Daily Endocrinology Research Analysis

Interrupting glucagon signaling decreases gluconeogenesis and the fractional extraction of amino acids by liver from blood, resulting in lower glycemia. The resulting hyperaminoacidemia stimulates α cell proliferation and glucagon secretion via a liver/α cell axis. We hypothesized that α cells detect and respond to circulating amino acids' levels via a unique amino acid transporter repertoire. We found that Slc7a2/SLC7A2 is the most highly expressed cationic amino acid transporter in α cells, with its expression being 3-fold greater in α than β cells in both mouse and human. Employing cell culture, zebrafish, and knockout mouse models, we found that the cationic amino acid arginine and SLC7A2 are required for α cell proliferation in response to interrupted glucagon signaling. Ex vivo and in vivo assessment of islet function in Slc7a2-/- mice showed decreased arginine-stimulated glucagon and insulin secretion. We found that arginine activation of mTOR signaling and induction of the glutamine transporter SLC38A5 was dependent on SLC7A2, showing that the role of both in α cell proliferation is dependent on arginine transport and SLC7A2. Finally, we identified single nucleotide polymorphisms in SLC7A2 associated with HbA1c. Together, these data indicate a central role for SLC7A2 in amino acid-stimulated α cell proliferation and islet hormone secretion.

BACKGROUND: Central precocious puberty (CPP), which is traditionally defined as the development of secondary sexual characteristics before age 8 years in girls and age 9 years in boys, results from the premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. CPP can be associated with short adult stature, adverse psychosocial outcomes, and increased cardiometabolic and cancer risks in adulthood. Gonadotropin-releasing hormone (GnRH) agonists can effectively suppress premature activation of the HPG axis and have the potential to increase adult height as well as improve psychosocial and long-term health outcomes among patients with CPP. However, as secular trends have continued to shift toward earlier age of pubertal onset, some subpopulations of children with CPP, as it is currently defined, may not require the same extent of diagnostic evaluation and treatment. OBJECTIVE: Develop evidence-based recommendations related to the diagnosis and treatment of CPP. METHODS: A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to address 10 clinical questions related to the diagnosis and treatment of CPP. Systematic reviews of health-related benefits and harms were conducted for each clinical question. The guideline development panel (GDP) also used the GRADE evidence-to-decision (EtD) framework to address stakeholder values and preferences, costs and required resources, cost-effectiveness, acceptability, feasibility, and potential impacts on health equity. RESULTS: In girls with thelarche (Tanner stage B2) between ages 7.0 and 8.0 years, the GDP suggests watchful waiting via periodic physical examinations (every 4-6 months) rather than immediately performing evaluation with laboratory testing or radiologic imaging. In addition, the GDP suggests that all girls with breast development (ie, Tanner stage B2) before age 7 years should first be observed for 4 to 6 months to differentiate unsustained or slowly progressive puberty vs rapidly progressive puberty. These recommendations are largely based on evidence that girls with slowly progressive puberty attain a normal adult height without treatment. When hormonal evaluation is performed to confirm central (GnRH-dependent) activation as the cause of precocious puberty, the GDP suggests starting the evaluation with ultrasensitive basal luteinizing hormone (LH) concentration rather than routine GnRH/GnRH agonist (GnRHa) stimulation testing for all patients. While brain magnetic resonance imaging has been a traditional part of CPP evaluation, the GDP suggests that it should not be routinely performed in girls ages 6.0 to 8.0 years and boys ages 8.0 to 9.0 years without central nervous system (eg, neuro-ophthalmologic) symptoms, largely based on a low prevalence of pathologic intracranial findings in these age groups. The GDP suggests against routine genetic testing for patients with CPP, although they judged that genetic testing (eg, MKRN3 sequencing) should be considered for patients with familial CPP through a shared decision-making process. The GDP suggests GnRHa treatment for many children with CPP, although available evidence suggests that some patient subgroups (eg, older girls with slowly progressive CPP) may be less likely to receive a net benefit with this treatment. Rather than always starting GnRHa treatment with a monthly injectable formulation, the GDP suggests that treatment should be initiated with the formulation (such as a longer-acting formulation) that is anticipated to be used long-term. The GDP suggests against routine addition of growth hormone therapy to increase adult height. They also suggest against the routine biochemical testing (eg, LH, sex steroids) to monitor pubertal suppression while receiving GnRHa, instead reserving biochemical testing to confirm clinically suspected treatment failure. Finally, the GDP suggests against routinely continuing GnRHa treatment beyond chronologic age 10.0 to 11.0 years (girls) or 11.0 to 12.0 years (boys) and/or bone age 11.0 to 12.0 years (girls) or 12.0 to 13.0 years (boys). CONCLUSION: These clinical recommendations were developed to address important uncertainties in the diagnosis and treatment of children with CPP. They are based on the best available scientific evidence regarding clinical outcomes judged to be most important to patients and families. The GDP's overarching goal was to suggest diagnostic and therapeutic strategies that will most likely provide net clinical benefits while simultaneously considering important contextual factors such as cost and feasibility. The guideline-development process highlighted important knowledge gaps and the substantial need for additional research.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) leads to life-long exposure to high low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease. Evidence supporting initiation of cholesterol-lowering medication (CLM) in childhood to lower this cumulative cholesterol burden and cardiovascular sequelae is sparse. This study assessed the long-term impact of contemporary management of FH on LDL-C and cardiovascular events. METHODS: Observational prospective cohort study (SAFEHEART) including children/adolescents (age <18 years) with genetically confirmed heterozygous FH (FH-Ch), their non-affected children and adolescents' relatives (non-FH-Ch), and FH parents (FH-P). Impact of CLM, LDL-C burden, and cardiovascular events were assessed. RESULTS: Overall, 348 FH-Ch, 165 non-FH-Ch and 288 FH-P were included (49.8% female; median untreated LDL-C: 5.46, 2.63, and 7.19 mmol/L, respectively). Median follow-up was 12.4 years (interquartile range 9.6-15.3). At follow-up, 84.5% FH-Ch, 4.2% non-FH-Ch, and 95.1% FH-P were receiving CLM. FH-Ch started therapy at a median age of 14.5, vs. 36.1 years in their FH-P. Latest on-treatment LDL-C was 3.00 mmol/L in FH-Ch (median change: -2.60 mmol/L, -47.4%) and 2.44 mmol/L in FH-P (-4.72 mmol/L, -67.6%); LDL-C among non-FH-Ch (not on CLM) was 2.72 mmol/L. By age 30-40 years, median LDL-C burden over life was 5909.0 and 10 206.8 mg/dL*years among FH-Ch and FH-P, respectively. By age 39 years, rate of cardiovascular events was 0.0%, 0.3% and 5.2% among non-FH-Ch, FH-Ch, and FH-P, respectively. CONCLUSIONS: Treatment of FH from childhood/adolescence reduces the cumulative LDL-C burden compared with later onset treatment from adulthood in affected parents and permits attainment of LDL-C levels close to non-FH individuals; this finding was associated with the observation of a reduction in the cardiovascular risk of young FH patients. These findings support FH as a paediatric condition requiring early-life detection and treatment. STUDY REGISTRATION NUMBER: ClinicalTrials.gov, NCT02693548.