Skeletal Muscle Insulin Resistance in Humans 
Diabetes  2013;62(7):2240-2248.
Several mechanisms, such as innate immune responses via Toll-like receptor-4, accumulation of diacylglycerols (DAG)/ceramides, and activation of protein kinase C (PKC), are considered to underlie skeletal muscle insulin resistance. In this study, we examined initial events occurring during the onset of insulin resistance upon oral high-fat loading compared with lipid and low-dose endotoxin infusion. Sixteen lean insulin-sensitive volunteers received intravenous fat (iv fat), oral fat (po fat), intravenous endotoxin (lipopolysaccharide [LPS]), and intravenous glycerol as control. After 6 h, whole-body insulin sensitivity was reduced by iv fat, po fat, and LPS to 60, 67, and 48%, respectively (all P < 0.01), which was due to decreased nonoxidative glucose utilization, while hepatic insulin sensitivity was unaffected. Muscle PKCθ activation increased by 50% after iv and po fat, membrane Di-C18:2 DAG species doubled after iv fat and correlated with PKCθ activation after po fat, whereas ceramides were unchanged. Only after LPS, circulating inflammatory markers (tumor necrosis factor-α, interleukin-6, and interleukin-1 receptor antagonist), their mRNA expression in subcutaneous adipose tissue, and circulating cortisol were elevated. Po fat ingestion rapidly induces insulin resistance by reducing nonoxidative glucose disposal, which associates with PKCθ activation and a rise in distinct myocellular membrane DAG, while endotoxin-induced insulin resistance is exclusively associated with stimulation of inflammatory pathways.
PMCID: PMC3712035  PMID: 23454694
2.  Comparison of Liver Fat Indices for the Diagnosis of Hepatic Steatosis and Insulin Resistance 
PLoS ONE  2014;9(4):e94059.
Hepatic steatosis, defined as increased hepatocellular lipid content (HCL), associates with visceral obesity and glucose intolerance. As exact HCL quantification by 1H-magnetic resonance spectroscopy (1H-MRS) is not generally available, various clinical indices are increasingly used to predict steatosis.
The purpose of this study was to test the accuracy of NAFLD liver fat score (NAFLD-LFS), hepatic steatosis index (HSI) and fatty liver index (FLI) against 1H-MRS and their relationships with insulin sensitivity and secretion.
Design, Setting and Participants
Ninety-two non-diabetic, predominantly non-obese humans underwent clinical examination, 1H-MRS and an oral glucose tolerance test (OGTT) to calculate insulin sensitivity and β-cell function. Accuracy of indices was assessed from the area under the receiver operating characteristic curve (AROC).
Median HCL was 2.49% (0.62;4.23) and correlated with parameters of glycemia across all subjects. NAFLD-LFS, FLI and HSI yielded AROCs of 0.70, 0.72, and 0.79, respectively, and related positively to HCL, insulin resistance, fasting and post-load β-cell function normalized for insulin resistance. Upon adjustment for age, sex and HCL, regression analysis revealed that NAFLD-LFS, FLI and HSI still independently associated with both insulin sensitivity and β-cell function.
The tested indices offer modest efficacy to detect steatosis and cannot substitute for fat quantification by 1H-MRS. However, all indices might serve as surrogate parameters for liver fat content and also as rough clinical estimates of abnormal insulin sensitivity and secretion. Further validation in larger collectives such as epidemiological studies is needed.
PMCID: PMC3986069  PMID: 24732091
3.  Risk for High Depressive Symptoms in Diagnosed and Previously Undetected Diabetes: 5-Year Follow-Up Results of the Heinz Nixdorf Recall Study 
PLoS ONE  2013;8(2):e56300.
The objective of this study was to determine the risk for the development of high depressive symptoms in study participants with diagnosed and previously undetected diabetes mellitus compared to those without diabetes in a prospective population-based cohort study in Germany.
We estimated the 5-year cumulative incidence of high depressive symptoms in participants without high depressive symptoms at baseline (n = 3,633, 51.4% men, mean age (SD) 59.1 (7.6) years, 7.0% diagnosed diabetes, 5.3% previously undetected diabetes) from the population-based Heinz Nixdorf Recall study. Diabetes was assessed by self-report, medication, and blood glucose. High depressive symptoms were assessed using CES-D. We calculated odds ratios and their corresponding 95% confidence interval, using multiple logistic regression analyses.
Cumulative 5-year incidences (95% CI) of high depressive symptoms in participants with diagnosed, undetected, and without diabetes were 7.1 (4.2–10.9), 4.1 (1.8–8.0), and 6.5 (5.6–7.4), respectively. The age-sex-adjusted OR for developing high depressive symptoms was 1.22 (0.74–2.03) in participants with diagnosed compared to those without diabetes, and 1.00 (0.59–1.68) after adjustment for BMI, physical activity, education, stroke, and myocardial infarction. The age-sex adjusted OR for developing high depressive symptoms in participants with previously undetected diabetes compared to those without diabetes was 0.72; 0.35–1.48; and fully adjusted 0.62; 0.30–1.30.
We found no significant associations, maybe due to low power. However, our results are in line with a recent meta-analysis suggesting that risk of developing high depressive symptoms in patients with diagnosed diabetes may be moderately higher than in those without diabetes, and that comorbidity may explain in part this association. In participants with previously undetected diabetes, this first longitudinal study indicates that the risk is not increased or may even be decreased. These results support the hypothesis that high depressive symptoms develop due to diabetes-related burden and comorbidity and not due to hyperglycemia or hyperinsulinaemia.
PMCID: PMC3575467  PMID: 23441174
4.  Inflammatory Adipokines, High Molecular Weight Adiponectin, and Insulin Resistance: A Population-Based Survey in Prepubertal Schoolchildren 
PLoS ONE  2011;6(2):e17264.
The aim of this study was to investigate sex differences and associations of high molecular weight (HMW) adiponectin, leptin and proinflammatory adipokines, individually or in combinations, with adiposity and insulin resistance (IR) measures in prepubertal childhood.
We studied 305 prepubertal children (boys/girls: 144/161; Tanner stage 1; age: 5-13 yr), included in a cohort of 44,231 adolescents who participated in an extensive Italian school-based survey. According to Cole's criteria, 105 individuals were lean (L; boys/girls: 59/46), 60 overweight (OW; boys/girls: 32/28) and 140 obese (OB; boys/girls: 70/70). Measurements comprised total and HMW adiponectin, leptin, as well as a panel of proinflammatory adipokines/chemokines associated with diabetes risk.
Principal Findings
Leptin-, and the leptin-to-HMW adiponectin ratio (L/HMW)-, increased progressively (p<0.0001) from L to OW to OB boys and girls. When compared with L peers, OW and OB girls exhibited lower (p<0.001) HMW adiponectin levels, while in boys the HMW multimers did not differ significantly across the BMI-stratified groups. OB girls displayed higher (p<0.05) IL-8, IL-18, monocyte chemoattractant protein-1 (MCP-1) and soluble intercellular adhesion molecule-1 levels (sICAM-1) than L girls, whereas increased macrophage migration inhibitory factor (MIF) concentrations in OB vs OW boys were seen. HMW adiponectin (negatively), leptin or inflammatory markers (positively) correlated with adiposity and IR measures. In multivariate models, leptin represented a strong and independent determinant of HOMA-IR (R2 0.378; p<0.01). Adjustment for age, BMIz-score, lipids and inflammatory mediators abolished the association between leptin and HOMA-IR in boys, while in girls leptin remained still a significant predictor of IR (R2 0.513; p<0.01). Finally, in both sexes, the joint effect of the L/HMW did not improve the prediction of basal IR as compared with leptin levels alone, which were mainly explained by the BMIz-score.
In prepubertal children, leptin emerges as a sex-independent discrimination marker of adiposity degree and as a useful, sex-associated predictor of the systemic insulin resistance.
PMCID: PMC3041818  PMID: 21365005
5.  Blood glucose testing and primary prevention of diabetes mellitus type 2 - evaluation of the effect of evidence based patient information 
BMC Public Health  2010;10:15.
Evidence-based patient information (EBPI) has been recognised as important tool for informed choice in particular in the matter of preventive options. An objective, on the best scientific evidence-based consumer information about subthreshold elevated blood glucose levels (impaired fasting glucose and impaired glucose tolerance) and primary prevention of diabetes, is not available yet. Thus we developed a web-based EBPI and aim to evaluate its effects on informed decision making in people 50 years or older.
We conduct a web-based randomised-controlled trial to evaluate the effect of information about elevated blood glucose levels and diabetes primary prevention on five specific outcomes: (i) knowledge of elevated blood glucose level-related issues (primary outcome); (ii) attitudes to a metabolic testing; (iii) intention to undergo a metabolic testing; (iv) decision conflict; (v) satisfaction with the information. The intervention group receives a specially developed EBPI about subthreshold elevated blood glucose levels and diabetes primary prevention, the control group information about this topic, available in the internet.
The study population consists of people between 50 and 69 years of age without known diabetes. Participants will be recruited via the internet page of the cooperating health insurance company, Techniker Krankenkasse (TK), and the internet page of the German Diabetes Centre. Outcomes will be measured through online questionnaires. We expect better informed participants in the intervention group.
The design of this study may be a prototype for other web-based prevention information and their evaluation.
Trial registration
Current Controlled Trial: ISRCTN22060616.
PMCID: PMC2819991  PMID: 20074337

Results 1-5 (5)