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Hormones of the Pancreas
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Insulin is synthesized by the β cells. Ribosomes translate mRNA at the endoplasmic reticulum to form preproinsulin (molecular weight, 11,500 Da). The preproinsulin is then cleaved in the endoplasmic reticulum to form proinsulin (molecular weight, 9000 Da). The proinsulin is cleaved in the Golgi apparatus to form insulin, which is stored in granules.
Diabetes Mellitus
Published in Victor A. Bernstam, Pocket Guide to GENE LEVEL DIAGNOSTICS in Clinical Practice, 2019
The insulin gene is located on the short arm of chromosome 11. Transcription of the insulin gene occurs in the β cells of the Langerhans islets where the mRNA transcripts are processed. Translation of the mature insulin mRNA yields preproinsulin, which is proteolytically cleaved to produce mature insulin as well as prepeptide and C-peptide sequences.
Why Cancer?
Published in John Melford, Pocket Guide to Cancer, 2017
One would expect the 51 amino acids that form the A and B chains of insulin to be conserved to a greater degree than the discarded 35 amino acids of the C peptide. Structural comparisons of multiple species confirm this is true. For example, the A chain of pig insulin is exactly the same as the A chain of man, while the B chain of pig insulin differs from the B chain of human insulin by a single amino acid. Incredibly, the 51 amino acids of human insulin differ from pig insulin by a single amino acid, even though man diverged from pigs to form a separate species some 88 million years ago. In stark contrast, the 35 amino acids of the discarded C peptide of pig preproinsulin, is only 74% similar to the C peptide of humans. This demonstrates the region of preproinsulin that is required for activity, the insulin part, to be highly conserved, while other regions of the molecule not required for activity, such as the C peptide, are not highly conserved. The closer species are in evolutionary terms, the smaller the divergence in the structure of insulin and other important proteins.
Emerging technologies in pediatrics: the paradigm of neonatal diabetes mellitus
Published in Critical Reviews in Clinical Laboratory Sciences, 2020
Nicolas C. Nicolaides, Christina Kanaka-Gantenbein, Nektaria Papadopoulou-Marketou, Amalia Sertedaki, George P. Chrousos, Ioannis Papassotiriou
Activating mutations in ABCC8 can cause transient or permanent NDM in 15% and 13% of patients, respectively [5]. The majority are de novo; however, they may be inherited in an autosomal dominant or recessive fashion. Moreover, ABCC8 mutations have been associated rarely with the DEND syndrome, probably due to differential expression of SUR1 versus SUR2 in the brain [15]. Genetic defects in INS, which encodes preproinsulin, have been associated with MODY and permanent NDM [40–44]. INS-related NDM seems to be caused by misfolding of proinsulin, which then remains in the endoplasmic reticulum, where it causes stress and leads β-cells to apoptosis due to unfolded protein response [44–48]. Finally, a number of homozygous or compound heterozygous mutations in GCK have been demonstrated to cause permanent NDM [49]. Clinicians should suspect this etiology in cases of known consanguinity or in family members with a history of mild diabetes or glucose intolerance. Patients with GCK mutations should be treated with insulin; however, glucokinase activators could be the choice of treatment in the era of applied pharmacogenetics [50,51].
Is insulin intoxication still the perfect crime? Analysis and interpretation of postmortem insulin: review and perspectives in forensic toxicology
Published in Critical Reviews in Toxicology, 2020
Charline Bottinelli, Nathalie Cartiser, Fabien Bévalot, Laurent Fanton, Jérôme Guitton
HI synthesis occurs in the beta-cells of Langerhans islets, located in the endocrine part of the pancreas. The first step is preproinsulin production, followed by conversion into proinsulin by endopeptidase, then maturation in the Golgi apparatus (Magnan and Ktorza 2005), catalyzed by specific prohormone convertases which truncate proinsulin in equimolar quantities of HI and C-peptide (Jarzuel 2008). When vesicles become mature and HI concentration increases, it precipitates with zinc ions to form hexamer crystals (Magnan and Ktorza 2005), which are an inactive and stable form. The vesicles are stored until the beta-cells are exposed to appropriate stimuli ordering the immediate secretion of HI. When HI is released in the interstitial space, dilution induces a change from hexamer to monomer, which is then able to diffuse in blood capillaries and enter the systemic circulation (Jarzuel 2008).
Blood-brain barrier receptors and transporters: an insight on their function and how to exploit them through nanotechnology
Published in Expert Opinion on Drug Delivery, 2019
Rui Pedro Moura, Cláudia Martins, Soraia Pinto, Flávia Sousa, Bruno Sarmento
The insulin receptor (InsR) is a tetrameric glycoprotein, composed of two α- and β- subunits, cross-linked by sulfide bonds. It has an approximate molecular weight of around 350–400 kDa at the BBB. Regarding the peripheral tissues, InsR seems to have a higher molecular weight, of about 420 kDa [53,54]. It is a tyrosine-kinase type receptor, and its main ligands are insulin and insulin-like growth factors. Nonetheless, there is also the insulin-like growth factor receptor [IGF-R], which is structurally similar to InsR that has a higher affinity for insulin-like growth factors [55]. InsR is produced as a single chain pre-receptor, coupled with a signal peptide, that is cleaved after synthesis. Then, the receptor undergoes post-translational modifications, including folding, dimerization, and glycosylation, essential for its activity and ligand-binding affinity [56]. Insulin, is synthesized by beta cells of the pancreas as the precursor preproinsulin. Afterward, preproinsulin is cleaved of its signal peptide, releasing proinsulin. Lastly, the exposure of proinsulin to proteases promotes the cleavage of the middle linking peptide, the C peptide to form mature insulin [57].