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Glucose metabolism and pancreatic defects in spinal muscular atrophy
Author(s) -
Bowerman Melissa,
Swoboda Kathryn J.,
Michalski JohnPaul,
Wang GenSheng,
Reeks Courtney,
Beauvais Ariane,
Murphy Kelley,
Woulfe John,
Screaton Robert A.,
Scott Fraser W.,
Kothary Rashmi
Publication year - 2012
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.23582
Subject(s) - sma* , spinal muscular atrophy , smn1 , endocrinology , medicine , hyperglucagonemia , carbohydrate metabolism , insulin , motor neuron , biology , glucagon , disease , mathematics , combinatorics
Abstract Objective: Spinal muscular atrophy (SMA) is the number 1 genetic killer of young children. It is caused by mutation or deletion of the survival motor neuron 1 ( SMN1 ) gene. Although SMA is primarily a motor neuron disease, metabolism abnormalities such as metabolic acidosis, abnormal fatty acid metabolism, hyperlipidemia, and hyperglycemia have been reported in SMA patients. We thus initiated an in‐depth analysis of glucose metabolism in SMA. Methods: Glucose metabolism and pancreas development were investigated in the Smn 2B /− intermediate SMA mouse model and type I SMA patients. Results: Here, we demonstrate in an SMA mouse model a dramatic cell fate imbalance within pancreatic islets, with a predominance of glucagon‐producing α cells at the expense of insulin‐producing β cells. These SMA mice display fasting hyperglycemia, hyperglucagonemia, and glucose resistance. We demonstrate similar abnormalities in pancreatic islets from deceased children with the severe infantile form of SMA in association with supportive evidence of glucose intolerance in at least a subset of such children. Interpretation: Our results indicate that defects in glucose metabolism may play an important contributory role in SMA pathogenesis. ANN NEUROL 2012;72:256–268.