[Treatment of acromegaly - data from the German Acromegaly Register]. / Therapie der Akromegalie ­ Daten aus dem Deutschen Akromegalie Register.

Acromegaly is a rare disease in which chronic growth hormone overproduction (usually from an anterior pituitary adenoma) leads to various systemic complications. The management of acromegaly and the comorbidities of the disease is complex and requires a multidisciplinary approach. Early diagnosis is extremely important, as then the chances of a complete cure are significantly higher. The operation is the therapy of first choice and should be performed at a specialized center with an experienced neurosurgeon. With good patient information and guidance, the drug therapy of acromegaly patients in specialized practices and clinics can usually lead to biochemical control and thereby normalization of mortality risk. As with numerous rare diseases, care in specialized centers and recording and evaluation in registry studies can contribute to better patient care and the optimization of therapy and diagnostic guidelines. We assume that with the help of the German Acromegaly Registry, which currently includes more than 2500 patients with acromegaly, we will be able to present a realistic picture of the care situation in Germany in the coming years.

[Update - Calcium Metabolism]. / Update ­ Kalziumstoffwechsel.

A finely balanced control system keeps the extracellular calcium concentration within narrow limits. Disorders of calcium metabolism are often based on altered parathormone levels. Symptoms are not always clear, sometimes they are even missing: the more it is important to know possible associated diseases. The author presents basics, current diagnostics and concrete therapy options. Central hormone for the regulation of the calcium balance is the parathyroid hormone. With decreasing calcium, PTH leads to an increase in extracellular free calcium concentration in three ways. The classic symptoms of pHPT (polyuria, polydipsia, "stone, leg, and stomach pain") are rare now, as the condition is diagnosed much earlier. Treatment of choice in all symptomatic patients with pHPT is surgery. FHH and pHPT are both characterized by hypercalcaemia and increased parathyroid hormone. The differential diagnosis of urinary calcium excretion, which is usually lower in FHH but normal or elevated in pHPT, is crucial. In primary hypoparathyroidism, parathyroid failure interferes with calcium homeostasis at a central location. Consequences are hypocalcaemia, hyperphosphatemia and lack of active vitamin D. Due to increased urinary calcium excretion, patients with ADH are at high risk for kidney stones, nephrocalcinosis and the development of renal insufficiency. Recently, rhPTH 1-84 has been available for the treatment of hypoparathyroidism. However, long-term data is still lacking to provide a safe indication, considering potential effects and side effects.

Personality Traits and Physical Complaints in Patients With Acromegaly: A Cross Sectional Multi-Center Study With Analysis of Influencing Factors.

Objective: Acromegalic patients display a distinct neuropsychological profile and suffer from chronic physical complaints. We aimed to investigate in more detail these aspects in acromegalic patients, dependent on influencing factors like disease activity, age, sex, chronic medication, surgery, pituitary radiation, pituitary insufficiency and comorbidities. Design: Cross sectional, multicentric. Methods: 129 patients (M/W 65/64, 58.3 ± 12.7 years, 53/76 with active/controlled disease). Acromegalic patients completed the following inventories: NEO-FFI, IIP-D, and the Giessen Complaints List (GBB-24), after written informed consent. Age, sex, IGF-1 concentrations, comorbidities, treatment modalities and pituitary insufficiency were documented. Results: Acromegalic patients or specific patient-subgroups were more agreeable, neurotic, exploitable/permissive, introverted/socially avoidant, non-assertive/insecure, nurturant and less open to experience, cold/denying, domineering, compared to normal values from the healthy population (controls). Multivariable analysis demonstrated that these overall results were due to the specific patient subgroups as patients on chronic medication, with arthrosis and pituitary insufficiency. Disease activity was only associated with the trait nurturant. Higher scores for introversion were associated with arthrosis. Lower domineering was independent of any disease- or treatment related variable or comorbidity. The GBB inventory showed overall higher scores in patients, with higher scores for exhaustion and general complaints being associated with pituitary insufficiency, coronary heart disease and history of malignancy in the multivariable analysis. Joint complaints were independent of any disease- or treatment- related variable. Conclusions: We define new aspects of a distinct neuropsychological profile in patients with acromegaly, which are largely independent of disease activity. Chronic physical complaints are more pronounced in patients than in controls, with exhaustion and general complaints showing no association with disease activity.

Polycystic Ovary Syndrome (PCOS) in Juvenile and Adult Type 1 Diabetes in a German/Austrian Cohort.

Context While an association between PCOS and type 2 diabetes is well established, to date there have been few data on clinical care of type 1 diabetes (T1D) patients with PCOS. Objective The aim of our study was to characterize T1D patients with the comorbidity of PCOS within the DPV cohort with regard to diabetes phenotype, therapy and metabolic control. Design and Setting Clinical data from the prospective German/Austrian DPV cohort on patients with T1D and documented PCOS (n=76) were compared to female T1D controls (n=32,566) in reproductive age. Results The age at T1D manifestation in PCOS patients was later than in the control group (14.9±8.2 vs. 11.8±7.0 years, p<0.001). PCOS patients had higher BMI-SDS (0.92±0.11 vs. 0.38±0.01, p<0.001), metformin and oral contraceptives were used more frequently (p<0.001). A1c levels were significantly lower (7.92 +/- 0.23% vs. 8.43±0.01%, p<0.05) despite of lower insulin requirements (0.76±0.04 IU/kg/d vs. 0.84±0.00 IU/kg/d, p<0.05). In the PCOS group, higher rates of dyslipidemia (63.4 vs. 48.7%, p =0.032) and thyroid disorders (42.2% vs. 21.2%, p<0.001) were present. Discussion While patients with T1D and comorbid PCOS showed features of a "type 1.5 diabetes" phenotype, insulin requirements per kg body weight were not higher and metabolic control was better, which could be explained only partially by additional metformin therapy. A more precise genetic and metabolic characterisation of these patients is needed to answer open questions on the underlying autoimmune process and residual ß-cell function.

Incidence of myocardial infarction and stroke in acromegaly patients: results from the German Acromegaly Registry.

PURPOSE: Acromegaly is a rare disease generally brought about by a benign tumour in the pituitary and characterized by growth hormone (GH) and insulin-like growth factor 1 (IGF-1) excess. Increased mortality has been related to cardiovascular events that could be linked to these hormones and patients suffer from high rates of diabetes and hypertension. In this study, we examine if the incidence of myocardial infarction (MI) and stroke differ from that of the general population. METHODS: Data from the German Acromegaly Registry in seven specialized endocrine centres were analysed (n = 479, 56% female, 46 years old at diagnosis, 5549 person-years from diagnosis). Standardized incidence ratios (SIR) were calculated as compared to the general population. RESULTS: MI and stroke incidences were very close to those of the general population with an SIR (95% CI) of 0.89 (0.47-1.52, p = 0.80) for MI and 1.17 (0.66-1.93, p = 0.61) for stroke. Acromegaly was uncontrolled in 16% of patients with MI or stroke versus 21% in those without (p = 0.56). Prevalence of hypertension at the initial visit was much higher in those with MI or stroke than those without (94 vs. 43%, p < 0.001). No association was seen between radiation therapy and stroke. CONCLUSIONS: For acromegaly patients being treated at specialized centres, the incidence of MIs and strokes does not seem to differ from the general population. Certainty regarding such statements requires large, prospective studies however.

T2-weighted MRI signal predicts hormone and tumor responses to somatostatin analogs in acromegaly.

GH-secreting pituitary adenomas can be hypo-, iso- or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyper-intense groups (P < 0.001). Tumor shrinkage on SSA was also significantly greater in the T2-hypo-intense group (38%) compared with the T2-iso- and hyper-intense groups (8% and 3%, respectively; P < 0.0001). The response to SSA correlated with the calculated T2 intensity: the lower the T2-weighted intensity, the greater the decrease in random GH (P < 0.0001, r = 0.22), IGF-1 (P < 0.0001, r = 0.14) and adenoma volume (P < 0.0001, r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly.

Achievement of treatment goals for secondary prevention of myocardial infarction or stroke in 29,325 patients with type 2 diabetes: a German/Austrian DPV-multicenter analysis.

BACKGROUND: To analyze whether medical care is in accordance with guidelines for secondary prevention of myocardial infarction (MI), or stroke in patients with type 2 diabetes from Germany and Austria. METHODS: 29,325 patients (≥ 20 years of age) with type 2 diabetes and MI, or stroke, documented between 2006 and 2015 were selected from the Diabetes-Patienten-Verlaufsdokumentation database. We analyzed medication, clinical characteristics, and lifestyle factors according to national secondary prevention guidelines in patients with MI, or stroke, separately. RESULTS: HbA1C <7.5 % was achieved in 64.9 % (MI), and in 61.1 % (stroke) of patients. LDL <100 mg/dl was documented in 56.2 % (MI), and in 42.2 % (stroke). Non-smoking was reported in 92.0 % (MI), and in 93.1 % (stroke), physical activity in 9.6 % (MI), and 5.5 % (stroke). Target values of blood pressure (<130/80 mmHg in MI, 120/70-140/90 in stroke) were reached in 67.0 % (MI), and in 89.9 % (stroke). Prescription prevalence of inhibitors of platelet aggregation (IPA) was 50.7 % (MI), and 31.7 % (stroke). 57.0 % (MI), and 40.1 % (stroke) used statins, 65.1 % (MI), and 65.8 % (stroke) used any type of antihypertensives, and ACE inhibitors were prescribed in 49.7 % (MI), and 41.3 % (stroke). A body mass index (BMI) <27 kg/m(2) and the use of beta blockers were only recommended in subjects with MI. Of the patients with MI, 32.0 % had a BMI <27 kg/m(2), and 59.5 % used beta blockers. CONCLUSIONS: Achievement of treatment goals in secondary prevention of MI, or stroke in subjects with type 2 diabetes needs improvement. Target goals were met more frequently in patients with MI compared to subjects with stroke. Especially the use of IPA was very low in patients with stroke. There remains great potential to reduce the risk of repeated macrovascular events and premature death, as well as to increase patients' quality of life.

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts.

The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper- or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper- and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect.

The Incidence of Cancer Among Acromegaly Patients: Results From the German Acromegaly Registry.

CONTEXT: Acromegaly is a rare disease characterized by high serum levels of GH and IGF-1. Animal studies have demonstrated links between these hormones and cancer, but data regarding cancer incidence among acromegaly patients are inconsistent. Moreover, therapy options have changed considerably since many of the aforementioned data were collected. OBJECTIVE: The objective was to determine whether the overall and site-specific incidence of cancer is comparable to that of the general population. DESIGN AND SETTING: Data from the German Acromegaly Registry for 446 patients (6656 person-years from diagnosis) treated in seven specialized endocrine centers were analyzed. MAIN OUTCOME MEASURE: Standard incidence ratios (SIRs) were calculated as compared to the general population. RESULTS: Overall cancer incidence was slightly but not significantly lower than in the general population (SIR, 0.75; 95% confidence interval, 0.55 to 1.00; P = .051) and was not significantly higher for colorectal, breast, thyroid, prostate, and lung cancers. The SIRs of those with GH in the ranges <1, 1-2.5, and ≥ 2.5 ng/mL were 0.75, 0.44, and 0.92, respectively (P = .94). There was not a significant dependence on normal vs elevated IGF-1 (P = .87), radiation therapy (P = .45), disease duration (P = .96), age at diagnosis (P = .15), or during a period of high GH and IGF-1 from 8 years before to 2 years after diagnosis of acromegaly (P = .41). CONCLUSIONS: Cancer screening strategies need to take incidence into account, which does not seem to be substantially higher in treated acromegaly patients than in the general population for any site of cancer.

Failure to achieve disease control in acromegaly: cause analysis by a registry-based survey.

CONTEXT: Disease control is a prime target in acromegaly treatment. This should be achievable in the vast majority of patients by available treatment options. For unknown reasons, however, a significant number of patients do not achieve disease control. OBJECTIVE: To investigate reasons for failure to achieve disease control in long-standing acromegaly. DESIGN AND METHODS: Survey based on the German Acromegaly Registry database (1755 patients in 57 centres). Questionnaires were sent to 47 centres treating 178 patients with elevated disease markers (IGF1 and GH) at the last documented database visit out of 1528 patients with a diagnosis dated back ≥2 years. Thirty-three centres returned anonymised information for 120 patients (recall rate 67.4%). RESULTS: Median age of the 120 patients (58 females) was 57 years (range 17-84). Ninety-four patients had at least one operation, 29 had received radiotherapy and 71 had been previously treated medically. Comorbidities were reported in 67 patients. In 61 patients, disease activity had been controlled since the last documented database visit, while 59 patients still had biochemically active disease. Reasons were patients' denial to escalate therapy (23.3%), non-compliance (20.6%), fluctuating insulin-like growth factor 1 (IGF-1) and growth hormone (GH) levels with normal values at previous visits (23.3%) and modifications in pharmacotherapy (15.1%). Therapy resistance (9.6%), drug side effects (4.1%) and economic considerations (4.1%) were rare reasons. CONCLUSIONS: Main reasons for long-standing active acromegaly were patients' lack of motivation to agree to therapeutic recommendations and non-compliance with medical therapy. Development of patient education programmes could improve long-term control and thus prognosis of acromegalic patients.

Carbohydrate intake and insulin requirement in children, adolescents and young adults with cystic fibrosis-related diabetes: A multicenter comparison to type 1 diabetes.

BACKGROUND & AIMS: In cystic fibrosis-related diabetes (CFRD), energy needs differ from type 1 (T1D) or type 2 diabetes, and endogenous insulin secretion is not totally absent. We analyzed whether daily carbohydrate intake, its diurnal distribution and insulin requirement per 11 g of carbohydrate differ between CFRD and T1D. METHODS: Anonymized data of 223 CFRD and 36,780 T1D patients aged from 10 to <30 years from the multicenter diabetes registry DPV were studied. Carbohydrate intake and insulin requirement were analyzed using multivariable regression modeling with adjustment for age and sex. Moreover, carbohydrate intake was compared to the respective recommendations (CFRD: energy intake 130% of general population with 45% carbohydrates; T1D: carbohydrate intake 50% of total energy). RESULTS: After demographic adjustment, carbohydrate intake (238 ± 4 vs. 191 ± 1 g/d, p < 0.001) and meal-related insulin (0.52 ± 0.02 vs. 0.47 ± 0.004 IU/kg*d, p = 0.001) were higher in CFRD, whereas basal insulin (0.27 ± 0.01 vs. 0.38 ± 0.004 IU/kg*d, p < 0.001) and total insulin requirement per 11 g of carbohydrate (1.15 ± 0.06 vs. 1.70 ± 0.01 IU/d, p < 0.001) were lower compared to T1D. CFRD patients achieved 62% [Q1;Q3: 47; 77] of recommended carbohydrate intake and T1D patients 60% [51; 71] of age- and gender-specific recommended intake (p < 0.001). CFRD and T1D patients had a carbohydrate intake below healthy peers (79% [58; 100] and 62% [52; 74], p < 0.001). The circadian rhythm of insulin sensitivity persisted in CFRD and the diurnal distribution of carbohydrates was comparable between groups. CONCLUSIONS: In pediatric and young adult patients, carbohydrate intake and insulin requirement differ clearly between CFRD and T1D. However, both CFRD and T1D patients seem to restrict carbohydrates.

Frequency of AIP gene mutations in young patients with acromegaly: a registry-based study.

CONTEXT: Familial and sporadic GH-secreting pituitary adenomas are associated with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. Patients with an AIP mutation (AIPmut) tend to have more aggressive tumors occurring at a younger age. OBJECTIVE: The objective of the study was to investigate the frequency of AIPmut in patients diagnosed at 30 years of age or younger. DESIGN: The German Acromegaly Registry database (1795 patients in 58 centers) was screened for patients diagnosed with acromegaly at 30 years of age or younger (329 patients). Sixteen centers participated and 91 patients consented to AIPmut analysis. INTERVENTION: DNA was analyzed by direct sequencing and multiplex ligation dependent probe amplification Main outcome Measures: The number of patients with AIPmut was measured. RESULTS: Five patients had either a mutation (c.490C>T, c.844C>T, and c.911G>A, three males) or gross deletions of exons 1 and 2 of the AIP gene (n = 2, one female). The overall frequency of an AIPmut was 5.5%, and 2.3% or 2.4% in patients with an apparently sporadic adenoma or macroadenoma, respectively. By contrast, three of four patients (75%) with a positive family history were tested positive for an AIPmut. Except for a positive family history, there were no significant differences between patients with and without an AIPmut. CONCLUSIONS: The frequency of AIPmut in this registry-based cohort of young patients with acromegaly is lower than previously reported. Patients with a positive family history should be tested for an AIPmut, whereas young patients without an apparent family history should be screened, depending on the individual cost to benefit ratio.

Activation of the Ca²+-sensing receptor induces deposition of tight junction components to the epithelial cell plasma membrane.

The Ca(2+)-sensing receptor (CaSR) belongs to the G-protein-coupled receptor superfamily and plays essential roles in divalent ion homeostasis and cell differentiation. Because extracellular Ca(2+) is essential for the development of stable epithelial tight junctions (TJs), we hypothesized that the CaSR participates in regulating TJ assembly. We first assessed the expression of the CaSR in Madin-Darby canine kidney (MDCK) cells at steady state and following manipulations that modulate TJ assembly. Next, we examined the effects of CaSR agonists and antagonists on TJ assembly. Immunofluorescence studies indicate that endogenous CaSR is located at the basolateral pole of MDCK cells. Stable transfection of human CaSR in MDCK cells further reveals that this protein co-distributes with ß-catenin on the basolateral membrane. Switching MDCK cells from low-Ca(2+) medium to medium containing a normal Ca(2+) concentration significantly increases CaSR expression at both the mRNA and protein levels. Exposure of MDCK cells maintained in low-Ca(2+) conditions to the CaSR agonists neomycin, Gd(3+) or R-568 causes the transient relocation of the tight junction components ZO-1 and occludin to sites of cell-cell contact, while inducing no significant changes in the expression of mRNAs encoding junction-associated proteins. Stimulation of CaSR also increases the interaction between ZO-1 and the F-actin-binding protein I-afadin. This effect does not involve activation of the AMP-activated protein kinase. By contrast, CaSR inhibition by NPS-2143 significantly decreases interaction of ZO-1 with I-afadin and reduces deposition of ZO-1 at the cell surface following a Ca(2+) switch from 5 µM to 200 µM [Ca(2+)]e. Pre-exposure of MDCK cells to the cell-permeant Ca(2+) chelator BAPTA-AM, similarly prevents TJ assembly caused by CaSR activation. Finally, stable transfection of MDCK cells with a cDNA encoding a human disease-associated gain-of-function mutant form of the CaSR increases the transepithelial electrical resistance of these cells in comparison to expression of the wild-type human CaSR. These observations suggest that the CaSR participates in regulating TJ assembly.

Molecular and functional properties of densely and sparsely granulated GH-producing pituitary adenomas.

OBJECTIVE: GH-producing pituitary adenomas display two distinct morphological patterns of cytoplasmic GH-containing secretory granules, namely the densely and sparsely granulated somatotroph adenoma subtype. It is unknown whether these morphological variants reflect distinct pathophysiological entities at the molecular level. METHODS: In 28 GH-producing adenoma tissues from a consecutive set of patients undergoing pituitary surgery for acromegaly, we studied the GH granulation pattern, the expression of somatostatin receptor subtypes (SSTR) as well as the calcium, cAMP and ZAC1 pathways in primary adenoma cell cultures. RESULTS: The expression of GSP oncogene was similar between densely and sparsely granulated somatotroph adenoma cells. There were no differences in the calcium, cAMP and ZAC1 pathways as well as in their regulation by SSTR agonists. SSTR2 was exclusively expressed in densely but not in sparsely granulated tumours (membrane expression 86 vs 0%; cytoplasmic expression 67 vs 0%). By contrast, expression of SSTR5 was only found in sparsely but not in densely granulated somatotroph adenomas (membrane expression 29 vs 0%; cytoplasmic expression 57 vs 0%). CONCLUSIONS: Our results indicate that different granulation patterns in GH-producing adenomas do not reflect differences in pathways and factors pivotal for somatotroph differentiation and function. In vitro, the vast majority of both densely and sparsely granulated tumour cells were responsive to SSTR activation at the molecular level. Sparsely granulated adenomas lacking SSTR2, but expressing SSTR5, might be responsive to novel SSTR agonists with increased affinity to SSTR5.

Cystic fibrosis-related diabetes compared with type 1 and type 2 diabetes in adults.

BACKGROUND: With increasing life expectancy of patients with cystic fibrosis (CF), secondary diabetes becomes more prevalent. It appears to be the most common co-morbidity in persons with cystic fibrosis. Therefore, the objective of our study was to describe characteristics of cystic fibrosis-related diabetes compared with type 1 and 2 diabetes (T1DM/T2DM) in adults. METHODS: Data from 218 436 patients >18 years with cystic fibrosis (n = 401), T1DM (n = 32,409) or T2DM (n = 185 626) in the multicenter Diabetes-Patienten-Verlaufsdokumentation or prospective documentation of diabetes patients registry were analysed. RESULTS: Diabetes onset [median (interquartile range)] in cystic fibrosis [18.70 (15.50-25.30) years] was between T1DM [16.40 (10.50-31.80) years] and T2DM [58.50 (48.80-68.00) years], with female preponderance. Body mass index (BMI) and glycosylated haemoglobin (HbA1c ) were lowest (19.6 [18.1-21.5] kg/m(2) )/50 mmol/mol (6.73%) versus T1DM (24.4 [22.1-27.4])/62 mmol/mol (7.83%) vs. T2DM (29.6 [26.1-33.9])/54 mmol/mol (7.06%); all p < 0.01. A total of 78.6% of cystic fibrosis patients with diabetes received insulin. Insulin dose (0.74 IE/kg bodyweight) was not significantly different from T1DM (0.73) and T2DM (0.76). Frequency of vascular complications, adjusted for confounding effects, across the groups was different: Hypertension (CFRD 16.1% vs. T1DM 24.0% vs. T2DM 32.2%; all p < 0.01), retinopathy (CFRD 10.7% vs. T1DM 10.4% vs. T2DM 10.5%, not significant), nephropathy (CFRD 25.2% vs. T1DM 17.2% vs. T2DM 24.7%; only T1DM/T2DM; p < 0.01). CONCLUSION: CFRD is a uniquely complex entity with clear differences from T1DM and T2DM in adults.

GLP-1 analogues as a new treatment option for hypothalamic obesity in adults: report of nine cases.

BACKGROUND: Patients with hypothalamic pathology often develop morbid obesity, causing severe metabolic alterations resulting in increased morbidity and mortality. Glucagon-like peptide-1 (GLP-1) analogues improve glycaemic control in type 2 diabetic patients and cause weight loss in obese patients by yet unknown mechanisms. Here we tested whether GLP-1 analogues were also effective in the treatment of obesity and associated metabolic alterations in patients with hypothalamic disease. METHODS: Nine patients (eight with type 2 diabetes mellitus) with moderate to severe hypothalamic obesity were treated with GLP-1 analogues for up to 51 months. Body weight, homeostasis model assessment - insulin resistance (HOMA-IR), HbA1c and lipids were assessed. RESULTS: Eight patients experienced substantial weight loss (-13.1±5.1 kg (range -9 to -22)). Insulin resistance (HOMA-IR -3.2±3.5 (range -9.1 to 0.8)) and HbA1c values (-1.3±1.4% (range -4.5 to 0.0)) improved under treatment (24.3±18.9 months (range 6 to 51)). Five patients reported increased satiation in response to the treatment. Two of the eight patients complained about nausea and vomiting and one of them abandoned therapy because of sustained gastrointestinal discomfort after 6 months. One patient suffered from intolerable nausea and vomiting and discontinued treatment within 2 weeks. CONCLUSION: GLP-1 analogues can cause substantial and sustained weight loss in obese patients with hypothalamic disease. This offers a new approach for medical treatment of moderate to severe hypothalamic obesity and associated metabolic alterations.

Long-term outcome in patients with acromegaly: analysis of 1344 patients from the German Acromegaly Register.

BACKGROUND: Acromegaly is a rare disease with significant morbidity and increased mortality. Epidemiological data about therapeutic outcome under 'real life' conditions are scarce. OBJECTIVE: To describe biochemical long-term outcome of acromegaly patients in Germany. DESIGN AND METHODS: Retrospective data analysis from 1344 patients followed in 42 centers of the German Acromegaly Register. Patients' data were collected 8.6 (range 0-52.6) years after diagnosis. Controlled disease was defined by an IGF1 within the center-specific reference range. RESULTS: Nine hundred and seventeen patients showed a normalized IGF1 (157 (range 25-443) ng/ml). In patients with a diagnosis dated back >2 years (n=1013), IGF1 was normalized in 76.9%. Of the patients, 19.5% had an elevated IGF1 and a random GH ≥1 ng/ml, 89% of the patients had at least one surgical intervention, 22% underwent radiotherapy, and 43% received medical treatment. After surgery 38.8% of the patients were controlled without any further therapy. The control rates were higher in surgical centers with a higher caseload (P=0.034). Of the patients with adjunctive radiotherapy 34.8% had a normal IGF1 8.86 (0-44.9) years post irradiation, 65.2% of the medically treated patients were controlled, and 47.2% of the patients with an elevated IGF1 received no medical therapy. CONCLUSION: The majority of acromegaly patients were controlled according to their IGF1 status. Long-term outcome could be improved by exploiting medical treatment options especially in patients who are not controlled by surgery and/or radiotherapy.

Craniopharyngioma in adults.

Craniopharyngiomas are slow growing benign tumors of the sellar and parasellar region with an overall incidence rate of approximately 1.3 per million. During adulthood there is a peak incidence between 40 and 44 years. There are two histopathological types, the adamantinomatous and the papillary type. The later type occurs almost exclusively in adult patients. The presenting symptoms develop over years and display a wide spectrum comprising visual, endocrine, hypothalamic, neurological, and neuropsychological manifestations. Currently, the main treatment option consists in surgical excision followed by radiation therapy in case of residual tumor. Whether gross total or partial resection should be preferred has to be balanced on an individual basis considering the extent of the tumor (e.g., hypothalamic invasion). Although the overall long-term survival is good it is often associated with substantial morbidity. Preexisting disorders are often permanent or even exacerbated by treatment. Endocrine disturbances need careful replacement and metabolic sequelae should be effectively treated. Regular follow-up by a multidisciplinary team is a prerequisite for optimal outcome of these patients.

Protein phosphatase 1 (PP-1)-dependent inhibition of insulin secretion by leptin in INS-1 pancreatic ß-cells and human pancreatic islets.

Leptin inhibits insulin secretion from pancreatic ß-cells, and in turn, insulin stimulates leptin biosynthesis and secretion from adipose tissue. Dysfunction of this adipoinsular feedback loop has been proposed to be involved in the development of hyperinsulinemia and type 2 diabetes mellitus. At the molecular level, leptin acts through various pathways, which in combination confer inhibitory effects on insulin biosynthesis and secretion. The aim of this study was to identify molecular mechanisms of leptin action on insulin secretion in pancreatic ß-cells. To identify novel leptin-regulated genes, we performed subtraction PCR in INS-1 ß-cells. Regulated expression of identified genes was confirmed by RT-PCR and Northern and Western blotting. Furthermore, functional impact on ß-cell function was characterized by insulin-secretion assays, intracellular Ca²(+) concentration measurements, and enzyme activity assays. PP-1α, the catalytic subunit of protein phosphatase 1 (PP-1), was identified as a novel gene down-regulated by leptin in INS-1 pancreatic ß-cells. Expression of PP-1α was verified in human pancreatic sections. PP-1α mRNA and protein expression is down-regulated by leptin, which culminates in reduction of PP-1 enzyme activity in ß-cells. In addition, glucose-induced insulin secretion was inhibited by nuclear inhibitor of PP-1 and calyculin A, which was in part mediated by a reduction of PP-1-dependent calcium influx into INS-1 ß-cells. These results identify a novel molecular pathway by which leptin confers inhibitory action on insulin secretion, and impaired PP-1 inhibition by leptin may be involved in dysfunction of the adipoinsular axis during the development of hyperinsulinemia and type 2 diabetes mellitus.

CRH and SRIF have opposite effects on the Wnt/ß-catenin signalling pathway through PKA/GSK-3ß in corticotroph pituitary cells.

The Wnt/ß-catenin signalling pathway is involved in tumorigenesis including endocrine tumors. We investigated the Wnt/ß-catenin pathway's modulation by corticotropin-releasing hormone (CRH) and somatostatin or somatotropin release-inhibiting factor (SRIF) in mouse pituitary AtT-20 corticotroph cells. The Wnt/ß-catenin signalling pathway was activated by CRH and inhibited by SRIF. We provide evidence that cAMP/PKA signalling is involved affecting the GSK-3ß phosphorylation status at phospho-GSK-3ß (Ser9), thereby altering ß-catenin degradation downstream. Furthermore, CRH and SRIF showed concordant effects on cell proliferation. Our data demonstrate an important role of the Wnt/ß-catenin pathway in the proliferative control of pituitary corticotroph cells and describe a mechanism for its regulation by CRH and SRIF.