Journal of Clinical Endocrinology & Metabolism最新文献

Context: Tirzepatide, a dual glucose-dependent insulinotropic peptide/glucagon-like peptide 1 (GIP/GLP1) receptor agonist, was recently approved for type 2 diabetes and weight management. Alström syndrome (AS) is a rare, genetic, multisystemic disorder, characterized by cone-rod dystrophy, progressive hearing loss, obesity, and diabetes with profound insulin resistance due to marked hyperphagia.

Objective: Here we highlight the potential of tirzepatide as a novel therapeutic option for improving glycemic outcomes, metabolic dysfunction-associated steatotic liver disease (MASLD), and effectively reducing body weight in individuals with AS.

Methods: We present the first 2 reported cases of people living with AS treated with tirzepatide.

Results: Two individuals with AS, previously treated with semaglutide, received tirzepatide at our clinic. The first, a 23-year-old man with 18 months of treatment, experienced a weight loss of -28 kg (113.6 to 83 kg, -26.9%); glycated hemoglobin A1c decreased by -0.4% (6.7% to 6.3%), with considerable reductions in daily insulin doses of -96 IU/day (-83%; 58 to 20 IU insulin glargine and 58 to 0 IU prandial insulin), while maintaining oral antidiabetics. Hepatic steatosis, with a previous fat fraction of 20%, resolved as confirmed by magnetic resonance imaging (MRI). The second, a 20-year-old man with previously well-controlled diabetes, was followed up for 9 months and showed a weight reduction of -9.5 kg (132 kg to 122.5 kg; -7.2%) with a reduction of hepatic lipid content from 21% at the latest MRI to 11% after approximately 3 months of therapy.

Conclusion: Tirzepatide shows great effectiveness with regard to body weight, MASLD, and insulin resistance in AS. Follow-up studies with larger cohorts have to be performed to confirm these findings.

Objective: The rate of decline in estimated glomerular filtration rate (eGFR) varies among patients with type 2 diabetes (T2D). We aimed to identify plasma proteins associated with diverse eGFR trajectories in T2D.

Methods: We performed latent class mixed models analysis among patients with T2D and relatively preserved kidney function (baseline eGFR ≥60 mL/min/1.73 m2) from the Singapore Study of Macro-angiopathy and Micro-Vascular Reactivity in Type 2 Diabetes (SMART2D) (n = 1285) and diabetic nephropathy (n = 798) cohorts to identify patterns of eGFR trajectories. Comprehensive proteomic association with eGFR trajectories was assessed using multivariable logistic regression in the SMART2D cohort.

Results: Three distinct eGFR trajectories groups-slow decline (92.2%), progressive decline (4.0%), and accelerated decline (3.8%)-were identified in SMART2D and validated in the diabetic nephropathy cohort. Participants in the accelerated decline group exhibited the highest risk of progression to end-stage kidney disease (log-rank test, P < .0001). Among 1448 proteins analyzed in the SMART2D cohort, 19 proteins, including KIM-1 (odds ratio [OR] = 2.95; 95% CI, 2.01-4.32; P = 2.95 × 10-8), MMP7 (OR = 16.5; 95% CI, 5.54-49.07; P = 4.61 × 10-7), and VSIG4 (OR = 7.38; 95% CI, 3.22-16.89; P = 2.24 × 10-6), were associated with accelerated decline and 1 protein (OR = 6.34; 95% CI, 2.77-14.52; P = 1.26 × 10-5) was associated with progressive decline, independent of traditional cardiorenal risk factors including baseline kidney function. Adding these proteins to clinical risk factors (age, sex, ethnicity, eGFR, urine albumin-to-creatinine ratio, HbA1c, diabetes duration, systolic blood pressure, triglyceride) improved area under the curve to 0.77 (delta 0.04, P = .057) for progressive decline and 0.93 (delta 0.09, P < .001) for accelerated decline.

Conclusion: Different plasma proteins are associated with progressive and accelerated eGFR decline, independent of traditional cardiorenal risk factors, some of which enhance eGFR trajectory prediction in patients with T2D.

Context: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an umbrella term for simple hepatic steatosis and the more severe metabolic dysfunction-associated steatohepatitis. The current reliance on liver biopsy for diagnosis and a lack of validated biomarkers are major factors contributing to the overall burden of MASLD.

Objective: This study investigates the association between biomarkers and hepatic steatosis and stiffness measurements, measured by FibroScan®.

Methods: Data from the National Health and Nutritional Examination Survey (2017-2020) were collected for 15 560 patients. Propensity score matching balanced the data with a 1:1 case to control for age and sex allowing for preliminary trend assessment. Random Forest machine learning determined variable importance for the incorporation of key biomarkers (age, sex, race, BMI, HbA1c, plasma fasting glucose, insulin, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, ALT, AST, ALP, albumin, GGT, LDH, iron, total bilirubin, total protein, uric acid, BUN, and hs-CRP) into logistic regression models predicting steatosis (MASLD indicated by a controlled attenuation parameter score of ≥238 dB/m) and stiffness (hepatic fibrosis indicated by a median liver stiffness ≥7 kPa). Sensitivity analysis using XGBoost and Recursive Feature Elimination was performed.

Results: The Random Forest models (the most accurate) predicted MASLD with 79.59% accuracy (P < .001) and specificity of 84.65% and predicted hepatic fibrosis with 86.07% accuracy (P < .001) and sensitivity of 98.01%. Both the steatosis and stiffness models identified statistically significant biomarkers, with age, BMI, and insulin appearing significant to both.

Conclusion: These findings indicate that assessing a variety of biomarkers, across demographic, metabolic, lipid, and standard biochemistry categories, may provide valuable initial insights for diagnosing patients for MASLD and hepatic fibrosis.

Context: Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators, such as elexacaftor/tezacaftor/ivacaftor (ETI), herald a new era in therapeutic strategy of cystic fibrosis (CF). ETI's effect on glucose tolerance remains controversial.

Objective: The study was undertaken to evaluate the effect of ETI treatment on glucose tolerance in youths with CF.

Methods: All the participants underwent a baseline oral glucose tolerance test (OGTT) before ETI initiation (M0) and 12 months (M12), and at 24 months if possible. The cohort was stratified in two subgroups based on the baseline OGTT: normal glucose tolerance (NGT) and abnormal glucose tolerance (AGT) defined by impaired fasting glucose or impaired glucose tolerance or diabetes not requiring insulin treatment.

Results: We included 106 adolescents with CF (age 14.1 ± 1.5 years), 75 with NGT, and 31 with AGT. The baseline characteristics of the two groups were similar except for a higher glucose level at 1- and 2-hour OGTT in the AGT group. ETI induced an increase in body mass index z score and in forced expiratory volume in 1 second (FEV1) (P < .001). After 12 months, participants with NGT did not experience any change of 1-hour and 2-hour glucose. By contrast, those with AGT displayed a reduction of 2-hour glucose at M12 (P = .006). Fifteen out of the 31 (48%) adolescents in the AGT group reversed to NGT but 9 of 75 (17%) in the NGT group progressed to AGT. Three participants with CF-related diabetes at baseline reversed to AGT. One-hour glucose concentrations at or above 8.7 mmol/L (157 mg/dL) during baseline OGTT had 80% sensitivity to identify those with AGT at 12 months (odds ratio 1.51; [1.20-1.92]; P = .001). Twenty participants had a 24-month OGTT that confirmed preserved insulin secretion.

Conclusion: ETI may improve glucose tolerance in adolescents with CF by preserving insulin secretion. One-hour glucose during the OGTT helps to detect risk for AGT after ETI treatment.

Context: Clinical case-based studies have identified rare pathogenic variants in several genes as causes of severe early-onset obesity, but their penetrance and interaction with polygenic susceptibility in the general population remain unclear.

Objective: We analyzed the United Kingdom Biobank (UKBB) whole-exome sequence data to assess the effects of heterozygous variants in 9 previously reported genes on adult body mass index (BMI) and recalled childhood adiposity.

Methods: Among 419 581 UKBB participants, we identified heterozygous carriers of coding variants that were (1) experimentally characterized as loss of function (LoF), or (2) bioinformatically predicted as rare (minor allele frequency <0.1%) LoF. We assessed variant-level and gene-level population penetrance of obesity and associations with adult BMI and recalled childhood adiposity, and tested the statistical interaction between rare variant carriage and a BMI polygenic score.

Results: Considering experimentally characterized LoF variants (excluding MC4R), we identified 22 heterozygous and 2 homozygous variants in 3 autosomal recessive genes (POMC, PCSK1, LEPR), and 3 autosomal dominant genes (SH2B1, SIM1, KSR2) with at least 10 carriers in the UKBB. Obesity penetrance among carriers ranged from 8% to 29% (median 23%), and none was significantly different from noncarriers (24%, all P > .05). For bioinformatically predicted rare LoF variants, gene-based burden tests showed that carriage of heterozygous variants in MC4R, PCSK1, and POMC was associated with higher adult BMI (effect sizes ranged from 0.5 to 2.5 kg/m2, all P < .003), with no significant interaction effects with common variant polygenic risk of BMI.

Conclusion: This study provides the population-specific report of variant penetrance of known obesity genes and confirmed the heterozygous rare variant effects in MC4R, POMC, and PCSK1. We also underscore the utility of population-based studies in supporting variant classifications.

Context: A continuum of non-suppressible aldosterone production has been demonstrated in normotensive individuals, termed subclinical primary aldosteronism (PA), and is consistently associated with increased risk for developing hypertension and cardiovascular disease. The hormonal mechanisms accounting for subclinical PA are not well understood.

Methods: To quantify the magnitude of subclinical PA, prospectively recruited normotensive participants (n = 75) had their maximally suppressed plasma aldosterone assessed after maintaining supine posture following an oral sodium loading protocol. To investigate the endocrine mechanisms involved with this continuum, multiple maneuvers were conducted to evaluate: (i) natriuretic peptide physiology (N-terminal pro B-type natriuretic peptide [NT-proBNP] suppression and stimulation using dietary sodium modulation); (ii) angiotensin II (AngII)-dependent aldosterone production (via dietary sodium restriction and via infusion of exogenous AngII); (iii) AngII-independent aldosterone production (via saline suppression test [SST]); and (iv) ACTH-mediated aldosterone production (via dexamethasone suppression test and ACTH-stimulation test).

Results: Greater magnitude of subclinical PA was associated with lower basal NT-proBNP (P-trend < .01) and blunted stimulation of NT-proBNP following sodium loading (P-trend = .023). The magnitude of subclinical PA was also associated with greater AngII-dependent (P-trend < .001) and AngII-independent (P-trend < .001) aldosterone production and paralleled the severity of ACTH-mediated aldosterone production (P-trends < .001). Following SST, 24.2% of participants had a post-saline aldosterone greater than 10 ng/dL and 72.7% had a post-saline aldosterone greater than 6 ng/dL, confirming that the continuum of subclinical PA included overt PA pathophysiology within these normotensive participants.

Conclusion: These findings demonstrate that the pathophysiologic continuum of subclinical PA in normotensive people is characterized by natriuretic peptide insufficiency and heightened aldosterone responses to both AngII and ACTH. These early maladaptive hormonal changes provide mechanistic explanations for the role of subclinical PA in the pathogenesis of hypertension.

Objective: The menopause transition (MT) may substantially contribute to increased systemic inflammation in later life, regardless of aging. We characterized inflammation trajectories over the MT and determined their associations with premenopausal obesity and race/ethnicity.

Methods: Data comprising 15 follow-up visits from Study of Women's Health Across the Nation participants who had a known date of their final menstrual period (FMP) and at least 3 measures of high-sensitivity C-reactive protein (hs-CRP) (n = 1470) or IL-6 (n = 779) were evaluated using group-based trajectory modeling and piecewise linear mixed-effects models.

Results: Based on 21 years of follow-up spanning the MT, we identified 3 trajectory groups for each inflammatory biomarker: (1) Low-Rise (hs-CRP = 27.2%; IL-6 = 36.0%); (2) Medium-Stable (hs-CRP = 41.9%) or Medium-Rise (IL-6 = 45.2%); and (3) High-Decline (hs-CRP = 30.9%) or High-Stable (IL-6 = 18.8%). The Low-Rise for both hs-CRP and IL-6 and the Medium-Rise for IL-6 trajectories showed significant increases as early as 1 year before to as late as 3 years after the FMP. The other trajectories showed either no change, or a decline around the FMP. Chinese and/or Japanese women were more likely to follow the Low-Rise hs-CRP and IL-6 trajectories, whereas Black women were more likely to follow the High-Decline hs-CRP and High-Stable IL-6 trajectories. Being overweight or obese was associated with the High-Decline hs-CRP and High-Stable IL-6 trajectories.

Conclusions: Midlife women experience distinct patterns of change in hs-CRP and IL-6 over the MT. Subgroups entering the MT with low-to-medium inflammation levels, particularly for IL-6, showed rises close to the FMP, supporting a contribution of menopause in progression of systemic inflammation.

Context: Electrolytes are essential for mineral and bone metabolism. However, their associations with fracture risk among older adults have not been extensively studied.

Objective: This work aimed to examine the associations of serum sodium, potassium, magnesium, calcium, and phosphorus levels with the risk of fracture.

Methods: A prospective cohort study of a US community comprised 5499 older adults from the Atherosclerosis Risk in Communities Study who completed visit 5 in 2011 to 2013. The analysis was replicated in 11 708 middle-aged adults who completed visit 2 in 1990 to 1992. Exposure included serum levels of sodium, potassium, magnesium, calcium, and phosphorus. The main outcome measure included hospitalization with fracture ascertained through diagnostic codes on hospital discharge records.

Results: In the visit 5 cohort (mean age, 75.4 years), multivariable Cox models with restricted cubic spline terms showed significant associations of lower sodium, magnesium, and calcium levels, and higher phosphorus levels with an increased risk of fracture. In clinical categories, this association remained significant for hyponatremia (≤135 vs 135-145 mEq/L) but not for hyperphosphatemia (≥4.5 vs 2.5-4.5 mg/dL) (HRs, 1.85 [95% CI, 1.22-2.81] and 2.18 [95% CI, 0.99-4.78], respectively). In the visit 2 cohort (mean age, 56.9 years), a significant association was observed for higher phosphorus levels, but not for other electrolytes, although findings were overall consistent.

Conclusion: In this community-based cohort, lower sodium, magnesium, and calcium levels, as well as higher phosphorus levels, were associated with greater fracture risk. These findings support the etiological link of serum electrolyte levels with the risk of fracture.

Context: The triglyceride-glucose (TyG) index is a reliable marker of insulin resistance. Although the TyG index is useful for identifying individuals at a high risk of future cardiovascular events and mortality in the general population, its clinical impact on young adults remains unclear.

Objective: This study aimed to investigate the association between the TyG index and mortality in young individuals.

Methods: We enrolled 6 667 138 individuals aged 20-39 years who underwent Korean national health screening between 2009 and 2012. Participants were categorized into quartiles based on their TyG indices. The study outcomes included all-cause and cause-specific mortality associated with cardiovascular events, cancer, and respiratory diseases.

Results: During a median follow-up duration of 10.7 years, 41 004 (0.6%) deaths occurred. The cumulative event rates for all-cause and cause-specific mortality were highest among participants in the TyG index quartile 4. In the multivariable Cox analysis, participants in the TyG index quartile 4 had significantly increased risks of all-cause, cardiovascular, and respiratory mortality compared with those in the quartile 1 (adjusted hazard ratio [HR] 1.21 (95% CI 1.17-1.24), 1.42 (1.29-1.56), and 1.68 (1.21-2.34), respectively). In contrast, the risk of cancer-related mortality was not increased in participants in the TyG index quartile 4. The risks of all-cause, cardiovascular, and respiratory mortality increased as the TyG index increased. However, there was no significant relationship between the TyG index and the risk of cancer-related mortality.

Conclusion: The TyG index can be a useful marker to identify young individuals at an increased risk of all-cause, cardiovascular, and respiratory mortality.

Context: Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is an inflammatory condition of the colon, characterized by watery diarrhea. Previous studies suggest an association between autoimmune thyroid diseases (AITDs) (Hashimoto thyroiditis and Graves disease) and MC; however, large-scale histology studies are lacking.

Objective: To assess the association between AITDs and future onset of MC.

Methods: We conducted a nationwide, matched case-control study. Patients with biopsy-confirmed MC diagnosed between 2006 and 2017 were identified through the population-based histopathology cohort ESPRESSO. Data on AITDs and covariates were retrieved from Swedish national health care registers. Odds ratios (ORs) for MC associated with prior AITDs were estimated using conditional logistic regression. Sibling comparisons were performed to minimize shared genetic and environmental confounding.

Results: Among 10 301 MC cases and 48 712 controls, AITDs were significantly more prevalent in MC patients (12.0%) than in controls (7.8%), yielding an adjusted OR of 1.65 (95% CI 1.54-1.77). This association was attenuated but remained significant in sibling analyses (OR 1.26; 95% CI 1.11-1.43) The association was stronger in patients diagnosed with MC before age 50 (OR 2.41; 95% CI 2.02-2.89). Subgroup analyses revealed no difference between CC and LC or between sexes.

Conclusion: Individuals with AITDs are at an increased risk of developing MC. That this association was robust across various subgroups may be indicative of shared underlying mechanisms. Our findings highlight the importance of being vigilant of gastrointestinal symptoms in patients with AITDs and that patients with persistent symptoms despite achieving euthyroidism should be evaluated for MC.