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Well-preserved insulin resistance does not accelerate onset of type 1 diabetes
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New findings suggest that increased insulin resistance accelerates progression in type 1 diabetes. The association was especially clear in antibody-positive relatives with reduced insulin secretion. However, well-preserved insulin resistance did not accelerate the onset of diabetes.
The European Nicotinamide Diabetes Intervention Trial Group conducted a retrospective cohort analysis of 213 first-degree family members. All were aged <25 years with at least one islet antibody in addition to islet cell antibody >20 Juvenile Diabetes Foundation units.
After four years of follow-up, 105 individuals developed diabetes. The researchers calculated a 54.1% overall cumulative five-year risk for diabetes. They reported several independent determinants of risk for progression to diabetes, including baseline first-phase insulin response, the number of additional antibody markers and 120-minute glucose as determined by an oral glucose tolerance test (all P<.001).
However, homeostasis model assessment of insulin resistance achieved only borderline significance in risk for progression to diabetes (P=.06). Particularly, it was not a determinant of individuals with preserved first-phase insulin response, according to the abstract data. The researchers concluded that insulin sensitivity modulated the onset of diabetes only in individuals with severely compromised cell function. – by Katie Kalvaitis
Diabetes Care. 2008;31:146-150.
The incidences of both type 1 and type 2 diabetes are increasing at an alarming rate. For type 2 diabetes, the explanation has been increased insulin resistance associated with the worldwide epidemic of obesity. Most dramatic has been a surge of type 2 diabetes in children, a condition rarely seen 20 years ago. This recent development has led to occasional difficulty determining whether a child with new-onset diabetes has type 1 or type 2 disease. As approximately 30% of children are overweight, it is expected that 30% of children with new-onset type 1 diabetes will be overweight. The presence of low titer antibodies in many of these children also contributes to this diagnostic dilemma. The “Accelerator Hypothesis” of Wilkin, et al. postulates that the presence of obesity results in early appearance of type 1 diabetes due to insulin resistance which, in turn, results in over-stimulation of the beta cells and consequent early auto-immune destruction of beta cells in individuals genetically predisposed to develop type 1 diabetes. Thus, the insulin resistance associated with obesity is associated with a younger age of diagnosis of type 1 diabetes in children at risk for the later development of autoimmune diabetes.
On the other hand, investigators from the SEARCH study found early age of developing diabetes in overweight children only occurs if the children have low C-peptide levels, indicating that obesity accelerates the onset of the disease only after substantial autoimmune destruction of ß-cells has occurred. The paper by Bingley, et al., in a retrospective cohort analysis of 213 family members who participated in the European Nicotinamide Diabetes Intervention Trial, found that insulin resistance as determined by HOMA2-IR predicted the development of diabetes only in subjects who had loss of first phase insulin response to intravenous tolerance testing. Those subjects with normal insulin responses did not develop diabetes, despite the presence of insulin resistance. This is in accord with the findings of the SEARCH study and suggests that the presence of obesity and consequent insulin resistance “accelerate” the progression of type 1 diabetes only in patients in whom the autoimmune process is advanced and has already destroyed sufficient beta cells to impair early insulin release. Thus, overweight patients who develop diabetes at an early age and have antibodies against islet antigens most likely have type 1 diabetes that was diagnosed early because they did not have enough insulin reserve to compensate for their obesity-induced insulin resistance. They, therefore, have more insulin production than is normally seen at the onset of type 1 diabetes and have a less acute clinical presentation. It is likely that many of the patients who have been labeled as “double diabetes” or “hybrid” diabetes fit into this category. It is also likely that some patients with presentations consistent with type 2 diabetes fit into this category, making it important to obtain blood for islet autoantibodies at disease onset to facilitate accurate categorization and appropriate treatment. Based on the pathophysiology and given our current state of knowledge, these patients should be treated with insulin at diagnosis in an effort to preserve as much beta cell function as possible. Randomized, controlled trials are essential to determine the efficacy of medications to reduce insulin resistance in this population.
– Janet H. Silverstein, MD
Endocrine Today Editorial Board member