Daily Endocrinology Research Analysis

Hepatic insulin resistance is central to type 2 diabetes (T2D) and metabolic syndrome, but defining the molecular basis of this defect in humans is challenging because of limited tissue access. Utilizing inducible pluripotent stem cells differentiated into hepatocytes from control individuals and patients with T2D and liquid chromatography with tandem mass spectrometry-based (LC-MS/MS-based) phosphoproteomics analysis, we identified a large network of cell-intrinsic alterations in signaling in T2D. Over 300 phosphosites showed impaired or reduced insulin signaling, including losses in the classical insulin-stimulated PI3K/AKT cascade and their downstream targets. In addition, we identified over 500 phosphosites of emergent, i.e., new or enhanced, signaling. These occurred on proteins involved in the Rho-GTPase pathway, RNA metabolism, vesicle trafficking, and chromatin modification. Kinome analysis indicated that the impaired phosphorylation sites represented reduced actions of AKT2/3, PKCθ, CHK2, PHKG2, and/or STK32C kinases. By contrast, the emergent phosphorylation sites were predicted to be mediated by increased action of the Rho-associated kinases 1 and 2 (ROCK1/2), mammalian STE20-like protein kinase 4 (MST4), and/or branched-chain α-ketoacid dehydrogenase kinase (BCKDK). Inhibiting ROCK1/2 activity in T2D induced pluripotent stem cell-derived hepatocytes restored some of the alterations in insulin action. Thus, insulin resistance in the liver in T2D did not simply involve a loss of canonical insulin signaling but the also appearance of new phosphorylations representing a change in the balance of multiple kinases. Together, these led to altered insulin action in the liver and identified important targets for the therapy of hepatic insulin resistance.

CONTEXT: Understanding the population prevalence of thyroid cancer-associated syndromes is important to guide germline genetic testing and clinical management. OBJECTIVE: To estimate the prevalence of the major thyroid cancer-associated syndromes in the United States using data from the All of Us Research Program (All of Us) and the UK Biobank. METHODS: In this cross-sectional study, we identified pathogenic and likely pathogenic (P/LP) variants from the ClinVar database in 245 394 All of Us and 469 558 UK Biobank participants. We calculated the prevalence of thyroid cancer-associated syndromes defined by the presence of P/LP variants. RESULTS: Using logistic regression, we found that 3 hereditary syndromes, multiple endocrine neoplasia type 2 (MEN2, RET gene, P = 3.23e-20), PTEN hamartoma tumor syndrome (PHTS, PTEN gene, P = 2.59e-15), and familial adenomatous polyposis type 1 (FAP, APC gene, P = 2.73e-10) were significantly associated with thyroid cancer. The prevalence of thyroid cancer-associated syndromes in the All of Us was 1:2172, 1:8764, and 1:8461, and in the UK Biobank, it was 1:2348, 1:13 043, and 1:8238 for MEN2, PHTS, and FAP, respectively. Three pathogenic RET variants that cause 2 amino acid substitutions, V804M and V804L, constitute 65% of all MEN2 variants in the All of Us, and none of these carriers were diagnosed with thyroid cancer. CONCLUSION: The prevalence of MEN2 and PHTS is ∼10 to 20 times higher than is currently estimated for the general population. Most affected individuals are not diagnosed with thyroid cancer. Our findings may change the clinical approach to patients with moderate-risk RET mutations.

OBJECTIVE: Adrenal vein sampling (AVS) is the standard-of-care for primary aldosteronism (PA) subtyping. Paradoxical bilateral aldosterone suppression (BAS), defined by lower aldosterone/cortisol ratio in both adrenal veins compared to peripheral circulation, has been reported in AVS studies, but the underlying causes remain poorly understood. We aimed to assess the prevalence of BAS in AVS without and with cosyntropin stimulation based on clinical immunoassays, and to probe the BAS results using liquid chromatography mass spectrometry (LC-MS/MS). METHODS: We retrospectively assessed the BAS prevalence among patients with confirmed PA who underwent AVS in a referral center between 2015 and 2023. Simultaneous AVS was performed both before and after cosyntropin stimulation. LC-MS/MS quantitation of cortisol and aldosterone was performed in patients with serum available. RESULTS: Of 402 patients, BAS was observed in 102 (25%): Pre-cosyntropin in 31, post-cosyntropin in 48 (including 10 who did not meet successful catheterization criteria in baseline samples), and both pre- and post- cosyntropin in 23. Paradoxically, AVS indicated lateralized PA in 36% and 43% of patients with BAS based on pre- and post-cosyntropin data, respectively. Using LC-MS/MS, BAS was not present in 42/53 (79%) patients with serum available. Compared to LC-MS/MS, immunoassays overestimated cortisol across the analytical range. In contrast, for aldosterone, immunoassays overestimated low concentrations, but underestimated high concentrations, such as those measured in adrenal veins. CONCLUSIONS: Apparent BAS derives primarily from artifacts in clinical immunoassays. These data caution against assuming that aldosterone suppression indicates contralateral aldosterone lateralization in cases with partial adrenal vein catheterization failure.