Abstract Human glucokinase (GCK) catalyzes the rate-limiting step of β-cell glycolysis and serves as a critical glucose sensor in the regulation of glucose homeostasis. Variants in GCK are a leading cause of maturity-onset diabetes of the young (MODY), accounting for 30-50% of MODY cases depending on the population studied. Clinical management of GCK-MODY during pregnancy poses particular challenges, as the fetal genotype, which influences fetal insulin secretion and growth, is typically unknown in utero. In this report, we present a case of GCK-MODY identified during pregnancy and provide a mechanistic assessment of the functional impact of a variant of uncertain significance (VUS). We identified a novel heterozygous in-frame indel VUS (NM_000162.5:c.311_325delinsTCCCCGAGGACG - p.(Lys104_Ser109delinsIleProGluAspAla) in GCK in a patient initially managed as type 2 diabetes. The affected region lies within a β-strand of the small domain that undergoes a major conformational transition during enzyme activation and is known to be intolerant of sequence variation. Structural modeling and molecular dynamics simulations reveal that this variant disrupts normal movement of the small domain, alters coordinated residue fluctuations, and impairs inter-domain communication during the activation process. These perturbations are accompanied by pronounced protein destabilization and a trend toward weaker ATP interaction, consistent with a loss-of-function mechanism. These findings provide a mechanistic framework for interpreting this novel variant, expanding the known genotypic spectrum of GCK-MODY, and may inform future structure-guided strategies for GCK-targeted therapeutics.
Abstract Kallmann syndrome (KS) is a rare form of congenital hypogonadotropic hypogonadism (CHH) that causes delayed puberty and infertility, accompanied by a lifelong loss of smell. While hormone replacement therapy restores (HRT) standard hormone levels, the specific impact of an absent sense of smell on sexual relationships and desire remains largely unstudied. This study examined how lifelong smell loss shapes the psychosexual experiences of affected individuals. 38 adults were evaluated: 19 patients receiving stable HRT (10 with KS who lacked a sense of smell and 9 with CHH but normal smell) and 19 healthy matched individuals. Participants completed validated questionnaires assessing sexual desire, physical arousal, romantic behaviors, and attitudes toward intimacy. HRT effectively restored baseline sexual desire and general attitudes across all patients. However, individuals with KS reported significantly lower physical sexual arousal and engaged in far fewer sexual behaviors than those with an intact sense of smell. The lack of smell independently predicted lower arousal levels, despite patients maintaining normal mental desire and positive attitudes toward sex. These findings show that hormone therapy alone is insufficient to fully restore the sexual experience in KS. The lifelong absence of smell creates a distinct divide between mental desire and physical arousal, undermining sexual confidence and intimacy. Healthcare providers should therefore incorporate psychosexual counseling into routine clinical care to help patients navigate these sensory and emotional challenges.
Abstract Context Congenital hyperinsulinism (HI) with polycystic kidney disease (PKD), or HIPKD is a recently described syndrome caused by a specific promotor variant in PMM2, a gene otherwise associated with PMM2 congenital disorder of glycosylation (PMM2-CDG). Objective To describe the HIPKD clinical phenotype, expanding our understanding and its distinction from the CDG phenotype. Design Retrospective multicentre cohort study of individuals with HIPKD identified through an international HI genetic referral centre. Patients 10 individuals from 9 families compound heterozygous for the promoter variant c.-167G>T and a pathogenic intragenic variant in PMM2. Intervention None Main Outcome Measures Observed clinical features and outcomes. Results Median age of presentation was 5 months (range 0-42). Median age at follow up was 12.7 years (range 5.4-20.1). HI was managed with diazoxide monotherapy (7/10 patients), diazoxide and nifedipine (2/10 patients) and carbohydrate supplementation alone (1/10 patient). PKD age at diagnosis and severity was variable, ranging from antenatal presentation requiring renal transplantation, to incidental detection in mid-childhood. Liver cysts were noted in 6/10 patients (5/6 with normal liver function). 5/7 patients had systemic hypertension and 3/5 were normotensive on losartan at last follow up. IBD with gastric antral foveolar hyperplasia occurred in 4/10 patients, and aortic root and/or ascending aortic dilatation in 4/7 patients who underwent echocardiography, 3 of whom also had IBD. Conclusions HIPKD due to a PMM2 promoter variant is associated with broad, multisystem phenotype, including IBD and aortic dilatation. These findings support targeted screening for IBD and cardiovascular surveillance in addition to standard endocrine and renal follow-up.
Abstract Aim We wanted to investigate whether the lipodystrophy (LD)-like phenotype increases mortality in type 2 diabetes. To this end we first developed and confirmed the triglyceride/BMI ratio (TBR index) as an inexpensive and widely available marker of the LD-like metabolic phenotype. The TBR index was then tested for association with all-cause mortality in patients with type 2 diabetes. Research Design and Methods Associations between TBR and mortality were assessed by Cox in three type 2 diabetes cohorts (n = 2,137, n = 960 and n = 5,060). A 20-SNP genotype risk score (GRS), associated with LD-like phenotype was investigated to identify the molecular basis of TBR variability. Main finding In all cohorts, the highest TBR decile showed features of LD-like phenotype, including atherogenic dyslipidemia, lower BMI, worse glycemic control, insulin resistance, elevated gamma-glutamyl transferase and hypoadiponectinemia. In the metanalysis, decile 10 had higher mortality risk (HR = 1.46, P < 0.0001). Finally, in a subset of one of the three cohorts, the LD-like GRS was significantly associated with TBR. Conclusions The TBR is a novel, inexpensive and easily available marker that identifies a subgroup of type 2 diabetes patients with a LD-like phenotype, partly explained by genetic factors. Our findings help disentangle the heterogeneity of death risk in diabetes, refine diagnostic and follow-up algorithms and enable specific treatments for improving long-term outcomes in LD-like individuals.
Abstract Background Osteoporosis is a well-recognised complication of primary hyperparathyroidism (PHPT). We aim to develop an osteoporosis prediction model for PHPT patients using opportunistic CT-derived Hounsfield unit (HU) measurements from sestamibi SPECT/CT. Methods Sestamibi SPECT/CT images from 81 PHPT patients (60 with and 21 without osteoporosis diagnosed by dual-energy x-ray absorptiometry) were analysed retrospectively. HU of vertebral bodies were measured. Receiver operating characteristics (ROC) analysis was performed to determine the optimal HU cutoff for each vertebra in predicting osteoporosis. Multivariable logistic regression was used to identify independent clinical parameters associated with osteoporosis. A prediction model based on clinical parameters alone was built. Another prediction model was constructed by further incorporating the HU of the vertebra. Model performance improvement was assessed. Results Age and body mass index (BMI) were independent risk factors for osteoporosis. The clinical prediction model (age and BMI) achieved an area under ROC (AUROC) of 0.874. Incorporation of HU of T4 vertebra into the clinical model showed the best performance with AUROC 0.966, sensitivity 98.2% and specificity 85.7%, representing a significant improvement in prediction with change in C-statistics 0.092 (95%CI 0.021–0.163, p = 0.011), net reclassification index 0.346 (0.041–0.650, p = 0.026) and incremental discrimination index 0.329 (0.116–0.542, p = 0.003). After bootstrap internal validation, the optimism-corrected AUROC was 0.949 (0.882–1.000). Conclusion Our study demonstrated the feasibility of integrating vertebral HU measurements from sestamibi SPECT/CT into a clinical prediction model for accurately identifying osteoporosis in PHPT patients, offering a potential tool for efficient bone health management and prioritising timely surgical interventions.
