Daily Endocrinology Research Analysis

BACKGROUND: Primary laminopathies are a heterogeneous group of rare diseases caused by nuclear lamina dysfunction due to pathogenic LMNA variants. However, despite their ubiquitous expression, LMNA variants have rarely been linked to chronic kidney disease (CKD). Here, we systematically investigate clinical implications and functional underpinnings of a distinct LMNA missense variant (lamin A/C p.(Arg349Trp)) that has sporadically been found in patients with a complex phenotype including lipodystrophy, proteinuria, and focal segmental glomerulosclerosis (FSGS). METHODS: In clinical and functional terms, we compare lamin A/C Arg349Trp with missense changes at Arg482, the most common hotspot residue for type 2 familial partial lipodystrophy (FPLD2). In particular, we assess renal endpoints in corresponding patient cohorts and investigate disease-associated alterations in vitro. RESULTS: In contrast to FPLD2 patients, individuals with lamin A/C Arg349Trp experience high-grade proteinuria and a rapid decline of glomerular filtration rate with kidney failure at a median age of 43 years. Mechanistically, we demonstrate that Arg349Trp associates with an abrogation of the structural interaction between lamin A/C and nucleoporin 155, nuclear pore complex aggregation, and an alteration of TGF-β1-dependent signaling. CONCLUSIONS: While patients with Lamin A/C Arg482 missense changes are at very low risk for progressive CKD, patients harboring Arg349Trp show nephrotic range proteinuria and kidney failure in midlife. Hence, high-grade proteinuric kidney disease is genotype-specific and patients with the Arg349Trp substitution require early renoprotective intervention to potentially halt progression and prevent kidney failure. FUNDING: German Research Foundation, project IDs 502928386, 445703531, and grants HA 9779/2-1, HA 6908/4-1, HA 6908/7-1, HA 6908/8-1, HA 6908/12-1.

OBJECTIVE: G protein-coupled receptor 180 (GPR180) has been implicated in systemic energy metabolism, primarily in adipose tissue and the liver. Given impaired whole-body glucose tolerance following GPR180 dysfunction, we aimed to determine whether GPR180 regulates pancreatic β-cell function. We investigated whether GPR180 contributes to β-cell insulin secretion by modulating metabolic processes that couple glucose sensing to mitochondrial energy production. METHODS: Phenotyping of whole-body (Gpr180 RESULTS: Loss of GPR180 impaired first-phase insulin secretion and glucose tolerance without affecting insulin sensitivity. These defects were β-cell-autonomous, as confirmed in the bGpr180-KO mice and in MIN6 cells. Functional studies revealed that GPR180 regulates mitochondrial substrate utilization, anaplerotic support of the TCA cycle, and ATP generation without affecting glucose uptake or mitochondrial biogenesis. In particular, Gpr180-deficient β cells showed mitochondrial membrane depolarization, reduced oxygen consumption, and endoplasmic reticulum remodeling, altering the local mitochondrial microenvironment. In vivo, Gpr180 deletion in β cells led to downregulation of mitochondrial gene programs in islets, along with altered endocrine cell identity. CONCLUSIONS: GPR180 is a previously unrecognized regulator of pancreatic β-cell metabolic competence and identity, linking defects in insulin secretion with alterations in mitochondrial function and endocrine cell identity.

OBJECTIVE: To identify glycemic trajectories following automated insulin delivery (AID) initiation in youth with type 1 diabetes and associated factors. RESEARCH DESIGN AND METHODS: We used group-based trajectory modeling to characterize groups for time in range (TIR) and hemoglobin A1c (HbA1c), measured at baseline and at 3, 6, 12, and 18 months of AID use, in 713 youth (ages 6-18). Multinomial logistic regression estimated associations between clinical and sociodemographic predictors and glycemic trajectories. RESULTS: Four TIR and three HbA1c trajectories emerged. All trajectories showed rapid improvement from baseline to 3 months, continued but gradual improvement between 3 and 6 months, followed by waning or sustained improvements after 6 months. Only a small subset (group 4, 12.7%) achieved TIR ≥70%, although more (43.3%) reached an HbA1c <7%. In the TIR model after adjusting for age, sex, type 1 diabetes duration, and prior treatment, participants with fewer user-initiated boluses (odds ratio [OR] 2.46; 95% CI 1.78, 3.39), higher insulin doses/kg (OR 1.54; 95% CI 1.25, 1.91), and fewer appointments (OR 2.69; 95% CI 1.21, 6.00) had higher odds of membership in the lowest TIR group (group 1) than in the highest TIR group (group 4). In the HbA1c model, lower baseline insulin doses/kg and more boluses were associated with membership in the most optimal group. CONCLUSIONS: Distinct glycemic trajectories exist following AID initiation, with all groups experiencing rapid early improvements in TIR and HbA1c that plateau or decline over time. Baseline bolus frequency and insulin doses/kg remain key predictors, highlighting the persistent influence of preexisting behaviors and insulin needs on long-term outcomes.