Researchers at Massachusetts General Hospital (MGH) have detected signs of continuing insulin production in patients with Type 1 diabetes decades after disease onset.
The findings challenge a 26-year-established model that pancreatic β-cell function ceases entirely within one to two years of onset. The study reveals that C-peptide production, a marker of insulin and active pancreatic β-cells, can persist for decades after disease onset and remains functionally responsive. This suggests that patients with advanced disease, whose β-cell function was thought to have long ceased, may benefit from interventions to preserve β-cell function or to prevent complications.
“The old model of Type 1 diabetes progression—a window of activity of one to two years before pancreas ‘death’—has driven every clinical trial design over the last 20 years. All recent Phase 3 human clinical trials for immune interventions to preserve pancreatic function were on children with days or weeks of disease duration. If you were beyond a few weeks you were most likely exempt from any such trial,” says Denise Faustman, MD, PhD, director of the Massachusetts General Hospital Immunobiology Laboratory.
“The opportunity to slow disease progression, perhaps even reverse it, is potentially longer than we think. Our data show the pancreas can be fighting a battle for survival up to 40 years after disease onset, and possibly longer,” she adds.
A novel ultrasensitive assay detected C-peptide in 80% of samples from Type 1 diabetes patients at up to 5 years after disease onset and in 10% of samples from patients with 31 to 40 years’ disease duration. While C-peptide levels showed a decline with increasing disease duration, the decline was over decades, not months as commonly thought. The assay, which is twenty-two times more sensitive than standard assays, was used to test blood samples from 182 patients between the ages of nine and 85 years old, with zero to 73 years’ disease duration.
The data show that C-peptide and glycaemic levels were related. The 182 patients were stratified into normoglycaemic and hyperglycaemic; with C-peptide levels grouped into four ranges: 0 to 1.5 pmol/L (non-responsive), 1.5 to 5 pmol/L (responsive), 5 to 100 pmol/L (responsive) and >100 pmol/L (responsive). Hyperglycaemic subjects had significantly higher C-peptide levels than those from normoglycaemic subjects in each of the C-peptide level ranges, except for the non-responsive group, which had C-peptide levels below the level of detection of the ultrasensitive assay.
The findings follow Faustman’s promising results from a Phase I clinical trial of the generic drug BCG (bacillus Calmette-Guérin) to treat advanced Type 1 diabetes, which showed that low doses of BCG could transiently reverse Type 1 diabetes in human patients, even in those with more than a decade’s disease duration. Currently approved for vaccination against tuberculosis and for the treatment of bladder cancer, BCG is known to elevate levels of the immune modulator tumour necrosis factor (TNF), which Faustman’s lab has shown can temporarily eliminate the abnormal white blood cells responsible for Type 1 diabetes in both humans and mice.
“One of the key components of the trial was our development of a way to measure the death of the auto-reactive T-cells that destroy the ability of the pancreas to produce insulin. Not only did we observe and measure the death of these self-targeting immune cells, but we also saw evidence of the restoration of insulin production in patients who had Type 1 diabetes for more than a decade,” says Faustman.
The research is published in Diabetes Care.
Release Date: Feb. 21, 2012
Source: Massachusetts General Hospital