Daily Endocrinology Research Analysis
Three clinically impactful endocrine studies stand out today: a simple C‑peptide/insulin molar ratio sharply distinguishes Type A insulin resistance syndrome from type 2 diabetes; 11C‑methionine PET/CT localizes recurrent corticotroph microadenomas when MRI is equivocal, enabling targeted therapy; and leukocytosis in Cushing’s syndrome persists after remission and predicts poorer surgical remission in Cushing’s disease. Together, they sharpen diagnostic accuracy and risk stratification across en
Summary
Three clinically impactful endocrine studies stand out today: a simple C‑peptide/insulin molar ratio sharply distinguishes Type A insulin resistance syndrome from type 2 diabetes; 11C‑methionine PET/CT localizes recurrent corticotroph microadenomas when MRI is equivocal, enabling targeted therapy; and leukocytosis in Cushing’s syndrome persists after remission and predicts poorer surgical remission in Cushing’s disease. Together, they sharpen diagnostic accuracy and risk stratification across endocrine practice.
Research Themes
- Advances in endocrine diagnostics and imaging
- Hematologic and peptide biomarkers for risk stratification in hypercortisolism
- Noninvasive identification of severe insulin receptor defects
Selected Articles
1. Utility of the C-Peptide/Insulin Molar Ratio for Distinguishing Type A Insulin Resistance Syndrome From Type 2 Diabetes.
In a retrospective OGTT-based comparison (18 Type A IRS vs 126 T2D), the circulating CPR/IRI molar ratio showed near-perfect discrimination (AUC 0.997–0.999; sensitivity 100%, specificity 95.1–99.2%) and outperformed insulin alone. The ratio was robust across BMI and hyperinsulinemia severity, supporting its use as a simple clinical marker to suspect insulin receptor defects.
Impact: Provides a widely accessible, non-genetic diagnostic tool to triage patients for INSR gene testing and targeted management of severe insulin resistance.
Clinical Implications: Use CPR/IRI molar ratio at baseline or during OGTT to flag suspected Type A IRS, prioritize genetic testing for INSR variants, and tailor therapy (e.g., avoid high-dose insulin escalation, consider insulin sensitizers and specialized care).
Key Findings
- CPR/IRI molar ratio was significantly lower in Type A IRS than T2D, while insulin levels were higher.
- AUCs for CPR/IRI at 0, 1, and 2 hours during OGTT were 0.997–0.999 with 100% sensitivity and 95.1–99.2% specificity.
- Diagnostic performance was robust irrespective of BMI and severity of hyperinsulinemia.
Methodological Strengths
- Clear case-control design with clinically defined groups (Type A IRS vs T2D).
- Comprehensive ROC analysis across multiple OGTT time points.
Limitations
- Retrospective single-population design with small Type A IRS sample (n=18).
- Lack of prospective validation and external cohorts.
Future Directions: Prospective, multicenter validation with predefined cutoffs; integration into diagnostic algorithms to guide genetic testing; evaluation of clinical outcomes/cost-effectiveness when using CPR/IRI for triage.
OBJECTIVE: Type A insulin resistance syndrome (IRS), characterized by impaired insulin receptor function due to variants of the insulin receptor gene, manifests as severe insulin-resistant diabetes. Differentiation of type A IRS from type 2 diabetes on the basis of hyperinsulinemia can be challenging. Given the association between insulin receptor dysfunction and reduced insulin clearance, we evaluated the potential of the circulating C-peptide reactivity (CPR)/immunoreactive insulin (IRI) molar ratio, a marker of insulin clearance, for distinguishing type A IRS from type 2 diabetes. METHODS: We retrospectively analyzed CPR and IRI levels measured during a 75-g oral glucose tolerance test (OGTT) in 18 individuals with type A IRS and 126 with type 2 diabetes. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic performance of the CPR/IRI molar ratio and IRI levels. RESULTS: IRI levels were significantly higher and the CPR/IRI molar ratio significantly lower in individuals with type A IRS compared with those with type 2 diabetes. The area under the ROC curve for the CPR/IRI molar ratio at baseline, 1 hour, and 2 hours after OGTT initiation was 0.997 (sensitivity 100%, specificity 99.2%), 0.999 (sensitivity 100%, specificity 97.6%), and 0.997 (sensitivity 100%, specificity 95.1%), respectively. The CPR/IRI molar ratio demonstrated robust diagnostic performance regardless of body mass index or hyperinsulinemia severity. CONCLUSION: The CPR/IRI molar ratio, both at baseline and during OGTT, exhibited higher sensitivity and specificity than IRI levels alone for distinguishing type A IRS from type 2 diabetes. This ratio may serve as a reliable clinical marker for early and accurate diagnosis of type A IRS.
2. Diagnostic Value of 11C-Methionine PET-CT Imaging in Persistent or Recurrent Cushing Disease After Surgery.
In 22 patients with persistent/recurrent Cushing disease and equivocal/negative pituitary MRI, 11C‑methionine PET/CT identified focal uptake in 64% and enabled targeted repeat surgery or radiosurgery with a 64% overall remission rate in PET‑positive cases. The positive PET/CT detection accuracy was 86%, supporting its role in surgical decision-making.
Impact: Addresses a major diagnostic gap by localizing microadenomas when MRI fails, directly influencing reoperation planning and remission outcomes.
Clinical Implications: Consider 11C‑MET PET/CT in persistent/recurrent Cushing disease with negative or equivocal MRI to guide targeted transsphenoidal reoperation or radiosurgery and improve remission likelihood.
Key Findings
- 11C‑MET PET/CT showed focal uptake in 14/22 (63.5%) patients with recurrent/persistent Cushing disease and non-diagnostic MRI.
- In PET‑positive cases, repeat TSS achieved remission in 7/12 and GKRS achieved remission in 2/2; overall remission 64%.
- Positive PET/CT had 86% detection accuracy; PET‑negative exploratory TSS yielded no remissions.
Methodological Strengths
- Dual-center cohort over two decades with standardized PET/CT and MRI co-registration in most cases.
- Objective clinical endpoints (biochemical remission) with pathologic confirmation in noncured TSS cases.
Limitations
- Small sample size and retrospective design with potential selection bias.
- Lack of standardized prospective imaging and uniform follow-up durations.
Future Directions: Prospective multicenter studies to define standardized PET/CT criteria, optimal timing, and cost-effectiveness; integration into consensus algorithms for recurrent Cushing disease.
CONTEXT: Equivocal or negative pituitary magnetic resonance imaging (MRI) findings pose a significant challenge in the management of persistent or recurrent Cushing disease (CD), compromising the chances of success of further transsphenoidal surgery (TSS). OBJECTIVE: To determine the diagnostic utility of 11C-methionine (11C-MET) positron emission tomography/computerized tomography (PET/CT) in localizing residual or relapsing corticotroph adenoma. METHODS: We retrospectively analyzed the results of all 11C-MET PET/CT performed at 2 tertiary medical centers between May 2002 and November 2023 in 22 patients with persistent/recurrent CD after initial TSS and equivocal/negative pituitary MRI. In 15 cases, 11C-MET PET/CT images were also co-registered with high-resolution 3D T1 or FLAIR MRI pituitary imaging. RESULTS: Of 22 patients (18 female; mean age 36 years at diagnosis; mean initial tumor maximum diameter 6.5 mm), 13 had a suspect anomaly on conventional MRI and 9 had a negative MRI. Maximal metabolic activity in the suspect area (SUVmaxT) was found in 14 patients (63.5%; 5/9 patients with negative pituitary MRI and 9/13 with equivocal findings). Based on positive imaging, 12 patients underwent repeat TSS, successful in 7, while 2 patients underwent Gamma Knife radiosurgery (GKRS), both resulting in remission (total remission rate of 64%). Among the 5 patients not cured by TSS, the presence of corticotroph adenoma in the resected tissue was found in 3 cases. Positive 11C-MET PET/CT had a detection rate accuracy of 86% (12/14). Of the 8 PET-negative patients, 2 underwent exploratory TSS, with no remission, and 2 underwent GKRS, with 1 long-term remission. CONCLUSION: 11C-MET PET/CT imaging can provide valuable diagnostic information to detect a corticotroph microadenoma in more than half of patients with persistent/recurrent CD and equivocal or negative MRI findings, allowing targeted TSS or radiosurgery with a global success rate of 64% in the selected subgroup with positive imaging.
3. Leukocytosis in Cushing's syndrome persists post-surgical remission and could predict a lower remission prognosis in patients with Cushing's disease.
In a nationwide matched cohort (297 CS, 997 controls), WBC, neutrophils, and NLR were elevated at diagnosis and declined after surgery yet remained higher than controls. In Cushing’s disease, baseline leukocytosis predicted a significantly lower remission rate, indicating prognostic utility.
Impact: Introduces simple hematologic markers for risk stratification in Cushing’s disease and highlights persistent immune alterations after biochemical remission.
Clinical Implications: Incorporate baseline WBC and NLR into preoperative risk assessment for Cushing’s disease; persistent leukocytosis after remission may warrant closer follow-up and evaluation for residual disease or comorbid inflammatory risks.
Key Findings
- Baseline leukocytosis was more common in CS than controls (21.5% vs 8.9%, P<0.001).
- After surgery, WBC, neutrophils, and NLR decreased but remained higher than controls in remission.
- Baseline leukocytosis in Cushing’s disease predicted lower remission (36.7% vs 63.9%, p=0.01).
Methodological Strengths
- Large, nationwide matched cohort with robust matching on age, sex, BMI, and socioeconomic status.
- Pre/post comparisons spanning two years around surgery enhance temporal inference.
Limitations
- Retrospective database study with potential residual confounding.
- Lack of mechanistic biomarkers to explain persistence of leukocytosis.
Future Directions: Prospective validation of WBC/NLR thresholds for prognostication; mechanistic studies on cortisol-related immune dysregulation post-remission; integrate hematologic markers into clinical prediction models.
CONTEXT: Leukocytosis frequently noted in Cushing's syndrome (CS), along with other blood cell changes caused by direct and indirect cortisol effects. OBJECTIVE: Assess baseline white blood cell (WBC) profile in CS patients compared to controls and WBC changes pre- and post-remission after surgical treatment for CS. DESIGN: A comparative nationwide retrospective cohort study. SETTING: Data from Clalit Health Services database. PATIENTS: 297 patients (mean age 51 ± 16.1 years, 73.0% women) with CS and 997 age-, sex-, body mass index-, and socioeconomic status-individually matched controls. Ectopic CS or adrenal cancer patients were excluded. MAIN OUTCOME MEASURE: Mean WBC, neutrophils, and neutrophil-to-lymphocyte ratio (NLR) two-years before and after pituitary or adrenal surgery. WBC and neutrophils are expressed as Kcells/µl. RESULTS: At baseline, leukocytosis was observed in 21.5% of patients with CS vs. 8.9% of controls (P < 0.001). Patients with CS had significantly higher WBC (8.8 ± 2.88 vs. 7.54 ± 2.45, p < 0.0001), neutrophils (5.82 ± 2.38 vs. 4.48 ± 1.97, p < 0.0001), and NLR (3.37 ± 2.63 vs. 2.27 ± 1.86, p < 0.0001) compared to controls, regardless of pituitary or adrenal source of hypercortisolemia. Post-surgery, patients with CS experienced significant decreases in mean WBC (-0.57 ± 2.56, p < 0.0001), neutrophils (-0.84 ± 2.55, p < 0.0001), and NLR (-0.63 ± 2.7, p < 0.0001). Despite achieving disease remission, patients with CS still had higher WBC (8.11 ± 2.4 vs. 7.46 ± 2.17, p = 0.0004) and neutrophils (4.71 ± 2.10 vs. 4.41 ± 1.87, p = 0.03) compared to controls. Patients with CD and baseline leukocytosis had lower remission rate than those with normal WBC (36.7% vs. 63.9%, p = 0.01). CONCLUSIONS: At diagnosis, CS patients have elevated WBC, neutrophils, and NLR compared to controls. Remission does not normalize WBC levels in all patients, and baseline leukocytosis predicts a poorer remission prognosis in CD.