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Diabetes is a well-recognised risk factor for the development of heart failure, with a prevalence higher than 30% in patients with diabetes aged over 60 years. Heart failure often emerges as the primary cardiovascular manifestation in patients with type 2 diabetes and appears to be even more prevalent in type 1 diabetes. In Switzerland, there are approximately 500,000 individuals with diabetes, and the number of affected people has been steadily rising in recent years. Therefore, the consequences of heart failure will affect an increasing number of patients, further straining the Swiss healthcare system. Early lifestyle modification and initiation of appropriate treatment can prevent or at least significantly delay the onset of symptomatic heart failure by several years. These facts underscore the urgent need for early detection of individuals with subclinical heart failure, which often remains undiagnosed until the first episode of acute heart failure requiring hospital admission occurs. To address this issue, the European Society of Cardiology, the American Diabetes Association (ADA) and other international professional societies have published recommendations on heart failure screening, diagnosis and management. To address this issue in Switzerland, experts from the Swiss Society of Endocrinology and Diabetology, the Swiss Society of Cardiology and the General Internal Medicine specialty met and prepared a consensus report including a simple diagnostic algorithm for use in everyday practice.

As a first step, the authors emphasise lifestyle changes (increased physical activity, stopping smoking), blood pressure control, and lowering cholesterol). The initial medical treatment should always be a combination treatment with metformin and a sodium-glucose transporter 2 (SGLT-2) inhibitor or a glucagon-like 1 peptide (GLP-1) receptor agonist. Metformin is given first and up-titrated, followed by SGLT-2 inhibitors or GLP-1 receptor agonists. In persons with type 2 diabetes, if the initial double combination is not sufficient, a triple combination (SGLT-2 inhibitor, GLP-1 receptor agonist, and metformin) is recommended. This triple combination has not been officially tested in cardiovascular outcome trials, but there is more and more real-world experience in Europe and in the USA that proves that the triple combination with metformin, SGLT-2 inhibitor, and GLP-1 receptor agonist is the best treatment to reduce 3-point MACE, total mortality, and heart failure as compared to other combinations. The treatment with sulfonylurea is no longer recommended because of its side effects and higher mortality compared to the modern treatment with SGLT-2 inhibitors and GLP-1 receptor agonists. If the triple combination is not sufficient to reduce the HbA1c to the desired target, insulin treatment is necessary. A quarter of all patients with type 2 diabetes (sometimes misdiagnosed) require insulin treatment. If insulin deficiency is the predominant factor at the outset of type 2 diabetes, the order of medications has to be reversed: insulin first and then cardio-renal protective medications (SGLT-2 inhibitors, GLP-1 receptor agonists).

GLP-1 Receptor Agonists: For Which Patients with Type-2 Diabetes? Abstract: In the last few years, the cardiovascular outcome trials for SGLT-2 inhibitors and GLP-1 receptor agonists showed them to significantly lower the risk of cardiorenal endpoints in patients with type-2 diabetes when compared to other antidiabetics. This effect was independent of concurrent medication. This additional benefit is well established in the case of SGLT-2 inhibitors, leading to increased prescription. Following the current evidence, GLP-1 receptor agonists should also be prescribed early in the treatment course of type 2 diabetes. In patients with very high cardiovascular risk, a combination therapy of a GLP-1 receptor agonist with a SGLT-2 inhibitor is an attractive option.

Aims: Glucose and insulin metabolism are altered in hemodialysis patients, and diabetes management is difficult in these patients. We aimed to validate flash glucose monitoring (FGM) in hemodialysis patients with and without diabetes mellitus as an attractive option for glucose monitoring not requiring regular self-punctures., Methods: We measured interstitial glucose using a FreeStyle Libre device in eight hemodialysis patients with and seven without diabetes mellitus over 14 days and compared the results to simultaneously performed self-monitoring of capillary blood glucose (SMBG)., Results: In 720 paired measurements, mean flash glucose values were significantly lower than self-measured capillary values (6.17±2.52 vs. 7.15±2.41 mmol/L, p=1.3 E-86). Overall, the mean absolute relative difference was 17.4%, and the mean absolute difference was 1.20 mmol/L. The systematic error was significantly larger in patients without vs. with diabetes (- 1.17 vs. - 0.82 mmol/L) and on dialysis vs. interdialytic days (-1.09 vs. -0.90 mmol/L). Compared to venous blood glucose (72 paired measurements), the systematic error of FGM was even larger (5.89±2.44 mmol/L vs. 7.78±7.25 mmol/L, p=3.74E-22). Several strategies to reduce the systematic error were evaluated, including the addition of +1.0 mmol/L as a correction term to all FGM values, which significantly improved accuracy., Conclusions: FGM systematically underestimates blood glucose in hemodialysis patients but, taking this systematic error into account, the system may be useful for glucose monitoring in hemodialysis patients with or without diabetes., Competing Interests: PW reports to have participated in the advisory board and received lecture fees from Abbott, Switzerland. The other authors have no conflict of interest to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

CME: Can Slim People Have Type-2 Diabetes? Abstract. Most patients with type-2 diabetes mellitus are obese or overweight. In slim patients with suspected type 2 diabetes mellitus the possibility of other types of diabetes must be considered. In addition to type-1 diabetes in adulthood and genetic forms of diabetes (MODY, mitochondrial diabetes), it could also be diabetes due to a disease of the exocrine pancreas, a condition which is generally underdiagnosed.

Aims: This study evaluated the effectiveness and safety of switching the basal insulin (BI) in a BI-supported oral therapy (BOT) to insulin glargine 300 U/ml (Gla-300) in adults with inadequately controlled type 2 diabetes (T2D)., Materials and Methods: This was a non-interventional, multicentre, prospective 12-month study, conducted in Germany, Austria and Switzerland. The study documented people with T2D with glycated haemoglobin (HbA1c) between 7.5% and 10.0%, currently treated by a non-Gla-300 BOT regimen, after the physician had decided to switch the BI to Gla-300. Primary endpoint was the proportion of patients achieving the fasting plasma glucose (FPG; ≤110 mg/dl) target., Results: In total, 1194 participants comprised the full analysis set, of which 793 completed documentation of 12 months Gla-300 treatment (FAS-M12). The main previous BI was insulin glargine 100 U/ml (Gla-100; 47.2%). Twelve months after switching to Gla-300, 27.0% of FAS-M12 participants achieved the FPG target and 44.8% their individualized HbA1c target. The greatest FPG target achievements were seen in previous Gla-100 (29.3%), and greatest HbA1c target achievements in previous insulin detemir users (57.7%). The mean FPG decreased by -36.3 ± 51.2 mg/dl to 135.5 ± 36.9 mg/dl and mean HbA1c by -0.79 ± 1.01% to 7.45 ± 0.94%. Symptomatic and nocturnal hypoglycaemia incidence significantly decreased over 12 months of Gla-300 treatment. Body weight remained unchanged., Conclusions: Switching the BI to Gla-300 in a BOT regimen improved metabolic control and treatment satisfaction in a substantial proportion of patients with T2D and inadequate target achievement within 12 months in clinical practice with a decreased risk of symptomatic and nocturnal hypoglycaemia and without weight gain., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

CME: Primary and Secondary Hypercholesterolemia Abstract. In patients with hypercholesterolemia and an LDL-cholesterol level >5 mmol/l, familial hypercholesterolemia (primary hypercholesterolemia) should be considered. This genetically determined illness should lead to medical therapy and screening for hypercholesterinemia in close relatives. Beside the superelevated LDL-cholesterol levels, additional clinically diagnostic findings and family anamnesis can support the diagnosis of familial hypercholesterolemia. The likelihood of familial hypercholesterolemia can be estimated using the Lipid Clinic Network Score. Additionally, a variety of exogenous factors may have an impact on lipoprotein metabolism and may lead to secondary hypercholesterolemia. Hypothyroidism, cholestasis, nephrotic syndrome or specific medications, among others, should be considered as potential factors leading to high cholesterol levels before familial hypercholesterolemia is suspected or lipid-lowering treatment is started.

Objectives: In acromegaly, disease activity is biochemically assessed by growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. However, they are often discrepant, as several factors including gender influence their relationship. We recently found excessively high serum levels of soluble Klotho (sKl) in acromegalic patients, which depended on GH to a comparable extent as IGF-1. To further elucidate the relationship between GH and sKl, we examined the effect of gender on sKl in patients with untreated acromegaly., Patients and Design: We determined GH, IGF-1 and sKl in sera of 62 consecutive patients with newly diagnosed acromegaly (31 females/31 males, aged 20-85 years)., Results: For their given GH excess at presentation with acromegaly, females had lower IGF-1 (490 ± 33 vs 604 ± 33 ng/ml, P = 0·02), but higher sKl [5171 ± 590 vs 3439 ± 431 pg/ml (mean ± SE), P = 0·02] levels than males. In multiple regression analysis, IGF-1 was closely associated with logGH (estimate 139, SE 47, P = 0·005) and BMI (estimate 14·2, SE 4·8, P = 0·005). sKl was closely associated with logGH (estimate 3088, SE 652, P = 0·0001) and gender (estimate 2034, SE 612, P = 0·002), and to a lesser extent with BMI (estimate 174, SE 66, P = 0·01)., Conclusions: For a given GH status, sKl concentrations are higher and IGF-1 concentrations are lower in women than in men. GH is the strongest predictor for both sKl and IGF-1, but gender needs to be considered when using these parameters for monitoring acromegalic patients., (© 2013 John Wiley & Sons Ltd.)

Background: Cystatin C (CysC) is an alternative marker to creatinine for estimation of the glomerular filtration rate (GFR). Hormones such as thyroid hormones and glucocorticoids are known to have an impact on CysC. In this study, we examined the effect of growth hormone (GH) on CysC in patients with acromegaly undergoing transsphenoidal surgery., Methods: Creatinine, CysC, GH and insulin-like growth factor-1 (IGF-1) were determined in 24 patients with acromegaly before and following transsphenoidal surgery. Estimated GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula., Results: In all patients, surgical debulking resulted in decreased clinical disease activity and declining GH/IGF-1 levels. Postoperatively, biochemical cure was documented in 20 out of 24 patients. Creatinine levels (mean ± SEM) increased from 72 ± 3 to 80 ± 3 µmol/l (p = 0.0004) and concurrently, estimated GFR decreased from 99 ± 3 to 91 ± 3 ml/min (p = 0.0008). In contrast to creatinine, CysC levels decreased from 0.72 ± 0.02 to 0.68 ± 0.02 mg/l (p = 0.0008)., Conclusions: Our study provides strong evidence for discordant effects of GH on creatinine and CysC in patients with acromegaly undergoing transsphenoidal surgery, thus identifying another hormone that influences CysC independent of renal function.

Objective: Surgical manipulation of the pituitary stalk, neurohypophysis or the hypothalamus may disturb control of the plasma sodium level. The factors that might predict the risk of postoperative sodium imbalance are not clear, and were investigated in this study., Methods: A retrospective survey of 129 surgical records for the occurrence of plasma sodium levels outside the normal range, following transsphenoidal procedures. Median patient age was 49 (range 20-78) years, 65 female. 73 of the operated lesions were non-functioning pituitary adenomas. Patients were considered to have impaired plasma sodium balance if the range of 135-145 mmol/L was not maintained., Results: Of all 129 surgical cases, 68 (53%) experienced an imbalance in sodium levels. Severe sodium imbalance (≥ 149 or ≤ 131 mmol/L) was observed in 28 patients (22%). 13 showed hypernatraemia (median day 1), and 15 hyponatraemia (median day 6). Tumour size was associated with an increased incidence of sodium imbalance, particularly in patients younger than 49 years; surgery resulted in sodium imbalance in 38% of young patients operated on for tumours < 22 mm and in 76% of young patients, operated on for tumours ≥ 22 mm. Overall, tumour size increased with patients' age, and tumour size was less predictive for sodium disturbances in elderly patients. Median time in hospital was 5 days for patients without sodium imbalance, 6 days for patients with hypernatraemia and 11 days for patients with hyponatraemia., Conclusions: Following pituitary surgery, patients with large tumours, in particular those of young age, are at higher risk for losing control of their plasma sodium level. Increased ADH secretion (hyponatraemia), but not transient diabetes insipidus was associated with a prolonged hospital stay. Postoperative follow-up of patients with sellar tumours should include careful monitoring of plasma sodium levels within the first two postoperative weeks and clear patients' instructions.

The case of a middle-aged woman with early-onset diabetes mellitus, hypertrophic cardiomyopathy, premature sensorineural hearing loss and neuropsychiatric symptoms is described. The patient's family history revealed the classical pattern of maternally inherited diabetes and deafness (MIDD) and isolation of mitochondrial DNA from peripheral blood leucocytes showed an A3243G transition in the gene encoding for the tRNA(Leu(UUR)). Thus, the suspected diagnosis of a mitochondrial disorder was confirmed. Cardiac involvement turned out to be the dominating clinical feature in the patient. She died of cardiogenic shock and multiple organ failure within 1 year of diagnosis. Three out of nine affected family members had hypertrophic cardiomyopathy.

Background: Serum cystatin C (CysC) is a marker for kidney function, possibly superior to serum creatinine (Cr). Cr is increased and CysC decreased in primary hypothyroidism; these changes are reversed upon thyroxine (T4) replacement therapy. This (pilot) study was performed to see whether these opposing changes of CysC and Cr could be confirmed in patients with central hypothyroidism., Methods: Prospective case series of consecutively referred patients with primary and central hypothyroidism. CysC and Cr were determined at the time of diagnosis and following T4 replacement therapy., Results: 32 patients with newly diagnosed hypothyroidism were included. In 16 patients with primary hypothyroidism, mean fT4 was 4.4 +/- 2.5 pmol/l (normal range 12 to 22) at diagnosis and increased to 20.1 +/- 5.2 pmol/l (p <0.001) following T4 replacement. CysC increased from 0.79 +/- 0.27 mg/l (normal range 0.63 to 1.33) to 1.03 +/- 0.42 mg/l (p = 0.007) whereas Cr declined from 104 +/- 21 micromol/l to 90 +/- 19 micromol/l (p <0.001). In 16 patients with central hypothyroidism, mean fT4 was 6.5 +/- 1.6 pmol/l at diagnosis and increased to 15.7 +/- 3.3 pmol/l (p <0.001) following T4 replacement. CysC increased from 0.74 +/- 0.27 mg/l to 0.83 +/- 0.30 mg/l (p = 0.01) whereas Cr was not elevated at baseline (83 +/- 11 micromol/l) and did not decrease following treatment (84 +/- 10 micromol/l)., Conclusions: CysC was low at diagnosis of hypothyroidism and significantly increased following T4 replacement in patients with primary as well as central hypothyroidism. T4 replacement decreased Cr levels in patients with primary hypothyroidism whereas Cr remained unchanged in;patients with central hypothyroidism. CysC may not accurately reflect kidney function in patients with primary and central thyroid dysfunction.

Principles: Small dense LDLs have been found to be associated with type 2 diabetes (T2DM). This association has been observed in the context of decreased HDL cholesterol and increased triglycerides., Methods: In the present study the relationship between LDL particle size and insulin sensitivity was assessed in 46 patients with T2DM (mean age 60 (11) years, HbA1c 7.6 (0.8) %). 75 g oral glucose tolerance testing was performed and composite insulin sensitivity index was calculated by the method of Matsuda and de Fronzo (ISI(comp)). Additional parameters included BMI, waist circumference, blood pressure, HDL cholesterol, triglycerides and LDL cholesterol. LDL particle size was measured by gradient gel electrophoresis., Results: Log ISI(comp) correlated most strongly with LDL particle size (R = 0.61), less closely with HDL cholesterol (R = 0.48) and plasma triglycerides (R = -0.45) and not at all with LDL cholesterol (R = 0.001), as supported by multiple regression analyses where log ISI(com) was associated with LDL particle size (p = 0.004) and HDL cholesterol (p = 0.027) but not with triglycerides and LDL cholesterol., Conclusion: Log ISI(comp) estimated by a formula using endogenous insulin levels is very closely associated with LDL particle size in patients with T2DM. Our data suggest that smaller LDL particle size reflects the impact of insulin resistance on lipoprotein metabolism more strictly than do the traditional lipid parameters.

Background: A genomic deletion of exon 3 (d3-GHR) of the growth hormone (GH) receptor (GHR) has been linked to the effectiveness of GH therapy in children with GH deficiency. Carriers of the d3-GHR genotype had higher GH-induced growth rates than children homozygous for the full-length (fl)-GHR. The aim of this study was to test whether the relationship between GH and insulin-like growth factor-1 (IGF-1) concentrations is influenced by the GHR genotype in patients with acromegaly., Methods: Study participants were 44 adult patients with established diagnosis of acromegaly. The genotype of the GHR was determined in leukocyte DNA from peripheral blood. Clinical and biochemical findings at the time of diagnosis of acromegaly were obtained from the medical records of the patients., Results: fl-GHR homozygosity was found in 22 (50%) of patients, and 22 (50%) of patients had at least 1 d3 allele (d3-GHR). Demographic and clinical characteristics (age, height, weight, estimated duration of disease, and mean tumor size) of the 2 groups were comparable. Median (range) serum IGF-1 concentrations at the time of diagnosis were 670 (447-1443) microg/L in the fl-GHR group and 840 (342-1494) microg/L in the d3-GHR group (P = not significant). Basal GH concentrations were higher in the fl-GHR group [29.7 (3.8-159) microg/L] than in the d3-GHR group [8.4 (2.6-74 microg/L), P = 0.002], and so were mean (30.4 vs 6.1 microg/L, P = 0.005) and nadir (20.5 vs 5.1 microg/L, P = 0.003) GH concentrations during an oral glucose tolerance test., Conclusions: The GHR fl/d3 genotype modulates the relationship between GH and IGF-1 concentrations in patients presenting with acromegaly.

Questions Under Study: We describe two narcotic addict women with recurrent hypoglycaemic episodes. In both patients, hyperinsulinaemic hypoglycaemia occurring in the fasting state was documented and computed tomography of the pancreas was normal., Methods and Results: In patient 1, selective arterial calcium stimulation with hepatic venous sampling (ASVS) revealed pronounced insulin hypersecretion predominantly in the tail and, to a lesser extent, in the corpus and the head of the pancreas. On laparoscopic exploration, tumours could not be detected be it grossly or by intraoperative ultrasound. Distal pancreatectomy was performed laparoscopically, and histological examination of the resected tissue revealed nesidioblastosis. ASVS was also performed in patient 2 revealing less marked increases in insulin secretion, ie up to 2.3-fold in response to calcium stimulation of the superior mesenteric artery, consistent with the presence of pathological beta-cells located predominantly in the head of the pancreas. Surgical exploration was not performed in this patient., Conclusion: HIV infection had been known in both women for around ten years and both patients were not on antiretroviral therapy. Because symptomatic nesidioblastosis in adult patients is a very rare disorder, we speculate that nesidioblastosis may develop in the context of HIV infection and/or abuse of narcotic drugs. Our observations illustrate that neurocognitive impairment in HIV positive patients is not always due to toxic compounds or a cerebral disorder but may be caused by an apparently rare pancreatic disorder, nesidioblastosis. Thus, the patients should be checked for the presence of hyperinsulinaemic hypoglycaemia.

Objective: To describe the effect of T4 replacement in patients with primary and central hypothyroidism on components of the IGF binding protein complex: IGF-I, the acid-labile subunit (ALS) and IGFBP-3., Patients and Methods: We determined IGF-I, ALS and IGFBP-3 (by 125I-IGF-II ligand blots and immunoblots) in serum of 19 patients with primary and 11 patients with central hypothyroidism., Results: Mean (+/- SD) free T4 (fT4) increased from 4.4 +/- 2.4 pmol/l at baseline to 18.6 +/- 5.2 pmol/l following T4 therapy. In patients with primary hypothyroidism, IGF-I concentrations increased from 101 +/- 57 to 158 +/- 60 microg/l (P < 0.001) and ALS from 12.6 +/- 4.7 to 15.6 +/- 5.2 mg/l (P = 0.001). IGFBP-3 levels (in arbitrary units, AU), assessed by 125I-IGF-II ligand blot and by Western blot (the intensity of the 45/42-kDa doublet following T4 replacement defined as 1 AU) increased from 0.74 +/- 0.47 to 1 (P = 0.029) and from 0.76 +/- 0.42 to 1 (P = 0.018), respectively. In patients with hypopituitarism, IGF-I and ALS concentrations increased on T4 therapy from 49 +/- 23 to 97 +/- 36 microg/l (P < 0.001) and from 7.8 +/- 4.1 to 11.0 +/- 2.7 mg/l (P = 0.010), respectively. IGFBP-3 remained unchanged during T4 replacement., Conclusions: T4 replacement increases the serum levels of IGF-I and ALS in patients with primary as well as central hypothyroidism. IGFBP-3 levels increase in response to T4 replacement in patients with primary hypothyroidism but not in those with central hypothyroidism, suggesting that thyroid hormones increase IGF-I and ALS but not IGFBP-3 in patients with GH deficiency.

Background: Minimally invasive pancreatic surgery, although known to be feasible and safe, is still not considered a standard procedure. We report our experience with laparoscopic pancreatic surgery in a retrospective case series., Materials and Methods: Fifteen consecutive patients (3 male, 12 female) underwent primarily laparoscopic pancreatic surgery from February 2000 to June 2005. Histologically confirmed diagnoses were: neuroendocrine pancreatic tumors (n = 11), adult nesidioblastosis (n = 1), serous cystadenoma (n = 1), and pseudocysts due to chronic pancreatitis (n = 2)., Results: Enucleation (n = 3) or left pancreatic resection with spleen preservation (n = 6) was performed laparoscopically in 9 patients. The mean (+/-standard deviation) operative time was 173 +/- 48 minutes (range, 120-250 minutes) and the mean postoperative hospital stay was 5.5 +/- 1.2 days (range, 5-8 days) for the laparoscopic cases. Conversion to open surgery was necessary in 6 patients because of: closeness of the lesion to the portal/mesenteric vein (n = 3), inadequate intraoperative tumor localization (n = 2), or stapler device dysfunction (n = 1). In these patients, open enucleation (n = 1), middle segment pancreatectomy (n = 2), left pancreatic resection (n = 2), and pylorus-preserving Whipple resection (n = 1) were performed. The mean operative time was 268 +/- 74 minutes (range, 150-360 minutes) with a mean postoperative hospital stay of 8 +/- 2 days (range, 6-10 days). Both operative time and hospital stay were significantly longer in patients with secondary open surgery compared to patients with successful laparoscopic operations., Conclusion: Laparoscopic enucleation or distal pancreatectomy with spleen preservation for benign lesions located in the body or tail of the pancreas can be performed safely, with all the potential benefits of minimally invasive surgery. Preoperative tumor localization is of utmost importance to limit pancreatic mobilization and to avoid blind pancreatic resection and conversion to open surgery.

The tumorigenesis of sporadic endocrine tumors is still not fully understood. It is well known that patients with von Recklinghausen syndrome (NF-1) (OMIM 162200) carrying NF1 germline mutations are predisposed to endocrine tumors including pheochromocytomas and duodenal somatostatinomas. It is unclear, however, whether the rarely reported occurrence of pancreatic insulinomas in NF-1 patients represents a coincidental finding or whether insulinomas are a rare manifestation of the NF-1 syndrome. To determine the potential association between the NF-1 syndrome and pancreatic endocrine tumors, we analyzed a NF-1 patient with a well-differentiated pancreatic endocrine carcinoma for NF1 mutation, allelic loss of the NF1 gene and its expression in peripheral blood and tumor cells. The germline mutation c. 499 del TGTT known in the family was confirmed by polymerase chain reaction (PCR) and direct sequencing of exon 4 in DNA extracted from peripheral blood. Loss of heterozygosity (LOH) analysis of the NF1 gene was carried out using 3 intragenic microsatellite markers on 17q11.2. RNA expression was examined by reverse transcription and a consecutive PCR spanning intron 3 of the NF1 gene including the mutated site in exon 4. Immunohistochemistry was used to analyze NF-1 protein expression. Mutation analysis of peripheral blood leukocytes confirmed the 4 base pair deletion in exon 4 starting at codon 167 (499 del TGTT). LOH analysis of tumor tissue revealed retention of both NF1 alleles. While reverse transcriptase-PCR of peripheral blood showed bi-allelic expression of both the wild-type NF1 and the mutated form, reverse transcriptase-PCR of tumor extracts demonstrated expression of the mutated but not the wild-type NF1 allele. Additionally, neurofibromin, the NF1 gene product, was absent in the tumor tissue of the NF-1 patient. These results show that the wild-type NF1 transcrips and protein are reduced, in the reported insulinoma, supposedly by epigenetic mechanisms. This provides strong evidence that there is a relationship between von Recklinghausen disease and the patient's insulinoma. In this line, insulinomas may be viewed as a rare manifestation of the NF-1 syndrome. Furthermore, the NF1 gene must be considered as a candidate tumor suppressor gene for sporadic insulinomas and probably other pancreatic endocrine tumors.

Background: In vitro and animal studies suggest that tumor necrosis factor alpha (TNF-alpha) modulates intestinal iron transport. We hypothesized that the effect of TNF-alpha might be particularly relevant if iron absorption is not effectively controlled by the HFE gene., Methods: In patients with homozygous C282Y hemochromatosis, we investigated the influence of TNF-alpha -308G>A allelic variant on total body iron overload, determined in all patients by measuring iron removed during depletion therapy, and hepatic iron index and need for phlebotomy to prevent iron reaccumulation, measured in patient subgroups., Results: Of 86 patients with hereditary hemochromatosis, 16 (19%) were heterozygous carriers and 1 (1%) was a homozygous carrier of the TNF-alpha promoter -308A allele. Mean (SD) total body iron overload was increased 2-fold in TNF-alpha -308A allele carriers [10.9 (7.6) g] compared with homozygous carriers of the G allele [5.6 (5.0) g, P<0.001]. Hepatic iron index differed markedly between TNF-alpha -308A allele carriers [5.6 (3.5) micromol/g/year] and homozygous G allele carriers [3.1 (2.2) micromol/g/year, P=0.040, n=30]. After iron depletion, the need for phlebotomy to prevent iron reaccumulation (maintenance therapy) was substantially higher in TNF-alpha -308A allele carriers than in homozygous G allele carriers (P=0.014, n=73). We used multiple regression analyses to exclude possible confounding effects of sex, age, family screening, body-mass index, and meat or alcohol intake., Conclusion: TNF-alpha -308G>A allelic variant modulates iron accumulation in patients with hereditary (homozygous C282Y) hemochromatosis, but the effect of the TNF-alpha -308A allele on clinical manifestations of hemochromatosis was less accentuated than expected from the increased iron load associated with this allele.

Background: Under most circumstances with altered growth hormone (GH) secretion, the changes of insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), and acid-labile subunit (ALS) are in parallel. The aim of the present study was to compare the effects of pregnancy in a hypopituitary patient with those of pregnancy in an acromegalic patient on IGF-I, IGFBP-3, and ALS., Methods and Results: IGF-I and ALS were low before pregnancy in the hypopituitary patient under glucocorticoid and thyroxine treatment. Gonadotropin treatment allowed her to become pregnant; IGF-I and ALS levels rose in the second half of pregnancy and fell again after delivery. IGF-I concentrations were elevated in the patient with persistent acromegaly before and dropped into the normal range during the first half of pregnancy. In the second half of pregnancy and following delivery, IGF-I levels increased again. IGFBP-3 levels (as assessed by immunoblot analysis as well as by 125I-IGF II ligand blotting) decreased markedly during pregnancy in both patients, suggesting that the placenta rather than pituitary GH regulates IGFBP-3 proteolysis in human pregnancy. The increase of IGF-I (and ALS) during the second half of pregnancy in the individual with pituitary GH deficiency may be attributed to placental GH. The fall of IGF-I (and ALS) into the normal range in the acromegalic patient during the first trimester of pregnancy may be related to decreased production or decreased half-life of these proteins., Conclusion: Our data suggest that measures to continuously replace GH or to suppress GH secretion during pregnancy in patients with GH deficiency or excess, respectively, may not be warranted.

Objective: To compare the effect of acute psychosocial stress on glucose concentrations in the fasting state and following food intake in patients with type 1 diabetes., Research Design and Methods: In study 1, 20 patients were exposed to moderate psychosocial stress by means of the Trier Social Stress Test (TSST) in the fasting state. In study 2, the TSST was applied to 20 additional patients 75 min after intake of a standard meal. Glucose concentrations (by continuous glucose monitoring system), blood pressure, and heart rate were monitored on the control day and on the stress testing day., Results: In both studies, blood pressure increased in response to TSST from 122/77 +/- 14/9 mmHg at baseline to a maximum of 152/93 +/- 21/13 mmHg (P < 0.001), and heart rate increased from 80 +/- 11 to 99 +/- 19 bpm (P < 0.001). In the fasting state (study 1), glucose concentrations remained unchanged during the control day as well as during the stress testing day. In study 2, glucose concentrations were similar on both days before and up to 75 min after the intake of the standard meal. However, a significant delay (of 45 min) in the decrease of glucose concentrations was induced by psychological stress. A two-factor repeated-measures ANOVA revealed a significant difference of glucose concentrations over time (F = 646.65/P < 0.001)., Conclusions: In the postprandial period, acute psychological stress induced a significantly delayed decrease of glucose concentrations, whereas in the fasting state, no effect on poststress glucose concentrations was observed.

A possible influence of Chlamydia pneumoniae seropositivity on the clinical course of peripheral arterial occlusive disease (PAOD) has not been investigated previously. Though roxithromycin therapy was found to inhibit progression of PAOD, the nature of this effect (antibiotic or anti-inflammatory) has remained elusive. The course of PAOD was prospectively assessed in elderly men during 4 years, comparing 51 C. pneumoniae seropositive (IgG>/=1:128) with 46 seronegative patients (IgG<1:64 and IgA<1:32). Twenty of the seropositive patients were treated with roxithromycin (400 mg daily) for 4 weeks. Limitation of the walking distance to 200 m or less was observed in 55% of the seropositive untreated patients as compared to 30% of both, seronegative and macrolide-treated patients. The number of invasive revascularizations per patient was 1.7 in the seropositive untreated group as compared to 0.5 in the seronegative and the macrolide-treated group. Considering possible confounding variables, such as classical vascular risk factors, ordinal regression analyses showed a significant association of C. pneumoniae seropositivity with limitation of the walking distance (p=0.027) and need for invasive revascularization (p=0.037). The effect of macrolide treatment on these outcome measures was marked (p<0.001 and p=0.040, respectively) during 2.7 years but decreased in the second part of the observation period. This study provides good evidence that C. pneumoniae are involved in the progression of PAOD and that antibiotic treatment directed against C. pneumoniae is effective in inhibiting this process.

Background: Thiazolidinediones increase adiponectin concentrations, improve insulin sensitivity and fatty liver disease (reflected by decreased alanine aminotransferase [ALT] activity) in type 2 diabetes. This study was performed to test the effect of neurosurgery in acromegaly (sharing at baseline insulin resistance but not increased visceral fat with type 2 diabetes) on insulin sensitivity, adiponectin concentrations and ALT activity., Methods: Sixteen patients with acromegaly undergoing pituitary surgery (and 16 patients with type 2 diabetes treated with pioglitazone) were included. Insulin sensitivity, adiponectin concentrations and ALT activity were determined at baseline and after 4 months., Results: Pituitary surgery in acromegalic patients increased adiponectin concentrations from mean (+/-S.D.) 9.3+/-3.8 to 10.2+/-4.4 mg/L (p<0.05). HOMA scores fell from 6.8+/-4 at baseline to 3.5+/-0.9 following neurosurgery (p<0.005) and ALT activity decreased from median (range) 21 (13-30) to 13 (10-42) U/L (p<0.05). In type 2 diabetics, pioglitazone treatment increased adiponectin concentrations; HOMA scores and ALT activity fell significantly., Conclusion: Pituitary surgery in patients with acromegaly led to a marked increase in insulin sensitivity and a slight increase in adiponectin serum concentrations, whereas ALT activity significantly decreased.

Paraprostatic pheochromocytoma is a very rare localization of extra-adrenal pheochromocytoma. The clinical and anatomical features of a 41-year-old man are described., (Copyright 2005 S. Karger AG, Basel.)

Objective: Abnormal proinsulin processing in insulinomas may result in secretory granules containing both insulin and proinsulin, a finding not encountered in healthy beta-cells. The aim of this study was to test whether such abnormalities in the proinsulin to insulin conversion have clinical implications in patients with hypoglycaemic disorders., Design: Case-series., Patients and Methods: Fifteen patients with histologically confirmed insulinoma and two patients with islet cell hyperplasia were included. The immunohistochemical distribution pattern of proinsulin within the tumour cells was classified as Golgi pattern (predominantly perinuclear immunolabelling) or diffuse pattern (immunolabelling in the periphery of the cells, indicating the presence of proinsulin in secretory granules). Data obtained from the 72-h fast and arterial calcium stimulation and hepatic venous sampling (ASVS) test were related to the morphological classification., Results: Six insulinomas exhibited a diffuse proinsulin distribution pattern, while nine insulinomas and two islet cell hyperplasias disclosed a Golgi pattern. Median proinsulin concentrations at the termination of the fast tended to be higher in patients with the diffuse proinsulin distribution pattern than in patients with the Golgi pattern (86.9 vs. 18.8 pmol/l, P = 0.07). Higher insulin (P < 0.005) and proinsulin (P < 0.05) concentrations were significantly correlated with earlier occurrence of hypoglycaemia during the prolonged fast. During the ASVS test, tumours with the diffuse proinsulin distribution pattern exhibited a higher increase in both insulin (median, 37.3- vs. 10.5-fold, P < 0.05) and proinsulin (6.3- vs. 1.6 fold, P < 0.005) concentrations following calcium stimulation than the tumours with the Golgi pattern., Conclusions: Abnormalities in the proinsulin to insulin conversion in patients with insulinomas and islet cell hyperplasia correlate with impaired regulation of both insulin and proinsulin secretion during the prolonged fast as well as the ASVS test.

Background: Traditional criteria to diagnose hyperinsulinaemic hypoglycaemia are based on insulin measurements by unspecific insulin assays. This study was performed to test whether these traditional criteria can be applied when insulin is measured by specific immunoassays., Methods: 29 consecutive patients undergoing a prolonged fast were included; 11 patients with insulinoma and 18 healthy individuals. We determined plasma glucose, insulin, C-peptide, proinsulin, and beta-hydroxybutyrate concentrations at the termination of the fast. Insulin was measured by an unspecific radioimmunoassay (RIA) and a specific enzyme-linked immunosorbent assay (ELISA)., Results: In 11 insulinoma patients, insulin concentrations at median plasma glucose concentration of 2.1 (range 1.3-2.5) mmol/l were 170 (76-340) pmol/l measured by RIA and 61 (11-156) pmol/l by ELISA. Insulin concentrations measured by RIA confirmed hyperinsulinaemia (i.e., >36 pmol/l, the proposed cut-off value for traditional insulin assays) in all insulinoma patients, whereas insulin concentrations measured by ELISA were <36 pmol/l in four patients. In three insulinoma patients, insulin concentrations measured by ELISA were <18 pmol/l, a proposed cut-off level to diagnose hyperinsulinaemia for specific insulin assays., Conclusion: When insulin concentrations are measured by specific immunoassays in patients evaluated for fasting hypoglycaemia, traditional reference values cannot be applied.

Background: Serum cystatin C (CysC) is a novel marker for kidney function. The impact of mild thyroid dysfunction on CysC has never been investigated., Methods: CysC was determined at the time of diagnosis of subclinical hypo- and hyperthyroidism, and when TSH returned into the normal range in 40 consecutive patients with mild thyroid dysfunction., Results: Twenty-six patients with subclinical hypothyroidism and 14 patients with subclinical hyperthyroidism were included. In patients with subclinical hypothyroidism median (range) TSH was 7.8 (4.3-26.7) mU/l (reference 0.27-4.2) at diagnosis and decreased to 2.3 (0.36-4.0) mU/l following treatment with levothyroxine. Mean (+/-S.D.) CysC increased from 0.88+/-0.23 mg/l (reference 0.63-1.33) in the hypothyroid state to 1.01+/-0.21 mg/l when TSH normalized (p<0.001). In patients with subclinical hyperthyroidism, median TSH at diagnosis was 0.08 (0.001-0.26) mU/l and increased to 1.6 (0.28-4.0) mU/l in the euthyroid state. CysC declined from 1.04+/-0.29 mg/l at diagnosis of subclinical hyperthyroidism to 0.91+/-0.25 mg/l when TSH normalized (p<0.05)., Conclusions: Mild thyroid dysfunction significantly alters CysC levels. Therefore, thyroid function has to be considered when CysC is used as a marker of kidney function.

Background: Serum cystatin C (CysC) is a novel marker for kidney function that has been claimed to be superior to serum creatinine. Thyroid dysfunction may alter creatinine, which has been found to be increased in hypothyroidism and decreased in hyperthyroidism. This study was performed to evaluate whether changes in CysC and creatinine are parallel during the treatment of hypo- and hyperthyroidism, respectively., Methods: Prospective case series of 22 consecutively referred patients with thyroid dysfunction. Creatinine and CysC were determined at the time of diagnosis of hypo- and hyperthyroidism, and when free thyroxine (fT4) returned into the normal range. Hypothyroid patients were treated with levothyroxine. Hyperthyroid patients were treated with antithyroid drugs, surgery, or radioiodine., Results: Nine patients with hypothyroidism and 13 patients with hyperthyroidism were included. In patients with hypothyroidism mean fT4 (+/-SD) was 4.9 +/- 2.5 pmol/L (reference, 12 to 22) at diagnosis and increased to 16.6 +/- 3.6 pmol/L when patients were treated with levothyroxine. Creatinine decreased from 86 +/- 13 micromol/L (reference, 70 to 105) in the hypothyroid state to 76 +/- 16 micromol/L when fT4 normalized (P = 0.062), whereas CysC increased from 0.84 +/- 0.17 mg/L (reference, 0.63 to 1.33) to 1.1 +/- 0.28 mg/L (P < 0.001). In patients with hyperthyroidism, mean fT4 was 54.6 +/- 22.7 pmol/L (reference, 12 to 22) at diagnosis and decreased to 15.8 +/- 3.6 pmol/L following treatment with antithyroid drugs, thyroid surgery, or radioiodine. Creatinine increased from 67 +/- 15 micromol/L at diagnosis of hyperthyroidism to 75 +/- 9 micromol/L when fT4 normalized (P = 0.004), whereas CysC declined from 1.32 +/- 0.17 mg/L to 0.95 +/- 0.19 mg/L (P < 0.001)., Conclusion: Thyroid dysfunction has a major impact on CysC levels. Therefore, thyroid function has to be considered when CysC is used as a marker of kidney function. In contrast to creatinine concentrations, CysC levels are lower in the hypothyroid and higher in the hyperthyroid state as compared with the euthyroid state.

In most patients with Type 2 Diabetes, the primary treatment goal is near-normoglycemia. If diet, physical activity, and oral hypoglycemic agents fail to achieve the individual treatment goal, insulin therapy must be considered. Insulin therapy in patients with Type 2 Diabetes is safe, highly efficient and should be initiated not too late. We recommend to perform the insulin therapy in Type 2 Diabetics individually upon the patients characteristics, no general recommendation can be given. Possible approaches to start an insulin therapy in general practice are discussed. Insulin therapy may be initiated as bedtime insulin (depot insulin at bedtime) in combination with oral agents. In patients who fail to achieve good glycemic control with this combination therapy, mealtime insulin (short-acting insulin before the meals) may be introduced instead of the oral agents (multiple injection regimen). Bedtime insulin may be discontinued when fasting glucose concentrations remain in the desired range and no rise of glucose concentrations occurs during the night. The two-insulin-injection regimen with mixed insulin formulations may be initiated in patients with Type 2 Diabetes when a multiple injection regimen is not feasible. The two-insulin-injection should not be considered as the primary insulin strategy in patients with Type 2 Diabetes.

Thyroid function is evaluated by measuring the serum concentrations of thyroid stimulating hormone (TSH) and free thyroxine (fT4). To confirm a normal thyroid function, a TSH within the normal range is usually sufficient. If hyperthyroidism or hypothyroidism is suspected clinically, the assessment of TSH in association with fT4 is recommended. Additional tests in the evaluation of hyper- and hypothyroidism should be performed depending on the clinically suspected diagnosis. Acquired primary hypothyroidism in the adult can be diagnosed by measurement of TSH and fT4. Additional investigations are usually unnecessary. The indications to perform a thyroid radionuclide scan, thyroid ultrasonography and the determination of thyroid antibodies in patients with primary hyperthyroidism are discussed.

We report a patient with a hepatic neuroendocrine tumor showing an extraordinary change of the tumor's humoral manifestations from a clinically documented extrapituitary acromegaly and a typical carcinoid syndrome toward a hyperinsulinemic hypoglycemia syndrome. At the primary manifestation of the tumor, an increased serum level of insulin-like growth factor I due to overproduction of GHRH and an increased urinary excretion of 5-hydroxyindoleacetic acid were found. The clinical manifestation of the GHRH excess was an arthralgia, which resolved completely after operative tumor debulking and normalization of insulin-like growth factor I and GHRH serum levels. The secretion of serotonin from the tumor resulted in a typical carcinoid syndrome including right-sided valvular heart disease. On the later course of the disease, the humoral manifestations of the tumor were supplemented by the secretion of insulin, leading to recurrent severe hyperinsulinemic hypoglycemia. The hepatic origin of hyperinsulinism was demonstrated by selective arterial calcium stimulation. Moreover, tumor cells revealed insulin and C-peptide immunoreactivity in the immunohistochemical analysis. The patient died 8 yr after the initial diagnosis of the tumor, and a carefully performed autopsy procedure confirmed the absence of any extrahepatic tumor manifestation.

The 34-year old woman, by profession a farmer, presented herself with the symptoms of hypothyroidism, which were confirmed by laboratory investigations. Chronic autoimmune thyroiditis was assumed due to the constellation of primary hypothyroidism in association with elevated thyroid autoantibodies. Substitution with levothyroxine induced a full clinical recovery, but persistent hyperthyroidism occurred even after discontinuation of levothyroxine treatment. Mild ophthalmopathy developed and Graves disease was diagnosed. The primary manifestation of Graves' disease with hypothyroidism was caused by blocking TSH receptor antibodies. Chronic autoimmune thyroiditis, Graves' disease and the importance of thyroid autoantibodies are discussed.

The 57 year old woman presented with diffuse muscle spasms and delirium. Prior to presentation, she complained of progressive muscle pain, weakness and a weight loss of 10 kg over several months. Laboratory investigation showed hypopituitarism and a syndrome of inappropriate antidiuretic hormone secretion. Magnetic resonance imaging revealed an empty sella. The primary and secondary syndromes of empty sella are discussed.

We describe the exceptional association of Vogt-Koyanagi-Harada syndrome (VKHS) and hypothyroidism in a 29-year-old man of Indian heritage. VKHS is a rare uveomeningoencephalitic syndrome with probably autoimmune pathogenesis. Nontraumatic uveitis, aseptic meningoencephalitis, vitiligo, alopecia and poliosis are the leading clinical features of VKHS. The reported patient presented with bilateral visual loss and progressive frontal headache. VKHS was diagnosed due to characteristic ophthalmological findings and the diagnosis of aseptic meningitis. Due to the autoimmune pathogenesis, VKHS may be rarely associated with other autoimmune disorders. Association of VKHS with autoimmune thyroid disease has been described in the literature in three patients. In the reported case hypothyroidism due to chronic autommune thyroiditis was diagnosed in association with VKHS. Routinely determination of thyroid function in patients with VKHS is recommended.

A 48-year old engineer presented with progressive decline in sports performance. A history of latent hypothyroidism was known since 3 years. Adrenocortical insufficiency was suggested and confirmed by further investigations. Because of additional autoimmune thyroiditis and family history with autoimmune diabetes of the son, the diagnosis polyglandular autoimmune syndrome type II was made.