Daily Endocrinology Research Analysis
Zonal hepatic insulin signaling was shown to differentially control glucose and lipid metabolism, suggesting new therapeutic strategies that decouple steatosis from glycemic control. A large prospective study revealed a high prevalence of hypercortisolism among individuals with difficult-to-control type 2 diabetes, supporting targeted endocrine screening. Early-life BMI trajectories in genetically confirmed monogenic obesity were characterized, yielding a practical diagnostic cut-off at age two.
Summary
Zonal hepatic insulin signaling was shown to differentially control glucose and lipid metabolism, suggesting new therapeutic strategies that decouple steatosis from glycemic control. A large prospective study revealed a high prevalence of hypercortisolism among individuals with difficult-to-control type 2 diabetes, supporting targeted endocrine screening. Early-life BMI trajectories in genetically confirmed monogenic obesity were characterized, yielding a practical diagnostic cut-off at age two.
Research Themes
- Hepatic insulin zonation and metabolic compartmentalization
- Endocrine screening in difficult-to-control type 2 diabetes
- Early diagnostic markers in monogenic obesity
Selected Articles
1. Spatial regulation of glucose and lipid metabolism by hepatic insulin signaling.
Using zonally targeted genetic disruption of hepatic insulin signaling, the authors show periportal insulin resistance increases gluconeogenesis but paradoxically reduces lipogenesis and steatosis, whereas pericentral insulin resistance lowers pericentral steatosis without impairing glucose control. A shift of glycolytic flux from liver to muscle contributes to preserved glucose homeostasis under pericentral insulin resistance.
Impact: This work disentangles zonal insulin actions in the liver, revealing therapeutic opportunities to reduce steatosis without worsening glycemia. It challenges the prevailing view that hepatic insulin resistance uniformly drives both hyperglycemia and lipogenesis.
Clinical Implications: Although preclinical, targeting pericentral hepatocyte insulin signaling or mimicking its downstream adaptations may offer strategies to attenuate hepatic steatosis without compromising glycemic control in type 2 diabetes and fatty liver disease.
Key Findings
- Periportal insulin resistance increased gluconeogenesis and circulating insulin yet impaired lipogenesis and reduced HFD-induced hepatosteatosis.
- Pericentral insulin resistance decreased pericentral steatosis while maintaining normal glucose homeostasis, partly by shifting glycolytic metabolism from liver to muscle.
- Insulin exerts distinct, zone-specific roles in hepatic metabolism, implying that selective modulation of zonal signaling can uncouple steatosis from hyperglycemia.
Methodological Strengths
- Zonal (periportal vs pericentral) CreER-mediated selective disruption of insulin signaling enabling causal inference.
- Physiological assessments under high-fat diet with multi-tissue metabolic readouts.
Limitations
- Findings are from mouse models; translatability to humans remains to be established.
- Potential Cre driver off-target effects and limited temporal resolution were not fully addressed.
Future Directions: Test pharmacologic or genetic strategies that selectively modulate pericentral insulin signaling in larger animals and human tissues; integrate single-cell spatial omics to map downstream pathways enabling steatosis-glycemia uncoupling.
Hepatic insulin sensitivity is critical for systemic glucose and lipid homeostasis. The liver is spatially organized into zones in which hepatocytes express distinct metabolic enzymes; however, the functional significance of this zonation to metabolic dysregulation caused by insulin resistance is undetermined. Here, we used CreER mice to selectively disrupt insulin signaling in periportal (PP) and pericentral (PC) hepatocytes. PP-insulin resistance has been suggested to drive combined hyperglycemia and excess lipogenesis in individuals with type 2 diabetes. However, PP-insulin resistance in mice impaired lipogenesis and suppressed high-fat diet (HFD)-induced hepatosteatosis, despite elevated gluconeogenesis and insulin. In contrast, PC-insulin resistance reduced HFD-induced PC steatosis while preserving normal glucose homeostasis, in part by shifting glycolytic metabolism from the liver to the muscle. These results demonstrate distinct roles of insulin in PP versus PC hepatocytes and suggest that PC-insulin resistance might be therapeutically useful to combat hepatosteatosis without compromising glucose homeostasis.
2. Early childhood height, weight, and BMI development in children with monogenic obesity: a European multicentre, retrospective, observational study.
In 147 children with genetically confirmed monogenic obesity, biallelic variants produced distinct early BMI trajectories: a steep rise in year one and a plateau thereafter (LEP/LEPR/MC4R), with accelerated linear growth only in biallelic MC4R. A BMI threshold around 24 kg/m2 at age two discriminated biallelic variants from controls.
Impact: Provides actionable growth-based criteria for early recognition of monogenic obesity subtypes, enabling timely genetic testing and targeted therapy (e.g., setmelanotide).
Clinical Implications: In children with severe early-onset obesity, a BMI ≥24 kg/m2 at age two and specific growth patterns should prompt evaluation for biallelic leptin–melanocortin pathway variants and consideration of precision therapies.
Key Findings
- From 6 months onward, biallelic LEP/LEPR/MC4R/POMC variants had substantially higher BMI than monoallelic MC4R and control children.
- Biallelic LEP/LEPR/MC4R variants showed a steep first-year BMI rise followed by a plateau to age 5, whereas biallelic POMC did not plateau.
- Accelerated linear growth occurred only in biallelic MC4R starting at age 1 year.
- A BMI cut-off of approximately 24 kg/m2 at age 2 optimized discrimination of biallelic variants from controls.
Methodological Strengths
- Multicentre dataset with genetically confirmed diagnoses across multiple loci.
- Comparative trajectories versus sequencing-negative obese controls and diagnostic performance analysis.
Limitations
- Retrospective design with heterogeneous measurement schedules across centres.
- Potential referral bias toward more severe phenotypes; external validation needed.
Future Directions: Prospective validation of the BMI cut-off in diverse populations, integration with early endocrine biomarkers, and evaluation of impacts on timing and outcomes of genetic testing and targeted therapies.
BACKGROUND: Monogenic defects in the leptin-melanocortin pathway are associated with hyperphagia and severe, early-onset obesity. Early childhood growth patterns in height, weight, and BMI, might serve as phenotypic markers for specific genetic disorders; however, reliable data are scarce. This study aimed to evaluate the natural history of height, weight, and BMI in early childhood in a large European group of individuals with monogenic obesity. METHODS: This multicentre observational study analysed height, weight, and BMI from birth to age 5 years in individuals diagnosed with biallelic (likely) pathogenic LEP, LEPR, POMC, PCSK1, or MC4R variants or monoallelic (likely) pathogenic MC4R variants from six European centres (Berlin and Ulm, Germany; Cambridge, UK; Madrid, Spain; Paris, France; Rotterdam, Netherlands). All patient data up to May 31, 2022 were included in this analysis. All individuals had at least two height or weight measurements between birth and age 5 years. Early childhood growth trajectories were compared with those of control children with obesity without a known genetic cause, following a negative next-generation sequencing panel. Diagnostic performance of BMI as a predictor test for monogenic obesity was also evaluated. FINDINGS: We included 147 individuals with monogenic obesity. From the age of 6 months onwards, children with biallelic variants (n=88, 55% female vs 45% male) had substantially higher BMIs than those with monoallelic MC4R variants (n=59, 53% female vs 47% male) and control children (n=113, 59% female vs 41% male). Children with biallelic LEP, LEPR, and MC4R variants showed a steep BMI increase during the first year of life, followed by a plateau until age 5 years, whereas those with biallelic POMC variants did not plateau. Accelerated linear growth was only observed in children with biallelic MC4R variants starting from age 1 year. The optimal BMI cut-off for distinguishing individuals with biallelic variants from control individuals was identified at age 2 years, with a test positivity cutoff of 24·0 kg/m INTERPRETATION: This study identified characteristic early childhood BMI trajectories for different forms of monogenic obesity. From age 6 months onwards, individuals with biallelic variants can be distinguished from those with monoallelic variants and common obesity. A BMI ≥24 kg/m FUNDING: Federal Ministry of Education and Research as part of the German Center for Child and Adolescent Health, German Research Foundation, Spanish Ministry of Health, The Wellcome Trust, Botnar Fondation, Leducq Foundation, National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, and NIHR Senior Investigator Award.
3. Prevalence of Hypercortisolism in Difficult-to-Control Type 2 Diabetes.
Among 1,057 individuals with difficult-to-control type 2 diabetes, 23.8% had unsuppressed cortisol after a 1-mg DST, with higher prevalence in those with cardiac disorders or taking ≥3 antihypertensive drugs. One-third of hypercortisolemic participants had adrenal imaging abnormalities, and several clinical and medication factors were associated with higher prevalence.
Impact: Quantifies a substantial burden of hypercortisolism in refractory type 2 diabetes using standardized DST screening, supporting targeted endocrine evaluation in a large at-risk population.
Clinical Implications: Consider dexamethasone suppression testing for patients with inadequately controlled diabetes, especially those with cardiac disease or multiple antihypertensives, to detect hypercortisolism and guide evaluation for adrenal pathology.
Key Findings
- Hypercortisolism (post-DST cortisol >1.8 μg/dL) was present in 23.8% (252/1,057) of difficult-to-control T2D participants.
- Prevalence was higher in those with cardiac disorders (33.3%) and in participants on ≥3 antihypertensive medications (36.6%).
- Adrenal imaging abnormalities were observed in 34.7% of participants with hypercortisolism; multiple factors (e.g., SGLT2i, GLP-1RA at maximal dose, tirzepatide, older age, BMI <30, non-Latino/Hispanic ethnicity) were associated with higher prevalence.
Methodological Strengths
- Prospective, predefined screening protocol with exclusion of common DST false positives.
- Large sample with multivariable modeling to identify associated factors and imaging correlation.
Limitations
- Observational design limits causal inference; DST threshold and single-time testing may miss cyclic hypercortisolism.
- Generalizability to broader T2D populations and medication confounding require further study.
Future Directions: Evaluate diagnostic algorithms that integrate DST with late-night salivary cortisol and imaging; conduct interventional studies assessing glycemic outcomes after treating identified hypercortisolism.
OBJECTIVE: Despite the use of multiple glucose-lowering medications, glycemic targets are not met in a significant fraction of people with type 2 diabetes. In this prospective, observational study we assessed the prevalence of hypercortisolism, a potential contributing factor to inadequate glucose control. RESEARCH DESIGN AND METHODS: Individuals with type 2 diabetes and HbA1c 7.5%-11.5% (58-102 mmol/mol) on two or more glucose-lowering medications with or without micro-/macrovascular complications or taking multiple blood pressure-lowering medications were screened with a 1-mg dexamethasone suppression test. Common causes of false-positive DSTs were excluded. The primary end point was the prevalence of hypercortisolism, defined as post-DST cortisol >1.8 μg/dL (50 nmol/L). Characteristics associated with hypercortisolism were assessed with multiple logistic regression. The percentage and characteristics of participants with hypercortisolism and adrenal imaging abnormalities were also assessed. RESULTS: Post-DST cortisol was unsuppressed in 252 of 1,057 participants (prevalence 23.8%; 95% CI 21.3, 26.5). Hypercortisolism prevalence was 33.3% among participants with cardiac disorders and 36.6% among those taking three or more blood pressure-lowering medications. Adrenal imaging abnormalities were reported in 34.7% of participants with hypercortisolism. Use of sodium-glucose cotransporter 2 inhibitors (odds ratio 1.558), maximum-dose glucagon-like peptide 1 receptor agonists (1.544), tirzepatide (1.981), or a higher number of blood pressure-lowering medications (1.390); older age (1.316); BMI <30 kg/m2 (1.639); non-Latino/Hispanic ethnicity (3.718); and use of fibrates (2.676) or analgesics (1.457) were associated with higher prevalence (all P < 0.03). CONCLUSIONS: Hypercortisolism was associated with hyperglycemia in approximately one-quarter of individuals with inadequately controlled type 2 diabetes despite multiple medications.