Daily Endocrinology Research Analysis

BACKGROUND: Insulin resistance (IR) correlates with a wide spectrum of diseases and death. However, the specific proteomic signatures of IR and their associations with health outcomes remain incompletely understood. METHODS: Leveraging data of 2,920 plasma proteins from 19,556 individuals in UK biobank study, we employed the elastic net model to dissect IR-related proteins and construct proteomic signature scores. Cox proportional hazards model was fitted to examine the longitudinal associations of distinct IR indicators and their proteomic signatures with multiple chronic disease and mortality. Mediation analyses were conducted to explore the role of individual proteins and proteomic signatures in IR-disease associations. RESULTS: Over a mean follow-up of over 12 years, higher levels of IR surrogate makers were linked to cardiovascular-kidney-metabolic events and mortality, with eGDR outperforming other metrics in predictive discrimination. Furthermore, most IR proteomic signatures were prospectively associated with the incidence of type 2 diabetes mellitus, ischemic heart diseases, stroke, chronic kidney diseases, and mortality. Proteins associated with IR were primarily enriched in inflammation, immune response, and lipid metabolism, with immune-related proteins holding crucial roles. Multiple IR-disease associations were significantly mediated by proteomic signatures and specific proteins, like HAVCR1, CXCL17, and GDF15. CONCLUSION: This study probed into the plasma proteomic profiles in IR settings and the associations of relevant protein signatures with multiple chronic diseases and mortality, providing additional guidelines on targeted intervention strategies for cardiovascular-kidney-metabolic outcomes.

RATIONALE: The Early versus Delayed Enteral Nutrition (EDEN) trial found no significant difference in mortality between trophic and full enteral nutrition strategies in acute respiratory distress syndrome (ARDS) patients. Heterogeneity of treatment effect (HTE) has been identified in prior ARDS trials. We previously identified intestine-derived incretin hormones (glucose-dependent insulinotropic peptide [GIP] and glucagon-like peptide [GLP]-1 as potential predictive biomarkers in the response to nutrition. OBJECTIVES: To investigate incretins as biomarkers predictive of HTE in EDEN. METHODS: GIP, GLP-1, and host immune response biomarkers were measured from pre-intervention EDEN plasma samples. We investigated HTE with 60-day mortality as a primary outcome by testing interaction of treatment with circulating incretin levels in analyses adjusted for demographics, severity of illness, diabetes mellitus, and circulating interleukin-6, and assessed mortality by treatment arm across incretin tertiles. We additionally tested for HTE by de novo ARDS subphenotypes and by risk of mortality. MEASUREMENTS & MAIN RESULTS: 889 participants were included (452 randomized to trophic and 437 to full enteral nutrition). GIP predicted HTE to enteral nutrition strategies (adjusted interaction p-value 0.01) with lower mortality from trophic feeds (14.1% vs 27.2% in full) in patients in the highest GIP tertile but similar mortality in other tertiles. GLP-1, ARDS subphenotypes, and baseline risk of mortality did not predict HTE. CONCLUSIONS: GIP was unique among incretins in predicting HTE to enteral nutrition strategies in EDEN. Further studies are needed to validate our findings as GIP might serve as a biomarker to guide level of enteral nutrition for ARDS patients.

Primary aldosteronism (PA) is commonly caused by somatic and germline mutations in various genes. Patients with unilateral PA may display classical or nonclassical histopathologic features in adrenal tumors. Somatic and germline mutations are linked to classical unilateral and familial PA, respectively. Herein, we aim to search for novel gene mutation causing nonclassical lateralizing PA. Surgically resected adrenal tumor tissues from patients enrolled in a PA cohort were subject to histopathologic evaluation. Genetic analyses were performed for genomic DNA isolated from peripheral blood leukocytes and CYP11B2 immunohistochemistry-guided macrodissected adrenal tissues to identify novel variants. A PA patient with a 1.8-cm mass in the right adrenal gland underwent laparoscopic right adrenalectomy, and achieved complete biochemical success at 12 months, but partial clinical improvement. Post-adrenalectomy tissues displayed the nonclassical histopathologic feature with multiple aldosterone-producing micronodules (mAPM), but no solitary aldosterone-producing adenoma. Genetic analyses identified a heterozygous CLCN2 germline variant, c.1087C>T (p.R363C), that was likely pathogenic based on bioinformatic evaluations. In vitro biochemical, electrophysiological, and hormone assays revealed that the human ClC-2 R363C channel displayed significant gain-of-function phenotypes, including enhanced protein stability and cell surface expression, higher channel open probability at physiological membrane potentials, and increased aldosterone production in human adrenocortical cells. Dominant gain-of-function effect of ClC-2 R363C was also observed when we co-expressed the variant with its wild-type counterpart. Altogether, we report the first association of gain-of-function CLCN2 germline mutation with nonclassical mAPM, providing new insight to the pathogenic mechanisms of PA.