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.
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.
Authors: Amy M Avila; Barrington G Burnett; Addis A Taye; Francesca Gabanella; Melanie A Knight; Parvana Hartenstein; Ziga Cizman; Nicholas A Di Prospero; Livio Pellizzoni; Kenneth H Fischbeck; Charlotte J Sumner Journal: J Clin Invest Date: 2007-02-22 Impact factor: 14.808
Authors: Zhuo Liu; Wook Kim; Zhike Chen; Yu-Kyong Shin; Olga D Carlson; Jennifer L Fiori; Li Xin; Joshua K Napora; Ryan Short; Juliana O Odetunde; Qizong Lao; Josephine M Egan Journal: PLoS One Date: 2011-01-25 Impact factor: 3.240
Authors: Marie-Therese Khairallah; Jacob Astroski; Sarah K Custer; Elliot J Androphy; Craig L Franklin; Christian L Lorson Journal: Hum Mol Genet Date: 2017-03-01 Impact factor: 6.150
Authors: Ravindra N Singh; Matthew D Howell; Eric W Ottesen; Natalia N Singh Journal: Biochim Biophys Acta Gene Regul Mech Date: 2017-01-15 Impact factor: 4.490
Authors: Suzan M Hammond; Gareth Hazell; Fazel Shabanpoor; Amer F Saleh; Melissa Bowerman; James N Sleigh; Katharina E Meijboom; Haiyan Zhou; Francesco Muntoni; Kevin Talbot; Michael J Gait; Matthew J A Wood Journal: Proc Natl Acad Sci U S A Date: 2016-09-12 Impact factor: 11.205