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  July 11, 2020
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Biotechnology and Development Journal. (c) 2020. Skyebluepublications.ca Port Coquitlam B. C. Canada V3B 1G3.
Nutraceuticals with T2 Diabetes for Drug Discovery: an update
Danny A. Flores1
1 Skye Blue Publications, 1440 Barberry Drive, Port Coquitlam, B. C. Canada V3B 1G3
*Correspondence Address:
  Danny A. Flores
  Skye Blue Publications, 1440 Barberry Dr., Port Coquitlam, B.C., V3B 1G3 Canada 
Source of Support: None, Conflict of Interest: None
Type 2 diabetes (T2D) and its condition is described in regards to the: immunogenic "cascade", insulin resistance in tissue, the low-intensity, chronic inflammatory response, and hyperglycaemia, which can aggravate resistance. Inflammation in diabetes can be addressed by nutraceutical agents and possible pharma and with life-style. Two nutraceuticals, fructan and vitamin D, have the following effects: fructan has significant effects on glycemia and cytokine biomarkers, fructan also results in improved glycemic indicators and use of vitamin D resulted in improved cytokine biomarkers IL-6 and TNF-alpha, as indicators of the inflammatory cascade. Mentioned here is drug discovery using molecular components JNK1 and MKP-1 (and also via the vitamin D receptor or VDR) with insulin resistance in macrophage and modulation of the immunogenic "cascade" in white blood cells (WBC), as with cytokines IL-6, TNF-alpha, IL-10 and IFN-gamma, respectively.  Other drug agents mentioned with immunomodulation, chronic inflammation, insulin resistance and beta cell function, in terms of, expansion, glucose tolerance and insulin secretion are: the G-protein coupled receptor (GPCR), leukotriene B4 receptor 1 (LTB4R1) as inhibitors of LTB4 cells, free fatty acid receptor 1 (FFAR1), free fatty acid receptor 4 (FFAR4), beta-cell glucose-dependent insulinotropic receptor (also known as GPR119) and with agonist; and CXC3C-chemokine ligand 1 (CXC3CL1) derived reagents on its beta cell receptor CXC3CR1.
Keywords: vitamin D, fructan, T2 diabetes (T2D), immunoresponse, chronic inflammation, drug discovery
      In particular the diabetic condition in type 2 diabetes (T2D) can comprise the following: a) challenge of the macrophage due to an associated risk from low-grade antigenic exposure from an infection, b) resulting in an expressed immunogenic "cascade" (an e. g. of which is the specific "cytokine storm"), c) cytokines lead directly to development of insulin resistance in the fat, liver and muscle tissue, d) next, a low-intensity, chronic inflammatory response condition ensues, and lastly, e) hyperglycaemia develops which can feedback directly to further aggravate the insulin resistance in tissue.  It has been noted that the inflammatory basis for diabetes is not well understood yet and in addition to use of nutraceuticals and other pharma interventives are lifestyle-related ones also, for e. g., diet, sugar intake, exercise and weight loss.
    Two nutraceuticals, in particular, also referred to here as prebiotics, due to their indigestibility and post-absorptive metabolic effects with T2D, are: a mixture referred to as fructan and vitamin D.
Anti-Diabetic Therapy with Fructan and Vitamin D.
      Metabolic dysregulation itself induces inflammation and with anti-diabetic treatments may alleviate inflammation by improving the metabolic state (R. M. Pollack et al., 2016).  Approaches for anti-diabetic therapy may not clearly differentiate effects on metabolism from direct effects on the immune system (R. M. Pollack et al., 2016).  Treatments addressing anti-inflammatory effects are partial and inconsistent, due to, incomplete normalization of metabolic dysregulation and being that diabetes-associated inflammation is multi-factorial, respectively; treatments to modulate the immune response have beneficial metabolic effects and opens new venues for treatment of diabetes (R. M. Pollack et al., 2016).

      According to P. Dehghan et al., 2014, they concluded in their study is that with use of a reagent enriched for fructo-oligosaccharide (FOS), a type of fructan prebiotic with another major fructan, inulin, demonstrated significant effects on glycemic blood levels and cytokine biomarker indicators of systemic chronic inflammation, a risk factor of the T2DM condition.
      In another study with F. J. Alarcon-Aguilar et al., 2010, using Pscacalium peltatum (H. B. K.) Cass. type-fructan with artificially induced diabetes in mice subjects from drug administered agent, streptozocin, demonstrated reduced TNF-alpha, increased interleukin-10 (IL-10) indicating an inhibition of inflammatory cytokines such as TNF-alpha and increased interferon-gamma (IFN-gamma) indicating beneficial effects on the immune system.
     In the study of L. Wang et al., 2019, ITF (viz. inulin, FOS, GOS) supplementation with a large study meta-analysis of randomized-controlled trials concluded that four parameters used were measured for risk factors of T2DM, that is for glycemia: fasting blood glucose- FBG; glycosylated haemoglogin- HbA1c; fasting insulin- FINS and, homeostasis assessment-insulin resistance (HOMA-IR), significantly reduced by supplementation amongst individuals.
    According to Y. Zhang et al. (2012) a new location was found where the vitamin D receptor appears to bind directly to DNA and activate the gene MKP-1 which interferes with the lipopolysaccharide (LPS) triggered inflammatory cascade including a molecule, p38, leading to increases in IL-6 and TNF-alpha.  In another study by M. Flores (2005) vitamin D can mediate low-intensity, chronic inflammation and insulin resistance in T2DM by down-regulating the production of pro-inflammatory cytokines, IL-6 and TNF-alpha; it also has been mentioned that for the characteristic inflammatory cascade tissue resistance results in the fat, liver and muscle.

Pharmacological Drug Discovery.
     The following present new opportunities for drug discovery in T2D:
     1) The macrophages which initiate the immune response leads to insulin resistance in fat, liver and muscle tissues and which results in chronic tissue inflammation should present perspective for drug agents that act against JNK1, the component in macrophage which leads to insulin resistance, sensitizing tissues to insulin, as a desired metabolic effect, in a great majority of individuals with T2DM. Another mechanism presented here is that of activation of the gene of component MKP-1 in white blood cells (WBC) to modulate the so-called immunogenic "cascade", viz., with TNF-alpha, IL-6, IL-10 and IFN-gamma and via another drug mechanism acting on the vitamin D receptor (VDR) which results also in activating MKP-1 gene in WBC.
    2) Cell receptors such as: a) G protein-coupled receptors (GPCR) affecting insulin action, insulin secretion and beta-cell expansion as possible drug targets, b) leukotriene B4 receptor 1 (LTB4R1) inhibitor drug agents may be anti-diabetic insulin sensitizers wherein LTB4 cells can potentially block cellular insulin signaling in liver cells (hepatocytes) and muscle cells (myocytes), c) free fatty acid receptor 1 (FFAR1) and free fatty acid receptor 4 (FFAR4) promote glucose-induced insulin secretion and also in addition may inhibit inflammatory signaling in immune cells, respectively, the latter of which otherwise leads to insulin resistance in tissue, d) beta-cell glucose-dependent insulinotropic receptor (GPR119) which leads to an increase in insulin secretion by beta-cells with further agonism of GPR119 on enteroendocrine cells promoting both glucagon-like peptide (GLP1) and gastric inhibitory polypeptide (GIP) release making it another potential anti-diabetic drug target to promote insulin secretion and e) CX3C-chemokine ligand 1 (CX3CL1) in mice may lead to CX3CL1-based reagents on its receptor CX3CR1 on beta-cells which can strikingly improve glucose tolerance and insulin secretion serving as another drug for anti-diabetic therapy, recently gathered from D. Da Young (2016).

The results from the literature indicate possible drug discovery approaches using nutraceuticals fructan and vitamin D include: 1) involving the immunogenic players, JNK1 and MKP-1, in the inflammatory response, for: a) insulin sensitization of tissues and b) modulating the so-called immunogenic "cascade". There are still outstanding issues in regards to this route of using drugs with the immune response: a) sensitivity - in terms of degree of responsiveness, b) efficacy - or how effective the response is, and c) safety - regards any potential dangers such as toxicity; and 2) another refers to receptor action regards, mainly, insulin action or sensitization of tissue or beta cell secretion.

Alarcon-Aguilar, F. J., Fortis-Barrera, A., Angeles-Mejia, S., Banderas-Dorantes, T. R., Jasso-Villagomez, E. I., Almanza-Peres, J. C., Blancas-Flores, G., Zamilpa, A., Diaz-Flores, M. and Roman-Ramos, R. 2010. Anti-inflammatory and anti-oxidant effects of hypoglycemic fructan fraction from Psacalium peltatum (H. B. K.) Cass. in drug-induced (viz. streptozocin) diabetic mice. Journal of Ethnopharmacology 132: 400-407.

Da Young, D. 2016. G protein-coupled receptors as targets for anti-diabetic therapeutics.  Nature Reviews Drug Discovery 15: 161-172.
Dehghan P., Gargari, P. B., and Jafar-abadi, M. A. 2014. Oligofructose-enriched inulin improves some inflammatory markers and metabolic endotoxemia in women with type 2 diabetes milletus: A randomized controlled clinical trial. Nutrition 30(2014): 418-423.

Flores, M. 2005. A role of vitamin D in low-intensity chronic inflammation and insulin resistance in type 2 diabetes milletus? Nutrition Research Reviews 18: 175-182.
Pollack, R. M., M. Y. Donath, D. LeRoith and G. Leibowitz. 2016. Anti-inflammatory Agents in the Treatment of Diabetes and Its Vascular Complications. Diabetes Care 39(S2): S244-S252.
Wang, L., Yang, H., Huang, H., Zhang, C., Zuo, H.-X., Xu, P., Niu, Y.-M. and Wu, S.-S. 2019. Inulin-type fructans supplementation improves glycemic control for the prediabetes and type 2 diabetes populations: results from a GRADE-assessed systematic review and dose-response meta-analysis of 33 randomizd controlled trials. 2019 Journal of Translational Medicine 17: 410-428. 

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