METHODS: The study primarily involved a family harboring a novel P/LP PDX1 variant. We then conducted an analysis of documented carriers of P/LP PDX1 variants, from the Human Gene Mutation Database (HGMD), RaDiO study, and Type 2 Diabetes Knowledge Portal (T2DKP) including 87 K participants.
RESULTS: Within the family, we identified a P/LP PDX1 variant encoding p.G232S in four relatives. All of them exhibited diabetes, albeit with very different ages of onset (10-40 years), along with caudal pancreatic agenesis and childhood-onset obesity. In the HGMD, 79 % of carriers of a P/LP PDX1 variant displayed diabetes (with differing ages of onset from eight days of life to 67 years), 63 % exhibited pancreatic insufficiency and surprisingly 40 % had obesity. The impact of P/LP PDX1 variants on increased risk of type 2 diabetes mellitus was confirmed in the T2DKP. Dipeptidyl peptidase 4 inhibitor (DPP4i) and glucagon-like peptide-1 receptor agonist (GLP1-RA), enabled good glucose control without hypoglycemia and weight management.
CONCLUSIONS: This study reveals diverse clinical presentations among the carriers of a P/LP PDX1 variant, highlighting strong variations in diabetes onset, and unexpectedly high prevalence of obesity and pancreatic development abnormalities. Clinical data suggest that DPP4i and GLP1-RA may be the best effective treatments to manage both glucose and weight controls, opening new avenue in precision diabetic medicine.
方法:该研究主要涉及一个拥有新型P/LPPDX1变异体的家族。然后,我们对P/LPPDX1变体的记录载体进行了分析,来自人类基因突变数据库(HGMD),RaDiO研究,2型糖尿病知识门户(T2DKP)包括87K参与者。
结果:在家庭中,我们在四个亲属中鉴定了编码p.G232S的P/LPPDX1变体。他们都表现出糖尿病,尽管发病年龄不同(10-40岁),以及尾胰腺发育不全和儿童期肥胖。在HGMD中,79%的P/LPPDX1变异体携带者表现为糖尿病(发病年龄从8天到67岁不等),63%的人表现出胰腺功能不全,令人惊讶的是40%的人患有肥胖症。在T2DKP中证实了P/LPPDX1变体对2型糖尿病风险增加的影响。二肽基肽酶4抑制剂(DPP4i)和胰高血糖素样肽-1受体激动剂(GLP1-RA),实现良好的血糖控制,没有低血糖和体重管理。
结论:这项研究揭示了P/LPPDX1变体携带者之间的不同临床表现,突出了糖尿病发病的强烈变化,肥胖和胰腺发育异常的患病率出乎意料地高。临床数据表明,DPP4i和GLP1-RA可能是控制血糖和体重的最佳有效治疗方法。开辟了精准糖尿病医学的新途径。