K. H. Usadel

Evaluation of factors controlling glucose tolerance in patients with HCV infection before and after 4 months therapy with interferon‐α

Epidemiological data suggest that chronic hepatitis C virus (HCV) infection may contribute to the development of diabetes mellitus. Therapy of HCV infection with recombinant interferon‐α (r‐IFN‐α) can also impair of glucose metabolism.

Metabolic (PET) and receptor (SPET) imaging of well- and less well-differentiated tumours: Comparison with the expression of the Ki-67 antigen

[111In-DTPA-D-Phe1]-pentetreotide has been shown to localize well-differentiated and slowly growing neuroendocrine tumours, whereas increased FDG uptake is associated with malignancy. This prospective study explores the role of metabolic (PET) and receptor (SPET) imaging in well- and less well-differentiated tumours--gastroenteropancreatic (GEP) tumours, medullary thyroid carcinomas (MTC) and thymic carcinomas--in comparison with the expression of the Ki-67 antigen. Ten patients with GEP tumours, five with MTC and five with thymic carcinomas were studied. Prior to PET, somatostatin receptor scintigraphy (SRS) was performed in all patients. Sixty minutes after the intravenous administration of 18F-FDG (370 MBq), whole-body PET was performed. In addition, the resected tissues were prepared for immunocytochemistry examination (cell cycle-associated Ki-67 antigen). Preoperative SRS detected multiple primary tumours and metastatic lesions in four patients with well-differentiated carcinoids (low Ki-67 expression). Whole-body PET demonstrated normal distribution of FDG in all of these patients. In patients with recurrent MTC and rapidly increasing CEA levels, SRS showed no in vivo somatostatin receptor expression, whereas whole-body PET localized 24 locoregional lymph node metastases with increased FDG uptake. Immunocytochemistry of the resected lymph nodes demonstrated high Ki-67 expression associated with a high proliferative activity. Similar results in receptor scintigraphic and metabolic behaviour were obtained from patients with metastasizing thymic carcinomas (high Ki-67 expression). In conclusion, SRS has been shown to localize well-differentiated GEP tumours. In contrast, FDG PET is only valuable for predicting malignancy in less well-differentiated GEP tumours and malignant MTC associated with rapidly increasing CEA levels. Therefore, an additional 18F-FDG PET procedure should only be performed if SRS is negative. Furthermore, our preliminary results suggest that increased FDG metabolism reflects the invasiveness of thymic carcinomas.

Molecular detection of thyroglobulin mRNA transcripts in peripheral blood of patients with thyroid disease by RT-PCR

The sensitive detection of circulating tumour cells in patients with differentiated thyroid cancer may precede the detection of relapse by other diagnostic studies – such as serum thyroglobulin – and thus may have important therapeutic and prognostic implications. We performed reverse transcription-polymerase chain reaction (RT-PCR) on blood samples from patients diagnosed with thyroid disease using two different RT-PCR sensitivities. Additionally, tissue specificity of TG mRNA-expression was determined using RNA extracts from 27 different human tissues. The lower limit of detection was 50–100 TG mRNA producing cells/ml blood using a ‘normal’ RT-PCR sensitivity and 10–20 cells/ml blood using a ‘high’ sensitivity. With the normal sensitivity TG mRNA was detected in 9/13 patients with thyroid cancer and metastasis, 63/137 patients with a history of thyroid cancer and no metastasis, 21/85 with non-malignant thyroid disease and 9/50 controls. With the high sensitivity TG mRNA was detected in 11/13 patients with thyroid cancer and metastasis, 111/137 patients with a history of thyroid cancer and no metastasis, 61/85 with non-malignant thyroid disease and 41/50 controls. Interestingly, using the normal RT-PCR sensitivity TG mRNA transcripts are specific for thyroid tissue and detectable in the peripheral blood of controls and patients with thyroid disease, which correlates with a diagnosis of metastasized thyroid cancer. However, with a high RT-PCR sensitivity, TG mRNA expression was found not to be specific for thyroid tissue and was not correlated with a diagnosis of thyroid cancer in patients. As a consequence, to date TG mRNA detected by RT-PCR in the peripheral blood cannot be recommended as a tumour marker superior to TG serum-level.

Elevated endothelin levels in patients with hyperlipoproteinemia

We determined lipoproteins, apolipoproteins, and endothelin in 98 patients (58 female and 40 male, age 18–72 years) with hyperlipidemia (plasma cholesterol > 2.5 g/l and/or triglycerides > 2.0 g/1) and in 50 healthy subjects (20 female, 30 male, age 19–68 years). In patients with hyperlipidemia endothelin levels were elevated compared to healthy controls. Patients with plasma cholesterol above 2.5 g/l had higher Endothelin and lipoprotein(a) concentrations than patients with plasma cholesterol levels less than 2.5 g/l. A positive correlation was found between the concentrations of endothelin and apolipoprotein B (r = 0.2137; P < 0.013). Smoking patients with lipoprotein (a) above 300 mg/l had higher endothelin levels than both nonsmoking patients with lipoprotein (a) above 300 mg/l and smokers with normal lipoprotein(a). In smokers endothelin correlated positively with Lp(a) (r = 0.709; P < 0.01). No correlation was found between endothelin and triglycerides nor between endothelin and age or sex. The results suggest that the vasoconstrictor endothelin contributes to the increased vasal tone in hyperlipidemia. Because endothelin also has mitogenic properties, it may play a relevant role in the development of premature atherosclerosis in patients with hyperlipidemia.

Severity of HCV-Induced Liver Damage Alters Glucose Homeostasis in Noncirrhotic Patients with Chronic HCV Infection

Background/Aims: To investigate the link between hepatitis C infection and glucose intolerance, we measured insulin sensitivity, glucose effectiveness and β-cell secretion in noncirrhotic HCV-infected patients with normal glucose tolerance according to WHO criteria as assessed by oral glucose tolerance tests. Methods: Glucose, insulin and C-peptide data from frequently sampled intravenous glucose tolerance tests were analyzed using the minimal modeling technique for glucose and C-peptide to determine insulin sensitivity, glucose effectiveness, first and second phase insulin secretion in noncirrhotic HCV-infected patients (n = 10) and in healthy control subjects (n = 10). Histological activity index (HAI) as well as the extent of fibrosis were evaluated by scoring liver biopsies. Results: Insulin sensitivity (2.72 ± 1.63 vs. 6.84 ± 1.20 10–4 min–1 per µU/ml, p < 0.01) and glucose effectiveness (2.29 ± 0.45 vs. 2.89 ± 0.39 10–2 min–1, p < 0.05) ere significantly lower in patients with HCV-induced liver disease. Insulin sensitivity was negatively related to serum alanine aminotransferase (r = –0.47, p < 0.05) and aspartate aminotransferase concentrations (r = –0.65, p < 0.05). Multiple linear regression analysis revealed a strong relation of insulin sensitivity with fibrosis score and HAI (r = –0.82, p < 0.02 for both). Second phase insulin secretion was significantly enhanced in HCV-infected patients (14.30 ± 2.04 vs. 8.29 ± 1.65 min–1, p < 0.05). Conclusions: HCV-infected patients with normal glucose tolerance are insulin and glucose resistant. The impairment of glucose tolerance appears to be closely related with the severity of HCV-induced liver damage.

Development of thyroid gland volume during the first 3 months of life in breast-fed versus iodine-supplemented and iodine-free formula-fed infants

SummaryThe spontaneous development of thyroid gland volume (TGV) during the first 3 months of life was studied in entirely breast-fed infants (n = 21) and compared to those fed an iodine-supplemented formula (n = 19), an iodine-free formula (n = 5), or partially breast-fed in addition to an iodine-free (n = 4) or an iodine-supplemented formula (n =16). The TGV of the infants and their mothers was determined sonographically in addition to their urinary iodine concentrations 57 days postpartum and 3 months later. In ten additional lactating mothers the breast milk concentrations of thyroid hormones and iodine were determined. It was shown that at 3 months of age an infant consuming about 1000 ml breast milk per day receives about 2 μg thyroid hormones and 55 μg iodine per day. At the end of their first week of life the infants showed a TGV between 0.28 and 1.5 ml (median 0.61 ml) and a urinary iodine concentration between 0.03 and 16.3 μg/dl (median 3.0 μg/dl). At 3 months of age the TGV of the breast-fed infants had decreased by a median of 0.24 ml (= −34%; median of percentage changes) whereas those fed a formula without iodine had increased by a median of 0.26 ml (= + 50%; median of percentage changes). Those receiving an iodine-supplemented formula showed a TGV reduction of 0.14 ml (= +2%; median of percentage changes). The TGV development of the partially breast-fed infants lay between those being exclusively breast or formula fed. It is concluded that with respect to the development of TGV, breast milk is superior even to the feeding of an iodine-supplemented formula.

Macrophage migration inhibitory factor and development of type-1 diabetes in non-obese diabetic mice.

AIMS/HYPOTHESIS T-cell activation by specific antigen has been found to increase macrophage migration inhibitory factor (MIF) expression, indicating its role as an important feature of T-cell activation in vitro and in vivo. To date, the potential role of MIF in the development of autoimmune-mediated diabetes mellitus has not been studied. METHODS MIF-mRNA expression in splenic lymphocytes of spontaneously diabetic non-obese diabetic (NOD) mice (n=6), cyclophosphamide-treated NOD mice (n=6), 14-day-old non-diabetic NOD mice (n=7) and C57/Bl6 control mice (n=6) was monitored using an internally standardised competitive reverse transcription-polymerase chain reaction, and the MIF-protein levels were determined using Western blot analysis. In addition, the impact of intraperitoneally administered recombinant MIF-protein treatment on diabetes incidence in NOD mice was evaluated. RESULTS MIF-mRNA expression was markedly increased in splenic lymphocytes of spontaneously diabetic NOD mice as well as in 8-week-old NOD mice treated with cyclophosphamide compared with 2-week-old non-diabetic NOD and healthy C57BL/6 control mice. Western blot analyses showed decreased lymphocytic MIF-protein content in diabetic as well as in cyclophosphamide-treated animals compared with 2-week-old non-diabetic NOD and healthy C57BL/6 mice, probably as a consequence of increased protein secretion. Furthermore, treatment of NOD mice with recombinant MIF-protein at 25 microg twice a week, from age 6 to 11 weeks, led to an increased diabetes incidence (86%; n=7) compared with untreated control groups (55%; n=20) at week 34. CONCLUSIONS/INTERPRETATION In this study, we report for the first time that MIF-mRNA expression in splenic lymphocytes is up-regulated during development of cell-mediated diabetes in non-NOD mice. The data of our preliminary study suggest a possible role of MIF in autoimmune-inflammatory events, such as type-1 diabetes and also that anti-MIF therapeutic strategy might serve to attenuate autoimmune processes.

SCREENING FOR THYROID DISORDERS IN A WORKING POPULATION

SummarySubclinical thyroid disorders have received increasing attention in recent years due to refined laboratory methods and a stronger emphasis on the role of preventive medicine. We performed a screening for thyroid-stimulating hormone (TSH) on 6884 persons in a working population. In cases in which TSH was not within the normal range we also measured the levels of triiodothyronine (T3), thyroxine (T4), and thyroxine-binding globulin (TBG). All persons who did not present with exclusion criteria or other nonthyroidal illnesses (n = 59) and the controls (n = 39) were submitted to thyrotropin-releasing hormone (TRH)-testing. Additionally, sonography of the thyroid was performed on 120 persons (59 subjects with abnormal hormone levels and 61 controls) to determine thyroid size and rule out morphological abnormalities. Based on the TRH test and T3, T4, and TBG measurements we found a prevalence of 0.03% (2/6884) for overt hyperthyroidism, 0.33% (23/6884) for subclinical hyperthyroidism, 0.09% (6/6884) for subclinical hypothyroidism, and 0.015% (1/6884) for overt hypothyroidism in the healthy population. In subjects with overt or subclinical hyperthyroidism the prevalence of goiters (thyroid volume > 18 ml in women, > 25 ml in men) was 28%. Of this group 48% had structural abnormalities. All persons with goiters and/or structural abnormalities were over 35 years of age. Among the euthyroid, 20% had thyroid enlargement, and the same proportion presented with structural abnormalities. There were no differences between the two age groups. In the group with overt/subclinical hypothyroidism 47% presented with structural abnormalities of the thyroid; however, none presented with thyroid enlargement. Thyroid nodules were found only in older persons (> > 35 years) with euthyroidism or hypothyroidism. These data confirm the relatively high prevalence of functional and morphological abnormalities of the thyroid. An early substitution with iodine is warranted to prevent functional and morphological disorders of the thyroid in older age. People with subclinical hyperthyroid disorders must avoid exposure to iodine, which can cause an exacerbation of the disease.

Mangan-enhanced MR imaging for the detection and localisation of small pancreatic insulinoma

Insulinoma is the most common pancreatic endocrine tumor. Localization of small tumors remains a diagnostic challenge. Recently, Mangafodipir-enhanced MR imaging using a whole-body coil has been shown to be effective in the detection and staging of pancreatic cancer [3]. Localization of even small tumors is improved and surgical techniques, such as robotic-assisted surgery, have been made possible.

A retroviral long terminal repeat adjacent to the HLA DQB1 gene (DQ-LTR13) modifies Type I diabetes susceptibility on high risk DQ haplotypes

Abstract.Aims/hypothesis:HLA-DQ genes, located in the human leukocyte antigen region on chromosome 6 p, are the main inherited factors predisposing to Type I (insulin-dependent) diabetes mellitus. Endogenous retroviral long-terminal repeats are integrated at several sites within this region, one of which is known to enhance susceptibility for Type I diabetes. We examined another LTR within the HLA-region as an additional genetic risk marker. Methods: We investigated the segregation of one long-terminal repeat (DQ-LTR13), located 1.3 kb upstream of HLA DQB1 with different HLA-DQ haplotypes, and its transmission to patients. A total of 284 Caucasian families (203 German and 81 Belgian) with at least one diabetic offspring were genotyped for DQA1, DQB1 and DQ-LTR13. Results:DQ8/LTR13+ was preferentially transmitted (139 transmitted vs 28 not transmitted; PTDT = 1.67 × 10–14) whereas no deviation from expected transmission frequencies was observed for DQ8/LTR13– (20 transmitted vs 17 not transmitted; PTDT = 1.00). DQ8/LTR13+ alleles conferred a significantly higher risk for Type I diabetes than DQ8/LTR13– alleles (pχ2 = 2.58 × 10–14). This difference remained significant even after DRB1 subtyping (pχ2 = 0.02). Also, there was a significant difference when comparing the transmission of DQ2/LTR13+ and DQ2/LTR13– alleles (pχ2 = 0.01), the latter conferring an increased risk. The transmission of DQ-LTR13+ haplotypes did not show any differences regarding paternal, maternal or gender-related stratification. However, DQ8/LTR13– was significantly more often transmitted from mothers (pχ2 = 0.01) and to female patients (pχ2 = 0.04). Conclusion/interpretation: We conclude that DQ-LTR13 marks additional genetic risk for Type I diabetes on predisposing DRB1*0401-DQ8 and DQ2 haplotypes and will help to further define susceptibility in this gene region. [Diabetologia (2002) 45: 443–447]