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? Cell dysfunction exists more than 5 years before type 1 diabetes diagnosis.

ABSTRACT: BACKGROUND:The duration and patterns of ? cell dysfunction during type 1 diabetes (T1D) development have not been fully defined. METHODS:Metabolic measures derived from oral glucose tolerance tests (OGTTs) were compared between autoantibody-positive (aAb+) individuals followed in the TrialNet Pathway to Prevention study who developed diabetes after 5 or more years or less than 5 years of longitudinal follow-up (Progressors?5, n = 75; Progressors<5, n = 474) and 144 aAb-negative (aAb-) relatives. RESULTS:Mean age at study entry was 15.0 ± 12.6 years for Progressors?5; 12.0 ± 9.1 for Progressors<5; and 16.3 ± 10.4 for aAb- relatives. At baseline, Progressors?5 already exhibited significantly lower fasting C-peptide (P < 0.01), C-peptide AUC (P < 0.001), and early C-peptide responses (30- to 0-minute C-peptide; P < 0.001) compared with aAb- relatives, while 2-hour glucose (P = 0.03), glucose AUC (<0.001), and Index60 (<0.001) were all higher. Despite significant baseline impairment, metabolic measures in Progressors?5 were relatively stable until 2 years prior to T1D diagnosis, when there was accelerated C-peptide decline and rising glycemia from 2 years until diabetes diagnosis. Remarkably, patterns of progression within 3 years of diagnosis were nearly identical between Progressors?5 and Progressors<5. CONCLUSION:These data provide insight into the chronicity of ? cell dysfunction in T1D and indicate that ? cell dysfunction may precede diabetes diagnosis by more than 5 years in a subset of aAb+ individuals. Even among individuals with varying lengths of aAb positivity, our findings indicate that patterns of metabolic decline are uniform within the last 3 years of progression to T1D. TRIAL REGISTRATION:Clinicaltrials.gov NCT00097292. FUNDING:The Type 1 Diabetes TrialNet Study Group is a clinical trials network currently funded by the NIH through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Juvenile Diabetes Research Foundation.

SUBMITTER: Evans-Molina C

PROVIDER: S-EPMC6129118 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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β Cell dysfunction exists more than 5 years before type 1 diabetes diagnosis.

Evans-Molina Carmella C Sims Emily K EK DiMeglio Linda A LA Ismail Heba M HM Steck Andrea K AK Palmer Jerry P JP Krischer Jeffrey P JP Geyer Susan S Xu Ping P Sosenko Jay M JM

JCI insight 20180809 15

<h4>Background</h4>The duration and patterns of β cell dysfunction during type 1 diabetes (T1D) development have not been fully defined.<h4>Methods</h4>Metabolic measures derived from oral glucose tolerance tests (OGTTs) were compared between autoantibody-positive (aAb+) individuals followed in the TrialNet Pathway to Prevention study who developed diabetes after 5 or more years or less than 5 years of longitudinal follow-up (Progressors≥5, n = 75; Progressors<5, n = 474) and 144 aAb-negative (a ...[more]

PMID: 30089716

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Project description:BackgroundPatients with type 2 diabetes vary greatly with respect to degree of obesity at time of diagnosis. To address the heterogeneity of type 2 diabetes, we characterised patterns of change in body mass index (BMI) and other cardiometabolic risk factors before type 2 diabetes diagnosis.Methods and findingsWe studied 6,705 participants from the Whitehall II study, an observational prospective cohort study of civil servants based in London. White men and women, initially free of diabetes, were followed with 5-yearly clinical examinations from 1991-2009 for a median of 14.1 years (interquartile range [IQR]: 8.7-16.2 years). Type 2 diabetes developed in 645 (1,209 person-examinations) and 6,060 remained free of diabetes during follow-up (14,060 person-examinations). Latent class trajectory analysis of incident diabetes cases was used to identify patterns of pre-disease BMI. Associated trajectories of cardiometabolic risk factors were studied using adjusted mixed-effects models. Three patterns of BMI changes were identified. Most participants belonged to the "stable overweight" group (n?=?604, 94%) with a relatively constant BMI level within the overweight category throughout follow-up. They experienced slightly worsening of beta cell function and insulin sensitivity from 5 years prior to diagnosis. A small group of "progressive weight gainers" (n?=?15) exhibited a pattern of consistent weight gain before diagnosis. Linear increases in blood pressure and an exponential increase in insulin resistance a few years before diagnosis accompanied the weight gain. The "persistently obese" (n?=?26) were severely obese throughout the whole 18 years before diabetes diagnosis. They experienced an initial beta cell compensation followed by loss of beta cell function, whereas insulin sensitivity was relatively stable. Since the generalizability of these findings is limited, the results need confirmation in other study populations.ConclusionsThree patterns of obesity changes prior to diabetes diagnosis were accompanied by distinct trajectories of insulin resistance and other cardiometabolic risk factors in a white, British population. While these results should be verified independently, the great majority of patients had modest weight gain prior to diagnosis. These results suggest that strategies focusing on small weight reductions for the entire population may be more beneficial than predominantly focusing on weight loss for high-risk individuals.

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? Cell dysfunction exists more than 5 years before type 1 diabetes diagnosis.

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β Cell dysfunction exists more than 5 years before type 1 diabetes diagnosis.

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