Insulin therapy has been the cornerstone of diabetes treatment for nearly a century, and numerous commercial alternatives are available to control blood glucose. Nonetheless, insulin therapy remains sub-optimal, as manifested by infrequent normalization of blood glucose and the risk of experiencing dangerously low blood glucose levels.
Numerous novel insulin analogues and formulations are in development with the goal of further optimizing the time–action profile. Several once-weekly candidates that might minimize the requirement for daily injection in certain patients are currently in early clinical trials.
Alternative methods to subcutaneous injection of insulin delivery should improve the convenience of treatment and should probably lead to enhanced diabetic care, especially in patients that resist using injectable therapy despite treatment failure on oral medications. Oral and inhalable insulin formulations currently represent the most promising prospects in non-injectable delivery and constitute a priority area in the refinement of insulin therapy.
Substantial interest persists in the development of glucose-sensitive therapy that is responsive to real-time changes in blood glucose. Direct and indirect methods to render insulin therapy less prone to life-threatening hypoglycaemia are being aggressively pursued. Most notably, the combination of insulin and incretin therapy has delivered superior clinical results as measured by improvements in mean plasma glucose concentration (HbA1C), with fewer occurrences of hypoglycaemia and less body weight gain. Separately, advances in glucagon therapy move the field closer to achieving closed-loop insulin pump therapy.
Advances in insulin synthesis have stimulated a renewed interest in structural analogues that enhance pharmacodynamic properties, through tissue targeting (hepatospecific), supplemental pharmacology (insulin sensitizers) or selective action only in hyperglycaemia. Given the seminal importance of insulin as a drug we anticipate the continued pursuit of perfect insulin. Normalization of glucose control without the risk of hypoglycaemia and delivery in a patient-friendly form remain the central objectives.
Insulin remains indispensable in the treatment of diabetes, but its use is hampered by its narrow therapeutic index. Although advances in peptide chemistry and recombinant DNA-based macromolecule synthesis have enabled the synthesis of structurally optimized insulin analogues, the growing epidemics of obesity and diabetes have emphasized the need for diabetes therapies that are more efficacious, safe and convenient. Accordingly, a broad set of drug candidates, targeting hyperglycaemia plus other disease abnormalities, is now progressing through the clinic. The development of an insulin therapy that is responsive to glucose concentration remains an ultimate goal, with initial prototypes now reaching the proof-of-concept stage. Simultaneously, the first alternatives to injectable delivery have progressed to registration.
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The authors wish to dedicate this review to the memory of Ronald Chance. They are also thankful for all the guidance provided to them over the years by multiple international authorities in the biology and chemistry of insulin, specifically J. Amatruda, J. Caro, P. Cryer, B. Frank, J. Galloway, V. Gelfanov, S. Kent, R. Kahn, D. Kelly, P. Li, F. Liu, D. Perez-Tilve, S. Taylor, M. Tschoep, L. Vignati, M. Weiss and R. Whitcomb.
R.D.D. is a founder and Chief Scientific Officer of Calibrium LLC. J.P.M. is employee and shareholder of Calibrium LLC. A.N.Z. is a consultant and shareholder of Calibrium LLC.
- Diabetes mellitus
A metabolic disease associated with elevated levels of glucose that results from pancreatic insufficiency in insulin production and/or reduced target-tissue insulin sensitivity. Type 1 or juvenile diabetes is caused by immunological destruction of insulin-producing pancreatic β-cells. Type 2 or adult-onset diabetes is a progressive condition characterized by insulin resistance and is often associated with obesity.
- Insulin analogues
Compounds derived from insulin that has been altered in its structure for the primary purpose of enhanced pharmaceutics or pharmacology. The two main types of insulin analogues are basal or sustained-action analogues, which are used for daytime and night time glucose control, and bolus or rapid-acting analogues, which are used for mealtime glucose control and pump administration.
- Subcutaneous delivery
The drug is delivered through injection to the subcutis, the layer of tissue located immediately beneath the skin layer. It remains the most common method of insulin administration.
- Extended time–action profile
Characteristic of long-acting insulin analogues, which produce relatively stable insulin levels for 12–24 hours after injection. These analogues are sometimes referred to as 'peakless' insulins by virtue of their flat pharmacokinetic profiles.
- Therapeutic index
The ratio between the dose of the drug that causes an adverse effect relative to the therapeutic dose. Insulin has an inherently low therapeutic index. This represents a persistent risk for overdosing that can result in life-threatening hypoglycaemia.
- Incretin hormone
A gut-derived peptide hormone that stimulates insulin secretion after food consumption. Additional functions of incretin hormones include inhibition of glucagon secretion, restriction of gastric motility and appetite suppression. The two most prominent physiological hormones within this class are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1).
- Single-chain insulin
(SCI). An insulin analogue or its precursor in which the two individual peptide chains (A and B) are covalently connected. The two chains can be linked by a connecting sequence (such as the proinsulin C-peptide), synthetic linker or fused directly through an amide bond.
Functional endocrine cells that are located in pancreatic islets and are responsible for biosynthesis, storage and secretion of insulin under glucose control.
- Gastric bypass surgery
A bariatric procedure that surgically reduces the size of the stomach. This restricts the quantity of absorbed nutrients and alters local hormone production and action to collectively achieve body weight reduction.
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Zaykov, A., Mayer, J. & DiMarchi, R. Pursuit of a perfect insulin. Nat Rev Drug Discov 15, 425–439 (2016). https://doi.org/10.1038/nrd.2015.36
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