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ORIGINAL CONTRIBUTION
Year : 1997  |  Volume : 51  |  Issue : 12  |  Page : 470-478
 

Non-insulin-dependent diabetes mellitus and secondary complications


Grat Al-Fateh University of Medical Sciences, Tripoli, Libya

Correspondence Address:
GMM Rao
Grat Al-Fateh University of Medical Sciences, Tripoli
Libya
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PMID: 9715547

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How to cite this article:
Rao G. Non-insulin-dependent diabetes mellitus and secondary complications. Indian J Med Sci 1997;51:470-8

How to cite this URL:
Rao G. Non-insulin-dependent diabetes mellitus and secondary complications. Indian J Med Sci [serial online] 1997 [cited 2014 Apr 23];51:470-8. Available from: http://www.indianjmedsci.org/text.asp?1997/51/12/470/11483


Diabetes mellitus is on the in­crease worldwide as many coun­tries are achieving greater affluence and as their populations are grow­ing greyer. If 25% of adults com­ing to health centers meet the WHO criteria for diabetes mellitus, [1] there would be one billion in the world who may suffer from eventual complications of the disease. [2] The magnitude of the problem is enor­mous and the implications for health services and budgets are staggering. The post-insulin era has permitted the expression of micro- and macro-vascular compli­cations of diabetes in the form of blindness, kidney dysfunction, neuropathic complications, myoar­dial infarction, stroke and peri­pheral vascular disease. Unless we begin to prevent or ameliorate them, diabetic complications and related morbidity threaten to inun­date and overwhelm the entire health care system.

Non-insulin-dependent diabetes (type II) is a heterogenous disease and several factors contribute to glycemic control in these patients. It is a disease with a very slow and progressive pathogenesis. Both genes and environment play a critical role in the development of type II diabetes.

Glucose homeostasis depends upon a balance between glucose production by liver and glucose utilization by insulin-dependent tissues such as fat and muscle and insulin-independent tissues such as brain and kidney. [3] The pattern of utilization is highly regulated by hormones secreted by pancreatic islet: insulin from beta-cells, and glucagon from alpha cells. Al­though the fine tuning of glucose metabolism may be influenced by many hormones and intermediate metabolites, normal glucose dis­posal depends on 3 important fac­tors : a) ability of the body to pro­duce insulin both acutely and in a sustained manner, b) ability of in­sulin to inhibit hepatic glucose output (insulin sensitivity) and to promote glucose disposal and c) ability of glucose to enter cells in the absence of insulin (glucose sensitivity). [3]

In type II patients, there are at least two pathological defects : a) decreased ability of insulin to act on peripheral tissues to stimulate glucose metabolism or inhibit glu­cose output a phenomenon known as insulin resistance, b) the ability of endocrine pancreas to fully compensate for the insulin resis­tance i.e., relative insulin defi­ciency. These two pathological defects are caused by a combina­tion of genetic and environmental factors which lead to progression from normal glucose tolerance to diabetes. In genetically prone in­dividuals, insulin resistance is the earliest detectable defect. This defect may occur 15-20 years or more before the clinical manifesta­tion of diabetes. This insulin resis­tance constitutes a marker for the disease. The exact site of insulin resistance is unknown but even early in the pahogenesis there are multiple alterations in the insulin action cascade. Initially, there is an attempt to compensate for in­sulin resistance with increased in­sulin secretion, but eventually, in­sulin secretion fails and type II diabetes develops.

This cascade of events is pro­grammed by a series of diabetes causing genes (diabetogenes). Some of these diabetogenes may be primary causing insulin resis­tance whereas others may be re­lated to diabetic state and be secondary.

Environmental factors particu­larly those leading to obesity fur­ther enhance this diabetogenic tendency by accentuating the in­sulin resistance. It was shown that insulin sensitivity is inherited and the decreases in insulin sensitivity precede and predict development of type II diabetes . [4]


 ¤ Obesity and Type II Diabetes Top


Physiologically, body weight is constantly changing. A healthy adult who is non-obese should not vary in weight from the age of 30 years onwards, and probably from the age of 20 years. [5] In urban society, food intake does not dimi­nish with increasing age, but phy­sical activity lessens and the weight is added. Even when weight is stationary, fat can be ad­ded at the expense of the muscles. [6] Overweight is multifactorial in ori­gin reflecting inherited, environ­mental, culturaI, socio-economic and psychological conditions. Obesity is the result of excessive expansion of adipose tissue mass. This disorder is often accompanied by abnormalities in systemic carbo­hydrate and lipid metabolism and in the secretion and action of in­sulin, alterations thought to reflect the diabetogenic effect of obesity. [7] Glucose intolerance is common in obese persons even in the absence of clinically manifest diabetes. Hyperglycemia worsens with in­creasing obesity. Epidemiological studies in different parts of the world indicate a close relationhsio between obesity and type II dia­betes.


 ¤ Glycated Hemoglobin Top


In diabetes, every system in the body is affected in the absence of satisfactory control of blood glu­close level. In recent years, mea­surement of Hb A1c once in three months is advised as an adjunct to blood glucose determination.

Glycated hemoglobin represents a series of electrophoretically and chromatographically separable minor components of hemoglobin present in normal red blood cell. The minor factions Hb Ala, Hb Alb, A1 c, Hb Al d and Hb Ale of which Hb Al c is the major faction are formed slowly and continuously through the life span of the red blood cell by a process of non­enzymatic glycosylation at a rate varying with the blood glucose con­centration. Thus, hyperglycemia in diabetes leads to an increase in the amount of glycated hemoglobin, two to threefold, as compared with non-diabetic persons. There is convincing evidence that glycated hemoglobin is an indicator of inte­grated blood glucose level over a few weeks. A high degree of cor­relation was found between gly­cated hemoglobin and several indices of diabetic control. [8]


 ¤ Secondary Complications of Diabetes Top


As at present we do not have therapeutic intervention for preven­tion of the onset of diabetes; hence the only alternative is to take mea­sures to prevent/ameliorate/delay the onset of secondary cornplictions of diabetes. In poorly con­trolled diabetes, all. biochemical parameyers are altered. [9] The micro­and macro vascular complications are expressed in the form of blind­ness (retinopathy), kidney dis­orders (nephropathy), neuropathic complications (neuropathy), myo­dial infarction, hypertension, stroke and peripheral vascular disease. The process of atherosclerosis is a complex one and is clearly de­monstrated to be accelerated in diabetic patients. [10] The abnormal carbohydrate and lipid profile re­sult in hypertriglyceridaemia and hypercholesterolaemia which coup­led with hyperglycemia - induced endothelial dysfunction, inireased platelet adhesiveness, increased growth factor mediated smooth muscle proliferation, increased se­cretion of altered collagen mole­cules, impaired intracellular degra­dation of low density lipoproteins may all contribute to the develop­ment of atheroma and subsequent microangiopathy of atherosclero­sis. [11] In our study of Libyan diabe­tic patients, 38% have secondary complications within 5 years of diagnosis of the disease. All these are type II patients. However, 35% of them were receiving insulin re­gularly as diet control and oral drugs have failed to regulate blood glucose levels. The actual time of onset of diabetes in these patients might have been much earlier than the time of diagnosis. However, the correlations between duration of diabetes from the time of diagno­sis and the various parameters appear to indicate the absence of proper metabolic control and that duration of diabetes influences the onset of secondary complications, and poor control is responsible for progression of these secondary complications.

Background retinopathy and cataract are more prevalent dis­orders of the eye. 14%, of the pa­tients have proliferative retino­pathy [Figure 1] and the duration of diabetes in these patients is more than 12 years. Changes in the heart rate were observed in these patients indicating autonomic neuropathy. The increased heart rate might be the result of para­sympathetic damage while the lower heart rate is due to sympa­thetic damage.

Among the patients with vas­cular complications. 50% have microangiopathy, 36% have peri­pheral vascular disease and 14% have both. [12] The Libyan diabetic patients under study were divided into responders (with plasma glu­cose less than 200 mg/dl and Abal below 10%) and non-responders (with plasma glucose above 200 mg/dl and HbA1 more than 10%). [13] The plasma glucose, body mass in­dex (Kg/m 2 ) and creatinine clearance were determined. [14] The responders were found to have lower levels of serum triglycerides, serum creatinine, blood urea and heart rate when compared with non-responders. However, serum cholesterol. levels of responders were not significantly different from those of non-responders. The Libyan diabetic patients under study have poorly controlled dia­betes with one or more secondary complications. It appears that back­ground retinopathy and peripheral vascular disease set in during the early stages of the disease while proliferative retinopathy and nep­hropathy develop in the advanced stages of the disease. Proper con­trol of blood glucose and Hb Al levels would delay the onset and progression of secondary conipli­cations. Although the pathogenesis of microangiopathy still remains elusive, the available evidence indicates the involvement of altered glycoprotein metabolism. Glycosi­dases are enzymes of lysosomal origin and are concerned with the degradation of glycoconjugates such as oligosaccharides, mu­cosaccharides, glycolipids and glycoproteins. The altered glyco­protein metabolism results in the development cf vascular lesions characterized by the thickening of the basement membrane. It is im­portant to see whether the thicken­ing of basement membrane is the result of increased synthesis or de­creased degradation of glycopro­tein material. The synthesis of basement membrane is analogous to the synthesis of other glycoproteins and involves (1) assembly of amino acids to form polypeptide chains on polysomes, (2) hydroxy­lation of prolyl and lysyl residues to hydroxyprolline and hydroxyly­sine respectively, (3) glycosyla­tion of some of the hydroxyl resi­dues to galactosylhydroxylysine and glucosyl-hydroxylysine and (4) formation of cross links.

It was shown in diabetic animal models that the activities of gluco­syltransferase and galactosyltrans­ferase were elevated resulting in the thickening of basement mem­brane. [15] β3-glucuronidase and β-N­acetylglucosaminidase are lysoso­somal enzymes concerned with the degradation of glycoprotein mate­rial. In genetically diabetic KK mice, a statistically significant decrease in the activity of β-N-acetylglucosa­minidase in the plasma, conjunc­tiva, thigh muscle, kidney cortex, retina and tear fluid as compared with non-diabetic Swiss Albino mice was reported. [16],[17] When the activities of the anabolic and cata­bolic enzymes are proportional, a normal basement membrane is pre­sent. An increase in the activities of anabolic enzymes and/or a de­crease in the activities of catabolic enzymes will result in the thicken­ing of the basement membrane.


 ¤ Can Diabetic Complications be Prevented? Top


For many years, there has been an attitude of helplessness and hopelessness which stemmed lar­gely from the belief that the long term complications of diabetes could not be prevented. It was believed that these complications would occur in spite of any treat­ment we might prescribe and that they are inexorable and progres­sive. However, new knowledge and technological advances have shown that this defeatist attitude has been superseded by a more optimistic outlook based on new evidence from several studies. The first and most important was the development of methods for moni­toring glycemic control. Newer im­proved glucometers were develop­ed for self monitoring blood glu­cose levels. [18] The second is the development of tests for glycated hemoglobin to find how well the tighter metabolic control was achieved. [19] Along with these have come better methods for detection of diabetic complications. [20],[21] It is now realized that tighter metabo­lic control could be achieved and this can prevent the progression to established or irreversible disease. The question is: Is hyperglycemia the culprit and does metabolic control matter? The answer for both is yes. Hyperglycemia harms and intensive therapy makes a diffe­rence. The Diabetic Control and Complications Trial. (DCCT) in Type I and the United Kingdom Prospective Diabetes Study (UKPDS) in Type II diabetes [22],[23] have shown that tighter metabolic control will delay the onset and pre­vent the progression of inevitable consequences of diabetes. Alter­ing the level of hyperglycemia at any level is helpful and even par­tial glycemic control is beneficial. The following diabetic regimen will help in the maintenance of stricter metabolic control 1) Dietary and weigh: control especially central or abdominal obesity; 2) Regular exer­cise; 3) Close monitoring and con­trol of blood glucose levels; 4) Con­trol of blood pressure levels; 5) Re­duction in elevated serum lipid levels; 6) Stop smoking; 7) Avoid drugs that worsen carbohydrate in. tolerence or raise serum lipids.

We have to convince the diabe­tics by education that they can lead almost normal lives with the new methods and approaches. We will be helped by our newer under­standing of older treatments and the availability of newer drugs. [24],[25] ­Moreover, better methods of thera­peutic intervention are being deve­loped. So let us take new heart and mount a new compaign to de­feat diabetes mellitus and its ravages.[Figure 2]

 
 ¤ References Top

1.Zurba Fl, AlGarf A. Prevalence of of diabetes mellitus in Bahrain. Bahrain Med Bull 1996;19:44-51.  Back to cited text no. 1      
2.Ferguson RK. New hope for pre­venting diabetic complications J Bahrain Med Soc 1996;8:141-143.  Back to cited text no. 2      
3.Bergman RN. Lily Lecture 1989. Toward physiological understand­ing of glucose tolerance : Minimal model approach. Diabetes 1989:38: 1512-1527.  Back to cited text no. 3      
4.Kahn CR. Banting Lecture 1994. Insulin action, diabetogenes and the cause of type II diabetes. Dia­betes 1994;43:1066-1084.  Back to cited text no. 4      
5.Slome C, Campsell B, Abramson JH, Scotch N. Weight, height and skin­fold thickness of Zulu adults in Durban. S Afr Med J 1960;34:505­510.  Back to cited text no. 5      
6.Krzywici J, Consolozio CF, Johnson HI. Alterations in exercise and body composition with age. Amster­dam : Excerpta Medica. 1970.  Back to cited text no. 6      
7.Salans LB, Knittle JL, Hircsh J. Diabetes mellitus, Theory and Prac­tice Eds. M. Ellenberg & H. Rifkin, New York : McGraw Hill 1970.  Back to cited text no. 7      
8.Rao GMM, Morghom LO, Abukhris AA, Mansori SS, Alpighi FA, Ragali LY. Glycosylated hemoglobin and blood glucose levels in Libyan dia­betic patients. Trop Geogr Med 1986;38:391-397.  Back to cited text no. 8      
9.Rao GMM, Morghom LO. Secon­dary diabetic complications and biochemical parameters. Indian J Med Sci 1990;44:299-303.  Back to cited text no. 9  [PUBMED]    
10.Gorden T, Castelli WP, Hjortland MC et al. Diabetes, blood lipids and role of obesity in coronary heart disease risk for women. The Framingham Study. Ann Intern Med 1977;87:393-397.  Back to cited text no. 10      
11.Brownlee M, Cerami A. Biochemis­try of the complications of diabetes mellitus. Ann Rev Biochem J 1981; 55:385-432.  Back to cited text no. 11      
12.Rao GMM, Gamra NS. Prevalence of secondary complications in diabetic patients. J Bahrain Med Soc 1993:5:68-72.  Back to cited text no. 12      
13.Osei K. Clinical evaluation of deter­minants of glycemic control. A new approach using serum glucose, C­p ptide and body mass index in type II diabetic patients. Arch In­tern Med 1986;146:281-285.  Back to cited text no. 13      
14.Cockcroft DW, Gault MH. Predic­tion of creatinine clearance from serum creatinine. Nephron 1983;16. 281-285.  Back to cited text no. 14      
15.Camerini-Davlos RA, Oppermann W, Reddi AS, Velasco CA. The development of microangiopathy In: Diabetische Angiopathien, New York : Berlag Gerhardwitzstrock 1977.  Back to cited text no. 15      
16.Rao GMM. Effect of genetic dia­betes on /3-N-acetylglucosaminidase activity in plasma, conjunctiva, muscle and kidney cortex of mice. Biomedicine 1981;35:159-161.  Back to cited text no. 16      
17.Rao GMM. Effect of genetic dia­betes on f3-N-acetylglucosaminidase activity in tears and retina. Horm rnetab Res 1981;13:533-534.  Back to cited text no. 17      
18.Berg B. Self monitoring of diabetes mellitus. Int J Diab 1993;1:21-29.  Back to cited text no. 18      
19.Klein R, Klein BEK, Moss SE et al. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA 1988; 260:2864-2871.  Back to cited text no. 19      
20.Morgensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity onset diabetes. New Eng J Med 1984;310: 356-360.  Back to cited text no. 20      
21.Klein BEK, Davis MD, Segal P et al. Diabetic retinopathy : Assessment of severity and progression. Ophthal­mology 1984;91:10-17.  Back to cited text no. 21      
22.DCCT Research Group. The effect of intensive treatment of diabetes on the development and progres­sion of long term complications in insulin dependent diabetes mellitus. New Eng J Med 1993;329:977-986.  Back to cited text no. 22      
23.United Kingdom Prospective Dia­betes Study Group. Epidemiology and early results. Ann Intern Med 1996;124:136-145.  Back to cited text no. 23      
24.Cheasson JL, Josse RG, Hunt JA et al. The efficacy of acarbose in the treatment of patients with non­insulin-dependent diabetes mellitus­A Multicenter Clinical Trial. Ann Intern Med 1994;121:928-934.  Back to cited text no. 24      
25.Lewis EJ, Hunsecker LG, Bain RP et al. The effect of angiotensin con­verting enzyme inhibition on dia­betic nephropathy. New Eng J Med 1993:329:1456-1461.  Back to cited text no. 25      


    Figures

  [Figure 1], [Figure 2]



 

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