Insulin: a small protein with a long journey

Abstract

Insulin is a hormone that is essential for regulating energy storage and glucose metabolism in the body. Insulin in liver, muscle, and fat tissues stimulates the cell to take up glucose from blood and store it as glycogen in liver and muscle. Failure of insulin control causes diabetes mellitus (DM). Insulin is the unique medicine to treat some forms of DM. The population of diabetics has dramatically increased over the past two decades, due to high absorption of carbohydrates (or fats and proteins), lack of physical exercise, and development of new diagnostic techniques. At present, the two largest developing countries (India and China) and the largest developed country (United States) represent the top three countries in terms of diabetic population. Insulin is a small protein, but contains almost all structural features typical of proteins: α-helix, β-sheet, β-turn, high order assembly, allosteric T®R-transition, and conformational changes in amyloidal fibrillation. More than ten years' efforts on studying insulin disulfide intermediates by NMR have enabled us to decipher the whole picture of insulin folding coupled to disulfide pairing, especially at the initial stage that forms the nascent peptide. Two structural switches are also known to regulate insulin binding to receptors and progress has been made to identify the residues involved in binding. However, resolving the complex structure of insulin and its receptor remains a challenge in insulin research. Nevertheless, the accumulated knowledge of insulin structure has allowed us to specifically design a new ultra-stable and active single-chain insulin analog (SCI-57), and provides a novel way to design super-stable, fast-acting and cheaper insulin formulations for DM patients. Continuing this long journey of insulin study will benefit basic research in proteins and in pharmaceutical therapy.

Introduction of mutations in insulin molecule: positive and negative mutations

“…Склонность к фибрилляции отрицательно сказывается на лиганд-рецепторном взаимодействии инсулина и инсулинового рецептора [18], поскольку функционально активной является мономерная форма молекулы. Известно, что образование гексамеров способно сдерживать процесс фибрилляции.…”

Hypertriglyceride Induced Acute Pancreatitis

“…VLDL is a triglyceride-rich lipid moiety and the use of insulin decreases hepatic production of apolipoprotein B-100 rich VLDL1 and intestinal production of VLDL2, rich in apoprotein B-48 while also increasing hydrolysis of TG by LPL 114,115 . Insulin promotes storage of both glucose and fatty acids, thus a continuous infusion of insulin should reduce serum levels of both of these fuels 116,117 . Intravenous (IV) insulin may be considered more effective and easier to titrate than subcutaneous (SQ) administration based upon absorption and delivery kinetics, although both have been used with some success 104,118,119 .…”

Interaction of insulin with methyl tert -butyl ether promotes molten globule-like state and production of reactive oxygen species

“…It has been suggested that a molten globule intermediate occurs during insulin thermal unfolding [25][26][27]. In addition, insulin as a control hormone binds to its receptor and regulates metabolism by suppressing gluconeogenesis enzymes.…”

“…In addition, insulin as a control hormone binds to its receptor and regulates metabolism by suppressing gluconeogenesis enzymes. Furthermore, induced conformational changes in insulin impair receptor binding and triggers diabetes mellitus [25]. Here we investigated the effect of different concentrations of MTBE on insulin conformation.…”