Association of adrenal insufficiency with insulin-dependent diabetes mellitus in a patient with inactivating mutations in nicotinamide nucleotide transhydrogenase: a phenocopy of the animal model
Bibliographic record
Abstract
We read with great interest the paper of Roucher-Boulez et al. in the July issue of the Journal reporting extra-adrenal phenotypes (i.e. gonadal, cardiac and thyroidal disorders) in a cohort of 18 patients with adrenal insufficiency due to nicotinamide nucleotide transhydrogenase (NNT) mutations (1). Indeed, NNT loss of function, which hampers NADPH production in mitochondria, was initially reported in families with familial isolated glucocorticoid deficiency (2). Yet, Nnt expression is severely reduced in pancreas of C57BL/6J mice due to a naturally occurring loss-of-function Nnt mutation in this strain. Consequently, C57BL/6J mice have reduced insulin secretion because of increased oxidative stress in pancreatic beta-cells (3). Here, we report a patient with NNT mutations who developed diabetes mellitus, thus recapitulating the Nnt-deficient C57BL/6J mouse phenotype (3). A 12-month-old previously healthy boy was admitted with severe retro-pharyngeal cellulitis, causing airway obstruction, thrombosis of the left jugular vein, compression of the left carotid artery and associated infarction of the left parietal lobe. After treatment of the infection, anorexia and vomiting persisted, with a loss of 18% of body weight over a period of 6 weeks despite tube feeding. Serum sodium was low (126 mmol/L) and potassium was high (8.7 mmol/L). Serum cortisol was <22 nmol/L and ACTH (466 pmol/L) and renin (202 ng/L) were very high, confirming primary adrenal insufficiency. The patient responded rapidly to glucocorticoid and mineralocorticoid replacement. We previously reported the patient as broadening the phenotype of NNT mutants to combined glucocorticoid and mineralocorticoid deficiencies (4). At 9.5 years, the patient presented with a two-week history of polyuria, polydipsia and weight loss. A glucose level of 42 mmol/L confirmed diabetes mellitus. There was no acidosis. Anti-GAD antibodies were slightly positive at 3.6 (normal <1), but anti-IA2 antibodies were negative. The patient is now 12 years old and requires 1 unit/kg/day of insulin to maintain good metabolic control.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".