Nearly a century ago, a revolutionary 'new therapy' for type 1 diabetes was introduced: the ability to deliver life-saving insulin following its extraction from animal pancreas (beef or cattle). Numerous advances have occurred over the ensuing years, each designed to improve both the quality of insulin preparations as well as to extend their duration of action within the body. Most remarkable amongst these involved the ability to produce so called 'recombinant' insulin as well as analogues of the molecule; insulins whose molecular structure had been slightly altered to provide different actions. These genetic changes alter how quickly the insulin takes effect, how long the effect lasts, and when it reaches a peak in terms of its ability to lower blood glucose. Revolutionary new treatments and technologies introduced in recent years include blood glucose monitoring devices, ultrafine needles and insulin pumps, insulin pumps and continuous glucose monitoring devices. Now, type 1 diabetes faces yet another time for revolution in new treatments, not only in terms of the addition even more insulin analogues, but also dramatic changes in technologies regulating the way insulin is delivered, the way blood glucose is monitored, and the way such information is evaluated by healthcare providers.
A new form of an ultralong-acting basal insulin analogue, Degludec, is now available for clinical use. This insulin, developed by Novo Nordisk, has a duration of action within the body of up to 40 hours, much longer than the 18–24 hours noted for currently defined 'ultralong acting insulins' (e.g. glargine and detemer). In phase III clinical trials, insulin degludec provided similar glycemic control to insulin glargine but was associated with less nocturnal hypoglycaemia. Alongside its longer action, Degludec insulin also provides the ability to readably be mixed with other insulins. In theory, this will allow for the type 1 diabetes patient to retain a constant (i.e. smooth level) of long-acting basal insulin in association with a rapid-acting bolus at mealtime (e.g. aspart, lispro or glulisine).
When proinsulin is cleaved by proteases into a metabolically active form of the hormone (i.e. insulin), a byproduct is formed, namely C-peptide. C-peptide is a 31 amino acid residue molecule that is co-secreted, along with insulin, in equimolar amounts into the portal circulation. Once the autoimmune destruction of type 1 diabetes occurs, insulin is no longer produced and while that hormone is replaced by injections, C-peptide is no longer produced nor replaced. Interest has grown in recent years for the notion that rather than a simple 'byproduct' of insulin production, C-peptide itself may play an important role in physiology. Indeed, this peptide has been tied to what has been termed 'vascular homeostasis' (vascular health) in several tissues, perhaps related to alterations in microvascular circulation and with its absence, contributing to subsequent damage to the nerves, kidneys and retina. To this end, studies of animal models have suggested that C-peptide replacement may be beneficial in terms of slowing and perhaps even preventing the disorder. Hence, it is possible that future interventions in type 1 diabetes may include not only exogenous insulin replacement, but that involving the provision of C-peptide.
A role for other hormones?
Increasing evidence suggests that other hormones primarily developed for the treatment of type 2 diabetes many, in fact, hold benefit for those with type 1 diabetes. As such, future treatments may include glucagon-like peptide-1 (GLP-1), agonists, sodium glucose like transport (SGLT) inhibitors, leptin, amylin and/or glucagon – either alone or delivered as part of a closed loop system.
Of these, glucagon, given its ability to release hepatic glucose, could be used as a means to counteract the effects of insulin. Taken together, this could lead to a more 'physiological-like' control of glucose regulation. However, for this to occur, new formulations must be developed as existing pharmacological preparations exist in powered form, rendering them unsuitable for pump application. To this end, formulations meeting this need (e.g. Eli Lilly/Roche, Biodel) are under development.
Not to be outdone, amylin, a hormone that suppresses glucagon, is also being tested in pump-based systems for its ability to improve post-meal glucose levels. An analogue of amylin, under the name Symylin, is currently underdevelopment by Amylin Pharmaceuticals. Amylin Pharmaceuticals is also overseeing the clinical development of a leptin equivalent, Metreleptin, for its ability to regulate blood glucose levels and insulin demands.
^ Heller S et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012 Apr 21;379(9825):1489-97.