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.
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