Daily Endocrinology Research Analysis
Three impactful studies span epidemiology, neuroendocrine mechanisms, and imaging diagnostics. A systematic review in Diabetologia shows high and rising prevalence of youth type 2 diabetes among Indigenous populations, especially young women. Mechanistic work links hypothalamic iron accumulation to age-related obesity via a ROS–FoxO1–AgRP axis, while a large adrenal imaging-pathology study supports using ≤20 HU on non-contrast CT to reliably exclude malignancy.
Summary
Three impactful studies span epidemiology, neuroendocrine mechanisms, and imaging diagnostics. A systematic review in Diabetologia shows high and rising prevalence of youth type 2 diabetes among Indigenous populations, especially young women. Mechanistic work links hypothalamic iron accumulation to age-related obesity via a ROS–FoxO1–AgRP axis, while a large adrenal imaging-pathology study supports using ≤20 HU on non-contrast CT to reliably exclude malignancy.
Research Themes
- Global disparities and trends in youth type 2 diabetes among Indigenous peoples
- Neuroendocrine mechanisms of aging-related obesity (iron–ROS–FoxO1–AgRP axis)
- Evidence-based imaging thresholds for adrenal incidentalomas
Selected Articles
1. Prevalence of youth type 2 diabetes in global Indigenous populations: a systematic review.
Across 36 Indigenous populations, youth type 2 diabetes prevalence ranged from 0–44 per 1000 and increased with age, with most populations exceeding 1 per 1000. In studies with sex data, 77% showed female predominance, and secular trends indicated rising prevalence over time. Heterogeneity precluded meta-analysis but highlighted a global, growing burden requiring Indigenous-led, age- and puberty-stratified prevention and surveillance.
Impact: This synthesis defines the scale, demographics, and trajectory of youth type 2 diabetes in Indigenous peoples, informing targeted prevention, surveillance, and policy. It consolidates a fragmented evidence base across regions and highlights critical sex and age patterns.
Clinical Implications: Programs should prioritize Indigenous-led, community-specific strategies, with routine age- and puberty-stratified screening and culturally safe prevention. Health systems should anticipate higher burden among adolescent/young adult females and design gender-informed interventions.
Key Findings
- Prevalence ranged 0–44 per 1000 across 36 Indigenous populations; 75% exceeded 1 per 1000.
- Prevalence increased with age: 0–4 per 1000 (<10 years), 0–44 (10–19), and 0–64 (15–25).
- Among 22 studies with sex data, 77% showed female predominance.
- Secular trends showed rising prevalence in most studies since 1981.
Methodological Strengths
- Comprehensive multi-database search with explicit inclusion criteria and quality assessment using a modified Newcastle-Ottawa Scale.
- Age- and sex-disaggregated analyses across multiple countries and populations, enabling pattern detection.
Limitations
- Marked heterogeneity in study design and diagnostic criteria precluded meta-analysis.
- Incomplete age/sex disaggregation in some studies limits precision of subgroup estimates.
Future Directions: Standardize diagnostic criteria and age/pubertal stratification, expand Indigenous-led surveillance, and identify protective and risk factors to inform tailored, gender-responsive prevention trials.
AIMS/HYPOTHESIS: We aimed to synthesise global prevalence estimates of type 2 diabetes among Indigenous youth aged under 25 years, and examine age- and gender-specific differences and secular trends. METHODS: We searched MEDLINE, Embase, CINAHL and Cochrane, and bibliographies of included studies, from 1 January 1980 to 14 September 2024. We included cross-sectional observational studies that reported diabetes point prevalence estimates (per 1000) and prevalence trends in Indigenous youth aged under 25 years from all regions. Age- and gender-specific analysis and secular trends were reported. Study quality was assessed using a modified Newcastle-Ottawa Scale adapted for Indigenous health research. RESULTS: From 2342 records and 27 additional references, 49 studies were retained for data extraction. Total type 2 diabetes prevalence, reported in 33 of 49 studies from 36 distinct populations across six countries and two self-governing states, varied widely (0-44 per 1000), with 75% (27/36) of the populations reporting a prevalence of over 1 per 1000. Age-specific data, available in 44 studies, showed increased prevalence with age: 0-4 per 1000 at age <10 years; 0-44 per 1000 at age 10-19 years; and 0-64 per 1000 at age 15-25 years.
2. Iron accumulation in hypothalamus promotes age-dependent obesity and metabolic dysfunction of male mice.
Aged mice accumulate iron in the hypothalamic arcuate nucleus. Reducing iron via intranasal deferiprone or by AgRP neuron–specific Tfrc knockout lowers ROS, prevents FoxO1 nuclear translocation, suppresses AgRP activity, and protects against age-related obesity and metabolic dysfunction. Excess iron induces mitochondrial dysfunction and a ROS–FoxO1–AgRP signaling cascade that drives obesity.
Impact: Identifies a previously unrecognized iron–ROS–FoxO1–AgRP axis linking brain iron homeostasis to energy balance with genetic and pharmacologic reversibility, opening a tractable target space for age-related obesity.
Clinical Implications: Therapeutic strategies that modulate hypothalamic iron handling or downstream ROS/FoxO1 signaling could be explored for age-related obesity. Translation will require safety and target engagement studies in humans, including evaluation of intranasal iron chelation.
Key Findings
- Aged mice show elevated hypothalamic iron, especially in the arcuate nucleus.
- Intranasal deferiprone reduces hypothalamic iron and improves metabolic function in aged mice.
- Iron overload triggers mitochondrial dysfunction and ROS-dependent FoxO1 nuclear translocation, upregulating AgRP.
- AgRP neuron–specific Tfrc knockout lowers ROS, blocks FoxO1 nuclear translocation, suppresses AgRP activity, and protects against age-related obesity.
Methodological Strengths
- Convergent evidence from in vivo aging models, pharmacologic iron chelation, in vitro iron overload, and cell-type–specific genetic manipulation.
- Clear mechanistic linkage (ROS–FoxO1–AgRP) with both gain- and loss-of-function validation.
Limitations
- Findings are preclinical and primarily in male mice; human relevance and sex differences remain to be established.
- Long-term safety and off-target effects of intranasal iron chelation were not addressed.
Future Directions: Test target engagement and metabolic effects of CNS-permeable iron modulators or FoxO1 pathway inhibitors in aged animal models of both sexes, followed by early-phase human translational studies.
With the progression of aging, age-dependent obesity and metabolic disorders have garnered increasing attention, yet their underlying mechanisms remain poorly understood. Dysregulation of iron homeostasis is strongly linked to aging; however, its role in age-dependent obesity remains unclear. As the hypothalamus, a key regulator of energy homeostasis, plays a pivotal role in metabolic regulation during aging, we investigated whether hypothalamic iron accumulation contributes to age-dependent obesity. We first observed elevated iron levels in the hypothalamus of aged mice, particularly in the arcuate nucleus. To test whether reducing iron could mitigate obesity, we intranasally administered the iron chelator deferiprone to aged mice and found that it effectively lowered hypothalamic iron levels and ameliorated metabolic function. Using a ferric ammonium citrate-induced iron overload cell model, we discovered that excess iron triggers mitochondrial dysfunction and oxidative stress, leading to ROS-dependent nuclear translocation of forkhead box protein O1 (FoxO1) and subsequent upregulation of AgRP expression. To confirm this mechanism in vivo, we generated agouti-related peptide (AgRP) neuron-specific transferrin receptor 1(Tfrc) knockout mice and found that reducing iron uptake in these neurons decreased ROS levels, inhibited FoxO1 nuclear translocation, and suppressed AgRP neuronal activity in aged mice.
3. Adrenal imaging features and associated pathologic diagnoses: A contemporary, longitudinal analysis.
In 250 adrenalectomy specimens, no malignant lesion had ≤20 HU on unenhanced CT or exhibited MRI signal loss, while malignancy risk rose to 31% for lesions >20 HU. Size >4 cm alone had low specificity; notably, many malignant lesions were <4 cm. A ≤20 HU threshold best identified benign pathology and could avoid unnecessary adrenalectomy in nearly half of benign cases.
Impact: Provides contemporary, pathology-anchored evidence supporting ≤20 HU on unenhanced CT as a reliable benign criterion and cautions against size-only thresholds, directly informing adrenal incidentaloma workups.
Clinical Implications: Adopt ≤20 HU on unenhanced CT as a strong benign feature and avoid relying on size >4 cm alone for malignancy risk. Integrate HU thresholds with MRI chemical shift and clinical context to reduce unnecessary adrenalectomy and improve triage.
Key Findings
- Among 250 adrenalectomy specimens, 21% were malignant and 79% benign; malignant lesions were larger on average.
- No malignant lesion had ≤20 HU on unenhanced CT or loss of signal on MRI; malignancy rate was 31% for lesions >20 HU.
- Size >4.0 cm alone had low specificity; 13.6% of adrenocortical carcinomas and 63.3% of other malignant lesions were <4.0 cm.
- A ≤20 HU threshold best identified benign lesions; 48% of benign lesions could be accurately classified as benign on imaging.
Methodological Strengths
- Relatively large, contemporary series with pathological gold standard correlation.
- Systematic assessment of multiple imaging criteria (HU thresholds, washout, MRI signal).
Limitations
- Retrospective, single-center design with potential selection bias (pheochromocytomas and incidental adrenalectomies excluded).
- Lack of external validation; generalizability across scanners and protocols may vary.
Future Directions: Prospective, multi-center validation of the ≤20 HU criterion integrated with MRI chemical shift and clinical predictors; develop decision tools to minimize unnecessary surgery.
BACKGROUND: Imaging features are key in preoperative risk assessment of adrenal nodules, but current recommendations stem from low quality evidence. This study evaluates the performance of cross-sectional imaging features in predicting adrenal pathology. METHODS: All adult adrenalectomy cases (2015-2023) with preoperative cross-sectional imaging were retrospectively reviewed; pheochromocytomas and incidental adrenalectomies were excluded. Benign imaging features were defined as size ≤4.0 cm; Hounsfield units ≤10, or Hounsfield units ≤20 on unenhanced computed tomography; absolute and relative contrast washout ≥60% and ≥40%, respectively, on adrenal protocol computed tomography; and loss of signal or homogeneity on T1-weighted magnetic resonance imaging. Performance of imaging features in identifying benign and malignant adrenal pathology were analyzed. RESULTS: Among the 250 adrenal specimens included, 21% were malignant, with 22 adrenocortical carcinomas and 30 other malignant lesions, whereas 79% were benign. Compared to benign, malignant lesions were larger (6.8 cm vs 4.4 cm, P = .002) and none had densities of ≤20 Hounsfield units on unenhanced computed tomography scan or loss of signal on magnetic resonance imaging.