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Abstract
Glycophagy is the autophagic degradation of glycogen by the enzyme acid alpha‐glucosidase
(GAA). Although GAA inhibitors improve metabolic health by inhibiting GAA in the intestine,
it is not clear if GAA inhibition in peripheral tissues such as the liver is metabolically
beneficial. This study tested if the heterozygous knockout of GAA (HetKO‐GAA) alters
liver metabolism and metabolic health in mice fed a low‐fat diet or a high‐fat diet
to induce obesity. HetKO‐GAA mice fed either diet did not have altered body weight,
glucose tolerance, insulin action, energy expenditure, substrate metabolism, liver
glucose output, or liver triglycerides compared to control wildtype mice. A liver
spatial transcriptomics analysis revealed that high‐fat diet feeding reduced the gene
abundance of predominantly metabolic pathways in both periportal and perivenous hepatocytes,
and uniquely reduced ribosome gene abundance in perivenous hepatocytes. HetKO‐GAA
mice did not have significantly altered transcriptomes in periportal or perivenous
hepatocytes compared to wildtype mice. In conclusion, heterozygous GAA knockout is
nonconsequential on metabolism and metabolic health in high‐fat diet induced obesity.
Spatial transcriptomics revealed alterations in the transcriptome of periportal and
perivenous hepatocytes from high‐fat diet induced obese mice, highlighting novel targets
that could be exploited to improve metabolic health in obesity.
Summary Background Diabetes is one of the leading causes of death and disability worldwide, and affects people regardless of country, age group, or sex. Using the most recent evidentiary and analytical framework from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), we produced location-specific, age-specific, and sex-specific estimates of diabetes prevalence and burden from 1990 to 2021, the proportion of type 1 and type 2 diabetes in 2021, the proportion of the type 2 diabetes burden attributable to selected risk factors, and projections of diabetes prevalence through 2050. Methods Estimates of diabetes prevalence and burden were computed in 204 countries and territories, across 25 age groups, for males and females separately and combined; these estimates comprised lost years of healthy life, measured in disability-adjusted life-years (DALYs; defined as the sum of years of life lost [YLLs] and years lived with disability [YLDs]). We used the Cause of Death Ensemble model (CODEm) approach to estimate deaths due to diabetes, incorporating 25 666 location-years of data from vital registration and verbal autopsy reports in separate total (including both type 1 and type 2 diabetes) and type-specific models. Other forms of diabetes, including gestational and monogenic diabetes, were not explicitly modelled. Total and type 1 diabetes prevalence was estimated by use of a Bayesian meta-regression modelling tool, DisMod-MR 2.1, to analyse 1527 location-years of data from the scientific literature, survey microdata, and insurance claims; type 2 diabetes estimates were computed by subtracting type 1 diabetes from total estimates. Mortality and prevalence estimates, along with standard life expectancy and disability weights, were used to calculate YLLs, YLDs, and DALYs. When appropriate, we extrapolated estimates to a hypothetical population with a standardised age structure to allow comparison in populations with different age structures. We used the comparative risk assessment framework to estimate the risk-attributable type 2 diabetes burden for 16 risk factors falling under risk categories including environmental and occupational factors, tobacco use, high alcohol use, high body-mass index (BMI), dietary factors, and low physical activity. Using a regression framework, we forecast type 1 and type 2 diabetes prevalence through 2050 with Socio-demographic Index (SDI) and high BMI as predictors, respectively. Findings In 2021, there were 529 million (95% uncertainty interval [UI] 500–564) people living with diabetes worldwide, and the global age-standardised total diabetes prevalence was 6·1% (5·8–6·5). At the super-region level, the highest age-standardised rates were observed in north Africa and the Middle East (9·3% [8·7–9·9]) and, at the regional level, in Oceania (12·3% [11·5–13·0]). Nationally, Qatar had the world's highest age-specific prevalence of diabetes, at 76·1% (73·1–79·5) in individuals aged 75–79 years. Total diabetes prevalence—especially among older adults—primarily reflects type 2 diabetes, which in 2021 accounted for 96·0% (95·1–96·8) of diabetes cases and 95·4% (94·9–95·9) of diabetes DALYs worldwide. In 2021, 52·2% (25·5–71·8) of global type 2 diabetes DALYs were attributable to high BMI. The contribution of high BMI to type 2 diabetes DALYs rose by 24·3% (18·5–30·4) worldwide between 1990 and 2021. By 2050, more than 1·31 billion (1·22–1·39) people are projected to have diabetes, with expected age-standardised total diabetes prevalence rates greater than 10% in two super-regions: 16·8% (16·1–17·6) in north Africa and the Middle East and 11·3% (10·8–11·9) in Latin America and Caribbean. By 2050, 89 (43·6%) of 204 countries and territories will have an age-standardised rate greater than 10%. Interpretation Diabetes remains a substantial public health issue. Type 2 diabetes, which makes up the bulk of diabetes cases, is largely preventable and, in some cases, potentially reversible if identified and managed early in the disease course. However, all evidence indicates that diabetes prevalence is increasing worldwide, primarily due to a rise in obesity caused by multiple factors. Preventing and controlling type 2 diabetes remains an ongoing challenge. It is essential to better understand disparities in risk factor profiles and diabetes burden across populations, to inform strategies to successfully control diabetes risk factors within the context of multiple and complex drivers. Funding Bill & Melinda Gates Foundation.
The human liver is an essential multifunctional organ, and liver diseases are rising with limited treatment options. However, the cellular composition of the liver remains poorly understood. Here, we performed single-cell RNA-sequencing of ~10,000 cells from normal liver tissue of 9 human donors to construct a human liver cell atlas. Our analysis revealed previously unknown sub-types among endothelial cells, Kupffer cells, and hepatocytes with transcriptome-wide zonation of some of these populations. We reveal heterogeneity of the EPCAM+ population, which comprises hepatocyte-biased and cholangiocyte populations as well as a TROP2int progenitor population with strong potential to form bipotent liver organoids. As proof-of-principle, we utilized our atlas to unravel phenotypic changes in hepatocellular carcinoma cells and in human hepatocytes and liver endothelial cells engrafted into a mouse liver. Our human liver cell atlas provides a powerful resource enabling the discovery of previously unknown cell types in the normal and diseased liver.
The liver is a critical hub for numerous physiological processes. These include macronutrient metabolism, blood volume regulation, immune system support, endocrine control of growth signaling pathways, lipid and cholesterol homeostasis, and the breakdown of xenobiotic compounds, including many current drugs. Processing, partitioning, and metabolism of macronutrients provide the energy needed to drive the aforementioned processes and are therefore among the liver's most critical functions. Moreover, the liver's capacities to store glucose in the form of glycogen, with feeding, and assemble glucose via the gluconeogenic pathway, in response to fasting, are critical. The liver oxidizes lipids, but can also package excess lipid for secretion to and storage in other tissues, such as adipose. Finally, the liver is a major handler of protein and amino acid metabolism as it is responsible for the majority of proteins secreted in the blood (whether based on mass or range of unique proteins), the processing of amino acids for energy, and disposal of nitrogenous waste from protein degradation in the form of urea metabolism. Over the course of evolution this array of hepatic functions has been consolidated in a single organ, the liver, which is conserved in all vertebrates. Developmentally, this organ arises as a result of a complex differentiation program that is initiated by exogenous signal gradients, cellular localization cues, and an intricate hierarchy of transcription factors. These processes that are fully developed in the mature liver are imperative for life. Liver failure from any number of sources (e.g. viral infection, overnutrition, or oncologic burden) is a global health problem. The goal of this primer is to concisely summarize hepatic functions with respect to macronutrient metabolism. Introducing concepts critical to liver development, organization, and physiology sets the stage for these functions and serves to orient the reader. It is important to emphasize that insight into hepatic pathologies and potential therapeutic avenues to treat these conditions requires an understanding of the development and physiology of specialized hepatic functions.
This is an open access article under the terms of the
http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
History
Date
revision received
: 06
March
2025
Date
received
: 20
February
2025
Date
accepted
: 06
March
2025
Page count
Figures: 8,
Tables: 0,
Pages: 18,
Words: 9200
Funding
Funded by: HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
, doi 10.13039/100000062;
Award ID: 125258
Funded by: HHS | NIH | National Institute of General Medical Sciences (NIGMS)
, doi 10.13039/100000057;
Award ID: 154665
Funded by: National Institute of Health (NIGMS)
, doi 10.13039/100000057;
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