When it comes to designing innovative and effective therapies for diabetes, Toronto scientists have often led the charge. The advances began with Frederick Banting and Charles Best, who purified insulin to treat diabetics in the 1920s, and the tradition is kept alive at Mount Sinai’s Centre for Diabetes. Recently, Dr. Ravi Retnakaran and his colleagues completed a meta-analysis of seven studies that showed short-term intensive insulin doses have the potential to prevent the pathology associated with Type 2 diabetes mellitus (t2dm).
t2dm is a metabolic disorder characterized by insulin resistance that renders cells unresponsive to the hormone and decreases insulin secretion by pancreatic β-cell, leading to β-cell deterioration. t2dm is of crucial importance due to the ever-increasing numbers of Canadians being diagnosed with it. According to Retnakaran, “one out of every eight Canadians will be at risk of developing diabetes by 2020, and the ratio will increase to one in three by 2050.” This means every single Canadian family will be dealing with diabetes in one way or another.
While several therapies are currently available for T2DM, they are all essentially supportive. “Unfortunately, none of the existing therapies have been shown to change the natural history of diabetes, which is the inability of β-cells to make enough insulin for our body’s needs,” says Retnakaran. Once a person is diagnosed, patients are advised to try to improve their lifestyles. As their β-cells deteriorate over time, patients are given anti-diabetics to take daily. Finally, when the β-cells completely deteriorate, insulin therapy is needed.
Retnakaran and his colleagues want to change this standard timeline for the disease. Their recent paper in The Lancet, “Short-term intensive insulin therapy in type 2 diabetes mellitus: a systemic review and meta-analysis,” establishes enough evidence to warrant novel clinical trials. The results show that in patients with newly diagnosed t2dm, short-term intensive insulin therapy is correlated with improvement in β-cell function and insulin resistance. In post-study examinations, around half the recipients were able to maintain normal glycemic levels for up to 12 months without any anti-diabetic medication.
Retnakaran and his colleagues at Mount Sinai are applying these findings to their new clinical trial, named reset it (Remission Studies Evaluating Type 2 Diabetes – Intermittent Insulin Therapy). “We want to give insulin to patients for two to three weeks early in their course of diabetes. This improves the body’s ability to produce and use its own insulin, a period of remission. But, as β-cell function wanes over time, we will administer another bout of insulin leading to another remission period.”
Essentially, the trials begin with three weeks of intensive insulin therapy, followed by insulin therapy every three months for a week’s duration. Trials will take place in Toronto, London and Hamilton, and will involve 150 patients over two years.
So why does this therapy work? The deterioration of β-cell function that patients with diabetes experience is due to an irreversible loss of β-cells and the reversible effect of hyperglycemia due to decreased insulin on β-cell secretory ability. The latter effect, termed “glucotoxicity,” occurs when excess glucose in the blood of a diabetic is toxic to the β-cells that secrete insulin. Earlier findings suggest that the effect of glucotoxicity is higher earlier on in diabetes, when the β-cell numbers are relatively high. Giving a patient intensive insulin therapy early on in diabetes eliminates the glucotoxicity, thereby preventing massive β-cell death.
“If the trial is successful, it [will] introduce a different way to treat diabetes,” says Retnakaran. “Firstly, it lets us treat diabetes in a cheap way. If it is able to stop the progressive deterioration of β-cells, people will not develop the complications associated with diabetes such as heart attacks, strokes, and problems with small blood vessels.
“Secondly, the therapy will improve people’s lifestyle as they will not be required to take medication or monitor blood glucose levels daily. Thus, our potential success has huge implications for society, in terms of reduction of costs and improvement in lifestyle.”
For more information on Dr. Retnakaran’s study, or to take part in the clinical trials, contact the Centre of Diabetes at Mount Sinai at 416-586-8775.1
