Nonprogression of Subclinical β-Cell Dysfunction Among First-Degree Relatives of IDDM Patients: 5-Yr Follow-Up of the Seattle Family Study

It is unknown among first-degree relatives of individuals with insulin-dependent diabetes mellitus (IDDM) whether the disease process occurs in relatively few but always progresses to clinical IDDM or whether subclinical disease is more common but remains nonprogressive in many cases. Islet cell antibodies (ICAs) were found in 21 of 724 (2.9%) first-degree relatives during screening in the greater Seattle area between 1983 and 1988. Measures of β-cell function (glucose disappearance rate [K_g], fasting insulin, acute insulin response to intravenous arginine [AIR_arg]. acute insulin response to intravenous glucose [AIR_gluc], slope of glucose potentiation of AIR_arg) and insulin sensitivity were obtained. Twenty individuals, 9 ICA⁺ relatives and 11 ICA⁻ relatives, were evaluated prospectively. When expressed in relation to the expected AIR_gluc based on each subject's sensitivity index, AIR_gluc in 18 of 20 relatives fell below 100%, indicating inappropriately low insulin secretion (subclinical β-cell dysfunction). After a median follow-up of 42 mo, 10 of 11 ICA⁻ relatives remained ICA⁻. None showed deteriorating β-cell dysfunction, and none developed diabetes. Five ICA⁺ relatives showed persistent immunologie positivity. β-Cell function remained remarkably stable in all except 2 relatives. One was a 15-yr-old boy who developed IDDM shortly after screening and before evaluation of β-cell function could be carried out. The other was an 18-yr-old monozygotic twin who developed IDDM after 27 mo. Both of these individuals had ICAs of 80 Juvenile Diabetes Foundation U and had been discordant for <5 yr. Five subjects showed fluctuating ICA status with stable β-cell function, and none have developed IDDM so far. These subjects were older and had been discordant for >10 yr at entry into the study. These data suggest that, although the persistent presence of ICAs is sometimes associated with deteriorating β-cell function, this is not invariable. Subclinical and nonprogressive β-cell dysfunction and fluctuation in ICA status can occur among first-degree relatives of individuals with IDDM. These data suggest that the disease process of IDDM encompasses a wide spectrum—relatively few people show the full-blown disease (clinical IDDM), whereas many more may have nonprogressive subclinical β-cell dysfunction.