Beyond bones and stones: the relationship between hyperparathyroidism and diabetes

To prevent the morbidity from the skeletal and renal manifestations of primary hyperparathyroidism (PHPT), patients have traditionally undergone parathyroidectomy (PTx), but new studies have shown that manifestations of PHPT are not limited to just these organ systems (1,2). Other new studies have shown that PTx in patients with PHPT improves neuropsychiatric disorders, cardiovascular risks and other disease processes (2,3). Even as the third most common endocrine disorder, PHPT is underdiagnosed, and when diagnosed many patients do not get referred for surgery (4,5). This recent study by Lui et al. provides insight into the potential metabolic sequelae that result from untreated PHPT.

To evaluate the incidence of new onset diabetes in patients with PHPT, Liu et al. used a large population-based cohort and grouped patients based on whether they had PTx (n=3,135). Patients were followed from time of diagnosis until development of diabetes, death, or study end point. Patients who underwent PTx had a lower incidence of new onset diabetes, which held true for subgroup and sensitivity analysis. Findings showed that patients with PHPT treated with PTx had a significantly lower risk of incident diabetes [hazard ratio (HR) 0.69, 95% confidence interval: 0.65–0.71]. In their subgroup analysis findings showed a greater reduction in HR for patients with higher calcium elevations (HR 0.58 for calcium >2.8 mmol/L compared to HR 0.69 for calcium ≤2.8 mmol/L) (1).

This relationship is biologically plausible, with the proposed mechanism being increased insulin resistance via elevated free intracellular calcium (Figure 1) (1,6). Increased levels of calcium reduce glucose transport through the insulin-stimulated glucose transport channel thus requiring higher levels of insulin and development of diabetes (7). Other proposed mechanisms include pancreatic beta cell dysfunction as a means for decreased insulin production (7,8).

Figure 1 Calcium’s role in glucose stimulated insulin release in pancreatic beta cells. Glucose enters pancreatic beta cells via glucose transporters and undergoes metabolism within the mitochondria. This causes an increase in intracellular ATP levels. This increased ATP concentration closes the ATP-sensitive potassium (K⁺) channel, in turn causing depolarization of the cell membrane. In turn, the voltage-dependent calcium (Ca²⁺) channel opens, and there is an influx of Ca²⁺. The influx of Ca²⁺ promotes exocytosis of secretory granules containing insulin (6). Figure created by the authors using Apple Freeform [version 3.5 (419.121.1) Apple Inc., Cupertino, CA]. ATP, adenosine triphosphate; Ca²⁺, calcium; GLUT, glucose transporter; K⁺, potassium.

Elevated parathyroid hormone (PTH) levels have also been implicated in metabolic liver disease. Similarly, these mechanisms and their relationship have not been clearly defined. There are several proposed mechanisms for this, such as PTH potentially stimulating hepatic lipogenesis. Other studies have shown that PTH may inhibit glucose uptake by adipocytes and cause insulin resistance (9). Metabolic liver disease and diabetes are closely related and a novel model generated to detect advanced fibrosis found significant association with PTH levels (10).

Although prospective randomized controlled trials are the gold standard for evaluating when an intervention improves an outcome, such trials are not always feasible for surgical interventions. This study is robust in its large sample size and confirmation of findings with sensitivity analysis, but with any retrospective observational study proving causality cannot be established with certainty. Additionally, the median follow-up time was 2 years for the nonsurgical group and 5 years for those who underwent PTx. Longer follow-up is needed to see if this reduction in diabetes persists long term, but these results present a strong argument for offering PTx. It is paramount to acknowledge that only 3.5% of the patients in their cohort were obese; this is significantly lower than the 40% of Americans who are obese (11). This limits the generalizability of their findings, although reflective of their population, it may not directly correlate in countries where obesity rates are high and are contributing to the incidence of diabetes.

This study raises an important question, should patients be referred for surgical evaluation even when they have asymptomatic PHPT? Current American Association of Endocrine Surgeons Guidelines are limited to operative intervention in symptomatic patients, serum calcium >1 mg/dL above normal, objective renal involvement, osteoporosis, and for all patients diagnosed at 50 years or younger (12). However, this study begs the question, should we be thinking of PHPT as a risk factor for metabolic disease? Although not currently indicated by guidelines, providers should consider additional screening for diabetes in patients with elevated fasting blood glucose found during workup for PHPT. Guidelines have specific criteria for PTx in asymptomatic patients, but it is probable that future revisions will incorporate asymptomatic patients for metabolic risk reduction.

Future research studies should, evaluate the prevalence of PHPT and diabetes in patients with broad demographics and varying comorbidities to limit confounding effects. Retrospective cohort studies can also compare PHPT and incident diabetes over a longer time course to see if this association holds true when patients are followed over their lifetime. Lastly studies should further investigate the relationship between PHPT and diabetes to further solidify the mechanism and dose-response relationship between the disease.

As our understanding of PHPT continues to expand beyond the traditionally thought of disease processes we must also expand the indications for surgical intervention. Continued evidence has shown that PHPT is a modifiable risk factor for metabolic disease and PTx not only offers a curative option for the disease but leads to risk reduction for metabolic disorders. As evidence continues to emerge it is imperative that guidelines are revised to reflect these advancements in disease understanding. PHPT still remains largely underdiagnosed and under-referred, highlighting the need for multidisciplinary collaboration between surgeons and primary/specialty care physicians to ensure patients receive appropriate treatment, especially as indications for surgery broaden. These findings show that PHPT has manifestations beyond an elevated serum calcium and the traditional symptoms.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gland Surgery. The article has undergone external peer review.

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-516/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-516/coif). R.C. is supported by the National Institutes of Health (NIH) under a Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant (T32), grant number T32CA229102, through University of Alabama. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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