Familial, Early-Onset T2D Shows Distinct Profile

Researchers published the study covered in this summary on researchsquare.com as a preprint that has not yet been peer reviewed.

Key Takeaways

  • In this case-control, age-matched study of hospitalized patients in China who had early-onset type 2 diabetes (diagnosed by age 40), 89 patients with three consecutive generations of early-onset diabetes (cases) were diagnosed at a younger age and had lower systolic blood pressure and a better metabolic profile compared with 89 patients without a family history of early-onset type 2 diabetes (controls).

  • Roughly 11% of patients with multigenerational, early-onset type 2 diabetes had pathogenic variants of maturity-onset diabetes of the young (MODY) genes compared with about 1% of the controls.

Why This Matters

  • There has been a remarkable global increase, especially in Asia, of the prevalence of early-onset diabetes. This is a heterogeneous disease often classified as simply type 1 or type 2 diabetes without greater detail on distinguishing clinical and genetic characteristics.

  • This is the first study to compare patients with early onset-type 2 diabetes who have or do not have a mutigenerational family history. The clinical differences identified may help diagnosis and treatment, and the genetic variants found may foster better understanding of the disease’s pathogenesis.

Study Design

  • From a cohort of 6470 patients with type 2 diabetes and an average age of 58 seen in a hospital in Beijing, China, the researchers identified 884 patients (13.7%) with early-onset diabetes including 105 patients (11.9%) with multigenerational early-onset type 2 diabetes, and 137 patients (15.5%) with no family history of early-onset diabetes.

  • The researchers matched by age 89 patients with mutigenerational early-onset type 2 diabetes and 89 control patients. They performed whole exome sequencing of DNA from blood samples from the patients with multigenerational, early-onset type 2 diabetes, primarily focusing on 14 known MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, and APPL1).

  • Suspected gene variants were validated by Sanger sequencing and further investigated in the proband families.

Key Results

  • Compared with the control group, patients with multigenerational, early-onset diabetes patients were younger when diagnosed (26.5 vs 29.4 years, P = .001) and they had a lower body mass index (25.5 vs. 27.4 kg/m2, P = .003), lower systolic blood pressure (120 vs 128 mm Hg, P = .003), and better metabolic profiles including glucose and lipids.

  • Of the 89 patients with multigenerational, early-onset diabetes, 10 patients (11.2%) carried likely pathogenic variants in MODY genes (KLF11, GCK, ABCC8, PAX4, BLK, and HNF1A).

  • In contrast with a previous report suggesting that HNF1A and GCK were the most common MODY gene variants, in this study KLF11 gene mutations were most frequent, associated with 30% of genetically confirmed MODY cases.


  • This was a hospital-based study of patients with relatively high A1c levels and a high prevalence of diabetic vascular complications, so results cannot be generalized to patients with mild asymptomatic hyperglycemia.

  • This was a small study and whole-exome sequencing was not carried out in the control group, so it is unclear whether any patients in that group had pathogenic variants of MODY genes.

  • Some relatives of the patients with MODY gene variants were unreachable for genetic testing.


  • The study did not receive commercial funding.

  • The authors report no financial disclosures related to this research.

This is a summary of a preprint research study , “Early-onset diabetes involving three consecutive generations had different clinical features from age-matched type 2 diabetes without a family history,” written by researchers at Beijing Tongren Hospital, China. Preprints from Research Square are provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.

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