Daily Endocrinology Research Analysis
Three studies advance endocrinology across prevention and surgical care. Parathyroidectomy in primary hyperparathyroidism was associated with a substantially lower risk of incident diabetes. Long-term DPP/DPPOS data show that first-degree family history raises type 2 diabetes risk beyond what polygenic scores explain, and a neurosurgical strategy integrating cavernous sinus exploration and early postoperative ACTH/cortisol metrics may improve remission pathways in Cushing disease.
Summary
Three studies advance endocrinology across prevention and surgical care. Parathyroidectomy in primary hyperparathyroidism was associated with a substantially lower risk of incident diabetes. Long-term DPP/DPPOS data show that first-degree family history raises type 2 diabetes risk beyond what polygenic scores explain, and a neurosurgical strategy integrating cavernous sinus exploration and early postoperative ACTH/cortisol metrics may improve remission pathways in Cushing disease.
Research Themes
- Endocrine surgery and metabolic outcomes
- Familial and genetic risk stratification in diabetes
- Strategy optimization in pituitary surgery for Cushing disease
Selected Articles
1. Parathyroidectomy and Risk of Incident Diabetes in Patients With Primary Hyperparathyroidism.
In a territorywide cohort of 3,135 PHPT patients, parathyroidectomy was associated with a 32% lower hazard of incident diabetes compared with nonsurgical care, with stronger effects in younger and more severe cases. Findings were robust to sensitivity analyses, suggesting potential metabolic benefits of parathyroidectomy beyond calcium-PTH normalization.
Impact: Links endocrine surgery to diabetes prevention at population scale and may influence surgical decision-making and counseling in PHPT.
Clinical Implications: When considering surgery for PHPT, potential reduction in future diabetes risk can be part of shared decision-making, especially in younger or biochemically severe patients.
Key Findings
- Parathyroidectomy was associated with lower incident diabetes risk (HR 0.68; 95% CI 0.65–0.71).
- Protective association was stronger in younger patients (≤65 years; HR 0.64) and in those with more severe PHPT (PTH >2× ULN or calcium >2.8 mmol/L; HR 0.58).
- Results were consistent across multiple sensitivity analyses using IPTW-adjusted Cox models.
Methodological Strengths
- Large territorywide cohort with inverse probability of treatment weighting to balance baseline factors
- Robust subgroup and sensitivity analyses demonstrating consistency
Limitations
- Observational design susceptible to residual confounding and indication bias
- Follow-up duration differed between surgical and nonsurgical groups
Future Directions: Prospective studies should assess glycemic trajectories and mechanisms post-parathyroidectomy and evaluate cost-effectiveness of earlier surgery in metabolically high-risk PHPT.
IMPORTANCE: Primary hyperparathyroidism (PHPT) is linked to insulin resistance, glucose intolerance, and diabetes. Whether parathyroidectomy is associated with lower risk of diabetes has not been evaluated in a large cohort. OBJECTIVE: To examine the independent association between parathyroidectomy and the risk of incident diabetes in patients with PHPT. DESIGN, SETTING, AND PARTICIPANTS: Patients diagnosed with PHPT between January 2006 and December 2023 were identified from a territorywide electronic health database in Hong Kong and classified into surgical and nonsurgical groups based on presence of subsequent parathyroidectomy. They were followed up with from the index date (first diagnosis of PHPT), until the outcome of interest (incident diabetes), death, or end of the study period (December 2023), whichever came first. EXPOSURE: Parathyroidectomy vs nonsurgical management. MAIN OUTCOMES AND MEASURES: The primary outcome of this study was incident diabetes. Inverse probability of treatment weighting was used to balance all baseline characteristics. Cox proportional hazards regression was used to evaluate the hazard of incident diabetes associated with parathyroidectomy. RESULTS: A total of 3135 patients with PHPT were included (596 [19.0%] surgical and 2539 [81.0%] nonsurgical). The mean (SD) age was 67.5 (14.2) years, and 2211 (70.5%) individuals were female. A total of 518 patients in the nonsurgical group developed incident diabetes during a median (IQR) follow-up of 2.2 (0.9-4.3) years, compared to 156 patients in the surgical group during a median (IQR) follow-up of 5.5 (3.3-8.0) years. Parathyroidectomy was associated with lower risk of incident diabetes (hazard ratio [HR], 0.68 [95% CI, 0.65-0.71]; P < .001). Results were consistent across multiple sensitivity analyses. Subgroup analyses revealed more prominent protective associations among younger patients (age ≤65 years vs >65 years: HR, 0.64 [95% CI, 0.60-0.68] vs HR, 0.68 [95% CI, 0.63-0.72]; interaction P < .001) and those with more severe PHPT (parathyroid hormone [PTH] > twice the upper limit of normal vs PTH ≤ twice the upper limit of normal: HR, 0.58 [95% CI, 0.53-0.63] vs HR, 0.73 [95% CI, 0.69-0.77]; calcium > 2.8 vs calcium ≤ 2.8 mmol/L : HR, 0.58 [95%CI, 0.54-0.63] vs HR, 0.69 [95%CI, 0.66-0.73]; interaction P < .001). CONCLUSIONS AND RELEVANCE: In this cohort of patients with PHPT, parathyroidectomy was associated with a lower risk of incident diabetes. The association was more prominent in younger patients and those with more severe PHPT. These results may suggest potential additional metabolic benefits of parathyroidectomy in PHPT.
2. Impact of Parental or First-Degree Family History of Diabetes on Diabetes Incidence and Progression During Long-term Follow-up in the Diabetes Prevention Program Outcomes Study.
Across 21 years of follow-up, first-degree family history increased diabetes incidence independent of DPP treatment arm, with the highest risk for biparental diabetes history (HR 1.44). Polygenic risk accounted for only 32% of the family history association, indicating additional genetic and shared environmental contributions.
Impact: Defines the long-term, independent contribution of family history beyond polygenic risk in a landmark prevention cohort, informing risk stratification for prediabetes.
Clinical Implications: Family history remains a powerful risk marker beyond PRS; clinicians should incorporate detailed family history into risk communication and consider intensified prevention strategies in individuals with biparental history.
Key Findings
- Any first-degree family history increased diabetes risk (adjusted HR 1.21; 95% CI 1.06–1.38).
- Biparental diabetes history conferred the highest risk (HR 1.44; 95% CI 1.22–1.69), exceeding maternal or paternal history alone (both HR 1.22).
- Polygenic risk score explained only 32% of the family history–diabetes association.
Methodological Strengths
- Landmark RCT cohort with 21-year median follow-up and 88% reenrollment into DPPOS
- Adjustment for treatment arm, demographics/clinical variables, and polygenic risk score
Limitations
- Family history is self-reported and may be misclassified
- Residual confounding (e.g., unmeasured shared environment, rare variants) cannot be excluded
Future Directions: Integrate rare variant sequencing and environmental exposures to parse residual familial risk; test targeted, intensified prevention in individuals with biparental history.
OBJECTIVE: To determine the effects of first-degree family history of diabetes on diabetes incidence in Diabetes Prevention Program (DPP) and Diabetes Prevention Program Outcomes Study (DPPOS) participants. RESEARCH DESIGN AND METHODS: In the DPP, adults with prediabetes were randomized to an intensive lifestyle intervention, metformin, or placebo and followed for incident diabetes. On study completion 88% of eligible DPP participants reenrolled in DPPOS for long-term follow-up. The present analysis includes all 3,072 participants with family history information through DPPOS, with a median follow-up of 21 years (1,975 had parental history of diabetes [PH] [312 biparental, 947 maternal, 716 paternal], 226 had only sibling history [SH], and 871 denied any family history). The primary outcome is incident diabetes based on American Diabetes Association criteria, with adjustment for demographic and clinical variables, DPP randomization arm, and polygenic risk score (PRS). RESULTS: Adjusted hazard ratio (HR) was 1.21 (95% CI 1.06, 1.38) for any family history, 1.19 (1.04, 1.35) for PH, and 1.15 (0.91, 1.44) for SH. Biparental history conferred greater hazard (HR 1.44 [95% CI 1.22, 1.69]) than maternal (1.22 [1.08, 1.38]) or paternal (1.22 [1.08, 1.39]) diabetes history alone. PRS explained 32% of the association of any family history with diabetes risk. CONCLUSIONS: PH increased type 2 diabetes risk after DPP treatment group was controlled for. That effect was only partially explained by PRS, suggesting that rare gene variants, familial, and environmental factors may contribute to type 2 diabetes risk in people with prediabetes.
3. Systematic Cavernous Sinus Exploration Combined With Early Hormonal Assessment in Cushing Disease.
Systematic CS exploration revealed medial wall adherence/invasion in most cases selected (64% invasion). Early postoperative ACTH/cortisol NEPV identified high-risk patients for adjuvant radiotherapy even after gross total resection; none of these selected patients recurred. The approach was safe, with only transient cranial neuropathies reported.
Impact: Introduces a practical, integrated surgical-biochemical strategy that can reduce occult residuals and guide early adjuvant therapy, potentially improving long-term remission in Cushing disease.
Clinical Implications: Consider routine CS exploration and medial wall resection when indicated, and incorporate early postoperative NEPV of ACTH/cortisol to triage patients to adjuvant radiotherapy to prevent recurrence.
Key Findings
- Among 50 patients undergoing CS exploration, medial wall adherence/invasion was found in 36%/64%.
- Early postoperative NEPV of ACTH/cortisol flagged 12/37 gross-total resection patients for radiotherapy; none recurred.
- Safety profile was favorable: only 4 transient cranial neuropathies (<90 days), no arterial injuries.
Methodological Strengths
- Systematic intraoperative assessment coupled with standardized early biochemical monitoring
- Clear, actionable thresholds (NEPV) informing adjuvant therapy decisions
Limitations
- Single-surgeon, single-center experience may limit generalizability
- Nonrandomized design without a control group for the NEPV-guided strategy
Future Directions: Multicenter validation of NEPV thresholds and standardized CS exploration protocols with prospective assessment of recurrence and quality-of-life outcomes.
BACKGROUND AND OBJECTIVES: Unrecognized cavernous sinus (CS) invasion by adenomas is a major factor in surgical failure and recurrence of Cushing disease (CD), and pituitary adenomas. Exploration of the CS during trans-sphenoidal surgery (TSS) and resection of the involved medial wall of CS (medial wall of the CS) can achieve apparent gross total resection. However, novel strategies are needed to identify patients with occult tumor residuals and direct them to early radiotherapy. We developed the normalized early postoperative value (NEPV) of adrenocorticotropic hormone (ACTH) and cortisol as potential early predictors of remission. In this study, we integrate exploration of CS and NEPV into a clinical decision-making strategy in CD. METHODS: We analyzed data from 315 patients (2012-2023) undergoing TSS by a single surgeon for CD. Surgical approaches included sublabial TSS, CS exploration, and medial wall resection based on preoperative imaging or intraoperative findings. Postoperative cortisol and ACTH levels were assessed at extubation and every 6 hours postoperatively for 72 hours before corticosteroid replacement. RESULTS: CS exploration was performed in 50 patients (33 female; median age 26.5 years) because of preoperative MRI findings (n = 37) or intraoperative findings (n = 13). Adenoma adherence (n = 18, 36%) or invasion (n = 32, 64%) of the medial wall was observed. Thirteen patients with subtotal resection were recommended for radiation. Among 37 patients with gross total resection, 12 (29.7%) received radiotherapy because of elevated postoperative hormone levels, including persistent hypercortisolemia (n = 5), elevated NEPV ACTH (n = 5), or cortisol (n = 5). No recurrence occurred in these 12 patients. Transient cranial neuropathies (<90 days) were observed in 4 patients, with no arterial injuries reported. CONCLUSION: Preoperative MRI often underestimates CS invasion. CS exploration and medial wall resection are safe and effective for durable remission. An integrated strategy, using intraoperative findings and postoperative biochemical monitoring, may guide effective adjuvant therapy in CD.