Sex differences in islet stress responses support female β cell resilience

Brownrigg, George P; Xia, Yi Han; Chu, Chieh Min Jamie; Wang, Su; Chao, Charlotte; Zhang, Jiashuo Aaron; Skovsø, Søs; Panzhinskiy, Evgeniy; Hu, Xiaoke; Johnson, James D.; Rideout, Elizabeth J.

doi:10.1016/j.molmet.2023.101678

Cited by 26 publications

(34 citation statements)

References 132 publications

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“…Moreover, studies have demonstrated that islet ECM is altered/remodeled in T1D in a fashion that renders islets more permissive to immune cell infiltration and impairment of β‐cell function. The higher collagen expression and secretion from the pancreas‐innervating thoracic DRG neurons in females (vs. males) is consistent with the recently evoked concept of β‐cell resilience in response to islet stress in female mice 64 . We did not observe major congruence in pathways identified by transcriptome and secretome analyses.…”

Section: Discussionsupporting

confidence: 89%

“…The higher collagen expression and secretion from the pancreas-innervating thoracic DRG neurons in females (vs. males) is consistent with the recently evoked concept of βcell resilience in response to islet stress in female mice. 64 We did not observe major congruence in pathways identified by transcriptome and secretome analyses. This is expected as the secretome does not necessarily reflect the proteome signature but rather the pool of molecules packaged in the secretory granules ready to be released in the extracellular media under stimulatory conditions such as occurring experimentally in response to KCL 75 mM (Figure 1).…”

Section: Discussionmentioning

confidence: 61%

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Transcriptome and secretome profiling of sensory neurons reveals sex differences in pathways relevant to insulin sensing and insulin secretion

Moon,

Alsarkhi,

Lin

et al. 2023

The FASEB Journal

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Sensory neurons in the dorsal root ganglia (DRG) convey somatosensory and metabolic cues to the central nervous system and release substances from stimulated terminal endings in peripheral organs. Sex‐biased variations driven by the sex chromosome complement (XX and XY) have been implicated in the sensory–islet crosstalk. However, the molecular underpinnings of these male–female differences are not known. Here, we aim to characterize the molecular repertoire and the secretome profile of the lower thoracic spinal sensory neurons and to identify molecules with sex‐biased insulin sensing‐ and/or insulin secretion‐modulating activity that are encoded independently of circulating gonadal sex hormones. We used transcriptomics and proteomics to uncover differentially expressed genes and secreted molecules in lower thoracic T5‐12 DRG sensory neurons derived from sexually immature 3‐week‐old male and female C57BL/6J mice. Comparative transcriptome and proteome analyses revealed differential gene expression and protein secretion in DRG neurons in males and females. The transcriptome analysis identified, among others, higher insulin signaling/sensing capabilities in female DRG neurons; secretome screening uncovered several sex‐specific candidate molecules with potential regulatory functions in pancreatic β cells. Together, these data suggest a putative role of sensory interoception of insulin in the DRG–islet crosstalk with implications in sensory feedback loops in the regulation of β‐cell activity in a sex‐biased manner. Finally, we provide a valuable resource of molecular and secretory targets that can be leveraged for understanding insulin interoception and insulin secretion and inform the development of novel studies/approaches to fathom the role of the sensory–islet axis in the regulation of energy balance in males and females.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 61%

Transcriptome and secretome profiling of sensory neurons reveals sex differences in pathways relevant to insulin sensing and insulin secretion

Moon,

Alsarkhi,

Lin

et al. 2023

The FASEB Journal

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show abstract

“…Estrogen levels may also contribute to female resilience against HFDinduced damage, as estrogens have a protective effect in islets and can even enhance beta cell function in rodents [56][57][58]. Furthermore, female islets exhibit greater resistance to endoplasmic reticulum stress than male islets [59], enabling them to respond more effectively to increased metabolic demands, such as higher insulin requirements, during HFD feeding. In all, our findings further emphasize the need to evaluate the influence of biological sex in metabolic studies.…”

Section: Discussionmentioning

confidence: 99%

CYP1A1/1A2 enzymes mediate glucose homeostasis and insulin secretion in mice in a sex-specific manner

Ching,

Hoyeck,

Basu

et al. 2024

Preprint

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Aims/hypothesis: The aryl hydrocarbon receptor (AhR) pathway is involved in cellular responses to a broad range of external stressors, making it an excellent candidate for understanding the interaction between environmental factors and type 2 diabetes risk. Studies suggest deleting or downregulating AhR protects against metabolic dysfunction in high-fat diet (HFD) fed mice; however, the contribution of downstream AhR targets in driving this phenotype remains unexamined. Cytochrome P450 1A1 and 1A2 (CYP1A1/1A2) are canonical AhR targets that encode xenobiotic metabolism enzymes. Interestingly, we have demonstrated that HFD feeding increases Cyp1a1 expression in mouse islets, which suggests CYP1A enzymes are involved in the response to metabolic stress. Since CYP1A1/1A2 activity can produce reactive oxygen intermediates, we hypothesized that chronic activation of these enzymes in tissues critical for regulating glucose homeostasis (e.g., liver, adipose, islets) will contribute to metabolic dysfunction following HFD feeding. Methods: At 29 to 31 weeks of age, male and female global Cyp1a1/1a2 knockout (CypKO) and wildtype littermate control (CypWT) mice were fed either a 45% HFD or standard rodent chow for 14 weeks. Metabolic assessments were conducted throughout the study. Results: CypKO females were partially protected from HFD-induced glucose intolerance compared to CypWT females, but both genotypes exhibited similar levels of insulin resistance. CypKO females also had lower plasma insulin levels in vivo and suppressed insulin secretion in isolated islets ex vivo compared to CypWT females. Gene expression patterns in female islets were generally similar across genotype and diet groups. In contrast, CypWT males became hyperinsulinemic and insulin resistant within 2 weeks of HFD feeding, while CypKO males maintained normal plasma insulin levels and insulin sensitivity. HFD feeding upregulated Cyp1a1 in CypWT male islets and this was accompanied by elevation of other islet stress genes. Interestingly, HFD feeding did not induce these stress gene responses in CypKO male islets, suggesting the islet stress response is mediated by activation of CYP1A1. We expected the global deletion of Cyp1a1/1a2 to have pronounced effects in the liver, but surprisingly, changes in liver pathology were predominantly driven by diet and not genotype in both sexes. Similarly, overall adiposity and adipose tissue inflammation were not affected by genotype. Conclusions: Our study highlights a novel role of islet Cyp1a1/1a2 in shaping the systemic metabolic response to HFD feeding. Our data suggest that CYP1A1/1A2 enzymes are involved in glucose homeostasis, insulin secretion, and the islet stress response. Importantly, the effects of Cyp1a1/1a2 deletion are sex-dependent.

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“…For example, under stress female human T2D islets maintain greater insulin secretion compared to males (51). Although greater β-cell Kcnk16 expression could also be responsible for the more significant impairment in glucose intolerance observed in Kcnk16 L114P male mice, there is only a trend for greater Kcnk16 expression in sorted male β-cells (average RPKM 6296.25 +/− 953.84) compared to sorted female β-cells (5148.25 +/− 1013.22); this is similar in β-cells from high-fat diet treated mice (average RPKM 8020.75 +/− 1944.41 for males, and average RPKM 7551 +/− 2952.70 for females) (51). Whether sex-differences exist in humans with TALK-1 L114P mutation remains to be determined as all affected individuals in both KCNK16 -MODY (p. TALK-1 L114P) families were females.…”

Section: Discussionmentioning

confidence: 99%

The MODY-associatedKCNK16L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

Nakhe

Dadi

Kim

et al. 2023

Preprint

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A strong association of the gain-of-function mutation in the TALK-1 K+channel (p.L114P) with maturity-onset diabetes of the young (MODY) was recently reported in two distinct families. TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion (GSIS).KCNK16, the gene that encodes TALK-1, is the most abundant and β-cell–restricted K+channel transcript andKCNK16locus is strongly associated to type-2 diabetes. To investigate the impact of TALK-1-L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing theKcnk16L114P mutation was generated. Heterozygous and homozygousKcnk16L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1(ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygousKcnk16L114P neonates due to lack of GSIS and can be reduced with insulin treatment. TALK-1-L114P drastically increases whole-cell β-cell K+currents resulting in blunted glucose-stimulated Ca2+entry and a complete loss of glucose-induced Ca2+oscillations. Thus, adultKcnk16L114P mice have reduced GSIS and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated TALK-1-L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by altering islet hormone secretion during development. These data strongly suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.

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Sex differences in islet stress responses support female β cell resilience

Cited by 26 publications

References 132 publications

Transcriptome and secretome profiling of sensory neurons reveals sex differences in pathways relevant to insulin sensing and insulin secretion

Transcriptome and secretome profiling of sensory neurons reveals sex differences in pathways relevant to insulin sensing and insulin secretion

CYP1A1/1A2 enzymes mediate glucose homeostasis and insulin secretion in mice in a sex-specific manner

The MODY-associatedKCNK16L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

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