Biomedical subjects

Daisuke Yabe

Publications and source records attributed to Daisuke Yabe.

3 recordsLinked to original sources

PubMed2026

Digenic HNF1A and ABCC8 variants provide mechanistic insight into early-onset diabetes.

CONTEXT: Oligogenic inheritance in maturity-onset diabetes of the young (MODY) remains poorly characterized, and the contribution of multiple candidate variants to disease pathogenesis is incompletely understood. OBJECTIVE: To investigate the pathogenicity and mechanistic contribution of multiple MODY gene variants identified in a MODY-like family and determine their role in early-onset diabetes. METHODS: Comprehensive genetic analysis of known MODY genes was performed in a MODY-like family. Functional effects of HNF1A and HNF1B variants were assessed using luciferase reporter assays in HEK293T cells. Functional characterization of ABCC8 variants included Kir6.2-dependent thallium (Tl+) flux assays, sulfonylurea responsiveness, and channel stability. RESULTS: Four variants in 3 MODY genes were identified in the proband: novel HNF1A p.Ser551Lysfs*2, HNF1B p.Glu102Ala, and ABCC8 p.Arg298Cys and p.Arg521Gln. Functional analysis showed that HNF1A p.Ser551Lysfs*2 retained approximately 5% of wild-type transactivation activity, consistent with loss-of-function, whereas HNF1B p.Glu102Ala and ABCC8 p.Arg521Gln exhibited wild-type-like function. In contrast, ABCC8 p.Arg298Cys reduced channel activity to 77% of wild-type levels while preserving sulfonylurea responsiveness. Segregation analysis identified HNF1A p.Ser551Lysfs*2 and ABCC8 p.Arg298Cys in affected parents. The proband, who inherited both pathogenic variants, developed diabetes earlier than either parent and was exposed to maternal hyperglycemia in utero, which may also have contributed to this early onset. CONCLUSION: Functional characterization distinguishes pathogenic from variants of unknown significance and supports digenic inheritance of HNF1A and ABCC8. Their additive effects, together with intrauterine hyperglycemia, likely accelerated disease onset. This study provides mechanistic evidence for oligogenic contributions to MODY and expands the genetic architecture of early-onset diabetes.

Humans↗

PubMed2026

Long-term safety of oral orforglipron in Japanese participants with type 2 diabetes (ACHIEVE-J): a multicentre, randomised, open-label, parallel-group phase 3 trial.

BACKGROUND: Orforglipron, an oral GLP-1 receptor agonist, requires further evaluation in east Asian populations with type 2 diabetes, given this group's distinct pathophysiological characteristics. This study aimed to assess orforglipron as add-on treatment to diet and exercise alone or to oral antihyperglycaemic medications in Japanese participants with type 2 diabetes. METHODS: This multicentre, randomised, open-label phase 3 study was conducted in 40 medical research centres and hospitals in Japan. Adults with type 2 diabetes and elevated glucose levels managing their condition with diet and exercise alone or with one or two oral antihyperglycaemic medications were assigned (1:1:1) via computer-generated random sequence to receive once-daily oral orforglipron (3 mg, 12 mg, or 36 mg). Randomisation was stratified by background therapy, baseline HbA1c (≤8·5% or >8·5%), and metformin use (yes vs no; applied only to α-glucosidase inhibitors, thiazolidinedione, and glinides). Investigators, participants, and site staff were not masked to treatment. The primary endpoint was safety for 52 weeks, assessed in all randomly assigned participants who received at least one dose of orforglipron. This study is registered with ClinicalTrials.gov, NCT06010004 (ACHIEVE-J). FINDINGS: Between Sept 28, 2023, and June 5, 2025, 450 participants were screened and 401 were randomly assigned to three groups (3 mg, n=132; 12 mg, n=135; and 36 mg, n=134). 352 (88%) completed study treatment. 339 participants (85%, 95% CI 80·7-87·8) had at least one treatment-emergent adverse event (TEAE), more frequently in the 36-mg group (118 [88%, 95% CI 81·5-92·5]) than in the 3-mg (107 [81%, 73·5-86·8]) and 12-mg (114 [84%, 77·4-89·6]) groups. Most TEAEs were of mild (267 [67%, 61·8-71·0]) or moderate (63 [16%, 12·5-19·6]) severity. Discontinuations due to an adverse event occurred in 19 of 134 participants (14%, 95% CI 9·3-21·1) in the 36-mg group compared with seven of 132 (5%, 2·6-10·5) in the 3-mg group and 11 of 135 (8%, 4·6-14·0) in the 12-mg group. Across treatment groups, gastrointestinal symptoms were the most common TEAEs leading to study treatment discontinuation (3 mg: 5 [3·8%, 1·6-8·6]; 12 mg: 8 [5·9%, 3·0-11·3]; and 36 mg: 11 [8·2%, 4·7-14·1]). Level 2 (blood glucose <54 mg/dL) hypoglycaemia events occurred in three of 135 participants in the 12-mg group (2%, 0·8-6·3) and in three of 134 in the 36-mg group (2%, 0·8-6·4) groups. No level 3 (severe) hypoglycaemia events occurred. Outcomes were generally similar across background therapies. INTERPRETATION: Treatment with orforglipron in combination with diet and exercise alone or one or two oral antihyperglycaemic medications for 52 weeks demonstrated an acceptable safety profile in Japanese adults with type 2 diabetes. FUNDING: Eli Lilly. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Aged↗

PubMed2025

Cardiovascular risk reduction with glucagon-like peptide-1 receptor agonists is proportional to HbA1c lowering in type 2 diabetes: An updated meta-regression analysis incorporating FLOW and SOUL trials.

AIMS: To evaluate relationships of cardiovascular and kidney outcomes with glycemic or bodyweight reductions in randomised placebo-controlled trials of glucagon-like peptide-1 receptor agonists (GLP-1RAs), incorporating data from FLOW and SOUL trials. MATERIALS AND METHODS: PubMed and EMBASE were searched up to 22 August 2025 for placebo-controlled randomized trials of oral or bolus-type, subcutaneous GLP-1RAs reporting major adverse cardiovascular events (MACE; a composite of cardiovascular death, myocardial infarction, and stroke) in adults with type 2 diabetes. The primary outcome was MACE; secondary outcomes included heart failure (HF) and kidney outcomes. Random-effects meta-analyses were followed by meta-regression evaluating associations with HbA1c and bodyweight reduction. RESULTS: A total of 73 263 individuals were included from 10 trials (ELIXA, LEADER, SUSTAIN-6, EXSCEL, Harmony Outcomes, PIONEER 6, REWIND, AMPLITUDE-O, FLOW, and SOUL). GLP-1RAs reduced MACE by 14% (hazard ratio: 0.86; 95% CI: 0.82 to 0.91; p <0.001), as well as hospitalisation for HF and the composite kidney outcome (both p <0.001). Meta-regression showed that every 1% extra reduction in HbA1c corresponded to a 27% lower HR for MACE (p = 0.015; R2 = 0.61). While HbA1c reduction was not significantly associated with secondary outcomes, the directionality was consistent with MACE. Bodyweight change was not associated with any of the analysed endpoints, including MACE (p = 0.13; R2 = 0.21). CONCLUSIONS: HbA1c reduction, not bodyweight change, was significantly and proportionally associated with MACE risk reduction. HbA1c lowering may serve as a useful surrogate for the cardiovascular improvements associated with GLP-1RAs in type 2 diabetes.

Humans↗