Summary In this study, we herein describe a 47-year-old Japanese woman who manifested inheritable non-alcoholic steatohepatitis (NASH) and severe dyslipidemia. Interestingly, her NASH progression was ameliorated by treatment with a sodium–glucose co-transporter 2 (SGLT2) inhibitor. This inheritability prompted us to comprehensively decode her genomic information using whole-exome sequencing. We found the well-established I148M mutation in PNPLA3 as well as mutations in LGALS3 and PEMT for her NASH. Mutations in GCKR may contribute to both NASH and dyslipidemia. We further mined gene mutations potentially responsible for her manifestations that led to the identification of a novel M188fs mutation in MUL1 that may be causally associated with her mitochondrial dysfunction. Our case may provide some clues to better understand this spectrum of disease as well as the rationale for selecting medications. Learning points While the PNPLA3 I148M mutation is well-established, accumulation of other mutations may accelerate susceptibility to non-alcoholic steatohepatitis (NASH). NASH and dyslipidemia may be intertwined biochemically and genetically through several key genes. SGLT2 inhibitors emerge as promising treatment for NASH albeit with interindividual variation in efficacy. Genetic background may explain the mechanisms behind the variation. A novel dysfunctional mutation in MUL1 may lead to metabolic inflexibilities through impaired mitochondrial dynamics and function.
Summary A paired homeodomain transcription factor, PAX6 (paired-box 6), is essential for the development and differentiation of pancreatic endocrine cells as well as ocular cells. Despite the impairment of insulin secretion observed in PAX6-deficient mice, evidence implicating causal association between PAX6 gene mutations and monogenic forms of human diabetes is limited. We herein describe a 33-year-old Japanese woman with congenital aniridia who was referred to our hospital because of her uncontrolled diabetes with elevated hemoglobin A1c (13.1%) and blood glucose (32.5 mmol/L) levels. Our biochemical analysis revealed that her insulin secretory capacity was modestly impaired as represented by decreased 24-h urinary C-peptide levels (38.0 μg/day), primarily explaining her diabetes. Intriguingly, there was a trend toward a reduction in her serum glucagon levels as well. Based on the well-recognized association of PAX6 gene mutations with congenital aniridia, we screened the whole PAX6 coding sequence, leading to an identification of a heterozygous Gln135* mutation. We tested our idea that this mutation may at least in part explain the impaired insulin secretion observed in this patient. In cultured pancreatic β-cells, exogenous expression of the PAX6 Gln135* mutant produced a truncated protein that lacked the transcriptional activity to induce insulin gene expression. Our observation together with preceding reports support the recent attempt to include PAX6 in the growing list of genes causally responsible for monogenic diabetes. In addition, since most cases of congenital aniridia carry PAX6 mutations, we may need to pay more attention to blood glucose levels in these patients. Learning points PAX6 Gln135* mutation may be causally associated not only with congenital aniridia but also with diabetes. Blood glucose levels may deserve more attention in cases of congenital aniridia with PAX6 mutations. Our case supports the recent attempt to include PAX6 in the list of MODY genes, and Gln135* may be pathogenic.
We aimed to investigate the status of falls and to identify important risk factors for falls in persons with type 2 diabetes (T2D) including the non-elderly. Participants were 316 persons with T2D. They were assessed for medical history, laboratory data and physical capabilities during the hospitalization and given a questionnaire on falls one year after discharge. Two different statistical models, logistic regression and random forest classifier were used to investigate important predictors of falls. The response rate to the survey was 72%; of the 226 respondents, there were 129 males and 97 females (median age 62 years). The fall rate during the first year after discharge was 19%. Logistic regression revealed that knee extension strength (β= -0.698, P = 0.002), fasting C-peptide (F-CPR) level (β= 0.492, P = 0.009) and dorsiflexion strength (β= -0.432, P = 0.047) were independent predictors of falls. The random forest classifier placed knee extension strength, grip strength (0.234), F-CPR level and dorsiflexion strength in the top 4 important variables for falls. Lower extremity muscle weakness as well as elevated F-CPR levels and reduced grip strength was shown to be important risk factors for falls in T2D.
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