PATHOPHYSIOLOGY OF SECONDARY COMPLICATIONS OF DIABETES MELLITUS

Authors

  • Pranav Kumar Prabhakar Lovely Faculty of Applied Medical Sciences, Lovely Professional University

Abstract

Diabetes mellitus (DM) is the most common endocrine metabolic disorder, characterised by hyperglycemia. The cause of this hyperglycemia is either insufficient or inefficient insulin which leads to the imbalance in the metabolism of not only carbohydrates but also protein and lipids. Diabetes mellitus is associated with various kind of abnormalities which affects almost all the parts of the body including eye, kidney, brain, foot etc. Hyperglycemia is not the only reason which gives diabetes mellitus a tag of most apocalyptic disease; it is the complications which arise from the higher concentration of glucose or metabolites comes from its variant metabolic pathways. DM causes both microvascular and macrovascular complications. Microvascular complications, caused by the damage of small blood vessels, includes nephropathy (kidney disease), retinopathy (eye damage) and neuropathy (nerve damage) whereas macrovascular complication, caused by the damage of large blood vessels, includes blood vessels arteries and veins. There are six metabolic pathways are there which normally leads to these complications. These pathways are sorbitol pathway, advanced glycation pathway, Hexosamine pathway, PKC pathway, ketoaldehyde pathway and oxidative stress.

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References

REFERENCES

Table 3: Long-term complications of diabetes caused because of hyperglycemia (reference)

Long-term complications of diabetes

Tissue or organ affected What happens Complications

Blood vessels Fatty material builds up and blocks large or medium-sized

arteries in the heart, brain, legs, and penis. The walls of

small blood vessels are damaged, and they do not transfer

oxygen to tissues

Alarcon-Aguilara FJ, Roman-Ramos R, Perez-Gutierrez S, AguilarContreras

A,

Contreras-Weber

CC,

Flores-Saenz JL.

Study of

the antihyperglycemic

effect

of

plants used

as antidiabetics. J

Ethnopharmacol

;61(2):101-10.

Poor circulation causes wounds to heal poorly and can

lead to heart disorders, strokes, gangrene of the feet

and hands, erectile dysfunction, and infections

Eyes The small blood vessels of the retina are damaged Decreased vision and ultimately, blindness occur

Kidneys Blood vessels in the kidney thicken. Protein leaks into urine Kidneys malfunction and ultimately kidney failure occur

Nerves Nerves are damaged because glucose is not metabolized

Autonomic nervous

system

normally and the blood supply is inadequate

Legs gradually weaken. People have reduced sensation,

tingling, and pain in their hands and feet

The nerves that control blood pressure and digestive

processes are damaged

Skin Blood flow to the skin is reduced, and sensation is

decreased resulting in repeated injury

Swings in blood pressure occur. Digestive function is

altered; Erectile dysfunction develops. Swallowing

becomes difficult

Sores and deep infections (diabetic ulcers) develop.

Healing is poor

Blood White blood cell function is impaired People become more susceptible to infections

(urinary tract and skin)

Connective tissue Glucose is not metabolized causing tissues to thicken

or contract

Carpal tunnel syndrome and Dupuytren’s contracture

develop

Inamdar N, Edalat S, Kotwal VB, Pawar S. Care with nature’s cure:

Herbal drugs. Pharmacogn Rev 2007;1:361-8.

Mohler ML, He Y, Wu Z, Hwang DJ, Miller DD. Recent and emerging

anti-diabetes targets. Med Res Rev 2009;29(1):125-95.

Hoogwerf B. Complications of diabetes mellitus. Int J Diabetes Dev

Ctries 2005;25:63-9.

Tiwari AK, Rao JM. Diabetes mellitus and multiple therapeutic

approaches of phytochemicals: Present status and future prospects.

Curr Sci 2002;83:30-8.

Virkamäki A, Ueki K, Kahn CR. Protein-protein interaction in insulin

signaling and the molecular mechanisms of insulin resistance. J Clin

Invest 1999;103(7):931-43.

Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose

and lipid metabolism. Nature 2001;414(6865):799-806.

Fonseca VA. Management of diabetes mellitus and insulin resistance in

patients with cardiovascular disease. Am J Cardiol 2003;92(4A):50J-60.

Firth R, Bell P, Rizza R. Insulin action in non-insulin-dependent

diabetes mellitus: The relationship between hepatic and extrahepatic

insulin resistance and obesity. Metabolism 1987;36:1091-5.

Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL,

Ferrante AW Jr. Obesity is associated with macrophage accumulation

in adipose tissue. J Clin Invest 2003;112(12):1796-808.

Kashyap S, Belfort R, Gastaldelli A, Pratipanawatr T, Berria R,

Pratipanawatr W, et al. A sustained increase in plasma free fatty acids

impairs insulin secretion in nondiabetic subjects genetically predisposed

to develop type 2 diabetes. Diabetes 2003;52(10):2461-74.

Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of

diabetes: Estimates for the year 2000 and projections for 2030. Diabetes

Care 2004;27(5):1047-53.

Weinstein AR, Sesso HD, Lee IM, Cook NR, Manson JE, Buring JE,

et al. Relationship of physical activity vs. body mass index with type 2

diabetes in women. JAMA 2004;292(10):1188-94.

Venables MC, Jeukendrup AE. Physical inactivity and obesity: Links

with insulin resistance and type 2 diabetes mellitus. Diabetes Metab

Res Rev 2009;25 Suppl 1:S18-23.

Duckworth WC. Hyperglycemia and cardiovascular disease. Curr

Atheroscler Rep 2001;3(5):383-91.

Jain S, Saraf S. Type 2 diabetes mellitus--its global prevalence and

therapeutic strategies. Diabetes Metab Syndr 2010;4:48-56.

Brownlee M. Biochemistry and molecular cell biology of diabetic

complications. Nature 2001;414(6865):813-20.

Robertson RP. Chronic oxidative stress as a central mechanism for

glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem

;279(41):42351-4.

Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic

vascular complications. Diabetes Care 1996;19(3):257-67.

Ginsberg HN. Insulin resistance and cardiovascular disease. J Clin

Invest 2000;106(4):453-8.

Maechler P, Jornot L, Wollheim CB. Hydrogen peroxide alters

mitochondrial activation and insulin secretion in pancreatic beta cells.

J Biol Chem 1999;274(39):27905-13.

Asian J Pharm Clin Res, Vol 9, Issue 1, 2016, 32-36

Prabhakar

Khamaisi M, Kavel O, Rosenstock M, Porat M, Yuli M, Kaiser N,

et al. Effect of inhibition of glutathione synthesis on insulin action:

In vivo and in vitro studies using buthionine sulfoximine. Biochem J

;349:579-86.

Urakawa H, Katsuki A, Sumida Y, Gabazza EC, Murashima S,

Morioka K, et al. Oxidative stress is associated with adiposity and

insulin resistance in men. J Clin Endocrinol Metab 2003;88(10):

-6.

Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y,

et al. Increased oxidative stress in obesity and its impact on metabolic

syndrome. J Clin Invest 2004;114(12):1752-61.

Lin Y, Berg AH, Iyengar P, Lam TK, Giacca A, Combs TP, et al. The

hyperglycemia-induced inflammatory response in adipocytes: The role

of reactive oxygen species. J Biol Chem 2005;280(6):4617-26.

Houstis N, Rosen ED, Lander ES. Reactive oxygen species

have a causal role in multiple forms of insulin resistance. Nature

;440(7086):944-8.

Engerman RL, Kern TS, Larson ME. Nerve conduction and aldose

reductase inhibition during 5 years of diabetes or galactosaemia in

dogs. Diabetologia 1994;37(2):141-4.

Chung SS, Ho EC, Lam KS, Chung SK. Contribution of polyol

pathway to diabetes-induced oxidative stress. J Am Soc Nephrol

;14 8 Suppl 3:S233-6.

Wells-Knecht KJ, Zyzak DV, Litchfield JE, Thorpe SR, Baynes JW.

Mechanism of autoxidative glycosylation: Identification of glyoxal and

arabinose as intermediates in the autoxidative modification of proteins

by glucose. Biochemistry 1995;34(11):3702-9.

Horal M, Zhang Z, Stanton R, Virkamäki A, Loeken MR. Activation of

the hexosamine pathway causes oxidative stress and abnormal embryo

gene expression: Involvement in diabetic teratogenesis. Birth Defects

Res A Clin Mol Teratol 2004;70(8):519-27.

Yki-Järvinen H, Daniels MC, Virkamäki A, Mäkimattila S,

DeFronzo RA, McClain D. Increased glutamine: fructose-6-phosphate

amidotransferase activity in skeletal muscle of patients with NIDDM.

Diabetes 1996;45(3):302-7.

Koya D, King GL. Protein kinase C activation and the development of

diabetic complications. Diabetes 1998;47(6):859-66.

Inoguchi T, Battan R, Handler E, Sportsman JR, Heath W, King GL.

Preferential elevation of protein kinase C isoform beta II and

diacylglycerol levels in the aorta and heart of diabetic rats: Differential

reversibility to glycemic control by islet cell transplantation. Proc Natl

Acad Sci U S A 1992;89(22):11059-63.

Ganz MB, Seftel A. Glucose-induced changes in protein kinase C

and nitric oxide are prevented by vitamin E. Am J Physiol Endocrinol

Metab 2000;278(1):E146-52.

Park JY, Takahara N, Gabriele A, Chou E, Naruse K, Suzuma K, et al.

Induction of endothelin-1 expression by glucose: An effect of protein

kinase C activation. Diabetes 2000;49(7):1239-48.

Aiello LP, Bursell SE, Clermont A, Duh E, Ishii H, Takagi C, et al.

Vascular endothelial growth factor-induced retinal permeability is

mediated by protein kinase C in vivo and suppressed by an orally effective

beta-isoform-selective inhibitor. Diabetes 1997;46(9):1473-80.

Feener EP, Xia P, Inoguchi T, Shiba T, Kunisaki M, King GL. Role of

protein kinase C in glucose- and angiotensin II-induced plasminogen

activator inhibitor expression. Contrib Nephrol 1996;118:180-7.

Pieper GM, Riaz-ul-Haq. Activation of nuclear factor-kappaB in cultured

endothelial cells by increased glucose concentration: Prevention by

calphostin C. J Cardiovasc Pharmacol 1997;30(4):528-32.

Wolff SP, Dean RT. Glucose autoxidation and protein modification.

The potential role of ‘autoxidative glycosylation’ in diabetes. Biochem

J 1987;245(1):243-50.

Hellman B, Idahl LÅ, Lernmark Å, Sehlin J, Täljedal IB. The pancreatic

[beta]-cell recognition of insulin secretagogues: Comparisons of

glucose with glyceraldehyde isomers and dihydroxyacetone. Arch

Biochem Biophys 1974;162:448-57.

Sakai K, Matsumoto K, Nishikawa T, Suefuji M, Nakamaru K,

Hirashima Y, et al. Mitochondrial reactive oxygen species reduce

insulin secretion by pancreatic beta-cells. Biochem Biophys Res

Commun 2003;300(1):216-22.

Du X, Matsumura T, Edelstein D, Rossetti L, Zsengellér Z, Szabó C,

et al. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase

activates three major pathways of hyperglycemic damage in endothelial

cells. J Clin Invest 2003;112(7):1049-57.

Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N,

et al. Reduced mitochondrial density and increased IRS-1 serine

phosphorylation in muscle of insulin-resistant offspring of type 2

diabetic parents. J Clin Invest 2005;115(12):3587-93.

Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F,

et al. Hyperglycemia-induced mitochondrial superoxide overproduction

activates the hexosamine pathway and induces plasminogen activator

inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad

Sci U S A 2000;97(12):12222-6.

Wang M, Wang XC, Zhang ZY, Mou B, Hu RM. Impaired mitochondrial

oxidative phosphorylation in multiple insulin-sensitive tissues of

humans with type 2 diabetes mellitus. J Int Med Res 2010;38(3):769-81.

Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2

diabetes. Science 2005;307(5708):384-7.

Schalkwijk CG, Stehouwer CD. Vascular complications in diabetes

mellitus: The role of endothelial dysfunction. Clin Sci (Lond)

;109(2):143-59.

Vander Jagt DL, Torres JE, Hunsaker LA, Deck LM, Royer RE.

Physiological substrates of human aldose and aldehyde reductases. In:

Lebing WR, Lee DC, Stenland CJ, editors. Enzymology and Molecular

Biology of Carbonyl Metabolism 6. New York: Plenum Press; 1996.

Brownlee M. Lilly Lecture 1993. Glycation and diabetic complications.

Diabetes 1994;43(6):836-41.

Stitt AW. The role of advanced glycation in the pathogenesis of diabetic

retinopathy. Exp Mol Pathol 2003;75(1):95-108.

Published

01-01-2016

How to Cite

Prabhakar, P. K. “PATHOPHYSIOLOGY OF SECONDARY COMPLICATIONS OF DIABETES MELLITUS”. Asian Journal of Pharmaceutical and Clinical Research, vol. 9, no. 1, Jan. 2016, pp. 32-36, https://innovareacademics.in/journals/index.php/ajpcr/article/view/9898.

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