- Email: [email protected]
Good and bad diabetes
Clin Biochern, Vol. 26, pp. 314-315, 1993 Printed in the USA. All rights reserved.
0009-9120/93 $6.00 + .00 Copyright © 1993 The Canadian Society of Clinical Chemists.
Good and Bad Diabetes ANNE B. KENSHOLE Department of Medicine, Women's College Hospital, 76 Grenville Street, Toronto, Ontario, Canada M5S 1B2 Introduction There is no doubt that diabetes is a serious condition that can result in significant disability and premature death. In Canada it accounts for 50% of blindness under the age of 65, 25% of hospitalizations for cardiovascular disease, and 40% of nontrauma related amputations. The estimated cost of diabetes management to the Ontario Health Care System in 1992 was $800 million. Nevertheless, a small but significant number of people with Type I diabetes remain complication-free 40, 50, and more years after diagnosis. Frequently their "control," as measured by patterns of blood sugar levels and glycosylated haemoglobins is indifferent (or worse). Similar patterns of complication are often found within affected families. These observations give support to the belief that genetics play a role in determining the development of microvascular complication either in the inheritance of a "protective" gene or one that increases risk. The recognition of "good" and "bad" outcomes in diabetes has also stimulated the search for markers of early compromise in the belief that intervention can favourably alter the subsequent course.
Bad prognostic indicators in Type I, IDDM Diabetes is the second commonest cause of endstage renal failure in North America. By 25 years after diagnosis, 45% of Type I diabetics require dialysis or, preferably, renal transplant from a live related donor. Microalbuminuria, defined as the excretion of 30-300 mg/24 h is now widely accepted as a valid marker of probable progression to overt proteinuria and progressive decline in glomerular filtration rate (1). Though considerable individual variation exists, microalbuminuria is typically present for 5 - 1 0 years before overt proteinuria develops, and the latter precedes elevation of serum creatinine by a further 2 - 5 years. Once glomerular filtration rate is reduced by 50% end-stage renal failure follows rapidly, again within a 2 - 5 year interval. In other words the finding of even modest persistent proteinuria is of grave prognostic signif-
Manuscript received March 23, 1993; revised May 17, 1993; accepted May 18, 1993. 314
icance. The relative mortality rate for a 35 year-old with IDDM is twice the normal rate in the absence of proteinuria but 100-fold increased when proteinuria is present. There are early but encouraging data to suggest that with management specifically tightening glycemic control in the early stages, and the use of angiotensin-converting enzyme inhibitors with a reduction in dietary protein, and meticulous control of hypertension in the later stages, the inexorable decline in function can be slowed, if not halted. A subtle elevation in blood pressure levels, though not necessarily to those traditionally labelled as hypertensive, typically occurs as microalbuminuria develops. A history of hypertension in one and especially in both parents significantly increases the risk of hypertension and renal failure in the offspring.
Proliferative retinopathy Whereas the majority of Type I diabetics will have developed the microaneurysms typical of background retinopathy (which is not a threat to vision) by 15 years after diagnosis, 10% will develop thinwalled, easily ruptured new vessels, the hallmark of proliferative retinopathy, the chief cause of visual loss in this type of diabetes. In 1976 the diabetic retinopathy study proved that panretinal photocoagulation could preserve useful vision in the majority of patients; but sadly, even in urban areas avoidable visual loss continues to occur because the patient has neglected regular ophthalmological assessment or the preproliferative signs have been missed. The development of retinopathy has been chosen as the outcome measure in the Diabetes Control and Complications Trial, the results of which should be available in the near future. From this landmark study it should be known whether a specific degree of glycemic control, as measured by glycosylated haemoglobins over a 10-year interval, seems to protect against the development of retinal change. Until then, glycemic control can only be categorized as being of uncertain prognostic value. The distinction between "good" and "bad" diabetes with respect to retinal and renal compromise can be made with reasonable certainty 25 years after diagnosis in the Type I diabetic. If the patient has not developed proliferative retinopathy or proteinuria by that time, they are unlikely to develop in the CLINICAL
BIOCHEMISTRY,
VOLUME
26, AUGUST
1993
GOOD AND BAD DIABETES future. The prognosis then will be that of the arterial tree. Interestingly, smoking was not found to impact negatively on the health of Type I diabetes when evaluated 25 years or more after diagnosis in the Pittsburgh Study (2).To the chagrin of the medical profession neither did the frequency with which the patient saw a physician! Onset of diabetes in early childhood was generally thought to carry a worse prognosis than onset at the more typical age, in the teens or early twenties; however, more recent studies have not supported this view. Prognosis in Type II, non-insulin dependent diabetes It has been stated that Type II diabetes "is a heart attack waiting to happen": the rate of coronary artery disease is increased two-fold, the risk of stroke three-fold, and diabetic women lose the traditional protection that women enjoy before and up to 10 years after menopause (3). The amputation rate is increased ten-fold because the diabetic foot is in double jeopardy from neuropathy and peripheral vascular disease. In Type I as in Type II, accelerated atherosclerosis, therefore, is a hallmark of the diabetic state. In addition to the traditional risk factors in the population at large, hypertriglyceridemia is now recognized as an independent risk factor in the diabetic, particularly women in whom HDL levels are excessively depressed. The diagnosis of Type II diabetes is most commonly made by routine testing in the asymptomatic individual, and it is thought that there are as many yet-to-be diagnosed as already diagnosed Type II diabetics in Canada. Typically, at diagnosis the Type II diabetic is more obese; has higher systolic blood pressure, LDL, and triglyceride levels; and lower HDL levels than their peer groups and therefore are already at increased risk for coronary artery disease. M a n y will have android obesity (waist to hip ratio >0.8 in the female and >0.9 in the male) and this phenotype is also feltto be a harbinger of coronary artery disease. Reaven (4) has drawn attention to the important role of endogenous hyperinsulinemia in the genesis of hyperglycemia, dyslipidemia, and hypertensionm"the deadly trio"--that he has termed "Syndrome X." This certainlyprovides a uni-
CLINICALBIOCHEMISTRY,VOLUME26, AUGUST1993
lying hypothesis that satisfactorilyexplains these otherwise disparate entities.Therapeutically, however, one is leftin a quandry. Aggressive use of sulfonylureas and insulin in the obese Type II diabetic will lower glycemic levelsbut m a y also increase vascular risk, so the need for 80, 100, or more units of insulin a day in these patients should probably also be included among the poor prognostic indicators. Good prognosis in Type II Diabetes Life expectancy in Type I diabetes is reduced by 30 years and in the Type II diabetic by 10 years. However, there is no evidence (5) that life expectation is reduced in patients whose diabetes was discovered after the age of 70 (and 8% of septuagenarians and 20% of octogenarians meet the diagnostic criteria for diabetes). Surely this is an important point for the physician involved in their care to keep in mind when planning treatment. In conclusion, nowhere in medical practice is the conjunction between clinical chemistry and patient care more valid than in diabetes. The widespread availability and reliability of glycosylated haemoglobin measurements, lipid fractions, and more recently microalbumin levels have revolutionized the clinician's ability to evaluate risk, adjust therapy, and enhance prognosis in their diabetic patients.
References 1. Messent JW, Elliott TG, Hill RD, Jarrett RJ, Keen H, Viberti GC. Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: A twenty-three year follow-up study. Kidney Int 1992; 41: 836-9. 2. Orchard TJ, Dorman JS, Maser RE, et al. Factors associated with avoidance of severe complications aider 25 years of IDDM. Diabetes Care 1990; 13: 741-7. 3. Morrish NJ, Stevens LK, Head J, Fuller JH, Jarrett RJ, Keen H. A prospective study of mortality among middle-aged diabetic patients (the London cohort of the WHO multinational study of vascular disease in diabetes) I: Causes and death rates. Diabetologia 1990; 33: 538-41. 4. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 538-60. 5. Wong JS, Pearson DW, Murchison LE, Williams MJ, Narayan V. Mortality in Diabetes Mellitus: Experience of a geographically defined population. Diabetic Med 1991; 8: 135-9.
315
0009-9120/93 $6.00 + .00 Copyright © 1993 The Canadian Society of Clinical Chemists.
Good and Bad Diabetes ANNE B. KENSHOLE Department of Medicine, Women's College Hospital, 76 Grenville Street, Toronto, Ontario, Canada M5S 1B2 Introduction There is no doubt that diabetes is a serious condition that can result in significant disability and premature death. In Canada it accounts for 50% of blindness under the age of 65, 25% of hospitalizations for cardiovascular disease, and 40% of nontrauma related amputations. The estimated cost of diabetes management to the Ontario Health Care System in 1992 was $800 million. Nevertheless, a small but significant number of people with Type I diabetes remain complication-free 40, 50, and more years after diagnosis. Frequently their "control," as measured by patterns of blood sugar levels and glycosylated haemoglobins is indifferent (or worse). Similar patterns of complication are often found within affected families. These observations give support to the belief that genetics play a role in determining the development of microvascular complication either in the inheritance of a "protective" gene or one that increases risk. The recognition of "good" and "bad" outcomes in diabetes has also stimulated the search for markers of early compromise in the belief that intervention can favourably alter the subsequent course.
Bad prognostic indicators in Type I, IDDM Diabetes is the second commonest cause of endstage renal failure in North America. By 25 years after diagnosis, 45% of Type I diabetics require dialysis or, preferably, renal transplant from a live related donor. Microalbuminuria, defined as the excretion of 30-300 mg/24 h is now widely accepted as a valid marker of probable progression to overt proteinuria and progressive decline in glomerular filtration rate (1). Though considerable individual variation exists, microalbuminuria is typically present for 5 - 1 0 years before overt proteinuria develops, and the latter precedes elevation of serum creatinine by a further 2 - 5 years. Once glomerular filtration rate is reduced by 50% end-stage renal failure follows rapidly, again within a 2 - 5 year interval. In other words the finding of even modest persistent proteinuria is of grave prognostic signif-
Manuscript received March 23, 1993; revised May 17, 1993; accepted May 18, 1993. 314
icance. The relative mortality rate for a 35 year-old with IDDM is twice the normal rate in the absence of proteinuria but 100-fold increased when proteinuria is present. There are early but encouraging data to suggest that with management specifically tightening glycemic control in the early stages, and the use of angiotensin-converting enzyme inhibitors with a reduction in dietary protein, and meticulous control of hypertension in the later stages, the inexorable decline in function can be slowed, if not halted. A subtle elevation in blood pressure levels, though not necessarily to those traditionally labelled as hypertensive, typically occurs as microalbuminuria develops. A history of hypertension in one and especially in both parents significantly increases the risk of hypertension and renal failure in the offspring.
Proliferative retinopathy Whereas the majority of Type I diabetics will have developed the microaneurysms typical of background retinopathy (which is not a threat to vision) by 15 years after diagnosis, 10% will develop thinwalled, easily ruptured new vessels, the hallmark of proliferative retinopathy, the chief cause of visual loss in this type of diabetes. In 1976 the diabetic retinopathy study proved that panretinal photocoagulation could preserve useful vision in the majority of patients; but sadly, even in urban areas avoidable visual loss continues to occur because the patient has neglected regular ophthalmological assessment or the preproliferative signs have been missed. The development of retinopathy has been chosen as the outcome measure in the Diabetes Control and Complications Trial, the results of which should be available in the near future. From this landmark study it should be known whether a specific degree of glycemic control, as measured by glycosylated haemoglobins over a 10-year interval, seems to protect against the development of retinal change. Until then, glycemic control can only be categorized as being of uncertain prognostic value. The distinction between "good" and "bad" diabetes with respect to retinal and renal compromise can be made with reasonable certainty 25 years after diagnosis in the Type I diabetic. If the patient has not developed proliferative retinopathy or proteinuria by that time, they are unlikely to develop in the CLINICAL
BIOCHEMISTRY,
VOLUME
26, AUGUST
1993
GOOD AND BAD DIABETES future. The prognosis then will be that of the arterial tree. Interestingly, smoking was not found to impact negatively on the health of Type I diabetes when evaluated 25 years or more after diagnosis in the Pittsburgh Study (2).To the chagrin of the medical profession neither did the frequency with which the patient saw a physician! Onset of diabetes in early childhood was generally thought to carry a worse prognosis than onset at the more typical age, in the teens or early twenties; however, more recent studies have not supported this view. Prognosis in Type II, non-insulin dependent diabetes It has been stated that Type II diabetes "is a heart attack waiting to happen": the rate of coronary artery disease is increased two-fold, the risk of stroke three-fold, and diabetic women lose the traditional protection that women enjoy before and up to 10 years after menopause (3). The amputation rate is increased ten-fold because the diabetic foot is in double jeopardy from neuropathy and peripheral vascular disease. In Type I as in Type II, accelerated atherosclerosis, therefore, is a hallmark of the diabetic state. In addition to the traditional risk factors in the population at large, hypertriglyceridemia is now recognized as an independent risk factor in the diabetic, particularly women in whom HDL levels are excessively depressed. The diagnosis of Type II diabetes is most commonly made by routine testing in the asymptomatic individual, and it is thought that there are as many yet-to-be diagnosed as already diagnosed Type II diabetics in Canada. Typically, at diagnosis the Type II diabetic is more obese; has higher systolic blood pressure, LDL, and triglyceride levels; and lower HDL levels than their peer groups and therefore are already at increased risk for coronary artery disease. M a n y will have android obesity (waist to hip ratio >0.8 in the female and >0.9 in the male) and this phenotype is also feltto be a harbinger of coronary artery disease. Reaven (4) has drawn attention to the important role of endogenous hyperinsulinemia in the genesis of hyperglycemia, dyslipidemia, and hypertensionm"the deadly trio"--that he has termed "Syndrome X." This certainlyprovides a uni-
CLINICALBIOCHEMISTRY,VOLUME26, AUGUST1993
lying hypothesis that satisfactorilyexplains these otherwise disparate entities.Therapeutically, however, one is leftin a quandry. Aggressive use of sulfonylureas and insulin in the obese Type II diabetic will lower glycemic levelsbut m a y also increase vascular risk, so the need for 80, 100, or more units of insulin a day in these patients should probably also be included among the poor prognostic indicators. Good prognosis in Type II Diabetes Life expectancy in Type I diabetes is reduced by 30 years and in the Type II diabetic by 10 years. However, there is no evidence (5) that life expectation is reduced in patients whose diabetes was discovered after the age of 70 (and 8% of septuagenarians and 20% of octogenarians meet the diagnostic criteria for diabetes). Surely this is an important point for the physician involved in their care to keep in mind when planning treatment. In conclusion, nowhere in medical practice is the conjunction between clinical chemistry and patient care more valid than in diabetes. The widespread availability and reliability of glycosylated haemoglobin measurements, lipid fractions, and more recently microalbumin levels have revolutionized the clinician's ability to evaluate risk, adjust therapy, and enhance prognosis in their diabetic patients.
References 1. Messent JW, Elliott TG, Hill RD, Jarrett RJ, Keen H, Viberti GC. Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: A twenty-three year follow-up study. Kidney Int 1992; 41: 836-9. 2. Orchard TJ, Dorman JS, Maser RE, et al. Factors associated with avoidance of severe complications aider 25 years of IDDM. Diabetes Care 1990; 13: 741-7. 3. Morrish NJ, Stevens LK, Head J, Fuller JH, Jarrett RJ, Keen H. A prospective study of mortality among middle-aged diabetic patients (the London cohort of the WHO multinational study of vascular disease in diabetes) I: Causes and death rates. Diabetologia 1990; 33: 538-41. 4. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 538-60. 5. Wong JS, Pearson DW, Murchison LE, Williams MJ, Narayan V. Mortality in Diabetes Mellitus: Experience of a geographically defined population. Diabetic Med 1991; 8: 135-9.
315