Celebration of a century of insulin therapy in children with type 1 diabetes

Abstract

Insulin is the key anabolic hormone of metabolism, with clear effects on glycaemia. Near-complete insulin deficiency occurs in type 1 diabetes (T1D), the predominant form affecting children, and uniformly fatal until the discovery of insulin. By the early 20th century, it was known that T1D was caused by the lack of a factor from pancreatic islets, but isolation of this substance proved elusive. In 1921, an unusual team in Toronto comprising a surgeon, a medical student, a physiologist and a biochemist successfully isolated a glucose-lowering pancreatic endocrine secretion. They treated an emaciated 14-year-old boy in 1922, restoring his health and allowing him to live for another 13 years. Thus began an era of remarkable progress and partnership between academia and the pharmaceutical industry to produce drugs that benefit sick people. The Toronto team received the 1923 Nobel Prize, and more Nobel Prizes for work with insulin followed: for elucidation of its amino acid sequence and crystalline structure, and for its role in the development of radioimmunoassays to measure circulating hormone concentrations. Human insulin was the first hormone synthesised by recombinant methods, permitting modifications to enable improved absorption rates and alterations in duration of action. Coupled with delivery via insulin pens, programmable pumps and continuous glucose monitors, metabolic control and quality of life vastly improved and T1D in children was converted from uniformly fatal to a manageable chronic condition. We describe this remarkable ongoing story as insulin remains a paradigm for human ingenuity to heal nature's maladies.

Keywords: endocrinology; paediatrics; technology.

Figure 1

(A) Amino acid sequence and structure of human insulin. (B) Three-dimensional structure of insulin. At high concentration, two insulin monomers self-associate to form a dimer, and three dimers (with two zinc ions, shown as grey sphere in 3D hexamer image) can self-associate into hexamers for efficient storage before exocytosis (The blue arrows in the monomer and dimer represent a beta sheet—a secondary structure element in a protein in which amino acids are arranged in an elongated fashion). Adapted from figure 2 in Hirsch et al, distributed under the terms of the Creative Commons CC BY license, using illustrations of crystal structures (PDB ID 6S34 and PDB ID 1MSO) determined and provided by Eva Johansson, Novo Nordisk.

Figure 2

Selected 20th century milestones, following its initial discovery in 1921, in further understanding of the insulin molecule and its physiology (green panels), and of diabetes (blue panels) and its treatment (grey panels). AGEs, advanced glycation end products; DCCT, Diabetes Control and Complications Trial; HbA1c, glycated haemoglobin; PD, pharmacodynamic; T1D, type 1 diabetes; T2D, type 2 diabetes.

Figure 3

Pharmacokinetic profiles of subcutaneously absorbed insulin products versus normal physiological secretion. (A) Insulin secretion in healthy subjects eating three meals per day. Republished with permission of American Society for Clinical Investigation, from Polonsky et al ; permission conveyed through Copyright Clearance Center. (B) A near-normal profile of insulin secretion can be reproduced (dotted light blue line) by using basal–bolus therapy: injections of a rapid-acting insulin analogue at mealtimes (dark blue) and a once-daily injection of a long-acting insulin analogue (green line). Alternatively, a rapid-acting insulin analogue can be used in a CSII pump to reproduce the desired profile. ISPAD now recommends intensive individualised insulin therapy given by multiple daily injections or CSII pump for paediatric patients with T1D of all ages. (C) The pharmacokinetic profiles of human insulin products given subcutaneously are suboptimal. Soluble human insulin (orange line) is too long-acting to accurately recreate the prandial insulin response of normal physiology. It must be injected in advance of meals to coordinate the peak effect with glucose absorption, but the prolonged action can risk postprandial hypoglycaemia. Longer-acting human insulin-based products, such as NPH insulin (grey line), poorly recreate basal insulin secretion, having a peak effect and being too short-acting. NPH insulin is therefore usually administered two times per day. Note that all traces in B and C are hypothetical schematics. CSII, continuous subcutaneous insulin infusion; ISPAD, International Society for Pediatric and Adolescent Diabetes; NPH, neutral protamine Hagedorn; T1D, type 1 diabetes.