Original Article
Effect of Strict Glycemic Control on Renal Hemodynamic Response to Amino Acids and Renal Enlargement in Insulin-Dependent Diabetes Mellitus
N Engl J Med 1991; 324:1626-1632June 6, 1991
- Abstract
- Abstract
Background.
Many patients with insulin-dependent diabetes mellitus have an increase in the glomerular filtration rate and renal enlargement early in the course of their disease. Both these changes may be risk factors for the later development of diabetic nephropathy. Their cause is not known, but they could be due to augmented renal responses to the increase in plasma amino acid concentrations that occurs when dietary protein intake is high, a factor known to increase glomerular filtration and renal blood flow in normal subjects.
Methods.
We measured the glomerular filtration rate and renal plasma flow after an overnight fast and during an infusion of amino acids in 12 patients with insulin-dependent diabetes mellitus and 9 normal subjects. The diabetic patients were studied when they were hyperglycemic, when they were euglycemic after an insulin infusion for 36 hours, and after intensive insulin therapy for 3 weeks. Kidney volume was measured by ultrasonography before and after the period of intensive insulin therapy.
Results.
The glomerular filtration rate and renal plasma flow were normal after fasting when the patients were hyperglycemic (mean [±SE] fasting plasma glucose level, 11.5±0.7 mmol per liter). After the amino acid infusion, these values increased more in the patients (glomerular filtration rate, 2.65±0.07 ml per second per 1.73 m2 of body-surface area; renal plasma flow, 13.30±0.68 ml per second per 1.73 m2; P<0.05 for both) than in the normal subjects (2.25±0.08 and 11.20±0.65 ml per second per 1.73 m2, respectively). The 36-hour infusion of insulin in the diabetic patients did not alter the glomerular filtration rate or renal plasma flow either before or during the amino acid infusion. After three weeks of intensive insulin therapy (fasting plasma glucose level, 5.3±0.2 mmol per liter), the glomerular filtration rate and renal plasma flow after the amino acid infusion (2.33±0.03 and 11.30±0.43 ml per second per 1.73 m2, respectively) were similar to those in the normal subjects. The kidney volumes in the normal subjects and the patients with diabetes were 219±14 and 312±14 ml per 1.73 m2, respectively (P<0.01); the volume decreased to 267±22 ml per 1.73 m2 (P<0.001) in the diabetic patients after three weeks of intensive insulin therapy, which was not significantly different from the volume in the normal subjects (P=0.1).
Conclusions.
Conventionally treated diabetic patients who have normal renal function while fasting have augmented renal hemodynamic responses to increased plasma amino acid concentrations. The concomitant decrease in these hemodynamic responses and in kidney size with strict glycemic control suggests that these phenomena are related and influenced by the metabolic state. (N Engl J Med 1991;324:1626–32.)
Media in This Article
Figure 1
Mean (±SE) 24-Hour Plasma Glucose Profiles for 12 Patients with Insulin-Dependent Diabetes Mellitus.Figure 2
Mean (±SE) Glomerular Filtration Rate in 9 Normal Subjects (Solid Circles) and 12 Patients with Insulin-Dependent Diabetes Mellitus (Open Circles).Article Activity
- Article
DIABETIC nephropathy occurs in up to half of patients with insulin-dependent diabetes mellitus, and it is the most common cause of endstage renal disease in the United States.1 , 2 However, many patients have increased glomerular filtration and renal enlargement early in the course of their illness.3 4 5 6 The increase in glomerular filtration has been considered a precursor of diabetic nephropathy,7 8 9 but its cause or causes are unknown. Highprotein diets raise the glomerular filtration rate and renal plasma flow10 11 12 and exacerbate glomerular hypertension and injury in animal models of diabetes and other renal diseases.8 , 13 , 14 Conversely, low-protein diets ameliorate the disturbances of renal hemodynamics in these models and slow the progression of diabetic nephropathy in humans.15 16 17 18 Nevertheless, the renal response of patients with diabetes to amino acids has not been well studied. We hypothesized that an augmented renal hemodynamic response to amino acids could contribute to glomerular hyperfiltration in such patients.
The influence of strict glycemic control on glomerular hyperfiltration and renal enlargement is unclear. One study showed that patients with insulin-dependent diabetes mellitus who have glomerular hyperfiltration may have a decrease in the glomerular filtration rate after insulin-pump therapy, but since the measurements were done in the postprandial state,19 the decrease may have been due to a correction of abnormal responsiveness to components of the meal, such as amino acids. Renal enlargement, in particular glomerular enlargement, has been implicated as a cause of renal injury in diabetes.20 Hypertrophy and hyperfiltration are associated with each other,21 , 22 but a reduction in kidney size after improved glycemic control has not been demonstrated consistently in patients with diabetes.19 , 23
We examined the renal hemodynamic responses to a physiologic increase in plasma amino acid concentrations in patients with insulin-dependent diabetes mellitus receiving conventional treatment before and after 36 hours and 3 weeks of strict glyc=emic control. We also measured kidney volume at the same times.
Methods
Subjects
We studied 12 patients (7 women and 5 men) with insulin-dependent diabetes mellitus who had received conventional insulin therapy (i.e., intermediate-acting and regular insulin given subcutaneously twice daily). The patients were recruited from the clinics of the University of Texas Health Science Center at San Antonio. All had sustained, moderate hyperglycemia and normal blood pressure, without clinically evident renal disease. Their fasting plasma glucose concentrations ranged between 9.0 and 14.0 mmol per liter. They had glycosylated-hemoglobin values in excess of 7 percent, blood pressure less than 140/90 mm Hg, negative urine dipstick tests for protein, and plasma creatinine concentrations of 115 mmol per liter or less on three consecutive occasions during the three months before the study. Their mean (±SD) age was 28±6 years, and they had had diabetes for an average of 6± 5 years. On the basis of a routine funduscopic examination, none had proliferative retinopathy or clinical evidence of autonomic neuropathy, and all had a stable body weight, which was 104±5 percent of the ideal body weight (on the basis of 1959 Metropolitan Life Insurance tables), for at least three months before the study. The patients' total daily insulin dose averaged 38± 10 units, and none were taking any other medication.
We also studied nine normal subjects (four women and five men) who were matched for age (mean, 29±4 years) and weight to the group with insulin-dependent diabetes mellitus. Their mean body weight, which had been stable for at least three months before the study, was 102 ±3 percent of the ideal body weight.
Study Protocol
All the subjects were studied at the Frederic C. Bartter Clinical Research Center of the Audie L. Murphy Memorial Veterans Affairs Hospital. Written informed consent was obtained from each participant before the study. The study protocol was approved by the institutional review board of the University of Texas Health Science Center at San Antonio.
The patients with diabetes were admitted to the clinical research center on the evening before the first study day. They continued to take their usual insulin doses on the next day (day 1), during which their plasma glucose concentrations were measured before meals (at 7 a.m., 11 a.m., and 5 p.m.), two hours after meals (at 9 a.m., 1 p.m., and 7 p.m.), at bedtime (11 p.m.), and at 3 a.m. A 24-hour urine sample was collected for the determination of albumin, urea nitrogen, and sodium levels (for the estimation of dietary intake of protein and sodium). A blood sample was also obtained for the measurement of glycosylated hemoglobin. Body weight was measured on day 1 and daily thereafter.
The first renal hemodynamic study was done on day 2 at 7 a.m. after a 12-hour overnight fast. The glomerular filtration rate and renal plasma flow were determined by measurement of inulin and paraaminohippurate clearance. The subjects were given intravenous loading doses followed by a continuous infusion of inulin (Isotex, Friendswood, Tex.) and paraaminohippurate (Merck Sharp & Dohme, West Point, Pa.). At the start of the infusion, they were given an oral water load (10 ml per kilogram of body weight). After a 1-hour equilibration period, urine and plasma were collected every 30 minutes for determinations of inulin and paraaminohippurate. The urine volume was quantitatively replaced with water to maintain a urine flow rate of 7 to 10 ml per minute.
After a two-hour base-line period, a balanced solution of amino acids (10 percent Travasol, Travenol Laboratories, Deerfield, Ill.) was infused at a rate of 0.043 ml per kilogram per minute for three hours. The amino acid composition of this solution (expressed in millimoles per liter) was as follows: leucine, 55.6; isoleucine, 45.7; lysine, 39.7; valine, 49.5; phenylalanine, 33.9; histidine, 30.9; threonine, 35.3; methionine, 26.8; tryptophan, 8.8; alanine, 232.3; arginine, 66.0; glycine, 137.2; proline, 59.1; serine, 47.6; and tyrosine, 2.2. The plasma glucose concentration was maintained ("clamped") at the fasting level (Table 1Table 1
Mean ±SE Plasma Concentrations of Metabolites and Hormones before and after an Amino Acid Infusion in Normal Subjects and Patients with Insulin-Dependent Diabetes Mellitus, before and after 36 Hours and 3 Weeks of Strict Glycemic Control.) by means of a variable infusion of insulin that ranged from 0.05 to 0.10 mU per kilogram per minute basally to 0.15 to 0.20 mU per kilogram per minute during the infusion of amino acids. Plasma glucose concentrations were measured every 10 minutes throughout the 6-hour study. Plasma samples for determinations of insulin, glucagon, and amino acid concentrations and renin activity were collected 60 and 30 minutes before the start of the amino acid infusion and 150 and 180 minutes thereafter. Blood pressure was measured every 30 minutes throughout the study.After the clearance study was completed, the intravenous insulin infusion was resumed at 6 p.m. on day 2. The rate was adjusted (to 0.20 to 0.25 mU per kilogram per minute) to maintain fasting and preprandial plasma glucose values at 6 mmol per liter or less and two-hour postprandial values at 9 mmol per liter or less. The infusion was continued throughout day 3, for a total duration of approximately 36 hours. The 24-hour profile of plasma glucose was measured on day 3, and a 24-hour urine sample was collected. The renal hemodynamic study was repeated on day 4 exactly as on day 2, except that the plasma glucose level was clamped at the fasting euglycemic level (Table 1) by means of a variable insulin infusion that ranged from 0.20 to 0.25 mU per kilogram per minute basally to 0.40 to 0.45 mU per kilogram per minute during the infusion of amino acids.
At discharge the patients were placed on a regimen of intensive insulin therapy consisting of subcutaneous extended insulin zinc suspension (Ultralente) that was given twice daily to maintain basal insulinization, as well as regular insulin administered before each meal, the dose being determined on the basis of frequent blood glucose measurements. All patients measured their blood glucose concentrations with a blood glucose meter four to six times daily. The mean (±SD) total daily dose of insulin during this period was 48±13 units, 28±7 units being given as Ultralente insulin and 19±5 units as regular insulin. The patients were instructed to consume a weight-maintaining diet with a caloric distribution of 55 percent carbohydrate, 25 percent fat, and 20 percent protein. Specifically, they were counseled to maintain their protein intake at 1 to 1.5 g per kilogram per day. After three weeks of strict glycemic control, the patients were readmitted to the clinical research center, where they underwent the same studies as during the first hospitalization, while continuing to receive intensive insulin treatment. During the renal hemodynamic study, the plasma glucose concentration was clamped at the fasting euglycemic level (Table 1) by a variable insulin infusion that ranged from 0.20 to 0.25 mU per kilogram per minute basally to 0.40 to 0.45 mU per kilogram per minute during the infusion of amino acids.
The normal subjects were admitted to the clinical research center at 6:30 a.m. after a 12-hour overnight fast. The renal hemodynamic study in these subjects was performed exactly as described above, except that no insulin was infused. A 24-hour urine sample was collected on the day before the hemodynamic study for the measurement of urea nitrogen and sodium levels.
Measurements of Kidney Volume
Kidney volume was measured on day 1 of each admission in the patients with diabetes and on the same day as the renal hemodynamic study in the normal subjects. Kidney volume was determined from ultrasonographic images acquired with real-time interactive viewing to assist in the appropriate positioning of the transducers. Longitudinal images were acquired in the coronal and sagittal planes. The coronal and sagittal outlines were traced and digitized for computer processing. The processing included alignment of the long axes of the two outlines and automatic determination of length and the maximal coronal and sagittal dimensions. Assuming an ellipsoidal shape to the kidney, we calculated the volume from these three measurements. Our method of calculation was similar to that reported previously by Jones et al.,24 except for the automated method of determining the kidney dimensions from the kidney outline. In order to assess reproducibility, four patients with diabetes underwent renal ultrasonography on two separate occasions within the month before the intensive insulin therapy began, and in one normal subject renal size was measured 11 times on the same day. The mean coefficient of variation between measurements in the diabetic patients was 5.5 percent, and the coefficient of variation between the measurements made on the same day in the normal subject was 6.3 percent. Kidney volume was expressed as the total volume of both kidneys corrected for deviations from the average adult body-surface area of 1.73 m2. The ultrasonographic studies were technically acceptable in 11 patients with diabetes and 8 normal subjects.
Laboratory Analysis
Plasma glucose was measured by the glucose oxidase method with a Beckman II Glucose Analyzer (Beckman Instruments, Fullerton, Calif.). Urinary urea nitrogen levels were determined with a Technicon SMAII AutoAnalyzer (Technicon, Tarrytown, N.Y.). Urinary sodium was measured by flame photometry (Model Klina, Beckman). Glycosylated hemoglobin was measured by the Bio-Rad Hemoglobin A1c Column Test (Bio-Rad Laboratories, Hercules, Calif.). Inulin and paraaminohippurate levels in plasma and urine were determined by standard colorimetric assays.25 , 26 Plasma levels of free insulin27 and glucagon and urinary concentrations of albumin were measured by radioimmunoassay with commercially available kits (Diagnostic Products, Los Angeles). Plasma renin activity was determined by measuring the generation of angiotensin I with a commercially available radioimmunoassay kit (New England Nuclear, Boston). Amino acids were measured with a Beckman amino acid analyzer and cation-exchange chromatography.
Statistical Analysis
Inulin and paraaminohippurate clearances were calculated with standard formulas and corrected to a body-surface area of 1.73 m2. The base-line values for glomerular filtration rate, renal plasma flow, and plasma concentrations of hormones (insulin, glucagon, and renin activity) and metabolites (glucose and amino acids) were taken as the mean of the measurements during the period before the amino acid infusions. The peak values for glomerular filtration rate and renal plasma flow were the results from the last period of clearance during the amino acid infusions. The amino acid—stimulated values for plasma concentrations of hormones and metabolites were taken as the average of two determinations during the last hour of the amino acid infusions. Dietary protein intake was estimated on the basis of the 24-hour urinary urea nitrogen excretion, as follows: protein intake = (urinary urea nitrogen + nonurea nitrogen) × 6.25. We used a value for nonurea nitrogen excretion of 0.031 g of nitrogen per kilogram per day, assuming the subjects were in nitrogen balance.28
Analysis of variance with repeated measures was used to compare the results of the three studies in the diabetic patients and assess changes during an individual study. Results for the patients with diabetes and for the normal subjects were compared by an unpaired t-test. The paired t-test was used to assess the responses before and after intensive insulin therapy in the diabetic patients. The results are expressed as means ±SE. The level of statistical significance was defined as P<0.05. All statistical tests were two-tailed.
Results
Glycemic Control
The initial fasting and mean 24-hour plasma glucose concentrations in the patients with diabetes were 11.5±0.7 and 12.2±0.8 mmol per liter, respectively. After 36 hours and 3 weeks of strict glycemic control, the mean fasting plasma glucose concentrations were 5.5±0.2 and 5.3±0.2 mmol per liter, respectively, whereas the 24-hour mean values were 6.7±0.3 and 6.8±0.3 mmol per liter (Fig. 1Figure 1
Mean (±SE) 24-Hour Plasma Glucose Profiles for 12 Patients with Insulin-Dependent Diabetes Mellitus.). The mean glycosylated-hemoglobin value declined from 8.4±0.4 percent to 6.9±0.4 percent (P<0.001) after three weeks of strict glycemic control.Dietary Protein and Sodium Intake
The estimated protein intake in the diabetic patients before the period of strict glycemic control (1.35±0.11 g per kilogram per day) was similar to that in the normal subjects (1.35±0.12 g per kilogram per day), and it did not change substantially after 36 hours (1.14±0.13 g per kilogram per day) or 3 weeks (1.15±0.08 g per kilogram per day) of strict glycemic control. The 24-hour urinary excretion of sodium was similar in the normal subjects (187± 15 mmol per day) and the diabetic patients when they were hyperglycemic (194±26 mmol per day). The patients' urinary sodium excretion was 172 ±22 mmol per day after 36 hours and 156 ± 21 mmol per day after 3 weeks of strict glycemic control. The mean body weight of the normal subjects was 66.7±3.3 kg, and it was initially 66.3±3.5 kg in the diabetic patients. After 36 hours and 3 weeks of strict glycemic control, the respective values in the diabetic patients were 66.7±3.4 and 66.8±3.2 kg.
Rate of Excretion of Urinary Albumin
The urinary albumin excretion rate was less than 20 μg per minute in 11 of the diabetic patients, but it was increased in 1 diabetic patient on the three occasions when it was measured (111, 32, and 105 μg per minute). The other results in this patient were similar to those in the other diabetic patients. When this patient was excluded from analysis, the mean albumin excretion was 8 ± 1, 7 ± 1, and 9 ± 2 μg per minute before and after 36 hours and 3 weeks of strict glycemic control, respectively.
Plasma Concentrations of Metabolites and Hormones
At the start of the study, the mean plasma concentrations of total, branched-chain, and individual amino acids were similar in the patients with diabetes and the normal subjects (Table 1). The concentrations did not change after the period of strict glycemic control, except for a slight decrease in the concentrations of branched-chain amino acids during the base-line period after the 36-hour insulin infusion.
The initial base-line plasma concentration of free insulin in the diabetic patients was similar to that in the normal subjects. During the infusion of amino acids, the plasma insulin concentrations approximately doubled in both the normal subjects and the diabetic patients, and in the diabetic patients the rate of insulin infusion had to be increased to maintain constant hyperglycemia. In order to achieve euglycemia, the total daily insulin dose was subsequently increased, so that the base-line plasma concentrations of free insulin in these patients were higher after 36 hours and 3 weeks of strict glycemic control. When amino acids were infused while the patients were euglycemic, the insulin-infusion rate again had to be approximately doubled to maintain euglycemia.
Both the base-line and the amino acid—stimulated plasma glucagon concentrations were similar in the normal subjects and the diabetic patients under all study conditions.
Studies of Renal Hemodynamics
In the hyperglycemic state, the base-line glomerular filtration rate in the diabetic patients (1.72±0.03 ml per second per 1.73 m2) was similar to that in the normal subjects (1.70±0.05 ml per second per 1.73 m2) (Fig. 2Figure 2
Mean (±SE) Glomerular Filtration Rate in 9 Normal Subjects (Solid Circles) and 12 Patients with Insulin-Dependent Diabetes Mellitus (Open Circles).). The values in the diabetic patients were similar after 36 hours (1.70±0.03 ml per second per 1.73 m2) and 3 weeks (1.68±0.3 ml per second per 1.73 m2) of strict glycemic control. During the amino acid infusions, however, the peak glomerular filtration rate (2.65±0.07 ml per second per 1.73 m2) in the diabetic patients when they had hyperglycemia was higher than that in the normal subjects (2.25±0.08 ml per second per 1.73 m2; P<0.05). After 36 hours of insulin infusion, the peak glomerular filtration rate in the patients (2.60±0.07 ml per second per 1.73 m2) during the amino acid infusion was similar to that when they were hyperglycemic. Intensive insulin therapy for three weeks reduced the peak glomerular filtration rate during the amino acid infusion (2.33±0.03 ml per second per 1.73 m2; P<0.05); at this time, the response was not different from that in the normal subjects.The changes in renal plasma flow paralleled those of the glomerular filtration rate in both the normal subjects and the diabetic patients. The base-line value (9.30±0.53 ml per second per 1.73 m2) in the diabetic patients when they were hyperglycemic was similar to that in the normal subjects (8.57±0.77 ml per second per 1.73 m2), and the values in the patients were similar after 36 hours (9.32±0.38 ml per second per 1.73 m2) and 3 weeks (9.17±0.33 ml per second per 1.73 m2) of strict glycemic control. The amino acid—stimulated peak value for renal plasma flow (13.30±0.68 ml per second per 1.73 m2) was higher in the diabetic patients when they were hyperglycemic than in the normal subjects (11.20±0.65 ml per second per 1.73 m2; P<0.05). The peak value for renal plasma flow was not altered by the 36-hour insulin infusion (13.17±0.58 ml per second per 1.73 m2), but after 3 weeks of strict glycemic control it changed to a value similar to that in the normal subjects (11.30± 0.43 ml per second per 1.73 m2; P<0.05).
The blood pressure in all subjects remained constant during the studies. In the hyperglycemic state, the patients with diabetes had a baseline blood pressure of 116±4/74±2 mm Hg, and the blood pressure was 117±4/70±3 mm Hg during the infusion of amino acids. In the normal subjects, the respective blood-pressure values were 118±4/ 72±3 and 116±4/74±3 mm Hg. The results in the diabetic patients were similar during the subsequent studies.
Kidney Volume
The mean initial kidney volume was 312±14 ml per 1.73 m2 in the diabetic patients and 219±14 ml per 1.73 m2 in the normal subjects (P<0.01) (Fig. 3Figure 3
Kidney Volume in 8 Normal Subjects (Solid Circles) and 11 Patients with Insulin-Dependent Diabetes Mellitus before (Open Triangles) and after (Solid Triangles) Three Weeks of Intensive Insulin Therapy.). After three weeks of intensive insulin therapy, the mean kidney volume in the patients with diabetes declined to 267±22 ml per 1.73 m2 (P<0.001 for the comparison with the initial value), a reduction of 16±3 percent. Although the mean value in the diabetic patients was no longer significantly different after three weeks of intensive insulin therapy from that in the normal subjects (P = 0.111), the kidneys in three of the diabetic patients were larger at this time than in any normal subject.Discussion
This study demonstrates that the renal hemodynamic response to a physiologic increase in plasma amino acid concentrations is augmented in diabetic patients with enlarged kidneys who receive conventional insulin therapy, despite normal base-line values for the glomerular filtration rate and renal plasma flow. Although these results may seem to be at variance with previous reports of increased glomerular filtration in such patients,3 4 5 6 , 19 in those studies dietary protein intake was not controlled, and the measurements of renal function were not always performed in the postabsorptive state. Indeed, Viberti and Walker recently reported that 25 percent or less of patients with diabetes have an increase in the basal glomerular filtration rate.29 Thus, the increased rates previously reported could reflect the short-term effect of meals recently consumed, long-term excess intake of dietary protein, or both. This is particularly likely because patients with diabetes often eat high-protein diets due to the hyperphagia associated with poor glycemic control or to fat and carbohydrate restriction. Although our diabetic patients with moderate hyperglycemia had a relatively normal protein intake, both their protein consumption and their basal glomerular filtration rates declined slightly during the period of strict glycemic control. Our results complement those of Kupin et al.,30 who found that the basal glomerular filtration rate increased from 1.88 to 2.38 ml per second per 1.73 m2 when dietary protein intake was raised from 1.5 to 3.5 g per kilogram per day in conventionally treated diabetic patients. Moreover, since their measurements were made after a 12-hour fast, the true change in renal function was probably greater. These observations indicate that postabsorptive measurements of renal function may underestimate the contribution of hemodynamic disturbances to renal injury.
Renal hemodynamic responses to protein feeding or amino acid infusion have been reported to be normal31 or blunted 32 , 33 in patients with diabetes. These studies, however, included patients with overt nephropathy,32 those with a long history of diabetes (mean, > 10 years),31 , 33 older patients (mean, >40 years),32 , 33 or a mixed group of insulin-dependent and non-insulin-dependent patients32 — characteristics that could attenuate the renal vasodilative and hyperfiltration response. Furthermore, since plasma concentrations of amino acids were not measured after the protein meals, it is possible that the stimulus was not equivalent in all patients, because of variability in gastrointestinal absorption.
How amino acids influence kidney function is unknown, but they could act directly or through a number of mediators. Castellino et al. found that the renal hemodynamic response to amino acids in normal subjects was inhibited by somatostatin.34 Although the augmented response to amino acids was not associated with an excessive rise in plasma glucagon levels in our patients with diabetes, it could still mediate the renal response. Parving et al. reported that similar increments in plasma glucagon nearly doubled the glomerular filtration rate in diabetic patients as compared with normal subjects,35 suggesting increased renal sensitivity to glucagon in diabetes. In addition, Slomowitz et al. found that the renal hemodynamic response to arginine was greatly exaggerated during treatment with captopril in diabetic patients but not in normal subjects.36 Thus, an inhibition of production of the vasoconstrictor angiotensin II or an increase in intrarenal levels of vasodilators — bradykinin, prostaglandins, or both — could potentiate the renal hemodynamic response to amino acids.
The augmented renal hemodynamic response was corrected by 3 weeks, but not 36 hours, of strict glycemic control. Therefore, chronic hyperglycemia, chronic insulin deficiency, or other associated metabolic disturbances lead to alterations in renal function that require sustained metabolic improvement for normalization. The minimal time needed to reverse the augmented renal hemodynamic response is unknown, but the study of Wiseman et al. was consistent with our findings; in their patients with diabetes, hyperfiltration decreased within three months of the institution of insulin-pump therapy.19
The mechanism responsible for the decrease in the augmented renal hemodynamic response that occurred during intensive insulin therapy cannot be determined from our data, but it is noteworthy that kidney size decreased substantially after three weeks of such therapy. This suggests that renal hypertrophy could be a permissive factor, perhaps providing an enlarged filtration surface or altering tubuloglomerular feedback because of tubular hypertrophy. It is reasonable to suggest that the renal vasodilative and hyperfiltration response to amino acids could be augmented once these changes have developed. Even though kidney size decreased, however, the kidneys remained enlarged in three patients with diabetes who had normal renal hemodynamics. Although we and others37 have suggested that hypertrophy may permit the expression of the hemodynamic disturbances, it cannot be the sole determinant of function.
Many studies in diabetic animals and humans have demonstrated a regression of renal enlargement and an improvement in histologic lesions after the normalization of the metabolic milieu by pancreatic transplantation,38 , 39 continuous subcutaneous insulin infusion,40 multiple insulin injections,41 or the transplantation of kidneys from diabetic to nondiabetic hosts.42 , 43 The results of serial ultrasonographic measurements of kidney size are conflicting. Wiseman et al. detected no change in kidney size in patients with long-standing diabetes who received insulinpump therapy for one year,19 but Feldt-Rasmussen et al. found a uniform regression of renal hypertrophy in similarly treated diabetic patients with microalbuminuria (a marker of early nephropathy).23 We believe that the available data, taken as a whole, indicate that renal enlargement can regress despite established diabetes and early evidence of nephropathy.
Since the augmented renal hemodynamic response to a physiologic rise in plasma amino acid concentrations is potentially deleterious, it may be prudent to avoid high-protein diets in diabetic patients receiving conventional insulin therapy. Most important, we have shown that both abnormal renal function and renal enlargement can regress after a period of strict glycemic control in patients with established diabetes.
Supported by a grant (88G–370) from the Texas affiliate of the American Heart Association and a grant (MO1–RRO1346) from the General Clinical Research Center Branch of the National Institutes of Health.
We are indebted to the nursing staff, dietitians, and laboratory technicians of the Frederic C. Bartter Clinical Research Center for their expert assistance; to Mr. Michael Luther of the research service at Audie L. Murphy Memorial Veterans Affairs Hospital for assistance with the statistical analyses; to Ms. Deborah Phillips-Windsor and Mr. Norbert Isaac for technical assistance; to Ms. Diana Metz and Ms. Molli Fleming for expert assistance in the preparation of the manuscript; to Robert T. Kunau, M.D., for valuable assistance in planning these studies; and to Meyer D. Lifschitz, M.D., and Jay H. Stein, M.D., for their constructive critiques of the manuscript.
Source Information
From the Division of Nephrology, Department of Medicine (K.R.T., J.L.B., R.A.D.), the Department of Radiology (M.C.P., J.L.L., D.T.K.), and the Division of Diabetes, Department of Medicine (R.A.D.), University of Texas Health Science Center at San Antonio. Address reprint requests to Dr. Tuttle at the Division of Nephrology, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78284–7882.
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