Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease

Kolic, Jelena; Sun, WenQing Grace; Cen, Haoning Howard; Ewald, Jessica D.; Rogalski, Jason C.; Sasaki, Shugo; Sun, Han; Rajesh, Varsha; Xia, Yi Han; Moravcova, Renata; Skovsø, Søs; Spigelman, Aliya F.; Manning Fox, Jocelyn E.; Lyon, James; Beet, Leanne; Xia, Jianguo; Lynn, Francis C.; Gloyn, Anna L.; Foster, Leonard J.; MacDonald, Patrick E.; Johnson, James D.

doi:10.1016/j.cmet.2024.06.001

Cited by 3 publications

(3 citation statements)

References 88 publications

(116 reference statements)

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“…2A ). However, we did observe considerable inter-islet differences in response to βHB, consistent with our recent study showing considerable donor-donor heterogeneity in insulin secretion in response to macronutrient stimuli ( 2 ). To explore this further, we stratified insulin secretion in response to either R-βHB or S-βHB treatment by donor body mass index (BMI).…”

Section: Resultssupporting

confidence: 92%

“…While the effects on islet hormone secretion seen in our study were subtle, several recent reports have suggested that elevated insulin levels under basal glucose conditions may be an early indicator of β-cell dysfunction and may contribute to the adaptive insulin resistance seen in individuals living with T2D ( 44-46 ). Moreover, both basal and nutrient-stimulated insulin secretion from human islet donors is highly variable ( 2 ). As such it is critical we understand how and if these subtle changes in islet hormone secretion upon βHB exposure, are physiologically relevant on an individual basis.…”

Section: Discussionmentioning

confidence: 99%

“…While glucose is the primary regulator of islet hormone secretion, other nutrients and metabolites also play important roles ( 1 ). Although previous studies have investigated the effects of non-glucose substrates on islet cell function ( 2 , 3 ), some metabolites, such as ketone bodies, remain understudied.…”

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confidence: 99%

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Beta-Hydroxybutyrate Promotes Basal Insulin Secretion While Decreasing Glucagon Secretion in Mouse and Human Islets

Banerjee,

Zhu,

Brownrigg

et al. 2024

Endocrinology

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Dietary carbohydrates raise blood glucose and limiting carbohydrate intake improves glycemia in patients with type 2 diabetes. Low carbohydrate intake (< 25 g) allows the body to utilize fat as its primary fuel. As a consequence of increased fatty acid oxidation, the liver produces ketones to serve as an alternative energy source. β-Hydroxybutyrate (βHB) is the most abundant ketone. While βHB has a wide range of functions outside of the pancreas, its direct effects on islet cell function remain understudied. We examined human islet secretory response to acute racemic βHB treatment and observed increased insulin secretion at low glucose concentrations (3 mM glucose). Because βHB is a chiral molecule, existing as both R and S forms, we further studied insulin and glucagon secretion following acute treatment with individual βHB enantiomers in human and C57BL6/J mouse islets. We found that acute treatment with R-βHB increased insulin secretion and decreased glucagon secretion at physiological glucose concentrations in both human and mouse islets. Proteomic analysis of human islets treated with R-βHB over 72 h showed altered abundance of proteins that may promote islet cell health and survival. Collectively, our data show that physiological concentrations of βHB influence hormone secretion and signaling within pancreatic islets.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Beta-Hydroxybutyrate Promotes Basal Insulin Secretion While Decreasing Glucagon Secretion in Mouse and Human Islets

Banerjee,

Zhu,

Brownrigg

et al. 2024

Endocrinology

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An INSULIN and IAPP dual reporter enables tracking of functional maturation of stem cell-derived insulin producing cells

Bayly,

Dai,

Nian

et al. 2024

Molecular Metabolism

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Single cell multiome profiling of pancreatic islets reveals physiological changes in cell type-specific regulation associated with diabetes risk

Mummey,

Elison,

Korgaonkar

et al. 2024

Preprint

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Physiological variability in pancreatic cell type gene regulation and the impact on diabetes risk is poorly understood. In this study we mapped gene regulation in pancreatic cell types using single cell multiomic (joint RNA-seq and ATAC-seq) profiling in 28 non-diabetic donors in combination with single cell data from 35 non-diabetic donors in the Human Pancreas Analysis Program. We identified widespread associations with age, sex, BMI, and HbA1c, where gene regulatory responses were highly cell type- and phenotype-specific. In beta cells, donor age associated with hypoxia, apoptosis, unfolded protein response, and external signal-dependent transcriptional regulators, while HbA1c associated with inflammatory responses and gender with chromatin organization. We identified 10.8K loci where genetic variants were QTLs forcisregulatory element (cRE) accessibility, including 20% with lineage- or cell type-specific effects which disrupted distinct transcription factor motifs. Type 2 diabetes and glycemic trait associated variants were enriched in both phenotype- and QTL-associated beta cell cREs, whereas type 1 diabetes showed limited enrichment. Variants at 226 diabetes and glycemic trait loci were QTLs in beta and other cell types, including 40 that were statistically colocalized, and annotating target genes of colocalized QTLs revealed genes with putatively novel roles in disease. Our findings reveal diverse responses of pancreatic cell types to phenotype and genotype in physiology, and identify pathways, networks, and genes through which physiology impacts diabetes risk.

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Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease

Cited by 3 publications

References 88 publications

Beta-Hydroxybutyrate Promotes Basal Insulin Secretion While Decreasing Glucagon Secretion in Mouse and Human Islets

Beta-Hydroxybutyrate Promotes Basal Insulin Secretion While Decreasing Glucagon Secretion in Mouse and Human Islets

An INSULIN and IAPP dual reporter enables tracking of functional maturation of stem cell-derived insulin producing cells

Single cell multiome profiling of pancreatic islets reveals physiological changes in cell type-specific regulation associated with diabetes risk

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