[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.

Daily adjustment of glucocorticoids by patients with adrenal insufficiency.

BACKGROUND: Patients with adrenal insufficiency (AI) require lifelong glucocorticoid (GC) replacement. AI patients need to adjust GC dosage in response to stressful events and illness in order to prevent life-threatening adrenal crisis (AC). AIM: To evaluate self-management of patients with AI. METHODS: Four German centres, which are using patient's diary as part of their routine clinical practice, instructed AI patients to prospectively document any discomfort, intercurrent illness or stressful events as well as changes in GC therapy on a daily basis. Diaries of 80 patients (44 females, 52.9 ± 15.9 years, 34 primary AI) were collected and analysed. A symptom score sheet was used to evaluate severity of discomfort. RESULTS: In total, 34 074 patient days (93.4 years) were recorded. 4622 days with discomfort were documented. On 35% of those days (n = 1621), patients increased their GC dose (4.8% of all days). Patients who recorded discomfort had a median of four episodes of discomfort, which lasted a median of 2 days. Women documented significantly more episodes of discomfort than men (P = 0.014). Low-to-median symptom scores resulted in GC increase by 50%-60%, whereas high symptom scores and/or fever resulted in doubling GC daily dose. However, dose increase was only 55% in situations indicating gastrointestinal (GI) infection. CONCLUSION: Severe discomfort did not always result in dose increase, especially in GI infection. However, low symptom scores resulted in an inappropriate GC increase in some patients. This underscores an urgent need for improved training methods. Keeping daily records might be a useful tool for continued and individualized patient education.

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.

The Effects of Different Isocaloric Oral Nutrient Solutions on Psychophysical, Metabolic, Cognitive, and Olfactory Function in Young Male Subjects.

Food intake influences human cognition, olfaction, hunger, and food craving. However, little research has been done in this field to elucidate the effects of different nutrients. Thus, the goal of our study was to investigate the effects of oral ingestion of different nutrient solutions on olfactory, cognitive, metabolic and psychophysical function. Twenty healthy men participated in our study employing a double-blind, cross-over, repeated measurement design. Participants were tested on four different study days. Each day participants received, in randomized order, one of three isocaloric (protein, carbohydrate or fat 600 kcal, 1,500 mL) solutions or a placebo. Olfactory and cognitive tests (monitoring only) were conducted three times, i.e., 60 min before the beginning of nutrient intake, following oral ingestion of the solution and 60, and 240 min after. Psychophysical and metabolic function tests (active grehlin, desacyl ghrelin, insulin, glucagon, glucose, triglyceride, urea) were performed 7 times on each examination day (observation period: -60 min, 0 = solution intake, +60, +120, +180, +240, and +300 min). Ratings of hunger and food craving significantly differed over the observation period with lowest ratings following application of the protein solution. Highest ratings of craving were found following placebo intake. We further observed a significant positive correlation of active grehlin with hunger and fat, protein and sweets craving for each nutrient solution. Active grehlin significantly correlated with carbohydrate craving for carbohydrate and fat solution and with vegetable craving for fat solution only. Hunger hormone levels, hunger and food craving ratings demonstrated that the hierarchical order that appears in satiating efficiencies of isovolumetric-isocaloric ingested macronutrients is protein > fat > carbohydrate. Our study reveals that the type of nutrient exerts a significant influence on metabolic parameters, hunger and food craving.

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.

The Effects of a Normal Rate versus a Slow Intervalled Rate of Oral Nutrient Intake and Intravenous Low Rate Macronutrient Application on Psychophysical Function - Two Pilot Studies.

Stomach distension and energy per time are factors influencing satiety. Moreover, different rates of nutrient intake induce different stomach distension. The goal of our studies was to elucidate the influence of different oral rates of nutrient intake (normal rate versus slow intervalled rate; study I) and intravenous low rate macronutrient application (protein, carbohydrate, fat) or placebo (study II) on psychophysical function. The pilot studies investigated the effects of 1) study I: a mixed nutrient solution (1/3 protein, 1/3 fat, 1/3 carbohydrates) 2) study II: intravenous macronutrient infusions (protein, carbohydrate, fat) or placebo on psychophysical function (mood, hunger, food craving, alertness, smell intensity ratings and hedonic ratings) in human subjects. In study I 10 male subjects (age range: 21-30 years) completed the study protocol participating in both test conditions and in study II 20 male subjects (age range: 19-41 years) completed the study protocol participating in all test conditions. Additionally, metabolic function was analyzed and cognitive and olfactory tests were conducted twice starting 100 min before the beginning of the intervention and 240 min after. Psychophysical (mood, hunger, fat-, protein-, carbohydrate-, sweets- and vegetable-craving), alertness and metabolic function tests were performed seven times on each examination day. Greater effects on hunger and food cravings were observed for normal rate of intake compared to slow intervalled rate of intake and intravenous low rate macronutrient application. Our findings potentially confirm that volume of the food ingested and a higher rate of energy per time contribute to satiety during normal rate of food intake, while slow intervalled rate of food intake and intravenous low rate macronutrient application showed no effects on satiation. Our results motivate the view that a certain amount of volume of the food ingested and a certain energy per time ratio are necessary to reduce hunger and food craving.

Heterozygous inactivating CaSR mutations causing neonatal hyperparathyroidism: function, inheritance and phenotype.

BACKGROUND: Homozygous inactivating mutations of the calcium-sensing receptor (CaSR) lead to neonatal severe hyperparathyroidism (NSHPT), whereas heterozygous inactivating mutations result in familial hypocalciuric hypercalcemia (FHH). It is unknown why in some cases heterozygous CaSR mutations cause neonatal hyperparathyroidism (NHPT) clinically similar to NSHPT but with only moderately elevated serum calcium. METHODS: A literature survey was conducted to identify patients with heterozygous CaSR mutations and NHPT. The common NHPT CaSR mutants R185Q and R227L were compared with 15 mutants causing only FHH in the heterozygous state. We studied in vitro calcium signaling including the functional consequences of co-expression of mutant and wild-type (wt) CaSR, patients' phenotype, age of disease manifestation and mode of inheritance. RESULTS: All inactivating CaSR mutants impaired calcium signaling of wt-CaSR regardless of the patients' clinical phenotype. The absolute intracellular calcium signaling response to physiologic extracellular calcium concentrations in vitro showed a high correlation with patients' serum calcium concentrations in vivo, which is similar in NHPT and FHH patients with the same genotype. Pedigrees of FHH families revealed that paternal inheritance per se does not necessarily lead to NHPT but may only cause FHH. CONCLUSIONS: There is a significant correlation between in vitro functional impairment of the CaSR at physiologic calcium concentrations and the severity of alterations in calcium homeostasis in patients. Whether a particular genotype leads to NHPT or FHH appears to depend on additional predisposing genetic or environmental factors. An individual therapeutic approach appears to be warranted for NHPT patients.

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.

Activating Calcium-Sensing Receptor Mutations: Prospects for Future Treatment with Calcilytics.

Activating mutations of the G protein-coupled receptor, calcium-sensing receptor (CaSR), cause autosomal dominant hypocalcemia and Bartter syndrome type 5. These mutations lower the set-point for extracellular calcium sensing, thereby causing decreased parathyroid hormone secretion and disturbed renal calcium handling with hypercalciuria. Available therapies increase serum calcium levels but raise the risk of complications in affected patients. Symptom relief and the prevention of adverse outcome is currently very difficult to achieve. Calcilytics act as CaSR antagonists that attenuate its activity, thereby correcting the molecular defect of activating CaSR proteins in vitro and elevating serum calcium in mice and humans in vivo, and have emerged as the most promising therapeutics for the treatment of these rare and difficult to treat diseases.

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.

Seasonal Variation in Blood Pressure in 162,135 Patients With Type 1 or Type 2 Diabetes Mellitus.

Seasonal variation in blood pressure (BP) has been observed in different populations. However, only few studies have focused on BP seasonality in diabetic patients. This study examined the seasonal patterns in BP in 62,589 patients with type 1 diabetes mellitus (T1DM) and in 99,546 patients with type 2 diabetes mellitus (T2DM) from the German/Austrian Diabetes Follow-up Registry. Adjusted mean BP values revealed seasonal cycles of 12 months, with higher BP in colder months. Using harmonic regression models, the estimated systolic BP difference throughout the year was 2.28/2.48 mm Hg in T1DM/T2DM (both P<.001). Interestingly, seasonal variation in diastolic BP was larger in T1DM than in T2DM (1.24/0.64 mm Hg, P<.001). A sex difference was observed in T1DM only, while age differences occurred in both types of diabetes. Correlations between BP and potentially related factors such as outdoor temperature indicated that reasons underlying BP seasonality are likely to be complex and vary by subgroup.

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.

Amino alcohol- (NPS-2143) and quinazolinone-derived calcilytics (ATF936 and AXT914) differentially mitigate excessive signalling of calcium-sensing receptor mutants causing Bartter syndrome Type 5 and autosomal dominant hypocalcemia.

INTRODUCTION: Activating calcium sensing receptor (CaSR) mutations cause autosomal dominant hypocalcemia (ADH) characterized by low serum calcium, inappropriately low PTH and relative hypercalciuria. Four activating CaSR mutations cause additional renal wasting of sodium, chloride and other salts, a condition called Bartter syndrome (BS) type 5. Until today there is no specific medical treatment for BS type 5 and ADH. We investigated the effects of different allosteric CaSR antagonists (calcilytics) on activating CaSR mutants. METHODS: All 4 known mutations causing BS type 5 and five ADH mutations were expressed in HEK 293T cells and receptor signalling was studied by measurement of intracellular free calcium in response to extracellular calcium ([Ca2+]o). To investigate the effect of calcilytics, cells were stimulated with 3 mM [Ca2+]o in the presence or absence of NPS-2143, ATF936 or AXT914. RESULTS: All BS type 5 and ADH mutants showed enhanced signalling activity to [Ca2+]o with left shifted dose response curves. In contrast to the amino alcohol NPS-2143, which was only partially effective, the quinazolinone calcilytics ATF936 and AXT914 significantly mitigated excessive cytosolic calcium signalling of all BS type 5 and ADH mutants studied. When these mutants were co-expressed with wild-type CaSR to approximate heterozygosity in patients, ATF936 and AXT914 were also effective on all mutants. CONCLUSION: The calcilytics ATF936 and AXT914 are capable of attenuating enhanced cytosolic calcium signalling activity of CaSR mutations causing BS type 5 and ADH. Quinazolinone calcilytics might therefore offer a novel treatment option for patients with activating CaSR mutations.

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.

A homozygous CaSR mutation causing a FHH phenotype completely masked by vitamin D deficiency presenting as rickets.

CONTEXT: Heterozygous inactivating calcium-sensing receptor (CaSR) mutations lead to familial hypocalciuric hypercalcemia (FHH), whereas homozygous mutations usually cause neonatal severe hyperparathyroidism. OBJECTIVE: The objective of the study was to investigate the pathophysiological mechanisms of a homozygous inactivating CaSR mutation identified in a 16-year-old female. DESIGN: Clinical, biochemical, and genetic analyses of the index patient and her family were performed. Functional capacity of CaSRQ459R and CaSR mutants causing FHH (Q27R, P39A, S417C) or neonatal severe hyperparathyroidism (W718X) was assessed. Activation of the cytosolic calcium pathway and inhibition of PTH-induced cAMP signaling were measured. RESULTS: A 16-year-old girl presented with adolescent rickets, vitamin D deficiency, and secondary hyperparathyroidism. Vitamin D treatment unmasked features resembling FHH, and genetic testing revealed a homozygous CaSRQ459R mutation. Two apparently healthy siblings were homozygous for CaSRQ459R and had asymptomatic hypercalcemia and hypocalciuria. The CaSRQ459R mutation leads to mild functional inactivation in vitro, which explains the FHH-like phenotype in homozygous family members and the grossly exaggerated PTH response to vitamin D deficiency in the index case. The patient's parents and two other siblings were heterozygous, had normal serum calcium and PTH, but had marked hypocalciuria, which appeared to be associated with impaired in vitro activation of the calcium signaling pathway by CaSRQ459R. The Q459R mutation responded well to calcimimetic treatment in vitro. CONCLUSION: CaSR mutations causing mild functional impairment can lead to FHH, even in homozygous patients. The skeletal deformities in the index case were mainly due to severe vitamin D deficiency, and the CaSR mutation did not appear to have played a major independent role in the skeletal phenotype.