Adventures with Insulin in the Islets of Langerhans

Abstract

Insulin is a small but beautifully organized protein with a unique two-chain structure, the first protein to be sequenced. The mechanism of its biosynthesis invited much initial speculation but was finally clarified by the discovery of proinsulin, its single-chain precursor. The rich present-day field of protein precursor processing via post-translational proteolysis within the secretory pathway arose in the early 1970s as an offshoot of studies on insulin biosynthesis, which provided a novel paradigm for the generation of many other small neuroendocrine peptides. Before long, this mechanism was also found to play a role in the production of a much wider spectrum of proteins traversing the secretory pathway (receptors, growth factors, blood-clotting components, and even many viral envelope proteins) occurring in almost all eukaryotic cells. Indeed, yeast provided a key clue in the search for the proprotein convertases, the endoproteases that work along with carboxypeptidases and other modifying enzymes, such as the amidating enzyme complex (PAM), in converting inactive or less active precursor proteins into their fully active peptide products. In this "Reflections" article, I have tried to recount the people and events in my life that led to my involvement first in basic biochemical research and then on to insulin, proinsulin, and many relevant related areas that continue to fascinate and challenge my colleagues and me, as well as many other biomedical scientists today, as diabetes mellitus increasingly threatens human health throughout our contemporary world.

New Insulin Glargine 300 Units·mL−1 Provides a More Even Activity Profile and Prolonged Glycemic Control at Steady State Compared With Insulin Glargine 100 Units·mL−1

“…In cohort 1 (n = 18) participants received, in randomized treatment order, Gla-300 0. 4 The total insulin dose was rounded to the nearest unit, meaning that the integer dose could be accurately administered using the graduation marks for Gla-100. If not exactly divisible by 3, the Gla-300 dose needed to be rounded to the nearest graduation mark (1 unit of Gla-300 corresponding to 10/3 mL).…”

“…Insulin glargine mimics the physiology of human insulin, where 31 B -Arg-32 BArg-insulin is a final intermediate of low solubility in the process of endogenous insulin production (4). Substitution of 21…”

Structural Integrity of the B24 Site in Human Insulin Is Important for Hormone Functionality

“…In addition, the A chain includes an intrachain Cys A6 -Cys A11 disulfide bond. Insulin is capable of dimerization at low micromolar concentrations (3), and the presence of divalent metal ions leads to the formation of insulin hexamers that represent the storage form of this hormone (2). There is overwhelming evidence that monomeric insulin, which dissociates from its storage forms, must undergo structural changes upon binding to IR.…”

“…Insulin is the final product of an extensive processing from single-chain preproinsulin (2) and consists of an A-chain (Gly A1 -Asn A21 ) and B-chain (Phe B1 -Thr B30 ) that are linked by two interchain disulfide bridges (Cys A7 -Cys B7 and Cys A20 -Cys B19 ). In addition, the A chain includes an intrachain Cys A6 -Cys A11 disulfide bond.…”

“…Insulin exerts its actions through binding as a monomer to the (␣␤) 2 -homodimeric, tyrosine kinase-type insulin receptor (IR) (1).…”