Insulin (source code)
= Insulin
{wiki}
<Insulin> is a <protein> <hormone>. Its mature form has two <polypeptide chains>; identifying their sequences and <protein disulfide bonds> provided the motivating example in <Sanger's insulin sequencing experiment>. See https://www.ncbi.nlm.nih.gov/books/NBK9879/[Cooper: insulin as a two-chain hormone, figure 2.16].
A meal illustrates the <insulin> side of <blood glucose> <homeostasis>: rising <glucose> stimulates <beta cells> in the <pancreatic islets>, and released <insulin> favors uptake and storage of fuel. <Alpha cells> produce <glucagon>, while <delta cells> produce <somatostatin>, which inhibits release of both <insulin> and <glucagon>. The <pancreas> therefore contains interacting sensor and secretory <biological cells>, rather than one undifferentiated source of <hormones>. <Anatomy and Physiology 2e by J. Gordon Betts and others/17.9 The Endocrine Pancreas>{ref}
<Insulin> and <glucagon> are <peptide hormones>, built from <amino acid residues> joined by <peptide bonds>; <glucose> is a small <carbohydrate> <molecule>. A <hormone> changes <signal transduction>, not the identity of the fuel it regulates. Human mature <insulin> has 51 <amino acid residues> in two <polypeptide chains>. <Beta cells> process <proinsulin> to <insulin> and <C-peptide>, storing the products in <secretory granules> for <exocytosis>. Increased <glucose> <metabolism> raises the <ATP>-to-<ADP> <ratio>, tending to close <ATP-sensitive potassium channels>; <depolarization> and entry of <calcium> <ions> then trigger <exocytosis>. This is an important triggering pathway, with additional amplification and modulatory inputs.<Endotext/Insulin Biosynthesis, Secretion, Structure, and Structure-Activity Relationships>[pp. 1, 4–8, 10–11]{ref}
\Image[/insulin-glucagon-tissue-control-circuit.png]
{title=<Insulin> and <glucagon> couple <pancreatic islets> to different tissue responses}
{description=Original qualitative <physiology> circuit. Each outer return closes a <negative feedback> loop for <blood glucose>; the arrows summarize direction, not measured gain or timing. <Insulin receptor> signaling changes <GLUT4> distribution in <skeletal muscle> and <adipose tissue>, while the <glucagon receptor> pathway principally supports <liver> <glucose> output. The local interactions within <pancreatic islets> explain why the two <hormones> are not independent switches.}
Binding to the <insulin receptor>, a <receptor tyrosine kinase>, starts <phosphorylation> of the <receptor> and <insulin receptor substrates>. Recruitment of <phosphoinositide 3-kinase> and activation of <Akt> transmit a major metabolic branch. In <skeletal muscle> and <adipose tissue>, that branch helps move <GLUT4> to the <cell membrane>, increasing <glucose> uptake by <facilitated diffusion>. <GLUT4> is a <membrane transport protein>, not an <insulin receptor>. <Insulin> also favors <glycogenesis> in <skeletal muscle> and the <liver>, and inhibits <lipolysis> in <adipose tissue>. In the <liver>, suppression of <glucose> output involves <enzyme> regulation, <gene expression>, and indirect changes in <substrate> supply. Its relative direct and indirect contributions are more complex than a single <Akt> arrow. <Insulin signaling in health and disease by Alan R. Saltiel>{ref}
<Insulin> is not a universal permission slip for <glucose> entry: <red blood cells> and much of the nervous system use uptake mechanisms that are not acutely dependent on <insulin>. Nor does the <liver> use the same <GLUT4> switch as <skeletal muscle>. This is why reduced <insulin> action can change <blood glucose> dramatically without stopping all <glucose> uptake. <The Genetic Landscape of Diabetes/Introduction to Diabetes>{ref}
<Diabetes> can disrupt production, response, and counterregulation. <Type 1 diabetes> usually involves destruction of <beta cells> and severe loss of endogenous <insulin>; <type 2 diabetes> combines <insulin resistance> with insufficient <beta cell> compensation. High circulating <insulin> can therefore coexist with impaired <insulin> action. Inappropriate <glucagon> release can add to excessive <liver> <glucose> output, and the response to low <blood glucose> can also be impaired: "more <glucagon>" is not a complete description of <diabetes>. These distinctions explain mechanisms, rather than prescribe treatment. <The Genetic Landscape of Diabetes/Introduction to Diabetes>{ref} <Endotext/Glucagon Physiology>{ref}
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