Medical Progress
Refer to: Davidson MB: The case for control in diabetes mellitus (Medical Progress). West J Med 129:193-200, Sep 1978
The Case for Control Diabetes Mellitus
in
MAYER B. DAVIDSON, MD, Los Angeles
In all diabetic animal models studied to date, microangiopathic complications develop which can be prevented by tight control and reversed by either islet cell transplantation or transplanting the diabetic kidney into a nondiabetic environment. In humans the prevalence of these complications in secondary diabetes mellitus is similar to the prevalence in genetic diabetes. Furthermore, mesangial basement membrane thickness is normal at the onset of the disease and increases shortly thereafter. These two facts strongly suggest that the microangiopathic complications are not an independent genetic componeqt but rather are secondary to the metabolic derangements of uncontrolled diabetes. Normal kidneys transplanted into diabetic recipients developed the vascular Conversely, two diabetic kidfleys inadvertently'transplanted into nondiabetic recipients showed clearing of the vascular lesions. Most retrospective studies support the conclusion that control is associated with/ lessened complications. The three prospective studies published to date also support this hypothesis. Because glucose concentrations cannot be brought to normal levels by present methods, the critical question is whether a major emphasis on restoring metabolism to as nearly normal as possible will help ameliorate the microangiopathic complications in our patients. The accumulated evidence would strongly favor an affirmative answer. Two daily injections of intermediate-acting insulin supplemented with small amounts of short-acting insulin as needed is one method to approach this goal. lesions
of
diabetes.
IN ANY LARGE DIABETIC CLINIC one is struck by the number of patients with devastating complications of diabetes mellitus. Their diabetic control over the years commonly attempted to maintain only 2-3 + urine tests for glucose in order to avoid hypoglycemia. Since the renal threshold for the appearance of glucose in the urine corresponds to a plasma glucose concentration of approxiFrom the Department of Medicine, UCLA School of Medicine (University of California, Los Angeles). Submitted March 7, 1978. Reprint requests to: Mayer B. Davidson, MD, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90024.
mately 200 mg per dl, frequently these patients had glucose levels between 250 and 400 mg per dl much of the time. Can chronic hyperglycemia contribute significantly to the complications of diabetes? The correlation between the usual indices of diabetic control and macroangiopathy is not convincing. However, much evidence is accumulating to suggest that the microangiopathic complications (retinopathy and glomerulosclerosis) can be forestalled or prevented if blood sugar is maintained near normal levels. This review will summarize current evidence, comment on older THE WESTERN JOURNAL OF MEDICINE
193
DIABETES MELLITUS
ABBREVIATIONS USED IN TEXT BMT=basement membrane thickness MNCV=motor nerve conduction velocity PAS=periodic acid-Schiff (staining)
L
i
(retrospective) studies which often failed to show correlations between diabetic control and complications, and present an approach to the use of insulin which can be effective in maintaining glucose concentrations at "reasonable" levels (to be defined later).
Studies in Animals Glomerulosclerosis and retinopathy occur in all animal models of diabetes, whether occurring spontaneously or induced by chemical or viral agents. Specifically, glomerulosclerosis has been documented in alloxan-diabetic monkeys,' diabetes spontaneously occurring in dogs2 or after alloxan or growth hormone administrations and rats rendered diabetic with streptozotocin,4 a high sucrose diet' or virus inoculation. Retinopathy occurs in streptozotocin-treated rats8'9 or after a high sucrose diet,9 as well as in alloxan-diabetic'" or spontaneously diabetic dogs.2 Increased basement membrane thickness (BMT) has been found in monkeys with spontaneous diabetes" and in alloxan-induced and growth hormoneinduced diabetic dogs.' Actual basement membrane thickness in spontaneously diabetic monkeys is proportional to the duration of diabetes." The influence of diabetic control on complications has been studied in dogs made diabetic with alloxan or growth hormone.12 In 16 diabetic dogs a suboptimal dose of intermediate-acting insulin was given once a day (poorly controlled), as compared with 16 diabetic animals given daily multiple injections of regular insulin based upon the results of glucose determinations throughout the day (tightly controlled). Fifty nondiabetic dogs served as controls. All dogs were followed for five years, which is equivalent to 25 years of human patient follow-up. In the tightly controlled group there developed minimal retinopathy, no cataracts, no glomerulosclerosis by light microscopy, minimal glomerular changes by electron microscopy and a mild increase of muscle BMT over age-matched controls. In the poorly controlled group, on the other hand, there developed definite retinal microaneurysms, hemorrhages and exudates and dense cataracts, in addition to 194
SEPTEMBER 1978
*
129
*
3
moderate glomerular changes by both light and electron microscopy plus a pronounced increase in muscle BMT. Approximately six months after diabetes is induced in rats by streptozotocin administration, increased periodic acid-Schiff (PAS) staining occurs in the glomerular mesangium.4 5 Glycoproteins, an important constituent of basement membranes, are selectively stained by PAS. Therefore, increased PAS staining signifies BMT. These diabetic rats can be treated with pancreatic transplants from syngeneic (genetically identical) nondiabetic litter mates since rejection does not occur. After transplantation, carbohydrate metabolism returns to normal.5 The increased PAS staining also regresses within several weeks.= If a kidney from a normal rat is transplanted into a diabetic litter mate, mesangial basement membrane thickening occurs within several months." Conversely, transplantation of a diabetic kidney into a normal recipient results in clearing of the mesangial changes.14 One of the functions of the glomerular mesangium is to take up and clear macromolecules. Macromolecules are taken up normally by the diabetic mesangium but clearing of these molecules from the glomerulus is delayed. Therefore, fluorescent-labeled antibodies directed against various macromolecules will stain glomeruli more intensely when diabetic changes are present. A normal glomerulus shows little or no fluorescent staining. Several months after streptozotocininduced diabetes, intense fluorescent staining appears in the mesangium4 which clears after pancreatic transplantation.5 Additionally, normal glomeruli (with no fluorescent staining) will acquire intense staining on transplantation of the kidney into a diabetic rat.'4 Decreased motor nerve conduction velocity (MNCV) is characteristic of diabetic neuropathy and can be shown in streptozotocin-induced diabetic rats.'5 When glucose concentrations are returned to normal by twice-daily injections of insulin, Mr4CV also returns to normal. '5 It should be pointed out that partial lowering of blood sugar has no effect on MNCV.15 The following summarizes the animal data: (I) glomerulosclerosis, retinopathy and decreased MNCV occur in spontaneous and chemicallyinduced diabetes in various species; (2) tight control in dogs retards the development of glomerulosclerosis, retinopathy, cataracts and BMT; (3) tight control in rats restores MNCV to normal;
DIABETES MELLITUS
(4) diabetic glomerular lesions, as evidenced by both increased PAS and immunofluorescent staining of the mesangium, clear after pancreatic transplantation (these changes are induced in normal kidneys placed into diabetic rats); (5) glomerular lesions, as evidenced by increased PAS staining of the mesangium, disappear from the diabetic kidney after renal transplantation into a nondiabetic rat.
Studies in Humans Those who would argue that the microangiopathic changes of diabetes mellitus are not caused by chronic hyperglycemia have to postulate that these complications follow an independent, but genetically-determined course. If this were true, patients with secondary diabetes mellitus should not show microangiopathic complications. However, the prevalence of both glomerular BMT in patients whose diabetes is secondary to pancreatitis, hemochromatosis or carcinoma'16 and of retinopathy in diabetes caused by hemochromatosis17,18 is similar to the prevalence in those with genetic diabetes mellitus. By the same token, if the complications follow an independent genetic course, it might be expected that in some patients the microangiopathic changes would be present before the metabolic abnormality occurs. However, glomerular basement membrane width is normal at the time of diagnosis in juvenile-onset diabetes and increases within 11/2 to 21/2 years.'9 A strong argument favoring the importance of controlling diabetes is the changes that occur in normal kidneys transplanted into diabetic recipients. Hyalinization (positive PAS staining) of both the afferent and efferent arterioles occurs in only two conditions, cyanotic heart disease and diabetes mellitus. This change, to a moderate or pronounced degree, occurred in all 12 kidneys placed into diabetic patients.20* Typical changes of Kimmelstiel-Wilson disease (nodular glomerulosclerosis) were seen in one of the diabetic recipients.20 In contrast, only three of 28 nondiabetic recipients showed a mild degree of hyalinization (and not of both afferent and efferent arterioles) at a much later time after transplantation. Immunofluorescent studies were also carried out on posttransplant renal biopsy specimens. Deposition of immunofluorescent material in ex*The published data indicate II of 12. Dr. Mauer described the appearance in the 12th patient at a talk given to the American Diabetes Association, Southern California Affiliate, in the spring
of 1977.
tracellular membranes of the renal tubule and Bowman capsule, as well as the glomerulus, has recently been shown to be characteristic of diabetic nephropathy." In this study, glomerular basement membranes, tubular basement membranes and Bowman capsules were stained for both albumin and IgG. Notable increases in immunofluorescence to both macromolecules were seen in most kidneys transplanted into diabetic patients, whereas nondiabetic recipients showed only occasional mildly positive immunofluorescent staining.22 The shorter mean time after transplantation to biopsy in the diabetics (39 months) compared with the nondiabetics (61 months) further highlights these differences in immunofluorescent staining. The converse experiment has also been carried out unintentionally. Vascular lesions cleared completely in two diabetic kidneys within six months after inadvertent transplantation into nondiabetic recipients.23 Retrospective studies have served as the main investigative tool to evaluate whether control in diabetic patients will ameliorate the complications. Knowles24 reviewed 300 such studies from 85 different centers. The conclusions from 50 of these centers were that poor control was positively correlated with vascular disease, 25 concluded that there was no relationship and 10 were undecided. However, Knowles himself felt that most of the reported data were inadequate to serve as a basis for any decision and therefore any association between control and vascular complications was unproven. A major shortcoming of all the studies is related to the small number of subjects. Therefore, results of two recent studies involving much larger numbers of patients are of special interest. Goodkin25 followed the cases of 10,538 diabetic persons who applied for life insurance between 1951 and 1970. Mortality was reported at the end of 10, 15 and finally 20 years of investigation. Applicants were classified as poorly or fairly well controlled on their initial examination. Poor control was defined as (1) excessive glycosuria (over 4 percent) or (2) a two hour postprandial blood glucose value over 250 mg per dl or (3) a history of a recent high blood glucose level or (4) a history of severe insulin reaction or onset of diabetic coma after the initial period of observation. The mortality of the poorly controlled group was approximately 21/2 times that of the fairly well controlled patients. This difference persisted despite the fact that a larger proportion THE WESTERN JOURNAL OF MEDICINE
195
DIABETES MELLITUS
of younger diabetics appeared in the poorly controlled group. Another study involved 4,400 diabetics whose indices of nephropathy, neuropathy, retinopathy and control were evaluated at least once a year for up to 20 years.2Y The incidence and prevalence of these three complications ran a parallel course and were closely related to control as well as duration of the diabetes. A unique retrospective study was published in 1960. Johnsson27 compared the prevalence of retinopathy and nephropathy in two series of diabetics. Series I contained all patients whose diagnosis of diabetes was made before the age of 40 in Malm6, Sweden, between 1922 and 1936. During this period attempts were made to keep the urine sugar-free by strict diet and shortacting insulin, the only preparation available. Series II contained all patients diagnosed between 1936 and 1945, during which period long-acting insulin became available. At this time, diet was liberalized and the importance of glycosuria was belittled as long as the patients had no polyuria or ketonuria. Series I contained 71 patients, 17 of whom were excluded from the study because they did not survive long enough to permit evaluation of the effect of treatment. Series Il contained 115 patients, 10 of whom were excluded for the same reason. At the time of review, records of the remaining 54 patients in series I and 105 patients in series II were available for analysis. Thirty-five of the patients in series I and 100 in series II were alive and could be questioned and examined. For the most part, the principles of treatment followed initially by series I patients were maintained after 1936. Frequent insulin reactions were much more common in series I patients, providing indirect evidence of tighter control. Nephropathy was diagnosed when proteinuria was present in more than half of all examinations during the preceding year. After 15 years of diabetes in both groups, nephropathy was seven times more prevalent in series II. The prevalence of advanced retinopathy was also increased sixfold in series II patients in spite of the fact that at the time of review the mean duration of diabetes was 15.9 years compared with 26.5 years in series I. Three recently published prospective studies also support a role for control in favorably affecting the development of diabetic complications. In a Japanese study28 serial renal biopsy studies were done on 23 patients whose fasting plasma glucose levels were measured every two weeks or more 196
SEPTEMBER 1978
*
129 * 3
frequently. Good control was defined as values never greater than 120 mg per dl, poor control as values greater than 150 mg per dl on "all or many occasions" and fair control as falling in between. The amount of PAS staining in the biopsy studies was evaluated independently by three nephrologists who had no knowledge of the clinical course. Of 13 patients with poor control, 10 showed progression of their nephropathy. Three of four with fair control also showed progression while none of the six patients with good control showed progression. The duration of diabetes at the time of the first biopsy (approximately 4½/2 years) and the follow-up period (approximately four years) were similar in the patients showing progression and nonprogression. The age (years ± SEM) of onset of diabetes in those 13 patients whose nephropathy progressed was significantly lower (36.3 ± 3.9) than in the 10 patients who showed no progression (52.6±1.9). However, these results do not support the supposition that good control and relative absence of glomerulosclerosis are associated only because the person with adult-onset diabetes, with less severe alteration of carbohydrate metabolism, also may have an independent genetic constitution which is less likely to lead to nephropathy. Two of the four persons with adult-onset diabetes with poor control in this study showed progression of their renal lesions. In another Japanese study,29 the progression of retinopathy was correlated with fasting blood glucose levels over six years in 356 diabetic patients (mostly maturity-onset). Good control was defined as at least 80 percent of the fasting glucose levels less than 140 mg per dl, poor control as more than 50 percent of the fasting glucose concentrations exceeding 170 mg per dl and fair control as lying in between. Retinopathy was graded at least once per year after bilateral dilation of the pupils and examination with magnifying lenses by an ophthalmologist who had no knowledge of the metabolic status of the patient. Two, four and six years after the study began, the percent of eyes in which new lesions appeared and old lesions progressed was lowest in the group with good control, midway in the patients with fair control and highest in those with poor control. Conversely, the percent of eyes in which old lesions improved was highest in the group with good control, intermediate in those with fair control and lowest in the group with poor control. The final prospective study to be considered comes from France.30 Fifty-two patients with the
DIABETES MELLITUS
TABLE 1.-Microaneurysms in Diabetic Patients Receiving Single or Multiple Injections of Insulin* Microaneurysms
(means±SEM)
Single
Injectiotn
Base line ........ 12.7±3.5 Last examination .. 33.0±7.9 Difference ........ 20.3 ±4.9 Increase/year . 7.2± 1.9
Multiple Injection
Pt
9.0±3.3 15.2±4.9 6.2±2.5 1.8±0.7
NS
Refer to: Davidson MB: The case for control in diabetes mellitus (Medical Progress). West J Med 129:193-200, Sep 1978
The Case for Control Diabetes Mellitus
in
MAYER B. DAVIDSON, MD, Los Angeles
In all diabetic animal models studied to date, microangiopathic complications develop which can be prevented by tight control and reversed by either islet cell transplantation or transplanting the diabetic kidney into a nondiabetic environment. In humans the prevalence of these complications in secondary diabetes mellitus is similar to the prevalence in genetic diabetes. Furthermore, mesangial basement membrane thickness is normal at the onset of the disease and increases shortly thereafter. These two facts strongly suggest that the microangiopathic complications are not an independent genetic componeqt but rather are secondary to the metabolic derangements of uncontrolled diabetes. Normal kidneys transplanted into diabetic recipients developed the vascular Conversely, two diabetic kidfleys inadvertently'transplanted into nondiabetic recipients showed clearing of the vascular lesions. Most retrospective studies support the conclusion that control is associated with/ lessened complications. The three prospective studies published to date also support this hypothesis. Because glucose concentrations cannot be brought to normal levels by present methods, the critical question is whether a major emphasis on restoring metabolism to as nearly normal as possible will help ameliorate the microangiopathic complications in our patients. The accumulated evidence would strongly favor an affirmative answer. Two daily injections of intermediate-acting insulin supplemented with small amounts of short-acting insulin as needed is one method to approach this goal. lesions
of
diabetes.
IN ANY LARGE DIABETIC CLINIC one is struck by the number of patients with devastating complications of diabetes mellitus. Their diabetic control over the years commonly attempted to maintain only 2-3 + urine tests for glucose in order to avoid hypoglycemia. Since the renal threshold for the appearance of glucose in the urine corresponds to a plasma glucose concentration of approxiFrom the Department of Medicine, UCLA School of Medicine (University of California, Los Angeles). Submitted March 7, 1978. Reprint requests to: Mayer B. Davidson, MD, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90024.
mately 200 mg per dl, frequently these patients had glucose levels between 250 and 400 mg per dl much of the time. Can chronic hyperglycemia contribute significantly to the complications of diabetes? The correlation between the usual indices of diabetic control and macroangiopathy is not convincing. However, much evidence is accumulating to suggest that the microangiopathic complications (retinopathy and glomerulosclerosis) can be forestalled or prevented if blood sugar is maintained near normal levels. This review will summarize current evidence, comment on older THE WESTERN JOURNAL OF MEDICINE
193
DIABETES MELLITUS
ABBREVIATIONS USED IN TEXT BMT=basement membrane thickness MNCV=motor nerve conduction velocity PAS=periodic acid-Schiff (staining)
L
i
(retrospective) studies which often failed to show correlations between diabetic control and complications, and present an approach to the use of insulin which can be effective in maintaining glucose concentrations at "reasonable" levels (to be defined later).
Studies in Animals Glomerulosclerosis and retinopathy occur in all animal models of diabetes, whether occurring spontaneously or induced by chemical or viral agents. Specifically, glomerulosclerosis has been documented in alloxan-diabetic monkeys,' diabetes spontaneously occurring in dogs2 or after alloxan or growth hormone administrations and rats rendered diabetic with streptozotocin,4 a high sucrose diet' or virus inoculation. Retinopathy occurs in streptozotocin-treated rats8'9 or after a high sucrose diet,9 as well as in alloxan-diabetic'" or spontaneously diabetic dogs.2 Increased basement membrane thickness (BMT) has been found in monkeys with spontaneous diabetes" and in alloxan-induced and growth hormoneinduced diabetic dogs.' Actual basement membrane thickness in spontaneously diabetic monkeys is proportional to the duration of diabetes." The influence of diabetic control on complications has been studied in dogs made diabetic with alloxan or growth hormone.12 In 16 diabetic dogs a suboptimal dose of intermediate-acting insulin was given once a day (poorly controlled), as compared with 16 diabetic animals given daily multiple injections of regular insulin based upon the results of glucose determinations throughout the day (tightly controlled). Fifty nondiabetic dogs served as controls. All dogs were followed for five years, which is equivalent to 25 years of human patient follow-up. In the tightly controlled group there developed minimal retinopathy, no cataracts, no glomerulosclerosis by light microscopy, minimal glomerular changes by electron microscopy and a mild increase of muscle BMT over age-matched controls. In the poorly controlled group, on the other hand, there developed definite retinal microaneurysms, hemorrhages and exudates and dense cataracts, in addition to 194
SEPTEMBER 1978
*
129
*
3
moderate glomerular changes by both light and electron microscopy plus a pronounced increase in muscle BMT. Approximately six months after diabetes is induced in rats by streptozotocin administration, increased periodic acid-Schiff (PAS) staining occurs in the glomerular mesangium.4 5 Glycoproteins, an important constituent of basement membranes, are selectively stained by PAS. Therefore, increased PAS staining signifies BMT. These diabetic rats can be treated with pancreatic transplants from syngeneic (genetically identical) nondiabetic litter mates since rejection does not occur. After transplantation, carbohydrate metabolism returns to normal.5 The increased PAS staining also regresses within several weeks.= If a kidney from a normal rat is transplanted into a diabetic litter mate, mesangial basement membrane thickening occurs within several months." Conversely, transplantation of a diabetic kidney into a normal recipient results in clearing of the mesangial changes.14 One of the functions of the glomerular mesangium is to take up and clear macromolecules. Macromolecules are taken up normally by the diabetic mesangium but clearing of these molecules from the glomerulus is delayed. Therefore, fluorescent-labeled antibodies directed against various macromolecules will stain glomeruli more intensely when diabetic changes are present. A normal glomerulus shows little or no fluorescent staining. Several months after streptozotocininduced diabetes, intense fluorescent staining appears in the mesangium4 which clears after pancreatic transplantation.5 Additionally, normal glomeruli (with no fluorescent staining) will acquire intense staining on transplantation of the kidney into a diabetic rat.'4 Decreased motor nerve conduction velocity (MNCV) is characteristic of diabetic neuropathy and can be shown in streptozotocin-induced diabetic rats.'5 When glucose concentrations are returned to normal by twice-daily injections of insulin, Mr4CV also returns to normal. '5 It should be pointed out that partial lowering of blood sugar has no effect on MNCV.15 The following summarizes the animal data: (I) glomerulosclerosis, retinopathy and decreased MNCV occur in spontaneous and chemicallyinduced diabetes in various species; (2) tight control in dogs retards the development of glomerulosclerosis, retinopathy, cataracts and BMT; (3) tight control in rats restores MNCV to normal;
DIABETES MELLITUS
(4) diabetic glomerular lesions, as evidenced by both increased PAS and immunofluorescent staining of the mesangium, clear after pancreatic transplantation (these changes are induced in normal kidneys placed into diabetic rats); (5) glomerular lesions, as evidenced by increased PAS staining of the mesangium, disappear from the diabetic kidney after renal transplantation into a nondiabetic rat.
Studies in Humans Those who would argue that the microangiopathic changes of diabetes mellitus are not caused by chronic hyperglycemia have to postulate that these complications follow an independent, but genetically-determined course. If this were true, patients with secondary diabetes mellitus should not show microangiopathic complications. However, the prevalence of both glomerular BMT in patients whose diabetes is secondary to pancreatitis, hemochromatosis or carcinoma'16 and of retinopathy in diabetes caused by hemochromatosis17,18 is similar to the prevalence in those with genetic diabetes mellitus. By the same token, if the complications follow an independent genetic course, it might be expected that in some patients the microangiopathic changes would be present before the metabolic abnormality occurs. However, glomerular basement membrane width is normal at the time of diagnosis in juvenile-onset diabetes and increases within 11/2 to 21/2 years.'9 A strong argument favoring the importance of controlling diabetes is the changes that occur in normal kidneys transplanted into diabetic recipients. Hyalinization (positive PAS staining) of both the afferent and efferent arterioles occurs in only two conditions, cyanotic heart disease and diabetes mellitus. This change, to a moderate or pronounced degree, occurred in all 12 kidneys placed into diabetic patients.20* Typical changes of Kimmelstiel-Wilson disease (nodular glomerulosclerosis) were seen in one of the diabetic recipients.20 In contrast, only three of 28 nondiabetic recipients showed a mild degree of hyalinization (and not of both afferent and efferent arterioles) at a much later time after transplantation. Immunofluorescent studies were also carried out on posttransplant renal biopsy specimens. Deposition of immunofluorescent material in ex*The published data indicate II of 12. Dr. Mauer described the appearance in the 12th patient at a talk given to the American Diabetes Association, Southern California Affiliate, in the spring
of 1977.
tracellular membranes of the renal tubule and Bowman capsule, as well as the glomerulus, has recently been shown to be characteristic of diabetic nephropathy." In this study, glomerular basement membranes, tubular basement membranes and Bowman capsules were stained for both albumin and IgG. Notable increases in immunofluorescence to both macromolecules were seen in most kidneys transplanted into diabetic patients, whereas nondiabetic recipients showed only occasional mildly positive immunofluorescent staining.22 The shorter mean time after transplantation to biopsy in the diabetics (39 months) compared with the nondiabetics (61 months) further highlights these differences in immunofluorescent staining. The converse experiment has also been carried out unintentionally. Vascular lesions cleared completely in two diabetic kidneys within six months after inadvertent transplantation into nondiabetic recipients.23 Retrospective studies have served as the main investigative tool to evaluate whether control in diabetic patients will ameliorate the complications. Knowles24 reviewed 300 such studies from 85 different centers. The conclusions from 50 of these centers were that poor control was positively correlated with vascular disease, 25 concluded that there was no relationship and 10 were undecided. However, Knowles himself felt that most of the reported data were inadequate to serve as a basis for any decision and therefore any association between control and vascular complications was unproven. A major shortcoming of all the studies is related to the small number of subjects. Therefore, results of two recent studies involving much larger numbers of patients are of special interest. Goodkin25 followed the cases of 10,538 diabetic persons who applied for life insurance between 1951 and 1970. Mortality was reported at the end of 10, 15 and finally 20 years of investigation. Applicants were classified as poorly or fairly well controlled on their initial examination. Poor control was defined as (1) excessive glycosuria (over 4 percent) or (2) a two hour postprandial blood glucose value over 250 mg per dl or (3) a history of a recent high blood glucose level or (4) a history of severe insulin reaction or onset of diabetic coma after the initial period of observation. The mortality of the poorly controlled group was approximately 21/2 times that of the fairly well controlled patients. This difference persisted despite the fact that a larger proportion THE WESTERN JOURNAL OF MEDICINE
195
DIABETES MELLITUS
of younger diabetics appeared in the poorly controlled group. Another study involved 4,400 diabetics whose indices of nephropathy, neuropathy, retinopathy and control were evaluated at least once a year for up to 20 years.2Y The incidence and prevalence of these three complications ran a parallel course and were closely related to control as well as duration of the diabetes. A unique retrospective study was published in 1960. Johnsson27 compared the prevalence of retinopathy and nephropathy in two series of diabetics. Series I contained all patients whose diagnosis of diabetes was made before the age of 40 in Malm6, Sweden, between 1922 and 1936. During this period attempts were made to keep the urine sugar-free by strict diet and shortacting insulin, the only preparation available. Series II contained all patients diagnosed between 1936 and 1945, during which period long-acting insulin became available. At this time, diet was liberalized and the importance of glycosuria was belittled as long as the patients had no polyuria or ketonuria. Series I contained 71 patients, 17 of whom were excluded from the study because they did not survive long enough to permit evaluation of the effect of treatment. Series Il contained 115 patients, 10 of whom were excluded for the same reason. At the time of review, records of the remaining 54 patients in series I and 105 patients in series II were available for analysis. Thirty-five of the patients in series I and 100 in series II were alive and could be questioned and examined. For the most part, the principles of treatment followed initially by series I patients were maintained after 1936. Frequent insulin reactions were much more common in series I patients, providing indirect evidence of tighter control. Nephropathy was diagnosed when proteinuria was present in more than half of all examinations during the preceding year. After 15 years of diabetes in both groups, nephropathy was seven times more prevalent in series II. The prevalence of advanced retinopathy was also increased sixfold in series II patients in spite of the fact that at the time of review the mean duration of diabetes was 15.9 years compared with 26.5 years in series I. Three recently published prospective studies also support a role for control in favorably affecting the development of diabetic complications. In a Japanese study28 serial renal biopsy studies were done on 23 patients whose fasting plasma glucose levels were measured every two weeks or more 196
SEPTEMBER 1978
*
129 * 3
frequently. Good control was defined as values never greater than 120 mg per dl, poor control as values greater than 150 mg per dl on "all or many occasions" and fair control as falling in between. The amount of PAS staining in the biopsy studies was evaluated independently by three nephrologists who had no knowledge of the clinical course. Of 13 patients with poor control, 10 showed progression of their nephropathy. Three of four with fair control also showed progression while none of the six patients with good control showed progression. The duration of diabetes at the time of the first biopsy (approximately 4½/2 years) and the follow-up period (approximately four years) were similar in the patients showing progression and nonprogression. The age (years ± SEM) of onset of diabetes in those 13 patients whose nephropathy progressed was significantly lower (36.3 ± 3.9) than in the 10 patients who showed no progression (52.6±1.9). However, these results do not support the supposition that good control and relative absence of glomerulosclerosis are associated only because the person with adult-onset diabetes, with less severe alteration of carbohydrate metabolism, also may have an independent genetic constitution which is less likely to lead to nephropathy. Two of the four persons with adult-onset diabetes with poor control in this study showed progression of their renal lesions. In another Japanese study,29 the progression of retinopathy was correlated with fasting blood glucose levels over six years in 356 diabetic patients (mostly maturity-onset). Good control was defined as at least 80 percent of the fasting glucose levels less than 140 mg per dl, poor control as more than 50 percent of the fasting glucose concentrations exceeding 170 mg per dl and fair control as lying in between. Retinopathy was graded at least once per year after bilateral dilation of the pupils and examination with magnifying lenses by an ophthalmologist who had no knowledge of the metabolic status of the patient. Two, four and six years after the study began, the percent of eyes in which new lesions appeared and old lesions progressed was lowest in the group with good control, midway in the patients with fair control and highest in those with poor control. Conversely, the percent of eyes in which old lesions improved was highest in the group with good control, intermediate in those with fair control and lowest in the group with poor control. The final prospective study to be considered comes from France.30 Fifty-two patients with the
DIABETES MELLITUS
TABLE 1.-Microaneurysms in Diabetic Patients Receiving Single or Multiple Injections of Insulin* Microaneurysms
(means±SEM)
Single
Injectiotn
Base line ........ 12.7±3.5 Last examination .. 33.0±7.9 Difference ........ 20.3 ±4.9 Increase/year . 7.2± 1.9
Multiple Injection
Pt
9.0±3.3 15.2±4.9 6.2±2.5 1.8±0.7
NS
