bims-glecem 2023-11-05 papers

Issue of 2023‒11‒05
four papers selected by
Dipsikha Biswas, Københavns Universitet

Sci Transl Med. 2023 Nov;15(720): eabn4214

The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI.

Glycogen storage disease XI, also known as Fanconi-Bickel syndrome (FBS), is a rare autosomal recessive disorder caused by mutations in the SLC2A2 gene that encodes the glucose-facilitated transporter type 2 (GLUT2). Patients develop a life-threatening renal proximal tubule dysfunction for which no treatment is available apart from electrolyte replacement. To investigate the renal pathogenesis of FBS, SLC2A2 expression was ablated in mouse kidney and HK-2 proximal tubule cells. GLUT2Pax8Cre+ mice developed time-dependent glycogen accumulation in proximal tubule cells and recapitulated the renal Fanconi phenotype seen in patients. In vitro suppression of GLUT2 impaired lysosomal autophagy as shown by transcriptomic and biochemical analysis. However, this effect was reversed by exposure to a low glucose concentration, suggesting that GLUT2 facilitates the homeostasis of key cellular pathways in proximal tubule cells by preventing glucose toxicity. To investigate whether targeting proximal tubule glucose influx can limit glycogen accumulation and correct symptoms in vivo, we treated mice with the selective SGLT2 inhibitor dapagliflozin. Dapagliflozin reduced glycogen accumulation and improved metabolic acidosis and phosphaturia in the animals by normalizing the expression of Napi2a and NHE3 transporters. In addition, in a patient with FBS, dapagliflozin was safe, improved serum potassium and phosphate concentrations, and reduced glycogen content in urinary shed cells. Overall, this study provides proof of concept for dapagliflozin as a potentially suitable therapy for FBS.

DOI: https://doi.org/10.1126/scitranslmed.abn4214

Mol Genet Metab. 2023 Oct 26. pii: S1096-7192(23)00345-1. [Epub ahead of print] 107715

Variant Classification for Pompe disease; ACMG/AMP specifications from the ClinGen Lysosomal Diseases Variant Curation Expert Panel.

Accurate determination of the clinical significance of genetic variants is critical to the integration of genomics in medicine. To facilitate this process, the NIH-funded Clinical Genome Resource (ClinGen) has assembled Variant Curation Expert Panels (VCEPs), groups of experts and biocurators which provide gene- and disease- specifications to the American College of Medical Genetics & Genomics and Association for Molecular Pathology's (ACMG/AMP) variation classification guidelines. With the goal of classifying the clinical significance of GAA variants in Pompe disease (Glycogen storage disease, type II), the ClinGen Lysosomal Diseases (LD) VCEP has specified the ACMG/AMP criteria for GAA. Variant classification can play an important role in confirming the diagnosis of Pompe disease as well as in the identification of carriers. Furthermore, since the inclusion of Pompe disease on the Recommended Uniform Screening Panel (RUSP) for newborns in the USA in 2015, the addition of molecular genetic testing has become an important component in the interpretation of newborn screening results, particularly for asymptomatic individuals. To date, the LD VCEP has submitted classifications and supporting data on 243 GAA variants to public databases, specifically ClinVar and the ClinGen Evidence Repository. Here, we describe the ACMG/AMP criteria specification process for GAA, an update of the GAA-specific variant classification guidelines, and comparison of the ClinGen LD VCEP's GAA variant classifications with variant classifications submitted to ClinVar. The LD VCEP has added to the publicly available knowledge on the pathogenicity of variants in GAA by increasing the number of expert-curated GAA variants present in ClinVar, and aids in resolving conflicting classifications and variants of uncertain clinical significance.

Keywords: ClinGen variant curation expert panel; ClinVar; GAA; Glycogen storage disease type II; Pompe disease; Variant classification

DOI: https://doi.org/10.1016/j.ymgme.2023.107715

Int J Sport Nutr Exerc Metab. 2023 Oct 11. 1-6

The Effect of Exercise Intensity on Carbohydrate Sparing Postexercise: Implications for Postexercise Hypoglycemia.

Raymond J Davey, Mohamad H Jaafar, Luis D Ferreira, Paul A Fournier.

The purpose of this study was to determine the effect of exercise intensity on the proportion and rate of carbohydrate oxidation and glucoregulatory hormone responses during recovery from exercise. Six physically active participants completed 1 hr of low-intensity (LI; 50% lactate threshold) or moderate-intensity (MI; 100% lactate threshold) exercise on separate days following a randomized counterbalanced design. During exercise and for 6 hr of recovery, samples of expired air were collected to determine oxygen consumption, respiratory exchange ratio, energy expenditure, and substrate oxidation rates. Blood samples were also collected to measure glucoregulatory hormones (catecholamines, GH) and metabolites (glucose, free fatty acids, lactate, pH, and bicarbonate). During exercise, respiratory exchange ratio, energy expenditure, and the proportion and rate of carbohydrate (CHO) oxidation were higher during MI compared with LI. However, during recovery from MI, respiratory exchange ratio and the proportion and rate of CHO oxidation were lower than preexercise levels and corresponding LI. During exercise and early recovery, catecholamines and growth hormone were higher in MI than LI, and there was a trend for higher levels of free fatty acids in the early recovery from MI compared with LI. In summary, CHO oxidation during exercise increases with exercise intensity but there is a preference for CHO sparing (and fat oxidation) during recovery from MI exercise compared with LI exercise. This exercise intensity-dependent shift in substrate oxidation during recovery is explained, in part, by the pattern of change of key glucoregulatory hormones including catecholamines and growth hormone and plasma fatty acid concentrations.

Keywords: exercise intensity; recovery; substrate oxidation

DOI: https://doi.org/10.1123/ijsnem.2023-0136

J Sports Med Phys Fitness. 2023 Oct 30.

Effects of exhaustive whole-body exercise and caffeine ingestion on muscle contractile properties in healthy men.

Julio C Schamne, Alisson H Marinho, Gislaine Cristina-Souza, Pâmela S Santos, Ana C Santos-Mariano, André Rodacki, Daniel B Coelho, Fernando R DE-Oliveira, Romulo Bertuzzi, Adriano E Lima-Silva.

BACKGROUND: The influence of exhaustive whole-body exercise and caffeine ingestion on electromechanical delay (EMD) has been underexplored. This study investigated the effect of exhaustive cycling exercise on EMD and other parameters of muscle contractile properties and the potential ability of caffeine to attenuate the exercise-induced impairments in EMD and muscle contractile properties.METHODS: Ten healthy men cycled until exhaustion (88±2% of V̇O<inf>2max</inf>) on two separate days after ingesting caffeine (5 mg.kg-1 of body mass) or cellulose (placebo). Parameters of muscle contractile properties of the quadriceps muscles were assessed via volitional and electrically evoked isometric contractions, performed before and 50 minutes after ingestion of the capsules, and after exercise. Muscle recruitment during volitional contractions was determined via surface electromyography.
RESULTS: Exhaustive cycling exercise did not affect volitional and relaxation EMD (P>0.05) but increased evoked EMD. In addition, the exhaustive cycling exercise also increased muscle recruitment at the beginning of volitional isometric muscle contraction (P<0.05). The peak twitch force, maximal rate of twitch force development, and twitch contraction time were all compromised after exhaustive cycling exercise (P<0.05). Acute caffeine ingestion had no effect on muscle contractile properties (P>0.05), except that caffeine increased twitch contraction time at postexercise (P<0.05).
CONCLUSIONS: Exercise-induced decline in peripheral components of the EMD might be compensated by an increase in the muscle recruitment. In addition, acute caffeine ingestion had minimal influence on exercise-induced changes in muscle contractile proprieties.

DOI: https://doi.org/10.23736/S0022-4707.23.15292-3