Fibrinolysis and Diabetes Mellitus
Pia Glas-Greenwalt in Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
Proinsulin is the prohormone from which C-peptide is cleaved to produce insulin. With the development of specific monoclonal antibody assays for insulin and its precursors, it has been recognized that the less specific insulin radioimmunoassays that have been in common use overestimate actual insulin concentration because of cross-reactivity with the insulin precursors (especially proinsulin and 32–33 split proinsulin).125 This is particularly important in type 2 diabetic patients, in whom proinsulin and split proinsulin may account for over 60% of total immunoreactive insulin.126,127 When allowing for this inaccuracy, it is argued that patients with type 2 diabetes have absolute hypoinsuhnemia rather than hyperinsulinemia in the presence of insulin resistance.128
Biocatalyzed Synthesis of Antidiabetic Drugs
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
After this pioneering work, some other strategies were developed using recombinant microorganisms that produce intact proinsulin instead of the A or B chains separately. Proinsulin is the pro-hormone precursor to insulin made in the β cells of the islets of Langerhans, consisting in 81 aminoacidic residues arranged in three chains, namely, the above mentioned A and B chains, connected each other by a C chain (Steiner and Oyer, 1967) between the C terminal end of chain B and the N terminal end of the A chain, as shown in Fig. 11.2. For instance, Novo used engineered Saccharomyces cerevisiae cells to secrete proinsulin; subsequently, two enzymatic cleavages, the first one catalyzed by trypsin leading to the removal of most of the C chain, and the second one catalyzed by caboxypeptidase to delete two Arg residues from ThrB30, yield the human insulin (Thim et al., 1986; Ladisch and Kohlmann, 1992). Preparation of human insulin from proinsulin.
Medicinal poisons
Jason Payne-James, Richard Jones in Simpson's Forensic Medicine, 2019
No discussion of forensic toxicology would be complete without some mention of insulin poisoning via the exogenous administration of insulin. Insulin poisoning was once a popular means of homicide; now it is rare. Insulin overdose can cause fatal brain damage, but if overdose is suspected it can be confirmed by several different methods. Analysis of homicidal insulin overdose is always a challenging task in forensic practice because of the difficulties in toxicological analysis as well as the elusive pathologic changes. C-peptide is a peptide that is made when proinsulin is split into insulin and its C-peptide fragment. This event occurs just before release of insulin from the pancreas. If concentrations of the peptide are very low and insulin very high, the disparity would suggest that exogenous insulin had been administered. However, unless the blood specimen is frozen, levels of C-peptide may degrade rapidly. DNA analysis offers another possible approach. Biosynthetic insulin is now produced by genetic engineering. Some of the bioengineered insulin has a slightly different structure than human insulin and these differences can be detected. A friend, relative or care-giver may be the one who carries out homicide by insulin injection. Suicide by insulin overdose is well recognised.
Improvement in the proinsulin/C-peptide ratio during treatment with ipragliflozin in Japanese patients with type 2 diabetes mellitus
Published in Expert Opinion on Pharmacotherapy, 2018
Takahiro Takase, Akinobu Nakamura, Chiho Yamamoto, Tatsuya Atsumi, Hideaki Miyoshi
Proinsulin is synthesized by the secreting granule of pancreatic beta cells and is a precursor molecule for insulin and C-peptide. Physiologically, almost all proinsulin molecules are intracellularly cleaved into insulin and C-peptide [1]. Therefore, serum proinsulin levels are greatly lower than those of insulin and C-peptide in healthy people. Presumably hyperproinsulinemia might be caused by inefficient proinsulin processing within the beta cell secretory granule, leading to an increased release of immature insulin precursors, or alternatively caused by an increased secretary demand on beta cells, leading to an increased insulin secretion from the reserve insulin granule pool, which could contain greater amounts of immature insulin precursors [2,6]. Our findings would support the latter explanation, since our results suggest that treatment with ipragliflozin ameliorated the increased demand for insulin, resulting in a decrease in the proinsulin/C-peptide ratio. Therefore, ipragliflozin treatment could improve beta cell function by reducing beta cell overload.
Beta-cell failure in type 2 diabetes: mechanisms, markers, and clinical implications
Published in Postgraduate Medicine, 2020
When beta cells produce insulin, it is first secreted as proinsulin. C-peptide is a 31-amino acid polypeptide that connects the alpha and beta chains of proinsulin [58]. Upon removal of C-peptide from the proinsulin molecule, the alpha and beta chains become linked, and proinsulin turns into insulin. Thus, C-peptide and insulin are present in beta cells in equal amounts and are co-secreted into the portal vein in equimolar amounts. In contrast to insulin, C-peptide does not undergo hepatic degradation and is cleared entirely in peripheral tissues at a relatively constant rate. C-peptide has a substantially longer half-life than insulin (approximately 35 min vs. 3–5 min) [59,60]. Furthermore, in individuals who are receiving insulin therapy, insulin assays cannot distinguish endogenous and exogenous insulin, but the differential kinetics of C-peptide mean that peripheral plasma C-peptide concentrations can be used to accurately estimate insulin secretion.
Doege-Potter syndrome in a patient with a giant abdominal solitary fibrous tumor: a case report and review of the literature
Published in Acta Clinica Belgica, 2023
Joris Rötgens, Bruno Lapauw, Guy T’Sjoen
The typical pattern for NICTH/Doege-Potter syndrome is low glucose, with simultaneous low insulin/proinsulin/C-peptide/beta-hydroxybutyrate and a negative oral hypoglycemic agent screening. Furthermore, GH and IGF-I levels are typically low (due to negative feedback), whereas IGF-II may or may be not elevated (depending on the assay used). So, it is important to notice that a normal IGF-II does not rule out a diagnosis of NICTH. The IGF-II:IGF-I ratio (which is normally no more than 3:1) is elevated. In many case reports, this ratio has been used as a surrogate biomarker for diagnosing NICTH, with a ratio greater than 10 reported to be virtually pathognomonic for NICTH [6,15]. In our case there was a low insulin, C-peptide and beta-hydroxybutyrate during hypoglycemia. Normally one would also expect a low proinsulin (due to negative feedback from the hypoglycemia). But that was not the case in our patient, possibly due to the longer half-life of proinsulin compared to insulin and C-peptide, as well as the fact that the available immunoassays are not free from interference [16]. GH and IGF-I were low. IGF-II:IGF-I ratio was 10.65.
Related Knowledge Centers
- Beta Cell
- Disulfide
- Insulin Receptor
- Pancreas
- Prohormone
- Amino Acid
- Insulin
- Pancreatic Islets
- Gene
- C-Peptide