Chapters authored
The Pancreas Secreting Insulin for Decades after Onset of Type I Diabetes — Implications for Care and Management
Up until recently, the prevailing dogma was that insulin secretion ceased within a couple of years after the diagnosis of type I diabetes, a clinical time period called the honeymoon. But a series of recent studies have established that release of C-peptide, which is the best measure of endogenous insulin production, can commonly persist for decades after disease onset. The release of C-peptide, even at low levels, is shown to have functional and clinical significance. For example, C-peptide levels >10 pmol/l are associated with fewer diabetes complications, i.e., nephropathy, neuropathy, foot ulcers, and retinopathy. The diabetic population may also be heterogeneous in risk for fall in C-peptide, with early age of diabetes onset a risk factor for more rapid C-peptide decline. The persistence of insulin release for decades and its functional and clinical significance suggest that assays for C-peptide should be a regular part of diabetes management. Furthermore, patients with established diabetes should be eligible to participate in clinical trials of immune therapies since preservation of these low levels appears clinically important to prevent complications.
Part of the book: Major Topics in Type 1 Diabetes
Early- Versus Late-Onset Type 1 Diabetes: Two Different Pathophysiological Subtypes with Implications for Therapy
Insulin, as measured by C-peptide, is produced for decades after onset of type 1 diabetes, and even very low levels of C-peptide have clinical significance. In this chapter we show that two distinct pathophysiological subtypes of type 1 diabetic subjects can be distinguished. Early-onset diabetic subjects (≤20 years) have rapid loss of C-peptide, whereas late-onset diabetic subjects (>20 years) have slower C-peptide declines over decades. Early-onset diabetics have significantly lower levels of persistent autoreactive CD8+ T cells than do late-onset diabetic subjects. In late-onset disease, robust production of autoreactive T-cells occurs even in the absence of C-peptide. Metabolomics analysis reveals frequent differences between the two subtypes of subjects in the levels of amino acids, carbohydrates, cofactors, lipids, peptides, and xenobiotics. There are statistically significant differences related to protective islet functions, islet health, development, blood sugar control, and regulation of exocrine pancreas function. Taken together these findings suggest that pancreas pathobiology, as well as durability of abnormal T-cell response should be considered in immune targeting treatments. Therapies aimed at immune defects alone are likely to work best in late-onset diabetics. Therapies aimed at islet cell preservation in early-onset diabetic subjects likely have greater efficacy if administered shortly after disease onset.
Part of the book: Immunopathogenesis and Immune-based Therapy for Selected Autoimmune Disorders