Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Feb;42(2):208-214.
doi: 10.2337/dc18-0431. Epub 2018 Oct 23.

A Type 1 Diabetes Genetic Risk Score Can Identify Patients With GAD65 Autoantibody-Positive Type 2 Diabetes Who Rapidly Progress to Insulin Therapy

Anita L Grubb  1 , Timothy J McDonald  1   2 , Femke Rutters  3 , Louise A Donnelly  4 , Andrew T Hattersley  1   2 , Richard A Oram  1   2 , Colin N A Palmer  4 , Amber A van der Heijden  5 , Fiona Carr  4 , Petra J M Elders  5 , Mike N Weedon  1 , Roderick C Slieker  3   6 , Leen M 't Hart  3   6   7 , Ewan R Pearson  4 , Beverley M Shields  1 , Angus G Jones  8   2
Affiliations

A Type 1 Diabetes Genetic Risk Score Can Identify Patients With GAD65 Autoantibody-Positive Type 2 Diabetes Who Rapidly Progress to Insulin Therapy

Anita L Grubb et al. Diabetes Care. 2019 Feb.

Abstract

Objective: Progression to insulin therapy in clinically diagnosed type 2 diabetes is highly variable. GAD65 autoantibodies (GADA) are associated with faster progression, but their predictive value is limited. We aimed to determine if a type 1 diabetes genetic risk score (T1D GRS) could predict rapid progression to insulin treatment over and above GADA testing.

Research design and methods: We examined the relationship between T1D GRS, GADA (negative or positive), and rapid insulin requirement (within 5 years) using Kaplan-Meier survival analysis and Cox regression in 8,608 participants with clinical type 2 diabetes (onset >35 years and treated without insulin for ≥6 months). T1D GRS was both analyzed continuously (as standardized scores) and categorized based on previously reported centiles of a population with type 1 diabetes (<5th [low], 5th-50th [medium], and >50th [high]).

Results: In GADA-positive participants (3.3%), those with higher T1D GRS progressed to insulin more quickly: probability of insulin requirement at 5 years (95% CI): 47.9% (35.0%, 62.78%) (high T1D GRS) vs. 27.6% (20.5%, 36.5%) (medium T1D GRS) vs. 17.6% (11.2%, 27.2%) (low T1D GRS); P = 0.001. In contrast, T1D GRS did not predict rapid insulin requirement in GADA-negative participants (P = 0.4). In Cox regression analysis with adjustment for age of diagnosis, BMI, and cohort, T1D GRS was independently associated with time to insulin only in the presence of GADA: hazard ratio per SD increase was 1.48 (1.15, 1.90); P = 0.002.

Conclusions: A T1D GRS alters the clinical implications of a positive GADA test in patients with clinical type 2 diabetes and is independent of and additive to clinical features.

PubMed Disclaimer

Conflict of interest statement

Duality of Interest

No potential conflicts of interest relevant to this article were reported.

Figures

Figure 1
Figure 1
Kaplan-Meier plot of probability of requiring insulin therapy during 5-year follow-up by risk group of T1D GRS. Solid lines represent GADA positive groups, dashed lines represent GADA negative groups. Blue = low T1D GRS (<5th centile of a type 1 diabetes population (< 0.234)), orange = medium T1D GRS (5th-50th centile of a type 1 diabetes population (>= 0.234 & <= 0.280)), red =high T1D GRS (>50th centile of a type 1 diabetes population (> 0.280)).
See this image and copyright information in PMC

References

    1. U.K. Prospective Diabetes Study Group: U.K. Prospective Diabetes Study 16: Overview of 6 Years' therapy of Type II Diabetes: A Progressive Disease. Diabetes. 1995;44:1249. - PubMed
    1. Fonseca VA. Defining and Characterizing the Progression of Type 2 Diabetes. Diabetes care. 2009;32:S151. - PMC - PubMed
    1. Groop LC, Bottazzo GF, Doniach D. Islet Cell Antibodies Identify Latent Type I Diabetes in Patients Aged 35–75 Years at Diagnosis. Diabetes. 1986;35:237. - PubMed
    1. Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. The Lancet. 350:1288–1293. - PubMed
    1. Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR. Antibodies to Glutamic Acid Decarboxylase Reveal Latent Autoimmune Diabetes Mellitus in Adults With a Non—Insulin-Dependent Onset of Disease. Diabetes. 1993;42:359. - PubMed

Publication types

MeSH terms