MAFA missense mutation causes familial insulinomatosis and diabetes mellitus.

The ß-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing MAFA variants have been previously described. We investigated a large pedigree with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, an adult-onset condition of recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumors of the pancreas. Using exome sequencing, we identified a missense MAFA mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes. This mutation was also found in a second unrelated family with the same clinical phenotype, while no germline or somatic MAFA mutations were identified in nine patients with sporadic insulinomatosis. In the two families, insulinomatosis presented more frequently in females (eight females/two males) and diabetes more often in males (12 males/four females). Four patients from the index family, including two homozygotes, had a history of congenital cataract and/or glaucoma. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in ß-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in ß-cell lines was enhanced compared with wild-type MAFA. In summary, the p.Ser64Phe missense MAFA mutation leads to familial insulinomatosis or diabetes by impacting MAFA protein stability and transactivation ability. The human phenotypes associated with the p.Ser64Phe MAFA missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet ß-cell activity.

Changes of Thyroid Hormones and Their Binding Proteins during Plasma Exchange for Polyneuropathy in a Patient with Substituted Hypothyroidism due to Hashimoto's Thyroiditis.

BACKGROUND: Pharmacodynamic studies and data concerning adaptation of thyroid substitution in patients with substituted hypothyroidism during plasma exchange (PE) is not available. CASE REPORT: We measured TSH, fT3 and fT4, total T4, thyroxin binding globulin (TBG), and albumin before and after 5 PE procedures in a 37-year-old women who underwent PE for a therapy-resistant polyneuropathy. Thyroxin was increased empirically by 8% resulting in a dose of 1.95 µg/kg per day. RESULTS: Despite larger reductions of total T4 and TBG over a series of 5 PEs (40-50% from baseline), only small reductions of 8% in fT3 and fT4 concentrations were documented with a concomittant increase in TSH level. Changes of fT4, fT3, and TSH remained within normal range. CONCLUSIONS: i) Despite a significant decrease in total thyroid hormone pool following PE, fT4, fT3, and TSH concentrations changed only slightly. ii) Based on this observation, a general increase in thyroid replacement therapy before PE cannot be recommended, but considered in case of a high normal TSH level.

The effect of exercise on intramyocellular acetylcarnitine (AcCtn) concentration in adult growth hormone deficiency (GHD).

To cover increasing energy demands during exercise, tricarboxylic cycle (TCA) flux in skeletal muscle is markedly increased, resulting in the increased formation of intramyocellular acetylcarnitine (AcCtn). We hypothesized that reduced substrate availability within the exercising muscle, reflected by a diminished increase of intramyocellular AcCtn concentration during exercise, might be an underlying mechanism for the impaired exercise performance observed in adult patients with growth hormone deficiency (GHD). We aimed at assessing the effect of 2 hours of moderately intense exercise on intramyocellular AcCtn concentrations, measured by proton magnetic resonance spectroscopy (1H-MRS), in seven adults with GHD compared to seven matched control subjects (CS). Compared to baseline levels AcCtn concentrations significantly increased after 2 hours of exercise, and significantly decreased over the following 24 hours (ANOVA p for effect of time = 0.0023 for all study participants; p = 0.067 for GHD only, p = 0.045 for CS only). AcCtn concentrations at baseline, as well as changes in AcCtn concentrations over time were similar between GHD patients and CS (ANOVA p for group effect = 0.45). There was no interaction between group and time (p = 0.53). Our study suggests that during moderately intense exercise the availability of energy substrate within the exercising muscle is not significantly different in GHD patients compared to CS.

Dehydroepiandrosterone sulfate in the assessment of the hypothalamic-pituitary-adrenal axis.

CONTEXT: The role of dehydroepiandrosterone-sulfate (DHEA-S) in assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with suspected insufficiency is uncertain. OBJECTIVE: The objective of the study was to prospectively evaluate the diagnostic value of DHEA-S on HPA function in consecutive patients with suspected HPA insufficiency with and without pituitary lesions at a tertiary referral center. DESIGN AND PATIENTS: In 70 consecutive patients, insulin tolerance test was accompanied by measurement of basal DHEA-S. Assessment of HPA axis was based on peak cortisol response in insulin tolerance test (normal > or = 550 nmol/liter). To account for the age and gender dependency of DHEA-S, a z-score was calculated using age- and gender-specific reference values of the assay. RESULTS: Individuals with HPA insufficiency had significantly lower z-scores than those with normal HPA function (-1.66 vs. -0.62, P < 0.0001). In individuals up to 30 yr of age, a z-score of -2.0 had 100% sensitivity and specificity regarding HPA function [area under receiver operating characteristics (ROC) curve 1.00], whereas z-scores proved less useful in older individuals. In individuals with pituitary macroadenoma, a z-score below -2.0 had 100% specificity to predict HPA insufficiency (area under ROC curve 0.82). In the absence of a pituitary adenoma, the diagnostic value of the z-score was reduced (area under ROC curve 0.71). CONCLUSIONS: Individuals with HPA insufficiency have lower z-scores for DHEA-S than those with normal HPA function. There is evidence that a z-score could be of diagnostic value in assessing HPA integrity, especially in younger patients and patients with pituitary macroadenoma, but further studies are needed to consolidate these findings.

Evaluation of the frequency of adrenal crises and preventive measures in patients with primary and secondary adrenal insufficiency in Switzerland.

AIMS OF THE STUDY: Adrenal insufficiency is a dangerous clinical condition, leading to significant morbidity or mortality in situations with inadequate glucocorticoid replacement treatment. We aimed to assess preventive measures in adrenal insufficiency and the incidence and risk factors of adrenal crisis, as well as to test the patients' knowledge about their disease. METHODS: All patients in May and June 2016 and December 2016 and January 2017 with primary (17.9%) or secondary (82.1%) adrenal insufficiency were prospectively included in this observational study. They completed questionnaires about their personal and medical background, including the occurrence of adrenal crises, and possession of an emergency card and medication. They were asked about self-perceived subjective knowledge of their disease and filled out two multiple-choice tests about the modalities of the glucocorticoid replacement therapy (test A) and dose adaptation in hypothetical clinical situations (test B) in order to objectively test their knowledge. RESULTS: A total of 56 datasets were available for descriptive and statistical analysis. Overall, 94.6% of the patients were equipped with an emergency card, 64.3% had their daily hydrocortisone with them and 57.1% carried spare hydrocortisone pills. Twelve patients had experienced at least one adrenal crisis. There were 4.4 adrenal crises per 100 disease-years. Precipitating causes for adrenal crises were mainly gastroenteritis, influenza and noncompliance. Globally, the patients' self-perceived, subjective knowledge level was good to very good. In the two objective knowledge tests, however, only 28.9% (test A) and 60.1% (test B) of the questions were answered correctly. Secondary adrenal insufficiency reduced the chance of being in the group with better knowledge in test A. CONCLUSIONS: The incidence of adrenal crisis in Switzerland is lower than described in recent European studies. Although nearly all of the patients carry their emergency cards with them, emergency treatment is available in only about half of the patients. There is a mismatch between subjective and objective knowledge of the disease and the education of patients with adrenal insufficiency needs to be improved.

Impaired repletion of intramyocellular lipids in patients with growth hormone deficiency after a bout of aerobic exercise.

BACKGROUND: Ectopic lipids such as intramyocellular lipids (IMCL) are depleted by exercise and repleted by diet, whereas intrahepatocellular lipids (IHCL) are increased immediately after exercise. So far, it is unclear how ectopic lipids behave 24 h after exercise and whether the lack of growth hormone (GH) significantly affects ectopic lipids 24 h after exercise. METHODS: Seven male patients with growth hormone deficiency (GHD) and seven sedentary male control subjects (CS) were included. VO2max was assessed by spiroergometry; visceral and subcutaneous fat by whole body MRI. 1H-MR-spectroscopy was performed in M. vastus intermedius and in the liver before and after 2 h of exercise at 50% VO2max and 24 h thereafter, while diet and physical activity were standardized. RESULTS: Sedentary male subjects (7 GHD, 7 CS) were recruited. Age, BMI, waist circumference, visceral and subcutaneous fat mass was not significantly different between GHD and CS. VO2max was significantly lower in GHD vs. CS. IMCL were diminished through aerobic exercise in both groups: (-11.5 ±â€¯21.9% in CS; -8.9% ±19.1% in GHD) and restored after 24 h in CS (-5.5 ±â€¯26.6% compared to baseline) but not in GHD (-17.9 ±â€¯15.3%). IHCL increased immediately after exercise and decreased to baseline within 24 h. CONCLUSION: These findings suggest that GHD may affect repletion of IMCL 24 h after aerobic exercise.

[Insulin therapy in type 2 diabetes: a review of "when" over "how" up to "why"]. / Insulintherapie bei Typ-2-Diabetes: ein Review vom «Wann¼ übers «Wie¼ bis zum «Warum¼

Type 2 Diabetes is characterized by its progressive character. An intensification of the therapy is necessary in most cases over the years and insulin is typically used as an add-on agent when oral antidiabetic regimes are judged to be no longer sufficient. However, insulin can also be used in the initial phase of the disease directly after diagnosis of diabetes. Intermittent worsening of glycemic control (e.g. due to infectious diseases or corticosteroids) may be additional indications for an insulin treatment at an earlier stage. Noticeably, insulin can often be stopped if the triggering event or treatment is reversible, thereby countering the widely spread fear of dependency on insulin. We recommend a rather cautious starting dose of insulin and individual adaptations thereafter. Well-informed patients can also perform such adaptations themselves.

Le caractère progressif du diabète de type 2 mène au long cours, dans de nombreux cas, à la nécessité d'introduire une insulinothérapie, lorsque le traitement uniquement par antidiabétiques oraux ne suffit plus. Néanmoins, l'insuline peut tout à fait être utile et indiquée plus tôt dans le cours de la maladie; par exemple, déjà dans la phase initiale après la pose du diagnostic, ou aussi, lors de courtes phases d'aggravation du contrôle glycémique, due à des facteurs déclenchants clairs (p. ex. infection, corticothérapie, etc.). Bien sûr, dans cette situation-là, l'insulinothérapie peut être arrêtée, dans la majorité des cas, après résolution de la décompensation glycémique. Il est important de rappeler que l'introduction d'une insulinothérapie doit être toujours prudente et nécessite une adaptation régulière du dosage, qui peut être faite aussi par le patient lui-même, après une instruction adéquate.

[A fever of finally known origin]. / FUO - alles in Butter?

We present the case of a 77 year old man with fever of unknown origin. Despite a thorough assessment in hospital the diagnosis could only be made after discharge when positive results for C. burnetii serology revealed acute Q-fever. However, retrospectively history and clinical findings matched well with acute Q-fever.

Noninvasive assessment of exercise-related intramyocellular acetylcarnitine in euglycemia and hyperglycemia in patients with type 1 diabetes using ¹H magnetic resonance spectroscopy: a randomized single-blind crossover study.

OBJECTIVE: Intramyocellular acetylcarnitine (IMAC) is involved in exercise-related fuel metabolism. It is not known whether levels of systemic glucose influence IMAC levels in type 1 diabetes. RESEARCH DESIGN AND METHODS: Seven male individuals with type 1 diabetes performed 120 min of aerobic exercise at 55-60% of Vo(2max) randomly on two occasions (glucose clamped to 5 or 11 mmol/l, identical insulinemia). Before and after exercise, IMAC was detected by ¹H magnetic resonance spectroscopy in musculus vastus intermedius. RESULTS: Postexercise levels of IMAC were significantly higher than pre-exercise values in euglycemia (4.30 ± 0.54 arbitrary units [a.u.], P < 0.001) and in hyperglycemia (2.44 ± 0.53 a.u., P = 0.01) and differed significantly according to glycemia (P < 0.01). The increase in exercise-related levels of IMAC was significantly higher in euglycemia (3.97 ± 0.45 a.u.) than in hyperglycemia (1.71 ± 0.50 a.u.; P < 0.01). CONCLUSIONS: The increase in IMAC associated with moderate aerobic exercise in individuals with type 1 diabetes was significantly higher in euglycemia than in hyperglycemia.

Exercise capacity in subjects with type 1 diabetes mellitus in eu- and hyperglycaemia.

BACKGROUND: Circumstantial evidence suggests that an increase in plasma glucose availability improves exercise capacity in subjects with type 1 diabetes mellitus. The aim of this study was to assess exercise capacity in eu- and hyperglycaemic conditions in subjects with type 1 diabetes. METHODS: Eight moderately exercise-trained male subjects with type 1 diabetes on continuous subcutaneous insulin infusion were studied. Using identical insulin infusion rates, the patients were randomly allocated to perform two stepwise ergometer tests in eu- and hyperglycaemic clamp conditions. The primary endpoint was the peak power output; the secondary endpoints comprised the rate of perceived exertion, lactate levels, heart rate, and respiratory exchange ratio. RESULTS: Eu- and hyperglycaemic clamp conditions were observed at a plasma glucose concentration of 5.3 +/- 0.6 mmol/L and 12.4 +/- 2.1 mmol/L, respectively (mean +/- SD), and remained stable throughout the physical exercise. Insulin levels were similar in both conditions. Hyperglycaemia did not result in a significant increase in the peak power output compared to euglycaemia (mean paired difference of 4.96 W, 95% CI - 11.3 to 21.2, p = 0.49). Hyperglycaemia did not have a significant impact on the secondary endpoints compared to euglycaemia. Sensitivity analyses confirmed these results. CONCLUSIONS: In subjects with type 1 diabetes, exercise capacity is not influenced by hyperglycaemia. Comparable levels of lactate and similar respiratory exchange ratio suggest that an increase in extracellular glucose availability did not translate into increased intracellular glucose oxidation.