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Increased risk for cancer in diabetic patients and innovative strategy to activate insulin receptor using a peptide independent of insulin

Diabetes has been described in ancient Egyptian documents as early as ca. 1500 B.C.  Yet, treatment has not been available until 1920s when insulin was first isolated (Nobel prize, 1923).  Worldwide, 425 million people are currently diagnosed with diabetes, affecting 8-9% of the global population with ~4 million deaths in 2017 (7th leading cause of mortality).  The global rate nearly doubled from 4.7% in 1980 to 8.8% in less than 30 years, and is expected to increase by another 48% in 2045.  In the U. S., the incidence of diabetes arose alarmingly from 0.9% in 1958 to 7.4% in 2015.

 Within the body, the level of glucose is regulated by insulin.  After eating, insulin is secreted by beta cells of pancreas to promote glucose uptake by the cells.  The secreted insulin binds to its receptor on the cell membrane activating its tyrosine kinase (through autophosphorylation), generating the binding site for substrates (to be kinased by the receptor).  This, in turn, activates a signaling cascade involving phosphoinositide 3-kinase (PI3K), PDK1, protein kinase B (Akt), etc., ultimately causing GLUT-4 to become embedded in the cell membrane.  GLUT-4 (encoded by SLC2A4 gene) then transports glucose into fat cells, muscle cells, etc. (Ijuin et al., 2012).

 In the event of an insulin insufficiency, the inability to store glucose by liver or muscle causes an abnormally high level of glucose in circulation, prompting its removal by the kidney through excretion.  The buildup of glucose in urine increases its osmotic pressure, causing water to be extracted from other body tissues leading to dehydration, causing further intake of fluids.  Diabetes can cause damages to the nerves, kidney, blood vessels, and may lead to dire conditions such as diabetic retinopathy (blindness) or even deaths (due to coronary artery disorder).   Currently, diabetic patients account for ~25% of kidney transplantations performed in the U.S.

The predisposition to develop type I diabetes is partly inherited and the symptoms manifest in adolescents and children (or adults).  It accounts for ~5-10% of diabetic cases and the underlying pathobiology involves the T cell mediated immunological destruction of pancreatic beta cells, causing a reduced insulin production.  In contrast, type 2 diabetes is characterized by the production of insulin by pancreas despite its inefficient usage by the body--i.e. 'insulin resistance' or reduced sensitivity to insulin.  The condition may worsen by the inability of pancreas to respond, eventually causing insulin shortage.  Specific genetic defects have not been identified though numerous DNA variations have been identified.  Type 2 diabetes accounts for 90-95% of total cases (risk increases significantly after 45 y), and lifestyles (ex. obesity, diet, lack of exercise, body fat) may contribute to the diabetic progression.

Earlier, insulin purified from animal source was used to treat diabetes.  After the determination of the amino acid sequence of insulin by F. Sanger (Nobel prize, 1958) (Stretton, 2002), other means of preparing insulin became available, ex. bovine insulin synthesized chemically.  Insulin is comprised of chain A (21 residues) and chain B (30 residues) that are held together by disulfide bonds.  In 1978, A. Riggs and K. Itakura (City of Hope National Medical Center, USA) used genetic engineering to produce synthetic human insulin in E. coli (Riggs, 2020), which was later marketed by Genentech to make it commercially available worldwide.  Currently the biosynthetically produced recombinant human insulin and/or its analogues are most widely administered.

                                         

Further advances have been made to facilitate diabetic treatment.  As insulin functions to activate the tyrosine kinase associated with insulin receptor to initiate signaling, an alternate means of activation was sought.  To this end, the investigators at Harvard Medical University (USA) discovered a 24-mer peptide derived from the transmembrane domain, which could activate the receptor in the absence of insulin (Lee et al., 2014).  Further, the peptide was able to activate insulin receptor from patients who suffer from insulin resistance--thus, bypassing the requirement for the presence of ligand-binding domain in receptor (for its activity).  Mechanistically, the peptide may disrupt the dimeric interaction of the transmembrane domains via intercalating, causing beta subunit to adopt an activate state (hence mimicking the effect of insulin binding).

Increasingly, diabetes is linked to cancer.  Multiple studies have found that diabetic patients may have an increased risk of developing cancers (liver, pancreatic, colorectal, kidney, bladder, breast, endometrial cancer but lesser risk for prostate cancer) (Abudawood, 2019; Wang et al. 2020) with diabetic women suffering from greater risk than diabetic men.  Though the precise underlying mechanism is not known, mitogenic (growth promoting) property of insulin or insulin-like growth factor (IGF), hyperglycemia (excess glucose promotes metabolism), and inflammation have been proposed.

 The key to preventing epidemic is the ability to diagnose the infected early to preempt further propagation.  For this, Bio-Synthesis, Inc. provides primers and probes (as well as synthetic RNA control) for COVID-19 diagnosis via RT-PCR assay.  It specializes in oligonucleotide modification and provides an extensive array of chemically modified nucleoside analogues (over ~200) including bridged nucleic acid (BNA).  A number of options are available to label oligonucleotides (DNA or RNA) with fluorophores either terminally or internally as well as to conjugate to peptides or antibodies.  It recently acquired a license from BNA Inc. of Osaka, Japan, for the manufacturing and distribution of BNANC, a third generation of BNA oligonucleotides.  To meet the demands of therapeutic application, its oligonucleotide products are approaching GMP grade.  Bio-Synthesis, Inc. has recently entered into collaborative agreement with Bind Therapeutics, Inc. to synthesize miR-21 blocker using BNA for triple negative breast cancer.  The BNA technology provides superior, unequalled advantages in base stacking, binding affinity, aqueous solubility and nuclease resistance.  It also improves the formation of duplexes and triplexes by reducing the repulsion between the negatively charged phosphates of the oligonucleotide backbone.  Its single-mismatch discriminating power is especially useful for diagnosis (ex. FISH using DNA probe).  For clinical application, BNA oligonucleotide exhibits lesser toxicity than other modified nucleotides. 

 

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References

Abudawood M. Diabetes and cancer: A comprehensive review.   J Res Med Sci.  24:94 (2019). PMID: 31741666

Ijuin T, Takenawa T. Regulation of insulin signaling and glucose transporter 4 (GLUT4) exocytosis by phosphatidylinositol 3,4,5-trisphosphate (PIP3) phosphatase, skeletal muscle, and kidney enriched inositol polyphosphate phosphatase (SKIP).  J Biol Chem. 287:6991-9 (2012). PMID: 22247557

Lee J, Miyazaki M, et al. Insulin receptor activation with transmembrane domain ligands.   J Biol Chem. 289:19769-77 (2014).  PMID: 24867955

Riggs AD.  Making, Cloning and Expression of Human Insulin Genes in Bacteria: The Path to Humulin@.  Endocr Rev. 2020 Dec 19:bnaa029. doi: 10.1210/endrev/bnaa029.   PMID: 33340315

Stretton AO.  The first sequence.  Fred Sanger and insulin.   Genetics.  162:527-32 (2002).   PMID: 12399368

Wang M, Yang Y, Liao Z. Diabetes and cancer: Epidemiological and biological links.  World J Diabetes. 11:227-238 (2020). PMID: 32547697