Background Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease. ALS is determined by gene-environment interactions and improved understanding of these interactions may lead to effective personalised medicine. The role of physical exercise in the development of ALS is currently controversial. Methods First, we dissected the exercise-ALS relationship in a series of two-sample Mendelian randomisation (MR) experiments. Next we tested for enrichment of ALS genetic risk within exercise-associated transcriptome changes. Finally, we applied a validated physical activity questionnaire in a small cohort of genetically selected ALS patients. Findings We present MR evidence supporting a causal relationship between genetic liability to frequent and strenuous leisure-time exercise and ALS using a liberal instrument (multiplicative random effects IVW, p=0.01). Transcriptomic analysis revealed that genes with altered expression in response to acute exercise are enriched with known ALS risk genes (permutation test, p=0.013) including C9ORF72 , and with ALS-associated rare variants of uncertain significance. Questionnaire evidence revealed that age of onset is inversely proportional to historical physical activity for C9ORF72 -ALS (Cox proportional hazards model, Wald test p=0.007, likelihood ratio test p=0.01, concordance=74%) but not for non -C9ORF72 -ALS. Variability in average physical activity was lower in C9ORF72 -ALS compared to both non -C9ORF72 -ALS (F-test, p=0.002) and neurologically normal controls (F-test, p=0.049) which is consistent with a homogeneous effect of physical activity in all C9ORF72 -ALS patients. Interpretation Our MR approach suggests a positive causal relationship between ALS and physical exercise. Exercise is likely to cause motor neuron injury only in patients with a risk-genotype. Consistent with this we have shown that ALS risk genes are activated in response to exercise. In particular, we propose that G4C2-repeat expansion of C9ORF72 predisposes to exercise-induced ALS. Funding We acknowledge support from the Wellcome Trust (JCK, 216596/Z/19/Z), NIHR (PJS, NF-SI-0617-10077; IS-BRC-1215-20017) and NIH (MPS, CEGS 5P50HG00773504, 1P50HL083800, 1R01HL101388, 1R01-HL122939, S10OD025212, P30DK116074, and UM1HG009442).

Although hyperlipidemia is traditionally considered a risk factor for type 2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL cholesterol (LDL-C) increases T2D risk. We thus sought to more comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that levels of circulating LDL-C were negatively associated with T2D prevalence (odds ratio 0.41 [95% CI 0.39, 0.43] per mmol/L unit of LDL-C), despite positive associations of circulating LDL-C with HbA 1c and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower circulating LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank (n 5 431,167) and the Global Lipids Genetics Consortium (n 5 188,577), and data on T2D from the Diabetes Genetics Replication and Meta-Analysis consortium (n 5 898,130). We identified 31 loci associated with lower circulating LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this dual phenotype, and nine have previously been implicated in nonalcoholic fatty liver disease. These findings extend our current understanding of the higher T2D risk among individuals with low circulating LDL-C and of the underlying mechanisms, including those responsible for the diabetogenic effect of LDL-C-lowering medications.

OBJECTIVE To determine the benefit of starting continuous glucose monitoring (CGM) in adult-onset type 1 diabetes (T1D) and type 2 diabetes (T2D) with regard to longer-term glucose control and serious clinical events. RESEARCH DESIGN AND METHODS A retrospective observational cohort study within the Veterans Affairs Health Care System was used to compare glucose control and hypoglycemia- or hyperglycemia-related admission to an emergency room or hospital and all-cause hospitalization between propensity score overlap weighted initiators of CGM and nonusers over 12 months. RESULTS CGM users receiving insulin (n = 5,015 with T1D and n = 15,706 with T2D) and similar numbers of nonusers were identified from 1 January 2015 to 31 December 2020. Declines in HbA1c were significantly greater in CGM users with T1D (−0.26%; 95% CI −0.33, −0.19%) and T2D (−0.35%; 95% CI −0.40, −0.31%) than in nonusers at 12 months. Percentages of patients achieving HbA1c <8 and <9% after 12 months were greater in CGM users. In T1D, CGM initiation was associated with significantly reduced risk of hypoglycemia (hazard ratio [HR] 0.69; 95% CI 0.48, 0.98) and all-cause hospitalization (HR 0.75; 95% CI 0.63, 0.90). In patients with T2D, there was a reduction in risk of hyperglycemia in CGM users (HR 0.87; 95% CI 0.77, 0.99) and all-cause hospitalization (HR 0.89; 95% CI 0.83, 0.97). Several subgroups (based on baseline age, HbA1c, hypoglycemic risk, or follow-up CGM use) had even greater responses. CONCLUSIONS In a large national cohort, initiation of CGM was associated with sustained improvement in HbA1c in patients with later-onset T1D and patients with T2D using insulin. This was accompanied by a clear pattern of reduced risk of admission to an emergency room or hospital for hypoglycemia or hyperglycemia and of all-cause hospitalization.

BackgroundAmyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease. ALS is determined by gene-environment interactions and improved understanding of these interactions may lead to effective personalised medicine. The role of physical exercise in the development of ALS is currently controversial.MethodsWe dissected the exercise-ALS relationship in a series of two-sample Mendelian randomisation (MR) experiments. We then we tested for enrichment of ALS genetic risk within exercise-associated transcriptome changes. Finally, we applied a validated physical activity (PA) questionnaire in a small cohort of genetically selected ALS patients.FindingsWe present MR evidence supporting a causal relationship between genetic liability to strenuous leisure-time exercise and ALS (multiplicative random effects IVW, p=0.01). Transcriptomic analysis revealed that genes with altered expression in response to acute exercise are enriched with known ALS risk genes (permutation test, p=0.013) including C9ORF72, and with ALS-associated rare variants of uncertain significance. Questionnaire evidence revealed that age of onset is inversely proportional to historical PA for C9ORF72-ALS (linear regression, t=-2.28, p=0.036) but not for non-C9ORF72-ALS. Moreover, compared to non-C9ORF72-ALS patients and neurologically normal controls, C9ORF72-ALS cases reported the highest minimum average PA (20.9kJ/kg/day) consistent with an exercise threshold for penetrance.InterpretationOur MR approach suggests a positive causal relationship between ALS and physical exercise. Exercise is likely to cause motor neuron injury only in patients with a risk-genotype. Consistent with this we have shown that ALS risk genes are activated in response to exercise. In particular, we propose that G4C2-repeat expansion of C9ORF72 predisposes to exercise-induced ALS.FundingWe acknowledge support from the Wellcome Trust (JCK, 216596/Z/19/Z), NIHR (PJS, NF-SI-0617-10077; IS-BRC-1215-20017) and NIH (MPS, CEGS 5P50HG00773504, 1P50HL083800, 1R01HL101388, 1R01-HL122939, S10OD025212, and P30DK116074, UM1HG009442).RESEARCH IN CONTEXTEvidence before this studyThe role of physical activity (PA) as a risk factor for ALS was evaluated in a systematic review of 26 studies performed by Lacorte et al. in 2016. The authors concluded that there was insufficient evidence to draw a firm conclusion. The authors highlighted limitations of previous studies relating to heterogeneous classification of PA and ALS. They noted that none of the published literature achieved the highest quality rating in the Newcastle Ottawa Scale, which they attribute to methodological challenges posed by the rarity and severity of the disease. Failure to address genetic subtypes of ALS was proposed as a shortcoming in the studies surveyed. To identify more recent publications, we conducted a literature search using the PubMed database for articles published between 01/01/2015 - 11/11/2020. The search terms used were (“Amyotrophic lateral sclerosis”[Title/Abstract] OR “motor neuron disease”[Title/Abstract] OR MND[Title/Abstract] OR ALS[Title/Abstract]) AND (PA[Title/Abstract] OR exercise[Title/Abstract] OR “physical activity”[Title/Abstract] OR sport[Title/Abstract]). This search strategy yielded 182 results and we filtered for original, observational, human-subject studies but we excluded case series with <10 participants and case reports. This process identified 12 further relevant publications which report opposite conclusions without significantly addressing the methodological issues highlighted above. A single recent study used linkage disequilibrium score regression and mendelian randomisation to test for a causal relationship between ALS and a number of UK biobank questionnaire items including participation in light DIY, walking for pleasure and moderate activity duration, but this study did not address the relationship between ALS and strenuous, frequent physical exercise.Added value of this studyIn the present study, we have exploited the methodological advantages of mendelian randomisation (MR) to counter bias, together with a tailored approach to PA exposure aimed at isolating strenuous, frequent physical exercise. We achieved this by selecting and combining UK biobank questionnaire items. In contrast to previous studies, we have addressed the gene-environment interaction by measuring the effect of exercise on expression of ALS risk genes. Furthermore, we have considered in detail the relationship between PA and the most frequent genetic risk factor for ALS: hexanucleotide (G4C2) repeat expansion of C9ORF72. Our data suggests that genetic liability to leisure time physical activity is a risk factor for ALS and C9ORF72-ALS in particular. In addition, we offer evidence that a number of known ALS-associated genetic variants are functionally linked to the physiological response to exercise.Implications of all the available evidenceOur results indicate that participation in leisure time physical activity is a risk factor for ALS particularly in the context of certain risk genotypes. This could explain some of the controversy in previous studies which have largely neglected genetic heterogeneity within ALS patients. Our results form a platform for future research to explore the interaction between specific genotypes and exercise-induced ALS in a prospective manner with larger numbers, and in selected pedigrees. Ultimately this could lead to the design of personalised medicine including lifestyle advice regarding physical activity, to patients with ALS and their family members.

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