bims-glecem 2023-02-12 papers

Issue of 2023–02–12
four papers selected by
Dipsikha Biswas, Københavns Universitet

Int J Mol Sci. 2023 Jan 29. pii: 2574. [Epub ahead of print]24(3):

Active Glycogen Synthase in the Liver Prevents High-Fat Diet-Induced Glucose Intolerance, Decreases Food Intake, and Lowers Body Weight.

Iliana López-Soldado, Joan J Guinovart, Jordi Duran.

Many lines of evidence demonstrate a correlation between liver glycogen content and food intake. We previously demonstrated that mice overexpressing protein targeting to glycogen (PTG) specifically in the liver-which have increased glycogen content in this organ-are protected from high-fat diet (HFD)-induced obesity by reduced food intake. However, the use of PTG to increase liver glycogen implies certain limitations. PTG stimulates glycogen synthesis but also inhibits the enzyme responsible for glycogen degradation. Furthermore, as PTG is a regulatory subunit of protein phosphatase 1 (PP1), which regulates many cellular functions, its overexpression could have side effects beyond the regulation of glycogen metabolism. Therefore, it is necessary to determine whether the direct activation of glycogen synthesis, without affecting its degradation or other cellular functions, has the same effects. To this end, we generated mice overexpressing a non-inactivatable form of glycogen synthase (GS) specifically in the liver (9A-MGSAlb mice). Control and 9a-MGSAlb mice were fed a standard diet (SD) or HFD for 16 weeks. Glucose tolerance and feeding behavior were analyzed. 9A-MGSAlb mice showed an increase in hepatic glycogen in fed and fasting conditions. When fed an HFD, these animals preserved their hepatic energy state, had a reduced food intake, and presented a lower body weight and fat mass than control animals, without changes in energy expenditure. Furthermore, 9A-MGSAlb animals showed improved glucose tolerance when fed an SD or HFD. Moreover, liver triacylglycerol levels that were increased after HFD feeding were lower in these mice. These results confirm that increased liver glycogen stores contribute to decreased appetite and improve glucose tolerance in mice fed an HFD. On the basis of our findings, strategies to preserve hepatic glycogen stores emerge as potential treatments for obesity and hyperglycemia.

Keywords: ATP; food intake; glucose; glycogen; glycogen synthase; high-fat diet; liver

DOI: https://doi.org/10.3390/ijms24032574

Obesity (Silver Spring). 2023 Feb 09.

A prolonged fast improves overnight substrate oxidation without modulating hepatic glycogen in adults with and without nonalcoholic fatty liver: A randomized crossover trial.

Kay H M Roumans, Anna Veelen, Charlotte Andriessen, Julian Mevenkamp, Esther Kornips, Pandichelvam Veeraiah, Bas Havekes, Harry P F Peters, Lucas Lindeboom, Patrick Schrauwen, Vera B Schrauwen-Hinderling.

OBJECTIVE: Increasing overnight fasting time seems a promising strategy to improve metabolic health in individuals with nonalcoholic fatty liver (NAFL). Mechanisms underlying the beneficial effects of fasting may be related to larger fluctuations in hepatic glycogen and higher fat oxidation. This study investigated whether prolonging an overnight fast depletes hepatic glycogen stores and improves substrate metabolism in individuals with NAFL and healthy lean individuals.
METHODS: Eleven individuals with NAFL and ten control individuals participated in this randomized crossover trial. After a 9.5-hour or 16-hour fast, hepatic glycogen was measured by using carbon-13 magnetic resonance spectroscopy, and a meal test was performed. Nocturnal substrate oxidation was measured with indirect calorimetry.
RESULTS: Extending fasting time led to lower nocturnal carbohydrate oxidation and higher fat oxidation in both groups (intervention × time, p < 0.005 for carbohydrate and fat oxidation). In both arms, the respiratory exchange ratio measured during the night remained higher in the group with NAFL compared with the control group (population p < 0.001). No changes were observed in hepatic glycogen depletion with a prolonged overnight fast in the group with NAFL or the control group.
CONCLUSIONS: These results suggest that acutely prolonging the overnight fast can improve overnight substrate oxidation and that these alterations are not mediated by changes in hepatic glycogen depletion.

DOI: https://doi.org/10.1002/oby.23676

Front Endocrinol (Lausanne). 2023 ;14 1116864

Continuous glucose monitoring for children with hypoglycaemia: Evidence in 2023.

Chris Worth, Lucy Hoskyns, Maria Salomon-Estebanez, Paul W Nutter, Simon Harper, Terry G J Derks, Kathy Beardsall, Indraneel Banerjee.

In 2023, childhood hypoglycaemia remains a major public health problem and significant risk factor for consequent adverse neurodevelopment. Irrespective of the underlying cause, key elements of clinical management include the detection, prediction and prevention of episodes of hypoglycaemia. These tasks are increasingly served by Continuous Glucose Monitoring (CGM) devices that measure subcutaneous glucose at near-continuous frequency. While the use of CGM in type 1 diabetes is well established, the evidence for widespread use in rare hypoglycaemia disorders is less than convincing. However, in the few years since our last review there have been multiple developments and increased user feedback, requiring a review of clinical application. Despite advances in device technology, point accuracy of CGM remains low for children with non-diabetes hypoglycaemia. Simple provision of CGM devices has not replicated the efficacy seen in those with diabetes and is yet to show benefit. Machine learning techniques for hypoglycaemia prevention have so far failed to demonstrate sufficient prediction accuracy for real world use even in those with diabetes. Furthermore, access to CGM globally is restricted by costs kept high by the commercially-driven speed of technical innovation. Nonetheless, the ability of CGM to digitally phenotype disease groups has led to a better understanding of natural history of disease, facilitated diagnoses and informed changes in clinical management. Large CGM datasets have prompted re-evaluation of hypoglycaemia incidence and facilitated improved trial design. Importantly, an individualised approach and focus on the behavioural determinants of hypoglycaemia has led to real world reduction in hypoglycaemia. In this state of the art review, we critically analyse the updated evidence for use of CGM in non-diabetic childhood hypoglycaemia disorders since 2020 and provide suggestions for qualified use.

Keywords: children; continuous glucose monitoring; glycogen storage disease; hyperinsulinism; hypoglycaemia; prematurity

DOI: https://doi.org/10.3389/fendo.2023.1116864