Glycemic Control and Diabetic Complications

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1 Glycemic Control and Diabetic Complications SUZANNE STROWIG, RN, MSN PHIUP RASKIN, MD The relationship between glycemic control and diabetic complications remains unclear. Epidemiological studies reveal that 25% of diabetic individuals do not develop complications, irrespective of degree of glycemic control. Studies of genetic factors, including HLA type, capillary basement membrane thickness, genetic predisposition to hypertension, and familial clustering of diabetic complications, suggest that there is a genetic component to developing the complications of diabetes. On the other hand, clinical trials have demonstrated that the progression of early, mild background retinopathy, microalbuminuria, and parameters of nervous system function are stabilized with improved glycemic control. Other metabolic parameters, such as serum lipoprotein levels, are significantly improved with near normoglycemia. No studies to date have evaluated the effect of blood glucose control on the prevention of diabetic complications. The degree of glycemic control required to impact on diabetic complications is unknown. In addition, achieving near normoglycemia carries increased risk for severe hypoglycemia and weight gain. Further study is needed to determine the long-term benefits of blood glucose control and to weigh that against the risks of improving glycemic control. Further investigation also is needed to address the probable interrelationship of genetic factors and glycemic control on the development of diabetic complications. I s there a relationship between blood glucose control and the development of the microvascular complications of diabetes? On the surface, this seems a basic question for which a simple "yes" or "no" answer would suffice. However, as with most issues in medicine, the relationship between glycemic control and diabetic complications is a complex one. Intuitively, it would seem that, by correcting the metabolic abnormality of diabetes, one also could avoid the longterm complications that presumably are caused by that abnormality. Striving to help patients improve their blood glu- FROM THE DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, DALLAS, TEXAS. ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO SUZANNE STROWIG, RN, MSN, FACULTY ASSO- CIATE, DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, 5323 HARRY HINES BOULEVARD, G4.100, DALLAS, IX U A E R, URINARY ALBUMIN EXCRETION RATE; G F R, GLOMERULAR FILTRATION RATE; I D D M, INSULIN- DEPENDENT DIABETES MELLITUS; CS11, CONTINUOUS SUBCUTANEOUS INSULIN INFUSION; ICT, INTENSIFIED CONVENTIONAL TREATMENT; RT, REGULAR TREATMENT; VLDL, VERY-LOW-DENSITY LIPOPROTEIN; LDL, LOW-DENSITY LIPOPROTEIN; HDL, HIGH-DENSITY LIPOPROTEIN; DCCT, DIABETES CONTROL AND COM- PLICATIONS TRIALS. cose control is a tangible goal that health care providers can pursue through specific interventions. The technologies available today, such as self-monitoring of blood glucose, multiple insulin injections, insulin pump (CSII) therapy, and measures of GHb levels, provide us with the ability to manage diabetes better than ever before. But do we really know if improving blood glucose control will impact on the development of diabetic complications? To examine this issue, many other questions must be asked. Can glycemic control prevent, delay, and/or reverse diabetic complications? Is blood glucose control the only cause of microvascular complications? Does the degree of glycemic control affect the development of complications equally in all patients with diabetes? What degree of glycemic control is necessary to be of benefit in the prevention of diabetic complications? Are current treatment methods for diabetes effective and practical enough to achieve the degree of long-term glycemic control needed to affect the development of complications? Are there any risks to achieving the desired level of glycemic control? Are the risks outweighed by the benefits? This review explores these questions and discusses our current understanding of the relationship between glycemic control and the microvascular complications of diabetes. An understanding of this issue can guide our approach to the management of diabetic patients. NATURAL HISTORY OF DIABETIC COMPLICATIONS Epidemiological studies show that not all diabetic patients develop microvascular disease. The results of two long-term studies of the microvascular complications in patients who had diabetes >40 yr showed that 60-75% of patients had retinopathy; however, <33% of all the patients had proliferative eye disease (1,2). Nephropathy was evident in 40% of patients, but <10% of all patients had renal failure DIABETES CARE, VOLUME 15, NUMBER 9, SEPTEMBER 1992

2 Strowig and Raskin ESRD Albuminuria Normal ESRD Albuminuria Normal =liiiiij,7» m 0% (0) Baa 17% (2) D * >/o (12) 41< '/o(12) Percent of Siblings Siblings of Probands with Diabetic Nephropathy ^BH 83% (10) Siblings of Probands Free of Diabetic Nephropathy Figure 1 Categorization of diabetic siblings according to renal status. Siblings are categorized as those with end-stage renal disease (ESRD), with albuminuria (AER >45 mg/24 h) and with normal AER C<45 mg/24 h). Number of siblings in each category is given in parentheses. Siblings of probands free of diabetic nephropathy had less evidence of renal disease than did siblings of probands with diabetic nephropathy (P < 0.001). From Seaquist et al. (11). by N EnglJ Med. The Steno group followed 1303 diabetic patients for >25 yr after the onset of diabetes through the patient's death. Diabetic nephropathy occurred in 41% of patients (protein excretion >0.5 g/24 h) (3). Other investigators retrospectively analyzed 112 type I diabetic patients listed in the death registry at the Joslin Clinic between 1962 and 1972, and data from patients who were diagnosed as having diabetic nephropathy from 1966 to This analysis showed that 59% of patients developed renal failure and that persistent proteinuria occurred an average yr after the onset of diabetes (4). These data suggest that 25-50% of diabetic patients do not develop serious small blood vessel complications, despite the existence of the disease for years. Presumably, these patients had differing levels of glycemic control, but certainly some degree of hyperglycemia existed throughout the duration of the disease. This variability in the appearance of diabetic complications has generated two major hypotheses to explain the pathogenesis of the complications. The genetic hypothesis suggests that microvascular complications of diabetes are genetically predetermined as part of the diabetic syndrome. The metabolic hypothesis suggests that diabetic complications develop as a direct result of the hyperglycemia of diabetes. THE GENETIC HYPOTHESIS The genetic hypothesis is supported by the findings of Siperstein et al. (5) regarding skeletal basement membrane width. Of the 51 diabetic patients examined, 98% had abnormal capillary basement membrane width compared with 8% of nondiabetic subjects. In addition, 16 of 30 adults (53%) with normal glucose tolerance, who were offspring of two overt diabetic parents, had thickened capillary basement membranes. No correlation was found between membrane thickness and the severity or duration of diabetes or the age at onset. The genetic hypothesis is further supported by the findings that 7 of 9 patients with acquired hyperglycemia caused by alcoholic pancreatitis had normal basement membranes. One patient had minimal basement membrane thickness, and only one had overt hypertrophy of capillary basement membranes (5). Marks et al. (6) found a striking relationship between the basement membrane thickness of skeletal muscle capillaries and the presence of HLA-DR4 in 38 unaffected parents of children with diabetes. Doman et al. (7) found that HL A-DR4 was present in 70% of patients with background and proliferative retinopathy and in only 54% without retinopathy. Retinopathy also was more common in patients with "poor diabetic control," such that the combination of poor control and the presence of HLA- DR4 increased the probability of having retinopathy to 33.3% (7). A relationship between HLA-DR4 and susceptibility to retinopathy has not been confirmed by other investigators (8-10). More recently, the role of heredity as a risk factor for diabetic kidney disease was studied at the University of Minnesota, whose registry represents almost 25% of all IDDM patients in the state. The concordance rates for diabetic nephropathy were examined in two sets of families in which both probands and siblings had diabetes mellitus. One set of probands (n = 11) had no evidence of diabetic nephropathy and had normal creatinine clearance and a UAER <45 mg/day. The other set of probands (n = 26) had undergone kidney transplantation because of diabetic nephropathy. Evidence for nephropathy was found in 2 of 12 diabetic siblings of probands without nephropathy (17%), whereas 24 of 29 siblings of probands with diabetic nephropathy (83%) had evidence of kidney disease. Furthermore, 12 of the 29 diabetic siblings of probands with diabetic nephropathy had end-stage renal disease (Fig. 1). Duration of diabetes was similar between the groups of siblings, and no significant differences were observed among siblings without end-stage renal disease in blood pressure, serum creatinine levels, creatinine clearance, or GHb levels. Multivariate analysis found the presence of nephropathy in the diabetic proband to be the only significant factor in predicting nephropathy in the diabetic sibling. The authors concluded that nephropathy occurs in familial clusters, supporting the hypothesis that heredity is a factor in DIABETES CARE, VOLUME 15, NUMBER 9, SEPTEMBER

3 Glycemic control and diabetic complications determining susceptibility to the development of complications (11). THE METABOLIC HYPOTHESIS The kidneys of diabetic individuals exhibit distinct histological changes not found in kidneys of normal individuals nor in patients with renal disease of nondiabetic origin. Among these changes is an intense immunofluorescent staining for IgG and albumin lining the tubular and glomerular basement membranes and Bowman's capsule (12). Studies have shown that this characteristic immunofluorescent staining may be directly influenced by the diabetic milieu. In rats, similar immunofluorescent staining for IgG and complement C3 occurred after 4-6 mo of hyperglycemia. When kidneys from diabetic rats were transplanted into normal rats, the characteristic immunofluorescent lesion disappeared in 2 mo, and if kidneys from nondiabetic rats were transplanted into diabetic rats, the lesions appeared after 2 mo (13). If diabetic rats developed normoglycemia after islet cell transplantation, regression of the immunofluorescent changes and reductions in glomerular volume and percentage of the mesangial volume occupied by the matrix component occurred (14). In humans, kidney tissue obtained from 12 diabetic and 17 nondiabetic patients 2-12 yr after renal transplantation showed significantly greater frequency and intensity of IgG and albumin stains of the tubular and glomerular basement membranes and Bowman's capsule in the diabetic patients (15). With the exception of some staining of the glomerular basement membranes in the nondiabetic kidneys, practically no overlap occurred between the two groups. Furthermore, 7 of the 9 kidneys received from living related donors showed no immunofluorescence at the time of transplantation. Similar results were obtained relative to hyaline changes of the glomerular arterioles. Examination of renal transplant tissue revealed that 10 of 12 kidneys from diabetic patients showed arteriolar hyalinosis compared with 3 of 28 transplant recipients without diabetes (16). Again, the kidneys from living related donors were free of blood vessel changes at the time of transplantation. Kidneys from a 37-yr-old man with a 17-yr history of IDDM were transplanted into 2 male recipients with chronic renal failure caused by polycystic kidney disease. At nephrectomy, both kidneys were grossly normal but showed features of glomerulosclerosis, increased mesangial matrixes, and thickening of capillary basement membranes. Urine analysis was positive for glucose and protein. Both kidneys functioned well after transplantation, with standard immunosuppression. A renal biopsy performed 7 mo after transplantation showed complete resolution of the abnormalities as determined by light microscopy, and both patients were without proteinuria (17). Engerman and Kern (18) compared the effect of glycemic control on retinopathy in normal and alloxaninduced diabetic dogs. Some 35 dogs were randomly assigned into one nondiabetic and three diabetic groups poor control for 5 yr, good control for 5 yr, and poor control for 2.5 yr followed by 2.5 yr of good control. Normal GHb levels were achieved in animals during their assigned periods of good control. The dogs in poor control developed significantly greater microvascular abnormalities of the retina than the dogs in good control. The mean aneurysm count in the well-controlled dogs was not significantly different than that of the nondiabetic dogs. The dogs who were poorly controlled for 2.5 yr showed no aneurysms, a normal prevalence of acellular capillaries, and no retinal hemorrhages. In contrast, when the contralateral eye of these same dogs was examined after 2.5 yr of good control had been substituted for poor control, the aneurysm count had increased to a mean of 29 aneurysms per eye. The capillary basement membrane width was significantly greater than normal, but less than in the dogs who had been in poor control for 5 yr. Other retinal abnormalities in the poor control-good control group were less severe than in the poor control group, but the differences were not statistically significant. Retinal abnormalities were significantly greater in the poor controlgood control group compared with the good control group at 5 yr. The authors concluded that good glycemic control can inhibit the development of diabetic retinopathy, but that this effect is markedly abated if postponed for many months after the onset of diabetes (18). This suggests that any beneficial effects of good control on the development or progression of diabetic complications may be greatly influenced by the prior history of glycemic control. CLINICAL TRIALS Retinopathy Although retrospective in design, several studies have demonstrated a beneficial relationship between blood glucose control and the development of retinopathy. Pirart followed 4400 diabetic patients between 1947 and 1973 (19). Of these, 2795 patients were followed from the time diagnosis was made. The frequency and severity of diabetic retinopathy were related to duration of diabetes and degree of glycemic control. After 25 yr duration, 80% of patients with poor glycemic control developed retinopathy, compared with 40% of patients with good control (Fig. 2). Only a few of the patients with good control had "severe" retinopathy compared with nearly 15% of patients with poor glycemic control (19). Johnsson reviewed retrospectively the records of patients diagnosed with diabetes between 1922 and 1945 (20). Subjects who had been treated with multiple daily injections and strict diet had significantly less severe retinopathy than subjects who had used long-acting insulin and a less regimented diet (3 vs. 19%). This occurred despite the fact that 1128 DIABETES CARE, VOLUME 15, NUMBER 9, SEPTEMBER 1992

4 Strowig and Raskin associated with worsening of retinopathy <D 100, CO ; CO characterized by the appearance of retinal infarcts and intraretinal microvascular 200- abnormalities. Retinopathy stabilized thereafter in the CSII group such that progression in both groups was similar after 2 yr of study (24). However, multiple 20. C 4,2 r treatment crossovers after the initial 8-mo study period diminished the validity o. " * : ; -J i i i ;^ J l 1 1 I I of the results obtained at 2 yr. Similarly, the Oslo study randomly assigned 45 patients to one of 10 o CO three groups: conventional treatment, too - multiple daily insulin injections, and insulin pump (25). Transient deterioration CO O 200- of retinopathy occurred in the insulin pump group during the first 3-6 mo of treatment. In the study, 7 pump patients and 8 patients using multiple daily insulin 20, injections developed cotton wool spots that regressed in all but 4 patients 0. by 12 mo. Those who developed cotton wool spots had a greater decrease in GHb level, longer duration of diabetes, and I II U IB KNOWN DURATION more severe retinopathy at the onset of the study. No patients treated with conventional treatment developed cotton Figure 2 Values for different grades of retinopathy (R) as a function of duration in patients withwool spots during the 1st yr. After 2 yr, severe diabetes with good (top) or poor (bottom) cumulative glycemic control. From Pirart (19). however, by the conventionally treated pa- Diabetes Care, the American Diabetes Association. subjects on the long-acting insulin had a duration of diabetes 10 yr shorter than those who were treated more intensively. The overall incidence of retinopathy, however, was not significantly different between groups (20). The results of prospective clinical trials have been less conclusive. The Steno group evaluated 30 patients with IDDM and background retinopathy who were randomly assigned to conventional insulin therapy or to treatment with CSII (21). Despite a significant improvement in glycemic control in the CSII group, these patients showed greater deterioration of retinopathy than the conventionally treated patients. During the 1st yr of study, retinal morphology deteriorated in 10 of 15 patients using insulin pumps, compared with 5 of 15 patients on conventional therapy. After 2 yr, however, retinopathy improved in the insulin pump group, whereas it continued to deteriorate in the conventionally treated group. Thus, no difference in retinopathy existed between groups after 2 yr despite significant differences in glycemic control throughout the study period (22). The tendency toward a transient deterioration of diabetic retinopathy after initiation of improved glycemic control was demonstrated by other groups. The Kroc Collaborative Multicenter Study prospectively evaluated 70 patients randomly assigned to CSII and conventional treatment (23). After 8 mo, improved glycemic control in the CSII group was tients exhibited significantly more microaneurysms and hemorrhages compared with the combined groups of patients using insulin pumps and multiple daily injections (26). In contrast to these studies, the Aarhus group randomly assigned 24 patients with minimal background retinopathy or none to CSII or conventional therapy (27,28). GHb levels decreased from 9.07% in both groups to 7.4% in the CSII group and 8.6% in the conventionally treated group. The difference in glycemic control was significant between the two groups. After 1 and 3 yr of study, progression of retinopathy was no different in either group. None of the patients developed soft exudates or neovascularization. Similarly, the Oxford Aylesbury Study demonstrated comparable rates of progression of retinopathy in 74 diabetic patients randomly assigned to conventional care or multiple daily insulin in- DIABETES CARE, VOLUME 15, NUMBER 9, SEPTEMBER

5 Glycemic control and diabetic complications jections (29). These subjects had mild background retinopathy at the onset of the study. The Stockholm group also showed significant and comparable increases in retinopathy in 97 patients randomly assigned to intensified conventional treatment (ICT) or regular treatment (RT) (30,31)- Despite significantly better glycemic control in the ICT group (ICT, 7.4% vs. RT, 9.0%), similar rates of deterioration of retinopathy occurred in both groups after 36 mo of follow-up. Proliferative retinopathy developed in at least one eye in 9 RT patients and in 7 ICT patients. In further contrast are the results of the Dallas Diabetes Prospective Trial (32,33). In that study, 30 type I diabetic patients on CSI1 and 24 diabetic patients on conventional treatment were followed for an average of >30 mo. HbA lc levels were significantly better in the CSII group compared with the conventional treatment group (mean HbA lc = 7.4 vs. 10.2%). Patients using the insulin pump had significantly less progression of diabetic retinopathy, as measured by macular aneurysm counts and modified Early Treatment Diabetic Retinopathy Study grading (Table 1). Furthermore, patients whose diabetic retinopathy progressed during the treatment period showed a tendency toward thickening of skeletal muscle capillary basement membrane width irrespective of treatment group (33). The Job Study also demonstrated an increase in microaneurysms in subjects randomly assigned to singleinjection therapy compared with those assigned to multiple-injection therapy (34). The study was flawed, however, by numerous treatment crossovers. Nephropathy Studies of transplanted kidneys suggest that the structural and functional changes that occur in kidneys exposed to the diabetic milieu can be reversed when that milieu is corrected. Clinical trials suggest that improving glycemic control can stabilize UAERs and normalize GFRs. However, improving glycemic control may be beneficial only during the early stages of the development of kidney disease. Several retrospective studies have evaluated the relationship between blood glucose control and the development of renal disease. Investigators in Malmo, Sweden, assessed two groups of subjects diagnosed between 1922 and All of the patients were <40 yr old at the onset of diabetes. Group 1 consisted of 56 patients diagnosed between 1922 and 1935 and who received strict diet control and multiple daily injections of insulin. Group 2 consisted of 104 patients diagnosed between 1935 and 1945 and who were treated with long-acting insulin and a less regimented diet. Although the mean duration of diabetes for patients in Table 1 Effect of diabetes control on progression of retinopathy in 30 subjects using experimental (intensive) therapy and 24 subjects using conventional therapy after 31A and 33.5 mo, respectively, of follow-up MODIFIED EARLY TREATMENT DIABETIC RETINOPATHY STUDY EXPERIMENTAL* TREATMENT CONVENTIONAL TREATMENT MACULAR MICROANEURYSM COUNT EXPERIMENTAL* TREATMENT BETTER (N) STABLE (N) WORSE (N) From Rosenstock et al. (33). e by Am] Med. *P < 0.05, experimental treatment vs. conventional treatment (log-likelihood CONVENTIONAL TREATMENT group 1 was 10 yr longer than in patients in group 2, 18 of 56 (32%) had nephropathy, compared with 58 of 104 (56%) in group 2. In those patients with duration of diabetes > 15 yr, 5 of 56 (9%) patients in group 1 had nephropathy, compared with 63 of 104 (61%) patients in group 2 (20). Pirart showed that, in 4400 diabetic patients followed between 1947 and 1973, the incidence of nephropathy was twice as likely if glycemic control was poor (19). More recently, retrospective analyses of glycemic control in adolescents demonstrated a relationship between antecedent GHb levels and UAERs (35,36). Prospective clinical trials also have shown a beneficial effect of glycemic control on parameters of kidney function. This has been most evident in subjects with mildly elevated UAERs. The Steno group demonstrated that in patients with an initial UAER >70 jig/ min, all of those treated with conventional therapy experienced an increase of UAER to >200 i,g/min after 2 yr of study (Fig. 3). Only 1 of 3 hyperalbuminuric patients in the CSII group progressed to a UAER >200 xg/min (37). Similarly, the Kroc study observed a significant reduction in elevated UAER during CSII therapy (48.9 ± 18.5 to 16.0 ± 5.3 xg/min) but not during conventional treatment (23). The Dallas study also observed a progressive increase in UAER over 3 yr in patients with microalbuminuria who were using conventional treatment (35.6 xg/min at entry to xg/min at 3 yr). This was in contrast to patients using CSII whose UAER remained unchanged during the 3 yr of observation (61.0 xg/min at entry to 69.7 xg/min at 3 yr) (38). Most studies have been unable to demonstrate any change in UAER, irrespective of treatment group or level of control when entry levels of UAER were normal (23,27,37,38). The Oslo study observed a significant decrease in normal urinary albumin levels after 3-4 yr of insulin pump therapy (26±3tol6± DIABETES CARE, VOLUME 15, NUMBER 9, SEPTEMBER 1992

6 Strowig and Raskin J URINARY ALBUMIN EXCRETION RATE pg mm 11 n \,»(9io) ^c::l^ f! v- y 24 mths Figure 3 UAER in 16 insulin-dependent diabetic patients before and during treatment with CSII and 13 1DDM patients treated with conventional therapy (UCT). Patients with UAER <70 \Lg/min, ( ), patients with UAER >70 \ig/min, ( ). From Deckert et al. (37). by Diab Nephrop. mg/24 h). This change was not apparent after 2 yr of study, nor did it occur at any point in subjects using conventional treatment or multiple daily injections (39). On the other hand, the Stockholm group observed that a significant number of patients on conventional therapy with normoalbuminuria at baseline progressed to microalbuminuria after 18 mo of study. No change was observed in intensively treated patients (30). GFRs also were evaluated in several studies. The Steno group observed a reduction in GFR to normal after 6 mo of treatment with CSII that remained stable after 8 yr of follow-up (124 ± 28 to 114 ± 24 ml/min). GFR continued to decline in patients undergoing conventional treatment, such that the annual change in GFR was 3.7 ml/min in the conventional treatment group compared with 1.0 ml/min in the CSII group (40,41). However, in phase 2 of the Steno study, which involved 35 more subjects, no significant differences in GFR were observed between groups during 5 yr of follow-up. Similarly, after 1 yr of study by the Aarhus group, the GFR decreased significantly to normal levels in the insulin pump group (130 ± 18 to 116 ± 15 ml/min). No change occurred in subjects treated with conventional therapy (130 ± 15 to 128 ± 14 ml/min) (27). The Oslo group also observed a significant decrease in GFR from 119 to 111 ml/min in subjects using insulin pumps, whereas no change occurred in those using multiple daily injections or conventional therapy (26). Both the Aarhus and Oslo Studies found a correlation between GHb levels and GFR (27,43). In the Oslo Study, note that those using multiple injections did not demonstrate the improvements seen in those using pumps, despite the fact that the GHb levels were significantly better in both of these groups than in the conventional treatment group. The average GHb level in the CSII group was slightly better, however, than in the multiple injection group (8.7 vs. 9.1%). In contrast to these reports, the Stockholm group observed a significant decrease in GFR after 3 yr (42) in both groups of subjects irrespective of treatment (ICT, 122 ± 3 to 115 ± 3 ml/min vs. RT, 126 ± 3 to 119 ± 3 ml/min). Although both groups experienced a reduction in HbA lc levels from baseline, the ICT group achieved a significantly lower HbA lc level than the RT group (7.4 ± 0.1 vs. 9.0 ± 0.2%). The results of these studies suggest that diabetic patients with microalbuminuria and hyperfiltration can benefit from improved glycemic control. The fact that subjects with normal UAER experienced little change in urinary albumin levels, irrespective of treatment or degree of glycemic control, may be attributable to the relatively short period of observation. Perhaps several more years of observation might have revealed different rates of progression to microalbuminuria relative to degree of glycemic control. What is clear, however, is that significant renal disease is not reversed with improvements in glycemic control (44,45). Neuropathy As with retinopathy and nephropathy, Pirart demonstrated that neuropathy occurred with greater frequency and severity in patients with poor glycemic control (19). Young also reported an association between deterioration of motor, sensory, and autonomic nerve function and glycemic control (46). Other investigators have shown that improved glycemic control increases nerve conduction velocity (47), peripheral nerve function, and vibratory sensation threshold (48,49). The Dallas study demonstrated an improvement in motor nerve conduction velocity after as little as 6 wk of insulin pump therapy (50). After 12 mo DIABETES CARE, VOLUME 15, NUMBER 9, SEPTEMBER

7 Glycemic control and diabetic complications Standard Therapy Insulin Pump Therapy Median lilnar Pcroneal Median Ulnar Peroneal in the Steno Study. No change occurred in patients using insulin pumps (22). Similarly, the Aarhus Group observed a deterioration of heart-rate variation at rest, at deep breathing, and standing in patients using conventional therapy, whereas autonomic nerve function re- Figure 4 Motor nerve conduction velocities mained stable in patients using insulin in three nerves in 1DDM patients treated for 1 yr with either standard or insulin pump therapy. Baseline, ( ); 1 yr, O; * P < 0.05 standard therapy vs. insulin pump therapy. Adapted from Ehle and Raskin (51). by J Neurol Scien. of pump treatment, motor nerve conduction velocity significantly increased in the median, peroneal, and ulnar nerves (average increase 2.5 m/s) (Fig. 4). No change occurred in subjects using conventional therapy. The average increase was larger in the nerves with the slowest conduction compared with nerves with faster conduction (5.1 vs. 3.8 m/s). No change in sensory action potential occurred in either treatment group (51). The Stockholm group demonstrated faster nerve conduction velocities in the peroneal, tibial, and sural nerves after 36 mo of intensive treatment compared with regular therapy (31). Similarly, subjects using insulin pumps in the Oslo Study had improved motor nerve conduction velocity of the ulnar, peroneal, and tibial nerves after the 2nd yr of study. Deterioration occurred in the conventional treatment group, and no change occurred in those using multiple injections. Proximal motor nerve function, as assessed by F-response latency, deteriorated in all nerves in the conventional treatment and multiple injection groups, but remained stable in the insulin pump group. Sensory action potential improved in all groups, but most prominently in those using insulin pumps (43). Autonomic nervous system function was measured by the Steno and Aarhus Groups. A deterioration in heart-rate variation at deep respiration was observed in conventionally treated patients pump therapy (53). Observations regarding vibration perception threshold are inconclusive. Measures of vibration perception threshold were unchanged, irrespective of treatment group and degree of glycemic control in the Stockholm, Steno, and Oslo Studies (22,31,43). On the other hand, improved glycemic control, subsequent to intensive insulin therapy, had a beneficial effect on vibration perception threshold in the Oxford and Aarhus studies (29,53). Thus, improved glycemic control seems to improve motor nerve conduction velocity and maintain autonomic nervous system function. The impact of improved glycemic control on sensory action potential or vibration perception threshold remains unclear. Other diabetic abnormalities Improved glycemic control has been shown to impact other diabetic abnormalities. Maintenance of near normoglycemia for 4-5 wk with use of a portable insulin infusion pump resulted in a significant reduction of glucagon levels to within the normal range (54). Similarly, normalization of blood glucose with insulin pump therapy resulted in the reduction of intermediate metabolites including lactate, 3-hydroxybutyrate, and alanine (55,56). Growth hormone and catecholamine responses to exercise normalized after 7-14 days of pump therapy (57). Total glucose uptake increased, and hepatic glucose production significantly decreased after 6 wk of insulin pump therapy, suggesting an improvement in insulin sensitivity with better glycemic control (58). Growth factors, such as somatomedin and somatomedin C, increased 70-75% after 16 wk of insulin pump therapy (59). Urinary calcium and phosphorus excretion significantly decreased after 7-14 days of normalization of blood glucose (60). It also has been shown that improved glycemic control in patients treated with CSII resulted in a significant reduction in skeletal muscle capillary basement membrane width (61). Little direct evidence of the effect glycemic control has on cardiovascular events in diabetic patients is available. The Steno Group reported that 3 patients on conventional treatment suffered five cardiovascular events causing two deaths, whereas 1 subject using intensive therapy survived a cardiovascular event (41). Studies regarding parameters, such as erythrocyte adhesion and platelet function, remain inconclusive (62,63). Improvements in lipid metabolism with better glycemic control are probably the most consistent findings relevant to the risk of cardiovascular disease. Several investigators demonstrated that near-normalization of blood glucose resulted in significant reductions in levels of plasma cholesterol, triglycerides, free fatty acids, and plasma apoprotein B (56,64,65). Raskin observed that as little as 3 wk of euglycemia resulted in significant decreases in plasma cholesterol, VLDL and LDL cholesterol, plasma triglycerides, and VLDL triglyceride levels (66,67). HDL cholesterol significantly increased after 2 mo of euglycemia. These changes persisted after 3 yr of improved glycemic control in patients using insulin pumps (Fig. 5). No such improvements were observed in patients whose blood glucose levels remained elevated while on conventional therapy (68) (Fig. 6). Kinetic studies revealed that decreases in VLDL triglyceride and LDL cholesterol levels resulted from decreased hepatic production of both lipoproteins rather than increased lipoprotein clearance (66,69). Direct measures of pulmonary function were assessed by Ramirez in 10 subjects on conventional therapy and 8 subjects using insulin pumps, all of whom had been followed for a 6 -yr pe DIABETES CASE, VOLUME 15, NUMBER 9, SEPTEMBER 1992

8 Strowig and Raskin c g 2 "c 0Oc o O 8 0 o O Years 200 CO O ^> a) E Figure 5 Plasma lipid and lipoprotein levels in 26 intensively treated patients. From Rosenstock et al. (68). by Diabetes Care. riod. GHb levels were significantly lower in the insulin pump group (conventional treatment, 9.0 vs. pump, 5.7%). Forced vital capacity and diffusing capacity for carbon monoxide were significantly diminished in the conventionally treated patients. Patients using insulin pumps had normal pulmonary function. The authors concluded that improved glycemic control preserves pulmonary function in 1DDM (70). DISCUSSION The results of the animal studies, the retrospective analyses of large patient populations, and the prospective clinical trials suggest that blood glucose control plays a role in the development of diabetic complications. However, data supporting the genetic hypothesis are also compelling. In all likelihood, the microvascular complications of diabetes develop as a result of an interplay between these factors; i.e., a given patient has a genetic predisposition to develop complications that makes him/her more or less vulnerable to the effects of hyperglycemia. This would explain why 25% of diabetic patients never develop microvascular disease, whereas possibly another 25-30% of patients develop serious complications. 50 c o c <D O c o O o > CO 0) o.c O (D The combined role of heredity and glycemic control in the development of diabetic complications is supported by the work of Krolewski. Patients with diabetic nephropathy were compared with patients without nephropathy as to degree of glycemic control, velocity of lithium-sodium countertransport, and presence of parental hypertension. Having a parent with hypertension tripled the risk for having nephropathy and was associated with significantly higher values for maximal velocity of lithium-sodium countertransport. The risk for nephropathy associated with these indicators of a predisposition to hypertension, however, was most evident in patients with poor glycemic control during the first decade of diabetes. The presence of poor glycemic control increased the odds ratio of developing nephropathy from 3.7 to 4.5 for patients with a parental history of hypertension, and to 7.7 for patients with a maximal velocity of lithium-sodium countertransport >0.35 mm of cells/h. Predisposition to hypertension did not increase the risk for renal disease among patients with hyperglycemia below the median of subjects in the study. The authors concluded that poorly controlled diabetes is a principal risk factor for renal disease whose effect is enhanced by a genetic predisposition to hypertension (71). Similarly, nearly 400 patients enrolled in the Diabetic Retinopathy Study Plasma-Choi 1_HDL-Chol f"vldl-chol Years 200 c q 150 r 0) o c 100 o O Figure 6 Plasma lipid and lipoprotein levels in 21 conventionally treated patients. From Rosenstock et al. (68). by Diabetes Care. 50 DIABETES CARE, VOLUME 15, NUMBER 9, SEPTEMBER

9 Glycemic control and diabetic complications were evaluated to assess risk of developing persistent proteinuria. The results showed that the incidence for developing persistent proteinuria markedly decreased after 20 yr of diabetes or after age 40. High mean blood pressure quadrupled the risk of persistent proteinuria in patients with high plasma glucose levels. However, hypertension had little effect on risk in patients whose glucose levels were below the median for the group. These data also suggest that individuals with a genetic predisposition to hypertension are more likely to develop renal disease in the presence of hyperglycemia (72). The fact that risk diminished after 20 yr duration might indicate that those diabetic individuals have some genetic protection from susceptibility to the complications of diabetes. Young also noted in a 2.5-yr study of subclinical polyneuropathy in diabetic adolescents that parameters of motor, sensory, and autonomic nerve function deteriorated at a rate that was linearly related to the degree of glycemic control. However, it also was noted that deteriorating nerve function was associated with the concomitant development of retinopathy and microalbuminuria, independent of their association with glycemia. Several patients in the study with poor glycemic control had electrophysiological and autonomic measurements that remained in the normal range. The authors concluded that hyperglycemia may be essential to developing the complications of diabetes, but that susceptibility to tissue damage may vary among patients given similar levels of glycemic exposure (46). Mechanisms of tissue damage by hyperglycemia In light of hyperglycemia's probable role in the development of diabetic complications, what are the mechanisms by which hyperglycemia causes tissue damage? Furthermore, how are these mechanisms influenced by genetic factors? Are the mechanisms by which hyperglycemia exerts its effects the same for all body tissues? The work of Pirart demonstrated a chronological coincidence of complications (19). Of 100 patients with nephropathy, 89 had neuropathy and 86 had retinopathy. On the other hand, of 100 patients affected with retinopathy, 61 had neuropathy and 24 had nephropathy. Of 100 patients affected with neuropathy, 26 had nephropathy and 65 had retinopathy. Thus, despite some coincidental occurrence of complications, the presence of different complications in the same patients varied. Interestingly, the presence of nephropathy was most closely associated with the presence of other complications. Several potential mechanisms by which hyperglycemia causes tissue damage have been proposed. One theory is that hyperglycemia affects hemodynamics. Researchers have suggested that microvascular pressures and flow are increased in early diabetes and that perfusion capacity fails with increasing duration. Elevated hydrostatic pressure is postulated to be at least partly responsible for leakage of plasma proteins as well as deposition of proteins in the walls of arterioles and capillaries in the kidneys (73-75). Glycosylation of tissue proteins also may cause tissue damage. Glycosylation of proteins has been identified in many tissues of the body, including the lens (76), albumin (77), collagen (78), lipoproteins (79), nerve protein (80), and, of course, hemoglobin (81). The change in physical-chemical structure that occurs with glycosylation has been postulated to alter the function of tissue proteins (82). Another mechanism by which glucose could cause tissue damage is by its metabolism through the polyol pathway. Aldose reductase, the first enzyme of the pathway, is thought to play a role in the pathogenesis of diabetic complications. The polyol pathway was first implicated in the etiology of diabetic cataracts (83). aldose Glucose ^. Sorbitol reductase sorbitol dehydrogenase Figure 7 The polyol pathway. Aldose reductase catalyzes the reduction of glucose to its sugar alcohol, sorbitol (Fig. 7). The accumulating sorbitol has been associated with cataract formation in hyperglycemic rats (84) and has been found in nerves (85) and kidneys (86) in diabetic animals. Furthermore, sorbitol accumulation has been found in the tissue of humans with diabetes (87). If hyperglycemia causes tissue damage through the polyol pathway, this system demonstrates a way in which genetic predisposition could play a role in determining which individuals are more susceptible to the development of diabetic complications. Individuals with higher aldose reductase activity might be at a greater risk of developing diabetic complications, given the same level of hyperglycemia, than individuals with lower levels. Hamada et al. (88,89) recently reported a fourfold variability in the activity of erythrocyte aldose reductase among diabetic patients. Their data showed that patients who had high activity of aldose reductase accumulated more sorbitol in their tissues compared with patients with low enzyme activity, for any given level of plasma glucose. Furthermore, diabetic patients who suffered from severe microvascular complications of diabetes after only a short duration of the disease had significantly higher erythrocyte aldose reductase activity than diabetic patients who had diabetes for >25 yr and had no significant diabetic complications (90). These data suggest that the individual differences in aldose reductase activity among patients with diabetes may confer a variable susceptibility to develop the complications of the disease. It is also possible that the activity 1134 DIABETES CARE, VOLUME 15, NUMBER 9, SEPTEMBER 1992

10 Strowig and Raskin of another enzyme in the polyol pathway, sorbitol dehydrogenase, could be implicated in susceptibility to and development of diabetic complications. Individuals with low levels of sorbitol dehydrogenase, the enzyme that metabolizes sorbitol to fructose in tissues, might be at greater risk to develop diabetic complications. Conversely, individuals with high levels of the enzyme given the same level of glycemia and the same aldose reductase activity might be protected from developing diabetic complications. No data exist regarding the activity of sorbitol dehydrogenase in diabetic patients to support this hypothesis. Effects of improved glycemic control Because hyperglycemia may exert its effects on tissues through similar or separate mechanisms, improving blood glucose control may have different effects on various body tissues. The effect of improving blood glucose control on retinopathy is unclear. Several studies observed transient worsening of retinopathy after institution of intensive treatment. Others found no differences between groups, despite significant differences in glycemic control. A few investigators reported lessened progression of retinopathy in subjects with improved glycemic control. Regression of retinopathy was not observed in the prospective studies reported. The reason for these discrepancies is not clear. The patients who experienced transient worsening tended to have worse stages of retinopathy at entry to the study. On the other hand, the work of Engerman and Kern suggest that the progression of retinopathy is a function of glycemic control from the onset of diabetes (18). Thus, any benefit that might be achieved from improving glycemic control later in the course of the disease would be modulated by the prior history of glycemic control. This might be one explanation for the lack of consistent findings regarding the effects of intensified treatment on retinopathy. It may be possible that the appearance of microaneurysms, the earliest observable manifestation of diabetic retinopathy, represents an advanced stage of tissue damage that cannot be affected by improving glycemic control. Perhaps the progression of very early diabetic retinopathy can be slowed or the occurrence prevented if near normoglycemic control is instituted before the appearance of any signs of retinopathy. No study to date has examined this issue. The Diabetes Control and Complications Trial, currently in progress, is the only study designed to examine the effect of improved blood glucose control in subjects who had diabetes <5 yr duration and had no evidence of retinopathy or renal disease at entry to the study (91). The results of this prospective randomized trial of >1400 patients should be available in In contrast to the results regarding retinopathy, the benefit of improved glycemic control on halting the progression of microalbuminuria was universally observed. Little change in UAER in patients with normoalbuminuria occurred, irrespective of degree of glycemic control during the relatively short periods of observation reported. Beneficial effects of glycemic control on GFR were observed, but these results were less conclusive. Thus, it appears that improved glycemic control can delay the progression of early renal disease but probably cannot reverse any damage that has already occurred. The long-term effect of glycemic control in patients with normoalbuminuria is not certain. Again, the Diabetes Control and Complications Trial (DCCT), a 10-yr study, may be able to address this question. Motor nerve conduction velocity was consistently shown to improve with better glycemic control. Measures of autonomic nerve function stabilized with improved glycemic control. The changes in other parameters of nerve function relative to glycemic control were less conclusive. Thus, unlike the other complications, some aspects of nervous system function may actually improve with better glycemic control. Lipid abnormalities were consistently reported to improve with better glycemic control as well. This may reduce the risk for developing cardiovascular disease. However, the benefit of reducing lipid levels in diabetic patients with varying degrees of cardiovascular impairment is not known. Thus, the time of appearance of diabetic complications varies within and among individuals. Furthermore, the benefit of improved glycemic control seems to vary among the organs affected by diabetes. At most, improving glycemic control may stop or delay the progression of early nephropathy and autonomic nervous system dysfunction. The progression of early mild retinopathy may be slowed with improved glycemic control but this remains uncertain. Parameters of nerve function, most likely motor nerve function, may be reversible with improved glycemic control. Established complications are not affected by changes in glycemic control. The effect of glycemic control on preventing complications is not known. Finally, a genetic predisposition probably plays a role in developing diabetic complications. However, the precise way in which glycemic control and genetic factors interact remains unknown. Intensive therapy: effectiveness and risk Although current treatment techniques, such as self-monitoring of blood glucose, multiple insulin injections, and insulin pumps, have enabled patients to significantly improve glycemic control, achieving long-term normoglycemia remains an elusive goal. None of the prospective studies examining the effects of intensive therapy and glycemic control on complications were able to show sustained normal GHb levels in the intensively treated groups. During the 1st yr of the DCCT, only 17% of intensively treated subjects achieved normal GHb levels despite optimal availability of health care resources DIABETES CARE, VOLUME 15, NUMBER 9, SEPTEMBER

11 Glycemic control and diabetic complications (92). The vagaries of the absorption and action of insulin and the lack of automatic feedback with blood glucose levels make current treatment techniques imperfect, at best. As long as managing diabetes requires patient-initiated behaviors to monitor and adjust for variables in food, exercise, and insulin, achieving long-term normoglycemia will remain a therapeutic challenge. What degree of glycemic control is required to prevent or delay diabetic complications? This also is unknown, and there is little agreement among the few investigators who have reported on this question. In a retrospective analysis of the relationship between glycemic control and microalbuminuria, more subjects with higher HbA lc levels had microalbuminuria. The authors determined that a threshold effect was at work a mean HbA lc >12.0%, above which the development of microalbuminuria was more likely (35). Selam et al. (93) found that HbA lc levels <8.5% (normal = %) were associated with greater improvement in retinal lesions. Reichard and Rosenqvist (42) observed that patients with a mean HbA lc value <9% had significantly lower UAER after 3 yr of study (normal HbA lc = 4.6%). Similarly, in the Oslo Study, subjects using multiple injections with a mean HbA lc level of 9.1% did not experience the improvement in complications that occurred in the subjects using insulin pumps who had a mean HbA lc of 8.7% (normal = %). Because long-term normoglycemia in subjects was rarely achieved in prospective clinical trials, it is not known if the effects on diabetic complications would have been more profound had glycemic control been closer to normal levels. The limiting factor in achieving near normoglycemia with existing treatment techniques is the risk for hypoglycemia. Most of the prospective clinical trials reported an increased frequency of severe hypoglycemia in subjects using intensive therapy (23,30,40). The DCCT observed a threefold increase in episodes Figure 8 Cumulative proportion of DCCT experimental (intensive treatment) and standard (conventional treatment) group patients who experienced severe hypoglycemia (P < 0.01). From DCCT Research Group (94). by AmerJ Med. of severe hypoglycemia in subjects using intensive therapy compared with subjects using conventional therapy (94) (Fig. 8). Severe hypoglycemia included all episodes in which neurological impairment was severe enough to require the assistance of others. Interestingly, 43% of episodes occurred during sleep. In addition, 51% of conscious episodes occurred without recognition of warning signs or symptoms (94). Investigators have reported a lowering of the glucose threshold for neurogenic warning symptoms with intensive therapy (95-97). The potentially life-threatening consequences of nocturnal and asymptomatic hypoglycemia (including impaired cognitive function, impaired judgment and performance, and coma and seizure) cannot be underestimated. Diabetic ketoacidosis also has occurred with increased frequency with intensive therapy, specifically insulin pump therapy (23,40). Because insulin pump therapy uses only regular insulin, any system malfunction that interrupts insulin delivery can cause a rapid rise in glucose and ketone levels. Significant weight gain has been associated with intensive insulin therapy. Reichard et al. (31) reported an increase in body mass index of 3.5% in intensively treated patients. No such change occurred in the conventionally treated patients. In the DCCT, intensively treated subjects gained an average 5.1 kg vs. the conventionally treated group, who gained an average 2.4 kg. (98) (Fig. 9). This may be an important problem, given the potential consequences of weight gain on blood pressure, serum lipid levels, and long-term compliance. CONCLUSIONS The development of diabetic complications is likely the result of an interplay between blood glucose control and genetic factors. The precise mechanisms by which hyperglycemia and genetic factors interact to cause diabetic complications is unknown. Any beneficial effect on improving blood glucose control is probably limited to halting or delaying the progression of early microvascular disease, although this may vary among the organs affected by diabetes. The prevention of diabetic complications by attaining near normoglycemia also is unknown. However, the development of complications may be related to glycemic exposure from the onset of diabetes, limiting the potential Months Figure 9 Percent of ideal body weight for 132 standard ( ) and 146 experimental (A) group subjects at baseline and quarterly visits through lyr (P < ). Reprinted with permission from DCCT Research Group (98). by Diabetes Care, the American Diabetes Association DIABETES CARE, VOLUME 15, NUMBER 9, SEPTEMBER 1992

12 Strowig and Raskin benefits of improving blood glucose control later in the course of the disease. The degree of glycemic control required to prevent or delay the progression of diabetic complications is unknown. The risks associated with achieving near normoglycemia have considerable consequence. Severe hypoglycemia can be life threatening, especially when warning symptoms are absent. The potential ramifications of excessive weight gain are of concern relative to long-term morbidity. The economic cost of intensive therapy is considerable indeed, two to four times more expensive than conventional therapy. Because many questions regarding the relationship between blood glucose control and complications remain, the risk-benefit ratio of achieving near normoglycemia must be ascertained before broad recommendations about glycemic control can be made. This is particularly relevant given the limitations of existing treatment techniques. At present, the most prudent approach is to provide patients with a comprehensive treatment program that meets their needs and abilities, and is based on mutually negotiated goals. Glycemic goals can be optimized based on the patient's abilities for self-management and history of severe and/or asymptomatic hypoglycemia (99). Ascertaining the magnitude of the risks and balancing them against the potential long-term benefits of achieving and maintaining blood glucose levels toward normal is a major goal of the DCCT (91). The results of this study should bring us closer to answering the many questions that remain about the relationship between blood glucose control and diabetic complications. References 1. Paz-Guevara AT, Hsu T-H, White P: Juvenile diabetes mellitus after forty years. Diabetes 24:559-65, Oakley WG, Pyke DA, Tattersall RB, Watkins PJ: Long-term diabetes: a clinical study of 92 patients after 40 years. Q JMed 43:145-56, Anderson AR, Christiansen JS, Anderson JS, Kreiner S, Deckert T: Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiologic study. Diabetologia 25: , Kussman MJ, Goldstein HH, Gleason RE: The clinical course of diabetic nephropathy. JAMA 236: , Siperstein MD, Unger RH, Madison LL: Studies of muscle capillary basement membranes in normal subjects, diabetic and prediabetic patients. J Clin Invest 47: , Marks JF, Raskin P, Stastny P: Increase in capillary basement membrane width in parents of children with type I diabetes mellitus: association with HLA-DR4. Diabetes 30:475-80, Dornan TL, Ting A, McPherson CK, Peckar CO, Mann Jl, Turner RC, Morris PJ: Genetic susceptibility to the development of retinopathy in insulin-dependent diabetics. Diabetes 31:226-31, Christy M, Nerup J, Platz P, Thomsen M, Ryder LP, Svejgaard A: A review of HLA antigen in long-standing 1DDM with and without severe retinopathy. Horm Metab Res 11 (Suppl.):73-77, Gray RS, Starkey 1R, Rainbow S, Kurtz AB, Abdel-Khalik A, Urbaniak S, Elton RA, Duncan LJP, Clarke BF: HLA antigens and other risk factors in the development of retinopathy in type 1 diabetes. BrJ Ophthalmol 66:280-85, Johnston PB, Kidd M, Middleton D, Greenfield AA, Archer DB, Maguire CJF, Kennedy L: Analysis of HLA antigen association with proliferative diabetic retinopathy. Br J Ophthalmol 66:277-79, Seaquist ER, Goetz FC, Rich S, BarbosaJ: Familial clustering of diabetic kidney disease: evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 320: , Miller K, Michael AF: Immunopathology of renal extracellular membranes in diabetes mellitus: specificity of tubular basement membrane immunofluorescence. Diabetes 25: , Lee CS, Mauer SM, Brown DM, Sutherland DER, Michael AF, Najarian JS: Renal transplantation in diabetes mellitus in rats. J Exp Med 139: , Mauer SM, Steffes MW, Sutherland DER, Najarian JS, Michael AF, Brown DM: Studies of the rate of regression of the glomerular lesions in diabetic rats treated with pancreatic islet transplantation. Diabetes 24:280-85, Mauer SM, Miller K, Goetz FC, Barbosa J, Simmons RL, Najarian JS, Michael AF: Immunopathology of renal extracellular membranes in kidneys transplanted into patients with diabetes mellitus. Diabetes 25:709-12, Mauer SM, Barbosa J, Vernier RL, Kjellstrand CM, Buselmeier TJ, Simmons RL, Najarian JS, Goetz FC: Development of diabetic vascular lesions in normal kidneys transplanted into patients with diabetes mellitus. N Engl J Med 295:916-20, Abouna GM, Al-Adnani MS, Kremer GD, Kumar SA, Daddah SK, Kusma G: Reversal of diabetic nephropathy in human cadaveric kidneys after transplantation into nondiabetic recipients. Lancet 2: , Engerman RL, Kern TS: Progression of incipient diabetic retinopathy during good glycemic control. Diabetes 36:808-12, PirartJ: Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and Diabetes Care 1:168-88, Johnsson SL: Retinopathy and nephropathy in diabetes mellitus: comparison of the effect of two forms of treatment. Diabetes 9:1-8, Lauritzen T, Frost-Larsen K, Larsen HW, Deckert T, Steno Study Group: Effect of 1 year of near-normal blood glucose levels on retinopathy in insulin-dependent diabetics. Lancet 1: , Lauritzen T, Frost-Larsen K, Larsen HW, Deckert T, The Steno Study Group: Two-year experience with continuous subcutaneous insulin infusion in relation to retinopathy and neuropathy. Diabetes 34 (Suppl. 3):74-79, Kroc Collaborative Study Group: Blood glucose control and the evolution of di- DIABETES CARE, VOLUME 15, NUMBER 9, SEPTEMBER

13 Glycemic control and diabetic complications abetic retinopathy and albuminuria: a preliminary multicenter trial. N Engl J Med 311:365-72, Kroc Collaborative Study Group: The Kroc study patients at two years: a report on further retinal changes (Abstract). Diabetes 34 (Suppl. 1):39A, Dahl-Jorgensen K, Brinchmann-Hansen O, Hanssen KF, Sandvik L, Aagenaes O, Aker Diabetes Group: Rapid tightening of blood glucose control leads to transient deterioration of retinopathy in insulin dependent diabetes mellitus: the Oslo study. Br MedJ 290:811-15, Dahl-Jorgensen K, Brinchmann-Hansen O, Hanssen KF, Ganes T, Kierulf P, Smeland E, Sandvik L, Aagenaes O: Effect of near normoglycemia for two years on progression of early diabetic retinopathy, nephropathy, and neuropathy: the Oslo study. Br MedJ 293: , Beck-Nielsen H, Richelsen B, Mogensen CE, Olsen T, Ehlers N, Nielsen CB, Charles P: Effect of insulin pump treatment for one year on renal function and retinal morphology in patients with 1DDM. Diabetes Care 8:585-89, Olsen T, Richelsen B, Ehlers N, Beck- Nielsen H: Diabetic retinopathy after 3 years' treatment with continuous subcutaneous insulin infusion (CS11). Ada Ophthalmol 68:185-89, Holman RR, Doman TL, Mayon-White V, Howard-Williams J, Orde-Peckar C, Jenkins L, Steemson J, Rolfe R, Smith B, Barbour D, McPherson K, Poon PYW, Rizza C, Mann Jl, Knight AH, Bron AJ, Turner RC: Prevention of deterioration of renal and sensory-nerve function by more intensive management of insulindependent diabetic patients: a two year randomised prospective study. Lancet 2: , Reichard P, Britz A, Cars 1, Nilsson BY, Sobocinsky-Olsson B, Rosenqvist U: The Stockholm diabetes intervention study (SDIS): 18 months' results. Acta Med Scand 224:115-22, Reichard P, Britz A, Carlsson P, Cars 1, Lindblad L, Nilsson BY, Rosenqvist U: Metabolic control and complications over 3 years in patients with insulindependent diabetes (1DDM): the Stockholm diabetes intervention study (SDIS). J Intern Med 280:511-17, Friberg TR, Rosenstock J, Sanborn G, Vaghefi A, Raskin P: The effect of longterm near normal glycemic control on mild diabetic retinopathy. Ophthalmology 92: , Rosenstock J, Friberg T, Raskin P: Effect of glycemic control on microvascular complications in patients with type 1 diabetes mellitus. Am J Med 81: , Job D, Eschwege E, Guyot-Argenton C, Aubry J-P, Tchobroutsky G: Effect of multiple daily insulin injections on the course of diabetic retinopathy. Diabetes 25:463-69, Kalk WJ, Osier C, Taylor D, Panz VR: Prior long-term glycaemic control and insulin therapy in insulin-dependent diabetic adolescents with microalbuminuria. Diabetes Res Clin Pract 9:83-88, Norgaard K, Storm B, Graae M, Feldt- Rasmussen B: Elevated albumin excretion and retinal changes in children with type 1 diabetes are related to long-term poor blood glucose control. Diabetic Med 6:325-28, Deckert T, Lauritzen T, Parving HH, Christiansen JS, the Steno Study Group: Effect of two years of strict metabolic control on kidney function in long-term insulin-dependent diabetics. Diabetic Nephrop 2:6-10, Rosenstock J, Raskin P: The effect of glycemic control on urinary albumin excretion rate (AER) in type I diabetes mellitus (Abstract). Diabetes 36 (Suppl. 1): 107A, Dahl-Jorgensen K, Hanssen KF, Kierulf P, Bjoro T, Sandvik L, Aagenaes O: Reduction of urinary albumin excretion after 4 years of continuous subcutaneous insulin infusion in insulin-dependent diabetes mellitus: the Oslo Study. Acta Endocrinol 117:19-25, Feldt-Rasmussen B, Mathiesen E, Deckert T: Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin-dependent diabetes. Lancet 2: , Feldt-Rasmussen B, Mathiesen ER, Jensen T, Lauritzen T, Deckert T: Effect of improved metabolic control on loss of kidney function in type 1 (insulindependent) diabetic patients: an update of the Steno studies. Diabetologia 34: , Reichard P, Rosenqvist U: Nephropathy is delayed by intensified insulin treatment in patients with insulin-dependent diabetes mellitus and retinopathy. J Intern Med 226:81-87, Dahl-Jorgensen K: Near-normoglycemia and late diabetic complications: the Oslo study. Acta Endocrinol 284 (Suppl.): 1-38, Tamborlane WV, Puklin JE, Bergman M, Verdonk C, Rudolf MC, Felig P, Genel M, Sherwin R: Long-term improvement of metabolic control with the insulin pump does not reverse diabetic microangiopathy. Diabetes Care 5 (Suppl. 1):58-64, Viberti GC, Bilous RW, Mackintosh D, Bending JJ, Keen H: Long-term correction of hyperglycemia and progression of renal failure in insulin dependent diabetes. 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14 Strowig and Raskin infusion pumps. Diabetes 29:668-71, Ehle AL, Raskin P: Increased nerve conduction in diabetics after a year of improved glucoregulation. ] Neurol Sci 74: , JakobsenJ, Christiansen JS, Kristoffersen 1, Christensen CK, Hermansen K, Schmitz A, Mogensen CE: Autonomic and somatosensory nerve function after 2 years of continuous subcutaneous insulin infusion in type 1 diabetes. Diabetes 37:452-55, Raskin P, Pietri A, Unger R: Changes in glucagon levels after four to five weeks of glucoregulation by portable insulin infusion pumps. Diabetes 28: , Pickup JC, Keen H, Parsons JA, Alberti KGMM, Rowe AS: Continuous subcutaneous insulin infusion: improved bloodglucose and intermediary-metabolite control in diabetics. Lancet 1: , Lawson P, Home PD, Bergenstal R, The Kroc Collaborative Study Group: Observations on blood lipid and intermediary metabolite concentrations during conventional insulin treatment or CS11. Diabetes 3 (Suppl. 3):27-30, Tamborlane WV, Sherwin RS, Koivisto V, Hendler R, Genel M, Felig P: Normalization of the growth hormone and catecholamine response to exercise in juvenile-onset diabetic subjects treated with a portable insulin infusion pump. Diabetes 28:785-88, Yki-Jarvinen H, Koivisto VA: Continuous subcutaneous insulin infusion therapy decreases insulin resistance in type I diabetes. J Clin Endocrinol Metab 58:659-66, Tamborlane WV, Hintz RL, Bergman M, Genel M, Felig P, Sherwin RS: Insulininfusion-pump treatment of diabetes: influence of improved metabolic control on plasma somatomedin levels. N EnglJ Med 305: , Gertner JM, Tamborlane WV, Horst RL, Sherwin RS, Felig P, Genel M: Mineral metabolism in diabetes mellitus: changes accompanying treatment with a portable subcutaneous insulin infusion system. J Clin Endocrinol Metab 50:862-65, Rosenstock J, Challis P, Strowig S, Raskin P: Improved diabetes control reduces skeletal muscle capillary basement membrane width in insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 4:167-75, Wautier JL, LeBlanc H, Wautier MP, Abadie E, Passa P, Caen JP: Erythrocyte adhesion to cultured endothelium and glycaemic control in type 1 (insulindependent) diabetic patients. Diabetologia 29:151-55, Mayfield RK, Halushka PV, Wohltmann HJ, Lopes-Virella M, ChambersJK, Loadholt CB, Colwell JA: Platelet function during continuous insulin infusion treatment in insulin-dependent diabetic patients. Diabetes 34: , Tamborlane WV, Sherwin RS, Genel M, Felig P: Restoration of normal lipid and amino acid metabolism in diabetic patients treated with a portable insulininfusion pump. Lancet 1: , Gonen B, White N, Schonfeld G, et al.: Plasma levels of apoprotein B in patients with diabetes mellitus: the effect of glycemic control. 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Am J Med 91:371-76, Krolewski AS, Canessa M, Warram JH, Laffel LMB, Christlieb AR, Knowler WC, Rand LI: Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N EnglJ Med 318: , Derby L, Warram JH, Laffel MB, Krolewski AS: Elevated blood pressure predicts the development of persistent proteinuria in the presence of poor glycemic control in patients with type I diabetes. Diabete Metab 15:320-26, Tooke JE: Microvascular haemodynamics in diabetes mellitus. Clin Sci 70:119-25, Parving HH, Viberti GC, Keen H, Christiansen JS, Lassen NA: Haemodynamic factors in the genesis of diabetic microangiopathy. Metabolism 32:943-50, Zatz R, Brenner BM: Pathogenesis of diabetic microangiopathy: the hemodynamic view. Am] Med 80:443-53, Stevens VJ, Rouzer CA, Monnier VM, Cerami A: Diabetic cataract formation: potential role of glycosylation of lens crystallins. Proc Natl Acad Sci USA 75: , Dolhofer R, Wieland OH: Increased glycosylation of serum albumin in diabetes mellitus. Diabetes 29:417-22, Robins SP, Bailey AJ: Age-related changes in collagen, the identification of reducible lysine-carbohydrate condensation products. Biochem Biophys Res Commun 48:76-84, Schleicher E, Deuffel T, Weiland OH: Non-enzymatic glycosylation of human serum lipoproteins. FEBS Lett 129:1-4, Vlassara H, Brownlee M, Cerami A: Nonenzymatic glycosylation of peripheral nerve protein in diabetes mellitus. Proc Nad Acad Sci USA 78: , Bunn HF, Gabbay KH, Gallop PM: The glycosylation of hemoglobin: relevance to diabetes mellitus. Science 200:21-27, Witztum JL, Mahoney EM, Branks MJ, Fisher M, Elam R, Steinberg D: Nonenzymatic glucosylation of low-density lipoprotein alters its biologic activity. Diabetes 31:283-91, Heyningen RV: Formation of polyols by DIABETES CARE, VOLUME 15, NUMBER 9, SEPTEMBER

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