Abstract：
OBJECTIVE: Heterozygous pathogenic or likely pathogenic (P/LP) PDX1 variants cause monogenic diabetes. We comprehensively examined the phenotypes of carriers of P/LP PDX1 variants, and delineated potential treatments that could be efficient in an objective of precision medicine.
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.
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.
摘要：
目的：杂合子致病或可能致病（P/LP）PDX1变异体可导致单基因糖尿病。我们全面检查了P/LPPDX1变体携带者的表型，并描述了在精准医学目标中可能有效的潜在治疗方法。
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。
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。
