👤 M Cristina Maggio

Cholesteryl ester transfer protein (CETP) inhibitors, initially developed for treating hyperlipidemia, have shown promise in reducing the risk of new-onset diabetes during clinical trials. This positions CETP inhibitors as potential candidates for repurposing in metabolic disease treatment. Given their oral administration, they could complement existing oral medications like sodium-glucose cotransporter 2 (SGLT2) inhibitors, potentially delaying the need for injectable therapies such as insulin. We conducted a 2x2 factorial Mendelian Randomization analysis involving 233,765 participants from the UK Biobank. This study aimed to evaluate whether simultaneous genetic inhibition of CETP and SGLT2 enhances glycemic control compared to inhibiting each separately. Our findings indicate that dual genetic inhibition of CETP and SGLT2 significantly reduces glycated hemoglobin levels compared to controls and single-agent inhibition. Additionally, the combined inhibition is linked to a lower incidence of diabetes compared to both the control group and SGLT2 inhibition alone. These results suggest that combining CETP and SGLT2 inhibitor therapies may offer superior glycemic control over SGLT2 inhibitors alone. Future clinical trials should investigate the potential of repurposing CETP inhibitors for metabolic disease treatment, providing an oral therapeutic option that could benefit high-risk patients before they require injectable therapies like insulin or glucagon-like peptide-1 (GLP-1) receptor agonists. Show less

Obesity is a chronical disease, which leads to multiple short- and long-term complications. 4% of Swiss children and adolescents are obese. A prompt diagnosis and multicomponent lifestyle intervention is mandatory to avoid persistence of the disease into adulthood. Growth and BMI charts are still the essential tools to diagnose and define the etiology of obesity. A precocious and severe obesity, accompanied by hyperphagia, will raise the suspicion of monogenic obesity. The precise molecular diagnosis enables in some patients the use of a specific treatment. Leptine in case of LEP gene defects, or setmelanotide when the affected gene is part of the MC4R signaling pathway (LEPR, POMC, PCSK1). Show less

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance. Show less

Aim of this study is to report on basal clinical phenotype and follow up after diagnosis, of patients with 17beta-hydroxysteroid-dehydrogenase type 3 (17beta-HSD3) deficiency in Italy. Pediatric Endocrine Departments, University Hospitals. The cases of 5 Italian subjects affected by 17beta-HSD3 deficiency are presented in this study. Laboratory and genetic assessment. Gonadectomy and female sex assignment (4 patients) or GnRH analog therapy to regress puberty and gender identity disorder (1 patient). Presentation lasted from pregnancy (pre-natal diagnosis of a 46,XY fetus with female external genitalia) to infancy (inguinal hernia containing testes/clitoromegaly) and adolescence (virilisation). All subjects but one (subject 1, Central-Northern Italy) were from small areas of Southern Italy. Endocrine data (baseline and/or stimulated testosterone/ Delta4-androstenedione ratio) were informative. Two girls were homozygous for 17beta-HSD3 gene mutations (G289S/G289S; R80W/R80W), while the others were compound heterozygous (IVS325+4 A>T/A203V; L212Q/M235V; R80W/A235E). Four patients were confirmed as females and were well-adjusted with assigned sex; gender identity disorder improved during treatment with GnRH analog in the last subject. 17betaHSD3 deficiency may present from pregnancy to puberty for different clinical issues. Albeit testosterone/Delta4-androstenedione ratio represents the most accurate endocrine marker to diagnose the disorder, hCGstimulation is mandatory in pre-puberty. Molecular analysis of 17beta-HSD3 gene should be performed to confirm the diagnosis. Temporary GnRH analog treatment may regress gender identity disorder and provide time to confirm or change the birth sex assignment. Female individuals seems to be compliant with their sex, providing that virilisation does not occur. In Italy, the disorder seems to be more prevalent in the Southern regions and shows genetic heterogeneity. Show less

Deficiency of 17beta-hydroxysteroid dehydrogenase type 3 (17beta-HSD3), due to mutations in the gene encoding the enzyme, results in a rare autosomal recessive form of male-to-female sex reversal. Mutated genes encode an abnormal enzyme with absent or reduced ability to convert Delta4-androstenedione to testosterone in the testis. Affected individuals are genetically males who developed internal male Wolffian structures but female external genitalia. Such individuals are usually raised as females and diagnosis is made at puberty, when they show virilization. Correct diagnosis is mandatory to optimize treatment and follow-up. In the present paper we report the clinical history, endocrine evaluation and molecular genetics of a prepubertal girl affected by 17beta-HSD3 deficiency, in whom an erroneous diagnosis of androgen insensitivity syndrome was made. The clinical, endocrine and genetic features of 17beta-HSD3 deficiency are also reviewed. Show less