SignificanceWe report a disease-causing mutation in the β-cell–enriched MAFA transcription factor. Strikingly, the missense p.Ser64Phe MAFA mutation was associated with either of two distinct phenotypes, multiple insulin-producing neuroendocrine tumors of the pancreas—a condition known as insulinomatosis—or diabetes mellitus, recapitulating the physiological properties of MAFA both as an oncogene and as a key islet β-cell transcription factor. The implication of MAFA in these human phenotypes will provide insights into how this transcription factor regulates human β-cell activity as well as into the mechanisms of Maf-induced tumorigenesis.

Aims/hypothesis We assessed systemic and local muscle fuel metabolism during aerobic exercise in patients with type 1 diabetes at euglycaemia and hyperglycaemia with identical insulin levels. Methods This was a single-blinded randomised crossover study at a university diabetes unit in Switzerland. We studied seven physically active men with type 1 diabetes (mean±SEM age 33.5±2.4 years, diabetes duration 20.1±3.6 years, HbA 1c 6.7±0.2% and peak oxygen uptake [V :O 2peak ] 50.3±4.5 ml min). Men were studied twice while cycling for 120 min at 55 to 60% of V : O 2peak , with a blood glucose level randomly set either at 5 or 11 mmol/l and identical insulinaemia. The participants were blinded to the glycaemic level; allocation concealment was by opaque, sealed envelopes. Magnetic resonance spectroscopy was used to quantify intramyocellular glycogen and lipids before and after exercise. Indirect calorimetry and measurement of stable isotopes and counter-regulatory hormones complemented the assessment of local and systemic fuel metabolism. Results The contribution of lipid oxidation to overall energy metabolism was higher in euglycaemia than in hyperglycaemia (49.4±4.8 vs 30.6±4.2%; p<0.05). Carbohydrate oxidation accounted for 48.2±4.7 and 66.6±4.2% of total energy expenditure in euglycaemia and hyperglycaemia, respectively (p<0.05). The level of intramyocellular glycogen before exercise was higher in hyperglycaemia than in euglycaemia (3.4±0.3 vs 2.7±0.2 arbitrary units [AU]; p<0.05). Absolute glycogen consumption tended to be higher in hyperglycaemia than in euglycaemia (1.3±0.3 vs 0.9±0.1 AU). Cortisol and growth hormone increased more strongly in euglycaemia than in hyperglycaemia (levels at the end of exercise 634±52 vs 501±32 nmol/l and 15.5±4.5 vs 7.4±2.0 ng/ml, respectively; p<0.05). Conclusions/interpretation Substrate oxidation in type 1 diabetic patients performing aerobic exercise in euglycaemia is similar to that in healthy individuals revealing a shift towards lipid oxidation during exercise. In hyperglycaemia fuel metabolism in these patients is dominated by carbohydrate oxidation. Intramyocellular glycogen was not spared in hyperglycaemia.

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.

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.

OBJECTIVEIntramyocellular 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 METHODSSeven male individuals with type 1 diabetes performed 120 min of aerobic exercise at 55–60% of Vo2max 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.RESULTSPostexercise 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).CONCLUSIONSThe increase in IMAC associated with moderate aerobic exercise in individuals with type 1 diabetes was significantly higher in euglycemia than in hyperglycemia.

In patients with Type 1 diabetes, GH concentrations during moderate aerobic exercise during stable hyperglycaemic conditions are significantly lower compared with euglycaemia. These findings are compatible with preserved glucose-mediated GH regulation during exercise in individuals with well-controlled Type 1 diabetes.

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.

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.