Loss of insulin-producing pancreatic β-cells causes insulin deficiency (ID). ID characterizes people with type 1 diabetes mellitus (T1DM), many of the ones suffering from type 2 diabetes mellitus (T2DM), and all people who underwent total pancreatectomy; hence, ID affects tens of millions worldwide. If untreated, ID is a lethal disease displaying several symptoms including, but not limited to, high levels of glucose and ketone bodies in the blood (i.e. hyperglycaemia and hyperketonaemia).
Since insulin was discovered in the early 1920s, ID has been treated with insulin therapy. Thus, daily insulin administrations and frequent glucose monitoring are amongst the daily activities of ID patients. Despite the fact that this approach has converted a lethal disease into one a person can live with, insulin therapy is sub-optimal. Indeed, ID subjects have higher risks for developing kidney failure, blindness, nerve damage, heart attack, stroke, and hypoglycemia. Some of these co-morbidities are favored by insulin therapy itself. For example, insulin stimulates lipid and cholesterol synthesis; thus, owing to its established lipogenic actions chronic insulin therapy promotes lipid deposition outside adipose tissue. This effect likely contributes to the extremely high incidence of coronary artery disease observed in ID subjects. In addition, these lipogenic actions of insulin promote lipid-induced insulin resistance and therefore underlie, at least in part, the increased insulin needs in long-term ID care. Insulin is also a potent glycemia-lowering hormone. Owing to this action, intensive insulin therapy causes hypoglycemia which can be disabling and sometimes fatal. Hypoglycemia occurs in these patients because of impaired glucose counter-regulation (mainly reduced epinephrine secretion) and reduced awareness of hypoglycemia (reduced neurogenic symptoms of hypoglycemia); a condition referred to as hypoglycemia-associated autonomic failure. It is well established that recent antecedent hypoglycemia predisposes to future hypoglycemic events, thus creating a vicious cycle of recurrent life-threatening hypoglycemia. Therefore, because insulin therapy does not restore metabolic homeostasis and does not eradicate the disabling co-morbidities of ID (e.g. heart attack, stroke, blindness, kidney failure, neuropathy) the costs needed for ID care are immense.
To tackle each of the aforementioned shortcomings of current insulin therapy we are currently investigating the potential of insulin-independent mechanisms. Our approach led to a newly discovered S100A9-driven mechanism able to improve survival and metabolic imbalance in pre-clinical models of ID. Our approach improves glucose control without causing hypoglycaemia. Indeed, we have recently shown that increasing the level of circulating S100A9 in ID mice improves the metabolic imbalance (including hyperglycaemia) caused by β-cell loss without causing hypoglycaemia. Thus, S100A9 administration lowers hyperglycaemia without bringing about the risks of hypoglycaemia. This is a unique feature of a glucose-lowering agent as many others (e.g. pramlintide, incretin mimetics, insulin, SGLT1/2 inhibitors) bring about an increased risk of life-threatening hypoglycaemia.
Also, our approach improves lipid metabolism. Indeed, in addition to improving glucose metabolism without causing hypoglycemia, we have shown that increasing the level of circulating S100A9 in ID mice normalizes the hyperketonemia and hypertriglyceridemia caused by β-cell loss. Thus, S100A9 administration lowers hyperglycaemia and at the same time improves key lipid metabolic defects. This is another unique feature of a glucose-lowering agent as many others (e.g. pramlintide, incretin mimetics, SGLT1/2 inhibitors) do not improve the elevated ketogenesis caused by β-cell loss.
We believe that S100A9-based therapeutics will reduce the burden of diabetes and improve the quality and quantity of life of the millions suffering from type 1 diabetes.
