Aims: Ataxia telangiectasia (A-T) is a rare genetic condition associated with diabetes. OGTT data show that nondiabetic adults with A-T are insulin resistant. ATM-ko mice are glucose intolerant, insulin resistant with abnormal fat distribution, which improve with TZD treatment. The RAMP study assessed the effects of pioglitazone in A-T.

Methods: This open label, non-randomised, crossover study compared 8 nondiabetic people with A-T and 15 healthy controls. Dual tracer mixed meal tests, indirect calorimetry, and adipocyte function were used to assess response to treatment.

Results: Groups were matched for age, BMI and HbA1c. Pioglitazone reduced fasting (61 [IQR 26 - 135] to 28.0 [IQR 20.9 - 110.1] pmol/l, p=0.008) and meal (393 [IQR 275 - 2103] to 252 [IQR 195 - 823], p=0.02) insulin in the A-T group, with unchanged fasting but reduced mean glucose (6.3 [IQR 6.1 - 6.7] to 5.9 [IQR 5.7 - 6.2] mmol/l, p=0.02). Pioglitazone did not affect glucose or insulin in controls. Pioglitazone improved insulin sensitivity in the A-T group, with reduced HOMA-IR (2.19 [IQR 0.96 - 4.14] to 0.97 [IQR 0.76 - 3.54], p=0.023) and increased Matsuda index (2.7 [IQR 1.2 - 5.9] to 5.3 [IQR 1.6 - 7.1], p=0.008). Pioglitazone increased adiponectin in both groups (A-T: 2528 [IQR 2008 - 4887] to 12461 [IQR 4451 - 15843] ng/ml, p=0.008; control 6262 [IQR 4051 - 89940] to 15123 [IQR 9594 - 19384] ng/ml, p=0.001). NEFAs were reduced in A-T (0.25 [IQR 0.22 - 0.28] to 0.18 [IQR 0.14 - 0.20] mmol/l, p=0.016). Pioglitazone increased the fasting respiratory quotient (RQ) in A-T (0.9 [IQR 0.8 - 1.0] to 1.1 [IQR 1.0 - 1.2], p=0.04). A mixed effects model of insulin sensitivity identified a significant gene * drug interaction (p=0.001) between A-T and pioglitazone.

Conclusion: Pioglitazone treatment improved insulin sensitivity and adipocyte function in A-T. Pioglitazone reduced NEFAs and increased RQ, indicating a reduction in fatty acid oxidation. These data suggest that pioglitazone may be an appropriate first line treatment for diabetes in A-T.

Disclosure

L.J. McCreight: None. A. Mari: Consultant; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim International GmbH. E. Pearson: None.

Funding

UK Wellcome Trust (to E.P.)

© 2019 by the American Diabetes Association.
2019
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