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ORIGINAL CONTRIBUTION |
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| Year : 1997 | Volume
: 51
| Issue : 12 | Page : 470-478 |
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Non-insulin-dependent diabetes mellitus and secondary complications
GMM Rao
Grat Al-Fateh University of Medical Sciences, Tripoli, Libya
Correspondence Address:
GMM Rao
Grat Al-Fateh University of Medical Sciences, Tripoli
Libya
PMID: 9715547
How to cite this article:
Rao G. Non-insulin-dependent diabetes mellitus and secondary complications. Indian J Med Sci 1997;51:470-8 |
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 | |  |
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 | | |
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 | | |
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? | | |
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 | | |
| 1. | Zurba Fl, AlGarf A. Prevalence of of diabetes mellitus in Bahrain. Bahrain Med Bull 1996;19:44-51.  |
| 2. | Ferguson RK. New hope for preventing diabetic complications J Bahrain Med Soc 1996;8:141-143. |
| 3. | Bergman RN. Lily Lecture 1989. Toward physiological understanding of glucose tolerance : Minimal model approach. Diabetes 1989:38: 1512-1527. |
| 4. | Kahn CR. Banting Lecture 1994. Insulin action, diabetogenes and the cause of type II diabetes. Diabetes 1994;43:1066-1084. |
| 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. |
| 6. | Krzywici J, Consolozio CF, Johnson HI. Alterations in exercise and body composition with age. Amsterdam : Excerpta Medica. 1970. |
| 7. | Salans LB, Knittle JL, Hircsh J. Diabetes mellitus, Theory and Practice Eds. M. Ellenberg & H. Rifkin, New York : McGraw Hill 1970. |
| 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. |
| 9. | Rao GMM, Morghom LO. Secondary diabetic complications and biochemical parameters. Indian J Med Sci 1990;44:299-303. [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. |
| 11. | Brownlee M, Cerami A. Biochemistry of the complications of diabetes mellitus. Ann Rev Biochem J 1981; 55:385-432. |
| 12. | Rao GMM, Gamra NS. Prevalence of secondary complications in diabetic patients. J Bahrain Med Soc 1993:5:68-72. |
| 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. |
| 14. | Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1983;16. 281-285. |
| 15. | Camerini-Davlos RA, Oppermann W, Reddi AS, Velasco CA. The development of microangiopathy In: Diabetische Angiopathien, New York : Berlag Gerhardwitzstrock 1977. |
| 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. |
| 17. | Rao GMM. Effect of genetic diabetes on f3-N-acetylglucosaminidase activity in tears and retina. Horm rnetab Res 1981;13:533-534. |
| 18. | Berg B. Self monitoring of diabetes mellitus. Int J Diab 1993;1:21-29. |
| 19. | Klein R, Klein BEK, Moss SE et al. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA 1988; 260:2864-2871. |
| 20. | Morgensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity onset diabetes. New Eng J Med 1984;310: 356-360. |
| 21. | Klein BEK, Davis MD, Segal P et al. Diabetic retinopathy : Assessment of severity and progression. Ophthalmology 1984;91:10-17. |
| 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. |
| 23. | United Kingdom Prospective Diabetes Study Group. Epidemiology and early results. Ann Intern Med 1996;124:136-145. |
| 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. |
| 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. |
[Figure 1], [Figure 2]
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