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Michael Roden, Peter Nowotny, Heinrich Vierhapper and Werner Waldhäusl

Abstract.

To evaluate the sensitivity of basal TSH concentrations as determined by an "ultrasensitive" IRMA-assay (RIA-gnost h-TSH-monoclonal, Behring) versus a "negative" TRH test (defined as an increment of TSH ≥0.2 mU/l 20 min after administration of 400 μg TRH iv) in the diagnosis of hyperthyroidism we examined 193 consecutive patients from our thyroid outpatient clinic: 34 patients displayed hyperthyroidism (total T4: 184.4±26.0 μmol/l, effective thyroxine index: 1.25±0.08), whereas 12 had isolated T3-hyperthyroidism (total T3: 3.47±0.48 nmol/l). Employing the producer's definition of subnormal ("suppressed") bTSH concentrations (≤0.1 mU/l), only 19 (41.3%) hyperthyroid patients would have been detected; on the other hand, one euthyroid patient would have been recognized false positively as hyperthyroid. Using the TRH test as criterion led to the correct diagnosis in 42 (sensitivity: 91.3%) hyperthyroid patients, whereas two had low bTSH concentrations (≤0.5 mU/l), but a normal TSH response to TRH (>2.0 mU/l). Raising the threshold concentration to 0.2 and, subsequently, to 0.4 mU TSH/l increased the number of correct results to 38 (sensitivity: 82.6%) and 43 (93.5%), respectively. This was associated with a concomitant decrease in specificity in the diagnosis of hyperthyroidism from 93.7 (0.1 mU/l) to 27.9% (0.4 mU/l). In conclusion, despite ultrasensitive methods for estimation of low TSH concentrations, the TRH test remains an irreplaceable tool for the correct diagnosis of hyperthyroidism.

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Clemens Fürnsinn, Peter Nowotny, Michael Roden, Madeleine Rohac, Thomas Pieber, Sabina Parzer and Werner Waldhäusl

To compare the effect of short- vs long-term amylin infusion on insulin sensitivity, glucose tolerance and serum calcemia, euglycemic-hyperinsulinemic clamp (26 pmol·kg−1·min−1) and glucose tolerance tests (2.4 mmol/kg over 30 min) were performed in lean Zucker rats. Three infusion protocols were employed: control group: 24 h of iv saline; short-term amylin exposure: 22 h of iv saline followed by 2 h of iv amylin (20 μg/h); long-term amylin exposure: 24 h of iv amylin (20 μg/h). Insulin resistance was induced by short-term amylin infusion during euglycemic clamping, as shown by a 41% decrease in space-corrected glucose infusion rates (μmol·kg−1·min−1; control group, 106.0±15.0; short-term iv amylin, 62.7±15.0; p<0.00 5). After long-term amylin exposure, insulin sensitivity was identical to control values (109.9±6.7). This fading action of amylin was confirmed by data from the glucose tolerance test, demonstrating glucose intolerance after short- but not after long-term amylin exposure. Serum calcium concentration decreased during short-term (2 h) amylin infusion (from 2.52±0.15 to 2.09±0.12 mmol/l; p<0.01) and hypocalcemia of a similar extent also was present after 22 h and 24 h of amylin exposure (2.10±0.09 and 2.04±0.14 mmol/l, respectively). The data demonstrate that short-term amylin infusion induces insulin resistance and glucose intolerance, both of which vanish during long-term (>22 h) amylin exposure, being apparently independent of induced hypocalcemia.

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Maren Carstensen, Christian Herder, Eric J Brunner, Klaus Strassburger, Adam G Tabak, Michael Roden and Daniel R Witte

Objective

Macrophage inhibitory cytokine-1 (MIC-1) belongs to the transforming growth factor (TGF)-β superfamily, and has been reported to be involved in energy homoeostasis and weight loss and to have anti-inflammatory properties. We hypothesized that decreased concentrations of MIC-1 would be associated with higher risk of developing type 2 diabetes.

Design and methods

We designed a nested case–control study within the Whitehall II cohort and measured serum concentrations of MIC-1 by ELISA in 180 individuals without type 2 diabetes at baseline who developed type 2 diabetes during the follow-up period of 11.5±3.0 years and in 372 controls frequency-matched for age, sex, and body mass index with normal glucose tolerance throughout the study.

Results

MIC-1 concentrations at baseline were higher in cases (median (25/75th percentiles) 537.1 (452.7–677.4) pg/ml) than in controls (499.7 (413.8–615.4) pg/ml; P=0.0044). In the age- and sex-adjusted model, a 1-s.d. increase in MIC-1 (206.0 pg/ml) was associated with an odds ratio (95% confidence interval) of 1.21 (0.997; 1.46; P=0.054) for type 2 diabetes. Adjustment for waist circumference, cardiovascular risk factors, socioeconomic status, proinflammatory mediators, and glycemia abolished the association.

Conclusions

Baseline MIC-1 concentrations were increased, not decreased, in individuals before type 2 diabetes manifestation, but not independently associated with incident type 2 diabetes in multivariable analyses. This upregulation of MIC-1 could be part of an anti-inflammatory response preceding the onset of type 2 diabetes, which has been described before for interleukin-1 receptor antagonist and TGF-β1.

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Laura Dauben, Marie-Christine Simon, Klaus Strassburger, Volker Burkart, Katharina S Weber, Sven Schinner, Michael Roden and Karsten Müssig

Objective

Insulinomas are rare pancreatic endocrine tumors characterized by hypoglycemia. Guidelines by the Endocrine Society (ES), the European (ENETS) and the North American (NANETS) Neuroendocrine Tumor Societies provide divergent diagnostic criteria. This study compared the diagnostic accuracy of these different criteria during the 72-h fasting test.

Design

Retrospective cohort study.

Methods

From 2000 to 2014, 64 patients with a suspected insulinoma underwent a 72-h fasting test and were included in the analysis. This study assessed the diagnostic sensitivity, specificity and accuracy based on venous blood glucose and corresponding insulin levels measured by electrochemiluminescence immunoassay (ECLIA).

Results

Based on 64 individuals (18 with, 46 without insulinoma), the ES criteria provided a diagnostic sensitivity of 0.94 (0.73–1.00), specificity of 0.89 (0.76–0.96) and accuracy of 0.91 (0.81–0.96). ENETS/NANETS criteria reached a diagnostic sensitivity of 0.78 (0.52–0.94), specificity of 1.00 (0.92–1.00) and accuracy of 0.94 (0.85–0.98).

Conclusions

These results point to a higher diagnostic sensitivity with less specificity for diagnosing insulinoma using ES criteria and a higher specificity at lower sensitivity by using ENETS/NANETS criteria. Before considering these results when applying the different criteria in clinical practice, the results should be confirmed in further studies comprising larger cohorts.

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Christian Herder, D Margriet Ouwens, Maren Carstensen, Bernd Kowall, Cornelia Huth, Christa Meisinger, Wolfgang Rathmann, Michael Roden and Barbara Thorand

Objective

Reduced circulating omentin levels have been reported in obesity and type 2 diabetes, but data were mostly derived from univariate analyses in small study samples. This study aimed to investigate the relationship between omentin, abnormal glucose tolerance and related metabolic factors in a large population-based cross-sectional study.

Design and methods

Serum omentin was measured by ELISA in 1092 participants of the German KORA F4 survey (2006–2008). Associations between omentin serum levels, glucose tolerance (assessed with an oral glucose tolerance test) and diabetes-related factors were estimated using logistic and linear regression models respectively.

Results

Serum levels of omentin were not related to categories of glucose tolerance. However, serum omentin was positively associated with whole-body insulin sensitivity index (ISI (composite)) and HDL cholesterol and showed inverse associations with 2-h post-load glucose, fasting insulin, homeostasis model assessment-estimated insulin resistance, BMI and triglycerides (all P≤0.03 after adjustment for age, sex and lifestyle factors). Further adjustment for BMI and/or serum lipids attenuated the associations with parameters of glucose metabolism, whereas adjustment for serum adiponectin virtually abolished all aforementioned associations. In contrast, adjustment for omentin had no effect on the positive association between adiponectin levels and ISI (composite).

Conclusions

The data from this large population-based cohort show that circulating omentin levels are associated with insulin sensitivity. Our observations further suggest that omentin acts via upregulation of adiponectin, which in turn affects lipid metabolism and thereby also indirectly enhances insulin sensitivity, but mechanistic studies are required to corroborate this hypothesis.

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Jochen Seissler, Nina Feghelm, Cornelia Then, Christa Meisinger, Christian Herder, Wolfgang Koenig, Annette Peters, Michael Roden, Andreas Lechner, Bernd Kowall and Wolfgang Rathmann

Background

Metabolic alterations and endothelial dysfunction are interrelated processes in type 2 diabetes (T2D) and metabolic syndrome (MetS) that often develop in parallel. We assessed the association of vasoactive precursor peptides (VPPs) with MetS and T2D.

Design and methods

Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and midregional pro-adrenomedullin (MR-proADM) were measured by novel sensitive assays in 1590 participants of the population-based KORA F4 study. The association of the VPPs with T2D, MetS defined by IDF criteria, the components of MetS, and insulin resistance (IR) was assessed in logistic regression models.

Results

Elevated levels of CT-proET-1 and MR-proADM were associated with T2D, MetS, and IR in age- and sex-adjusted models. After adjustment for age, sex, former vascular complications, lifestyle factors, high-sensitive C-reactive protein, and serum creatinine, significant associations with MetS were found for MR-proADM (OR=5.94, 95% CI 3.78–9.33) and CT-proET-1 (OR=5.18, 95% CI 3.48–7.71) (top quartile vs bottom quartile). CT-proET-1 and MR-proADM were strongly associated with all components of MetS as defined by IDF criteria. After multivariable adjustment, association of CT-proET-1 and MR-proADM with pathological glucose tolerance and T2D disappeared and a borderline association with IR was found only for CT-proET-1 (OR=1.34, 95% CI 0.96–1.87).

Conclusions

We here demonstrate for the first time that plasma levels of both MR-proADM and CT-proET-1 levels are related to MetS and its components, thus suggesting that they possibly have a role as a surrogate biomarker for the disease and its complications.

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Christian Herder, Kristine Færch, Maren Carstensen-Kirberg, Gordon D Lowe, Rita Haapakoski, Daniel R Witte, Eric J Brunner, Michael Roden, Adam G Tabák, Mika Kivimäki and Dorte Vistisen

Objective

Higher systemic levels of pro-inflammatory biomarkers and low adiponectin are associated with increased risk of type 2 diabetes, but their associations with changes in glycaemic deterioration before onset of diabetes are poorly understood. We aimed to study whether inflammation-related biomarkers are associated with 5-year changes in glucose and insulin, HbA1c, insulin sensitivity and beta-cell function before the diagnosis of type 2 diabetes and whether these associations may be bidirectional.

Design and methods

We used multiple repeat measures (17 891 person-examinations from 7683 non-diabetic participants) from the Whitehall II study to assess whether circulating high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), IL1 receptor antagonist (IL1Ra) and adiponectin are associated with subsequent changes in glycaemia, insulin, insulin resistance and beta-cell function (based on oral glucose tolerance tests). We examined bidirectionality by testing if parameters of glucose metabolism at baseline are associated with changes in inflammation-related biomarkers.

Results

Higher hsCRP and IL6 were associated with increases in fasting insulin, insulin resistance and, for IL6, with beta-cell function after adjustment for confounders. Higher adiponectin was associated with decreases in fasting glucose, HbA1c, fasting insulin, insulin resistance and beta-cell function. The reverse approach showed that 2-h glucose and insulin sensitivity were associated with changes in IL1Ra. Fasting insulin and insulin resistance showed inverse associations with changes in adiponectin.

Conclusions

Subclinical inflammation is associated with development of increased glycaemia, insulin resistance and beta-cell function in non-diabetic individuals. These findings are consistent with the hypothesis that inflammation-related processes may increase insulin resistance and lead to a compensatory upregulation of beta-cell function.

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Christian Herder, Julia M Kannenberg, Corinna Niersmann, Cornelia Huth, Maren Carstensen-Kirberg, Clemens Wittenbecher, Matthias Schulze, Matthias Blüher, Wolfgang Rathmann, Annette Peters, Michael Roden, Christa Meisinger and Barbara Thorand

Objective

Cross-sectional studies found that higher levels of the novel adipokine omentin-1 were associated with higher adiponectin and lower levels of risk factors for type 2 diabetes, but its relevance for incident type 2 diabetes is currently not understood. Therefore this study investigated whether serum omentin-1 was associated with changes in glycaemia and incident type 2 diabetes independently of adiponectin.

Design and methods

The study was based on participants aged 62–81 years from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort. Associations of baseline serum levels of omentin-1 and adiponectin with changes in glycaemia were assessed in 471 non-diabetic participants, and associations between both adipokines and incident type 2 diabetes were assessed in 76 cases and 430 non-cases (follow-up time 6.5 years). Multivariable linear and logistic regression models were adjusted for multiple potential confounders.

Results

Higher serum levels of omentin-1 were associated with increases in fasting glucose, 2-h glucose and HbA1c (all P < 0.001) and with incident type 2 diabetes (adjusted odds ratio (OR) (95% CI): 1.40 (1.03; 1.90) per s.d. of log2-transformed omentin-1; P = 0.032). These associations were independent from adiponectin levels, which showed associations with changes in glycaemia and risk of type 2 diabetes in the opposite direction. We found no statistically significant interactions of omentin-1 with adiponectin or sex in the association with incident type 2 diabetes (all P > 0.1).

Conclusions

Systemic levels of omentin-1 were positively associated with increases in glycaemia and incident type 2 diabetes in this older population. These associations were independent of potential confounders including adiponectin.

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Imke Schamarek, Christian Herder, Bettina Nowotny, Maren Carstensen-Kirberg, Klaus Straßburger, Peter Nowotny, Alexander Strom, Sonja Püttgen, Karsten Müssig, Julia Szendroedi, Michael Roden, Dan Ziegler and on behalf of the German Diabetes Study Group

Objective

Subclinical inflammation has been implicated in the development of diabetic sensorimotor polyneuropathy (DSPN), but studies using electrophysiological assessment as outcomes are scarce. Therefore, we aimed to investigate associations of biomarkers reflecting different aspects of subclinical inflammation with motor and sensory nerve conduction velocity (NCV) in individuals with diabetes.

Design and methods

Motor and sensory NCV was assessed in individuals with recently diagnosed type 2 (n=352) or type 1 diabetes (n=161) from the baseline cohort of the observational German Diabetes Study. NCV sum scores were calculated for median, ulnar and peroneal motor as well as median, ulnar and sural sensory nerves. Associations between inflammation-related biomarkers, DSPN and NCV sum scores were estimated using multiple regression models.

Results

In type 2 diabetes, high serum interleukin (IL)-6 was associated with the presence of DSPN and reduced motor NCV. Moreover, higher levels of high-molecular weight (HMW) adiponectin, total adiponectin and their ratio were associated with prevalent DSPN and both diminished motor and sensory NCV, whereas no consistent associations were observed for C-reactive protein, IL18, soluble intercellular adhesion molecule-1 and E-selectin. In type 1 diabetes, only HMW and total adiponectin showed positive associations with motor NCV.

Conclusions

Our results point to a link between IL6 and both DSPN and slowed motor NCV in recently diagnosed type 2 diabetes. The reverse associations between adiponectin and NCV in type 1 and type 2 diabetes are intriguing, and further studies should explore whether they may reflect differences in the pathogenesis of DSPN in both diabetes types.

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Cornelia Huth, Simon Beuerle, Astrid Zierer, Margit Heier, Christian Herder, Thorsten Kaiser, Wolfgang Koenig, Florian Kronenberg, Konrad Oexle, Wolfgang Rathmann, Michael Roden, Sigrid Schwab, Jochen Seissler, Doris Stöckl, Christa Meisinger, Annette Peters and Barbara Thorand

Objective

Iron has been suggested to play a role in the etiology of type 2 diabetes mellitus (T2DM). Except for ferritin, evidence is sparse for other markers of iron metabolism that are regulated differently and might act through independent pathways. We therefore investigated the associations of serum ferritin, transferrin, soluble transferrin receptor (sTfR), transferrin saturation (TSAT), sTfR-to-log10ferritin (sTfR-F) index, and iron with impaired glucose metabolism (IGM/‘prediabetes’), T2DM, and four continuous glucose and insulin traits.

Design and methods

Data from 2893 participants of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study (Germany) was investigated through regression analysis. The results were adjusted for socio-demographic, life-style, and obesity measures as well as metabolic, inflammatory, and other iron biomarkers following a step-wise approach. Non-linearity was tested by adding a non-linear spline component to the model.

Results

Ferritin and transferrin were positively associated with IGM (fourth vs first sex-specific quartile: ferritin odds ratio (OR)=2.08 (95% CI 1.43–3.04) and transferrin OR=1.89 (95% CI 1.32–2.70)), T2DM (ferritin OR=1.98 (95% CI 1.22–3.22) and transferrin OR=2.42 (95% CI 1.54–3.81)), and fasting as well as 2-h glucose. TSAT (OR=0.55 (95% CI 0.34–0.88)) and iron (OR=0.61 (95% CI 0.38–0.97)) were inversely associated with T2DM, sTfR-F-index was inversely associated with IGM (OR=0.67 (95% CI 0.48–0.95)). There was no strong evidence for non-linear relationships.

Conclusions

The observed associations of several markers of iron metabolism with hyperglycemia and insulin resistance suggest that iron stores as well as iron-related metabolic pathways contribute to the pathogenesis of IGM and T2DM. Moreover, TSAT levels are decreased in T2DM patients.