A further review of the genetic and phenotypic nature of diabetes mellitus

Graham Wilfred Ewing, Igor Gennadyevich Grakov

MIMEX Inc, Sochi, Russia.
Montague Healthcare, Mulberry House, Nottingham, England;.

DOI: 10.4236/crcm.2013.29140                

Abstract

Background: The organs in the body function in coherent organ networks. These organ networks are commonly known as physiological systems. Blood Glucose, Blood Pressure and pH exhibit the characteristics of neurally regulated Physiological Systems. Any medical condition, such as diabetes, has origins which are due to systemic dysfunction. This influences the genetic expression of proteins and the rate at which such expressed proteins subsequently react. Increased levels of acidity influence the levels of available minerals, protein conformation, and hence the rate at which expressed proteins such as insulin and leptin react or function. This is particularly significant in diabetes etiology where a deficiency of insulin and insulin-“resistance” are significant features of type 1 and type 2 diabetes. Proteins such as Insulin absorb and emit light. Moreover, the spectrum and intensity of the bioluminescence emitted from glycated proteins (which are more significantly bioluminescent) influence colour perception. Accordingly, changes to the diabetic’s colour perception can be used as the basis of a cognitive screening technique which is able to quantify the influence of genotype and phenotype. This may have significant advantages over current biomarker techniques which are not able to satisfactorily determine the earliest onset of diabetes or distinguish between the symptomatic and presymptomatic onset of diabetes. Such methodology, based upon the properties of proteins, i.e. effectively, the rate at which proteins are expressed and the rate at which such expressed proteins subsequently react, allows the clinician to quantify genotype and phenotype and may contribute to a greater understanding of the processes responsible for what are commonly known as type 1 and type 2 diabetes. The aim of this article is to highlight the limitations of the current techniques used to diagnose diabetes and to highlight, at least from the theoretical perspective, the significance of the autonomic nervous system and physiological systems; in particular, how changes to colour perception are related to the function and/or stability of the autonomic nervous system; and how such phenomena can be used diagnostically. This article discusses this method—a mathematical model of the autonomic nervous system and physiological systems—which has been incorporated into the prototype technology Virtual Scanning; and in conclusion, illustrates how Diabetes appears to be a problem of acidity and consequently of mineral deficiency. It outlines how genotype and phenotype are both significant factors in the regulation of Blood Glucose, i.e. type 1 diabetes is predominantly genetic and is associated with hypoglycaemia whilst type 2 diabetes is due to environmental or phenotypic cause and is associated with hyperglycaemia. Both can occur simultaneously and hence explain why someone with type 2 diabetes may be prescribed insulin, i.e. in order to quantify the extent of a pathology such as diabetes mellitus and/or any other common pathology, it appears necessary to quantify the influence of genotype (genetic capacity) and phenotype (physiological demand). Accordingly the categorisation of diabetes as type 1 and type 2 may be misleading.

Keywords

Autonomic Nervous System (ANS); Physiological Systems; Mathematical Modelling; Blood Glucose; Diabetes; Genotype; Phenotype; Sensory Input; Visual Perception; Colour Perception

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	[1] Ewing, G.W. (2009) Does an improved understanding of the nature and structure of the Physiological Systems lead to a better understanding of the therapeutic scope of Complementary & Conventional Medicine? Journal of Computer Science and Systems Biology, 2, 174-179.
[2]	Ewing, G.W. and Ewing, E.N. (2008) Cognition, the autonomic nervous system and the physiological systems. Biogenic Amines, 22, 140-163.
[3]	Ewing, G.W. (2010) Mathematical modeling the neuroregulation of blood pressure using a cognitive top-down approach. North American Journal of Medical Sciences, 2, 341-352.
[4]	Ewing, G.W. and Parvez, S.H. (2011) Mathematical modeling the systemic regulation of blood glucose: A topdown systems biology approach. NeuroEndocrine Letters, 32, 371-379.
[5]	Ewing, G.W. (2012) The regulation of pH is a physiological system. Increased acidity alters protein conformation and cell morphology and is a significant factor in the onset of diabetes and other common pathologies. The Open Systems Biology Journal, 5, 1-12. http://dx.doi.org/10.2174/1876392801205010001
[6]	Ewing, G.W. (2009) A theoretical framework for photosensitivity: Evidence of systemic regulation. Journal of Computer Science and System Biology, 2, 287-297. http://dx.doi.org/10.4172/jcsb.1000044
[7]	Ewing, G.W. and Parvez, S.H. (2010) The dynamic relationship between cognition, the physiological systems, and cellular and molecular biochemistry: A systemsbased perspective on the processes of pathology. Activitas Nervosa Superior Rediviva, 52, 29-36.
[8]	Ewing, G.W. and Ewing, E.N. (2008) Neuroregulation of the physiological systems by the autonomic nervous system: Their relationship to insulin resistance and metabolic syndrome. Biogenic Amines, 22, 208-239.
[9]	Sim, X., Ong, RT.-H., Suo, C., Tay, W.-T., Liu, J., et al. (2011) Transferability of type 2 diabetes implicated loci in multi-ethnic cohorts from southeast Asia. PLOS Genetic, 7, e1001363. http://dx.doi.org/10.1371/journal.pgen.1001363
[10]	Bodhini, D., Radha, V., Ghosh, S., Majumder, P. and Mohan, V. (2011) Lack of association of PTPN1 gene polymorphisms with type 2 diabetes in south Indians. Journal of Genetics, 90,323-326. http://dx.doi.org/10.1007/s12041-011-0060-3
[11]	Wagenknecht, L.E., Roseman, J.M. and Herman, W.H. (1991) Increased incidence of insulin-dependent diabetes mellitus following an epidemic of Coxsackievirus B5. American Journal of Epidemiology, 133, 1024-1031.
[12]	Helmke, K., Otten, A., Willems, W.R., et al. (1986) Islet cell antibodies and the development of diabetes mellitus in relation to mumps infection and mumps vaccination. Diabetologia, 29, 30-33. http://dx.doi.org/10.1007/BF02427277
[13]	Tuomilehto, J., Rewers, M., Reunanen, A., et al. (1991) Increasing trend in type 1 (insulin-dependent)diabetes mellitus in childhood in Finland. Analysis of age, calendar time and birth cohort effects during 1965 to 1984. Diabetologia, 34, 282-287. http://dx.doi.org/10.1007/BF00405089
[14]	Kelly, H.A., Russel, M.T., Jones, T.W. and Byrne, G.C. (1994) Dramatic increase in incidence of insulin dependent diabetes mellitus in Western Australia. Medical Journal of Australia, 161, 426-429.
[15]	Rewers, M., LaPorte, R.E., Walczak, M., Dmochowski, K. and Bogaczynska, E. (1987) Apparent epidemic of insulin-dependent diabetes mellitus in Midwestern Poland. Diabetes, 36, 106-113. http://dx.doi.org/10.2337/diab.36.1.106
[16]	Toth, E.L., Lee, K.C., Couch, R.M. and Martin, L.E. (1997) High incidence of IDDM over 6 years in Edmonton, Alberta, Canada. Diabetes Care, 20, 311-313. http://dx.doi.org/10.2337/diacare.20.3.311
[17]	Blom, L., Nystrom, L. and Dahlquist, G. (1991) The Swedish childhood diabetes study: Vaccinations and infections as risk determinants for diabetes in childhood. Diabetologia, 34, 176-181. http://dx.doi.org/10.1007/BF00418272
[18]	Jang, W.G., Kim, E.J., Park, K.G., Park, Y.B., Choi, H.S., Kim, H.J., Kim, Y.D., Kim, K.S., Lee, K.U. and Lee, I.K. (2007) Glucocorticoid receptor mediated repression of human insulin gene expression is regulated by PGC-1alpha. Biochemical and Biophysical Research Communications, 352, 716-721. http://dx.doi.org/10.1016/j.bbrc.2006.11.074
[19]	Booth, F.W., Chakravarthy, M. and Spangenburg, E.E. (2002) Exercise and gene expression: Physiological regulation of the human genome through physical activity. Journal of Physiology, 543, 399-411. http://dx.doi.org/10.1113/jphysiol.2002.019265
[20]	Ewing, G.W., Parvez, S.H. and Grakov, I.G. (2011) Further observations on visual perception: The influence of pathologies upon the absorption of light and emission of bioluminescence. The Open Systems Biology Journal, 4, 1-7. http://dx.doi.org/10.2174/1876392801104010001
[21]	Daley, M.L., Watzke, R.C. and Riddle, M.C. (1987) Early loss of blue-sensitive color vision in patients with type I diabetes. Diabetes Care, 10, 777-781. http://dx.doi.org/10.2337/diacare.10.6.777
[22]	Kurtenbacha, A., Schiefera, U., Neub, A. and Zrennera, E. (1999) Preretinopic changes in the colour vision of juvenile diabetics. British Journal of Ophthalmology, 83, 43-46. http://dx.doi.org/10.1136/bjo.83.1.43
[23]	Beisswenger, P.J., Makita, Z., Curphey, T.J., Moore, L.L., Jean, S., Brinck-Johnsen, T., Bucala, R. and Vlassara, H. (1995) Formation of immunochemical advanced glycosylation end products precedes and correlates with early manifestations of renal and retinal disease in diabetes. Diabetes, 44, 824-829. http://dx.doi.org/10.2337/diab.44.7.824
[24]	Hardy, K.J., Lipton, J., Scase, M.O., Foster, D.H. and Scarpello, J.H. (1992) Detection of colour vision abnormalities in uncomplicated type 1 diabetic patients with angiographically normal retinas. British Journal of Ophthalmology, 76, 461. http://dx.doi.org/10.1136/bjo.76.8.461
[25]	Ismail, G.M. and Whitaker, D. (1998) Early detection of changes in visual function in diabetes mellitus. Ophthalmic and Physiological Optics, 18, 3. http://dx.doi.org/10.1016/S0275-5408(97)00043-4
[26]	Wald, G. (1967) George Wald Nobel prize lecture. In: Nobel Lectures, Physiology or Medicine 2963-1970, Elsevier Publishing Company, Amsterdam. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1967/
[27]	Sortino, S. (2010) Light-controlled nitric oxide delivering molecular assemblies. Chemical Society Reviews, 39, 2903-2913. http://dx.doi.org/10.1039/b908663n
[28]	Venturini, C.M., Palmer, R.M. and Moncada, S. (1993) Vascular smooth muscle contains a depletable store of a vasodilator which is light-activated and restored by donors of nitric oxide. Journal of Pharmacology and Experimental Therapeutics, 266, 1497-1500.
[29]	Nagase, S., Hirayama, A., Ueda, A., Oteki, T., Takada, K., Inoue, M., Shimozawa, Y., Terao, J. and Koyama, A. (2005) Light-shielded hemodialysis prevents hypotension and lipid peroxidation by inhibiting nitric oxide production. Clinical Chemistry, 51, 2397-2398. http://dx.doi.org/10.1373/clinchem.2005.058669
[30]	Furchgott, R.F. and Jothianandan, D. (1991) Endotheliumdependent and -independent vasodilation involving cyclic GMP: Relaxation induced by nitric oxide, carbon monoxide and light. Blood Vessels, 28, 52-61.
[31]	Oren, D.A. (1996) Humoral phototransduction: Blood is a messenger. Neuroscientist, 2, 207-210. http://dx.doi.org/10.1177/107385849600200408
[32]	Ewing, G.W. (2012) The regulation of pH is a physiological system. Increased acidity alters protein conformation and cell morphology and is a significant factor in the onset of diabetes and other common pathologies. The Open Systems Biology Journal, 5, 1-12. http://dx.doi.org/10.2174/1876392801205010001
[33]	Kashyap, S.R., Roman, L.J., Lamont, J., Masters, B.S.S., Bajaj, M., Suraamornkul, S., Belfort, R., Berria, R., Kellogg, D.L., Liu, Y. and DeFronzo, R.A. (2005) Insulin resistance is associated with impaired nitric oxide synthase activity in skeletal muscle of type 2 diabetic subjects. Journal of Clinical Endocrinology & Metabolism, 90, 1100-1105. http://dx.doi.org/10.1210/jc.2004-0745
[34]	Tucker, K.L., Morita, K., Qiao, N., Hannan, M.T., Cupples, L.A. and Kiel, D.P. (2006) Colas, but not other carbonated beverages, are associated with low bone mineral density in older women: The framingham osteoporosis study. American Journal of Clinical Nutrition, 84, 936-942.
[35]	Considine, R.V., Sinha, M.K., Heiman, M.L., Kriauciunas, A., Stephens, T.W., Nyce, M.R., Ohannesian, J.P., Marco, C.C., McKee, L.J. and Bauer, T.L. (1996) Serum immuno-reactive-leptin concentrations in normal-weight and obese humans. The New England Journal of Medicine, 334, 292-295. http://dx.doi.org/10.1056/NEJM199602013340503
[36]	Banks, W.A., Coon, A.B., Robinson, S.M., Moinuddin, A., Shultz, J.M., Nakaoke, R. and Morley, J.E. (2004) Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes, 53, 1253-1260. http://dx.doi.org/10.2337/diabetes.53.5.1253
[37]	Zakhari, S. (2006) Overview: How is alcohol metabolized by the body? Alcohol Research & Health, 29, 245-254.
[38]	Shapiro, A., Mu, W., Roncal, C., Cheng, K.Y., Johnson, R.J. and Scarpace, P.J. (2008) Fructose-induced leptin-resistance exascerbates weight gain in response to subsequent high-fat feeding. American Journal of Physiology. Regulatory, Integrative Comparative Physiology, 295, R1370-R1375. http://dx.doi.org/10.1152/ajpregu.00195.2008
[39]	Zhou, H., Zhang, T., Harmon, J.S., Bryan, J. and Robertson, R.P. (2007) Zinc, not insulin, regulates the rat α-cell response to hypoglycemia in Vivo. Diabetes, 56, 1107-1112. http://dx.doi.org/10.2337/db06-1454
[40]	Chang, X., Jorgensen, A.M., Bardrum, P. and Led, J.J. (1977) Solution structures of the R6 human insulin hexamer. Biochemistry, 36, 9409-9422. http://dx.doi.org/10.1021/bi9631069
[41]	Hellman, B., Gylfe, E., Grapengiesser, E., Dansk, H. and Salehi, A. (2007) Insulin oscillations-clinically important rhythm. Antidiabetics should increase the pulsative component of the insulin release (in Swedish). Lakartidningen, 104, 2236-2239.
[42]	Scheen, A.J., Sturis, J., Polonsky, K.S. and Van Cauter, E. (1996) Alterations in the ultradian oscillations of insulin secretion and plasma glucose in aging. Diabetologia, 39, 564-572. http://dx.doi.org/10.1007/BF00403303
[43]	Polonsky, K.S., Given, B.D., Hirsch, L.J., Tillil, H., Shapiro, E.T., Beebe, C., Frank, B.H., Galloway, J.A. and Van Cauter, E. (1988) Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. New England Journal of Medicine, 318, 1231-1239. http://dx.doi.org/10.1056/NEJM198805123181903
[44]	Lardner, A. (2001) The effects of extracellular pH on immune function. Journal of Leukocyte Biology, 69, 522-530.
[45]	Blasetti, A., Verrotti, A., Chiarelli, F. and Morgese, G. (1992) Immunologic changes in diabetic ketoacidosis. Minerva Pediatrica, 44, 181-184.
[46]	Schulz, H.U., Niederau, C., Klonowski-Stumpe, H., Halangk, W., Luthen, R. and Lippert, H. (1999) Oxidative stress in acute pancreatitis. Hepatogastroenterology, 46, 2736-2750.
[47]	Ewing, G.W., Ewing, E.N. and Nwose, E.U. (2008) Virtual Scanning technology—The relationship to oxidative stress and applicability to diabetes management. Biogenic Amines, 22, 195-207.
[48]	Stitt, A.W. (2005) The Maillard Reaction in eye diseases. Annals of the New York Academy of Sciences, 1043, 582-597. http://dx.doi.org/10.1196/annals.1338.066
[49]	Baker, L.H., Lieberman, D. and Oehlke, M. (1995) Psychological distress in patients with gastroesophageal reflux disease. American Journal of Gastroenterology, 90, 1797-1803.
[50]	McDonald-Haile, J., Bradley, L.A., Bailey, M.A., Schan, C.A. and Richter, J.E. (1994) Relaxation training reduces symptom reports and acid exposure in patients with gastroesophageal reflux disease. Gastroenterology, 107, 61-69.
[51]	Esquivel, G., Schruers, K.R., Maddock, R.J., Colasanti, A. and Griez, E.J. (2010) Acids in the brain: A factor in panic? Journal of Psychopharmacology, 24, 639-647. http://dx.doi.org/10.1177/0269881109104847
[52]	Ewing, G.W. and Parvez, S.H. (2010) The multi-systemic nature of diabetes mellitus: Genotype or phenotype? North American Journal of Medical Sciences, 2, 444-456. http://dx.doi.org/10.4297/najms.2010.2444
[53]	Fonseca, V.A. (2007) The effects of insulin on the endothelium. Endocrinology and Metabolism Clinics of North America, 36, 20-26. http://dx.doi.org/10.1016/S0889-8529(07)80009-0
[54]	Hovorka, R., Powrie, J.K., Smith, G.D., Sonksen, P.H., Carson, E.R. and Jones, R.H. (1993) Five-compartment model of insulin kinetics and its use to investigate action of chloroquine in NIDDM. American Journal of Physiology, 265, E162-E175.
[55]	Sato, H., Terasaki, T., Mizuguchi, H., Okumura, K. and Tsuji, A. (1991) Receptor-recycling model of clearance and distribution of insulin in the perfused mouse liver. Diabetologia, 34, 613-621. http://dx.doi.org/10.1007/BF00400989
[56]	Duckworth, W.C., Hamel, F.G. and Peavy, D.E. (1988) Hepatic metabolism of insulin. The American Journal of Medicine, 85, 71-76. http://dx.doi.org/10.1016/0002-9343(88)90399-3
[57]	Duckworth, W.C., Bennett, R.G. and Hamel, F.G. (1998) Insulin degradation: Progress and potential. Endocrine Reviews, 19, 608-624. http://dx.doi.org/10.1210/er.19.5.608