Microalbuminuria in type 2 diabetic patients: a cross-sectional study of frequency, sex distribution and relation to hypertension

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1 Original Article Ann Clin Biochem 1994; 31: Microalbuminuria in type 2 diabetic patients: a cross-sectional study of frequency, sex distribution and relation to hypertension Thorkild Friis, Laurids R Pedersen, Susanne Arnold-Larsen and Dorthe B Nielsen From the Endocrinologic Department E and the Department of Clinical Chemistry, Frederiksberg Hospital, Copenhagen, Denmark SUMMARY. We studied 112 type 2 diabetic patients. Fourteen patients had frank proteinuria, and 37 of the remaining 98 had microalbuminuria which was more frequent in men than in women (P<0 02). Hypertension was found in 47 of the patients, equally distributed between sexes. Male diabetics with microalbuminuria had higher systolic blood pressure than diabetics without microalbuminuria (P< O' 02). Body mass index was higher in both sexes with hypertension compared to patients without hypertension. In the hypertensive men plasma C-peptide values were higher compared to patients without hypertension (P<O'OI) irrespective of the presence of microalbuminuria. A positive correlation between blood pressure and C-peptide was found (P<O'OI) in the men. We suggest that gender should be taken into account in the analysis and interpretation of microalbuminuria in type 2 diabetes. Additional key phrases: insulin C-peptide; body mass index; proteinuria Several authors have studied microalbuminuria in type 2 (non-insulin-dependent) diabetic patients. Microalbuminuria predicts clinical proteinuria and increased mortality':" and also predicts increased morbidity, especially hypertension and cardiovascular disease. 1,s - 8 The reported frequency of microalbuminuria in type 2 diabetes is approximately /0, but Schnack? found a prevalence of 59%. Prevalence of micro albuminuria has been reported to be higher in men than in women.' We studied the frequency of microalbuminuria in type 2 diabetic patients from a diabetic out-patient clinic with reference to sex distribution and relation to established complications. PATIENTS AND METHODS One hundred and twelve consecutive type 2 diabetic patients attending the outpatient clinic of Frederiksberg Hospital (Copenhagen, Denmark) Correspondence: Dr T Friis. were studied, None had urinary tract infections. The patients were referred by their general practitioners mainly because of problems with control of blood glucose and body weight. None was referred because of microalbuminuria, which was not measured by the general practitioner. Fourteen patients (nine men and five women) had frank proteinuria (N-Labstix, Ames Division, Miles Laboratories, Elkhart, IN, USA) and were excluded from the study because it was not our intent to investigate people with established renal disease. Forty-nine men and 49 women (age range years) participated in the study. About 50% received oral antidiabetic treatment, 25% were treated by diet alone and 25% received insulin treatment. We defined type 2 diabetes as diabetic patients who did not receive insulin treatment or, if insulin was given, the age of onset of diabetes was more than 40 years. We performed a C peptide test in all patients. A C-peptide value > 0 6 nmol/l in blood taken 6 min after intravenous injection of I mg glucagon is 160

2 Microalbuminuria in type 2 diabetic patients 161 indicative of type 2 diabetes mellitus in about of cases. IO, l1 Overnight urinary albumin excretion rates were determined by immunoturbidimetry on a Cobas Bio centrifugal analyzer (Roche Products, Basle, Switzerland). Rabbit antibody (DAKO, Copenhagen, Denmark) was diluted twofold with phosphate buffer (0'06 mol/l, ph = 7 4) containing 40 gil polyethylene glycol Forty microlitres of urine was mixed with 225 J.LL phosphate buffer and 25J.LL diluted antibody. The change in absorbance at 340 nm was related to the concentration of albumin. The detection limit was 1 mg/l and the coefficient of variation (CV) was less than 4% at an albumin concentration of 5 mg/l. Albumin excretion rate (AER) was calculated from the albumin concentration, urine volume and the collection time. Values higher than 20 J.Lg/min in two successive samples were considered as pathological. 12 In 40 normal subjects; AER was found to be below 8 J.Lg/min. Other parameters measured were fasting blood glucose," glycated haemoglobin 14 and serum creatinine. IS The clinical examination included ophthalmoscopy by an ophthalmologist, 12 lead electrocardiograph, recording of body mass index (kg/rn-) and determination of arterial systolic and diastolic blood pressure with a standard clinical sphygmomanometer after 10 min of rest in the sitting position (cuff size 12x 35 em) in both arms. Ifthe circumferences of the upper arms were more than 35 em a 15x 43 em cuff was used. Hypertension was defined as a systolic pressure of 160 mmhg or more, a diastolic pressure of 95 mmhg or more, or treatment for hypertension and a current history ofhypertension. A total of 36 patients had received antihypertensive treatment with diuretics and/or {j-blocking drugs/calcium antagonists. In these patients antihypertensive therapy was stopped 1 week before measurement of the blood pressure. Systolic blood pressure was determined when Korotkoff sound phase 1 was observed, diastolic pressure when Korotkoff sound V was observed. STATISTICS Comparison of two independent continuous sample distributions was done by the Mann Whitney non-parametric test for unpaired data. A two-sided P-value <0-05 was regarded as statistically significant. The correlation coefficient used was Spearman's rank correlation coefficient. A x 2 test with Yates' correction was used for statistical analysis of 2 x 2 contingency tables. The analytical results are given as median and range. RESULTS Ninety-eight type 2 diabetic patients (49 men and 49 women) without proteinuria were analysed. Age, body mass index, blood pressure, and medical treatment are shown in Table 1. No differences in age, body mass index, blood pressure or medical treatment were found between the sexes. Table 2 shows the incidence of complications in patients with and without microalbuminuria. We found a higher prevalence of microalbuminuria among the men (P<0-02). Thirty-seven of the patients had microalbuminuria, of whom 25 were men. There was no difference in age or duration of diabetes between the micro albuminuric and non-microalbuminuric groups. Systolic blood pressure was higher in men with microalbuminuria compared to men without microalbuminuria (P< 0-02). Body mass index (BMI), C-peptide values, serum creatinine, blood glucose, HbA l c and albumin excretion rate are shown in Table 3, where the patients are further divided into hypertensive and non-hypertensive groups. Both men and women with hypertension had higher body mass index (P<0'05) than those without TABLE I. Characteristicsof98 type 2 diabetic patients without proteinuria (median, range in parentheses) Women Men n=49 n=49 Age (years) (40-86) (33-86) BMI (kg/m") (19,7-42'6) (15'0-49'4) Systolic BP (mmhg) ( ) ( ) Diastolic BP (mmhg) (60-130) (65-120) Medical treatment (No. of patients) insulin OAA AH BMI = Body mass index; BP = blood pressure; OAA = oral antidiabetic agents; AH = antihypertensive treatment

3 162 Friis et al. Distribution ofage, duration ofdiabetes and blood pressure (systolic and diastolic) TABLE 2. in type 2 diabetics with and without microalbuminuria (median, range in parentheses) Duration Systolic Diastolic Age (years) (years) (mm Hg) (mmhg) With microalbuminuria (n = 37) Men (n=25) (37-86) (0-22) ( ) (70-120) Women (n = 12) 70'5 6' (40-78) (0-16) ( ) (70-110) Without microalbuminuria (n = 61) Men (n = 24) 62' '5 (33-76) (0-30) ( ) (65-120) Women (n = 37) (46-86) (0-23) ( ) (60-130) P<0 05 versus results for patients without microalbuminuria. hypertension. The C-peptide concentration was higher in men with hypertension than in men without hypertension (P<O OI). A positive correlation (P<O OI) was found between blood pressure and C-peptide concentration. but only for the men. Two men had 6 min post-glucagon C-peptide values below O' 6 nmol/l (0'40 and 0.46 nmoill). The age ofonset of diabetes in these patients was 51 and 58years. The albumin excretion rate was higher in men with hypertension compared to men without hypertension (P<0 02). This difference was not seen in the women. There were no significant differences between the values ofserum creatinine. blood glucose and HbA 1c ' Table 4 shows the prevalence of complications in the patients with and without rnicroalbuminuria. Forty-seven patients had hypertension, 29 coronary heart disease, 28 diabetic retinopathy, 19 diabetic neuropathy and 11 peripheral vascular disease. No significant differences in prevalence of complications could be shown. DISCUSSION The prevalence of micro albuminuria in type 2 diabetic patients from our outpatient clinic is rather high (380/0) compared to the findings of Mattock et ai. (26%),4 Kikhava et ai. (21%),6 Torffvitt et al. (20%),7 Gall et al. (26-29%).8 However, no patient was referred to us because of microalbuminuria. Our finding that men had microalbuminuria more often than women agrees with the report of Mattock et al.,s who found a similar male dominance. This is not in agreement with the experience of Gall et al., 8 who reported a higher frequency of macroalbuminuria in men, but not microalbuminuria. However, Damsgaard et al." found a male dominance of microalbuminuria in older patients with fasting hyperglycaemia without earlier known diabetes (42' 9% against 13'0%). Given the known preponderance of men compared to women diabetics with nephropathy,"!" and since microalbuminuria is predictive of future clinical proteinuria in type 2 diabetic patients," a sex difference in microalbuminuria is not unexpected although it is unexplained. This finding suggests that gender should be taken in account in the analysis and interpretation of microalbuminuria in type 2 diabetic patients. The observation that systolic blood pressure is higher in patients with microalbuminuria is in accordance with several other studies,3,6-8,18 but it has not been reported before that the male sex dominance is so pronounced. No relation between microalbuminuria and coronary heart disease could be found in our study. Others have the same experiencet-'? in contrast to several other authors.l-v' Some investigations suggest that diabetic retinopathy is correlated to microalbuminuria.3,6-8,2o We were not able to confirm this finding. The significant increase in body mass index in both sexes with hypertension agrees with clinical experience. It is remarkable that only the men had increased C-peptide concentration both in the

4 TABLE 3. Body mass index (BMI), plasma Cspeptide and creatinine concentrations, blood glucose and HbA/ c and urinary excretion rate in type 2 diabetic patients with and without microalbuminuria or hypertension (median, range in parentheses) Venous C-peptide (nmol/l) Plasma creatinine Blood glucose HbA 1c BMl (kg/m 2 ) Fasting 6 min (}.mol/l) (mmol/l) (010 total Hb) AER (}.g/min) With microaibuminuria (n =37) Men (n=25) (20' 3-36' 7) ( ) (0'4-5 '2) (57-138) (5'3-17'1) (5'4-13' 5) (21-164) Women (n = 12) (23' 2-39' 6) (0'05-1'4) (0'67-2'5) (59-110) (5'4-14'1) (5'9-12'9) (22-89) Without microalbuminuria (n =61) Men (n=24) ' ( '4) (0'3-1 5) 0'46-2'8) (71-127) ( ) (4 3-15'1) (1-19) Women (n=37) 26' II !:i (19'7-42'6) (0'41-2'3) ( ) (55-110) (5' 3-24'1) (4'4-14'7) (1-18) c I:l With hypertension (n =47) Men (n=24) S s (22'1-49'4) ( ) (0'61-5 '2) (67-130) (5 3-17'1) (5'4-1I '2) (5-135).., l::: Women (n =23) ' II (22' ) (0'59-1'5) (0'92-2'6) (59-1I0) (6'1-21 2) (4'4-14'7) (2-63) 'ti Without hypertension (n =51) Men (n=25) ' ' (15'0-31-3) (0'2-1'3) ( ) (57-138) (5'3-16,8) (4'3-15'1) (1-164) '" ),. c:::j< Women (n=26) 25' ;:;. Q " (19'7-42'6) (0 05-2' 3) (0'67-5 '0) (55-107) (5' 3-24'1) (5'9-13'4) (1-89) s I:l P<0 05 versus results for patients without hypertension. o' iii' AER =Albumin excretion rate. :::s ;;;-.ṡ 01 too = l::: i:;' S - - -

5 164 Friis et a/. TABLE 4. Prevalence of complications in type 2 diabetic patients with and without microalbuminuria (numbers ofpatients) H IHD DR DN PVD With m/alb Men (n=25) Women (n = 12) Total (n = 37) Without m/alb Men (n = 24) Women (n = 37) Total (n = 61) m/alb = Microalbuminuria; H = hypertension; IHD = ischaeic hart disease; DR = diabetic retinopathy; DN = diabetic neuropathy; PVD = peripheral vascular disease. fasting state and after glucagon stimulation as well as a significant positive correlation between blood pressure and C-peptide concentration. We cannot explain these findings in any other way than suggesting that gender plays a role in patients with type 2 diabetes. REFERENCES Jarrett RJ, Viberti CG, Argyropoulos A, Hill RD, Mahmud U, Murrells TJ. Microalbuminuria predicts mortality in non-insulin-dependent diabetes. Diabet Med 1984; 1: Mogensen CEo Microalbuminuria predicts clinical proteinuria and early mortality in maturity onset diabetes. N Engl J Med 1984; 310: Schmitz A, Vaeth M. Microalbuminuria: a major risk factor in non-insulin-dependent diabetes. A 10-year follow-up study of 503 patients. Diabet Med 1988' 5: ' 4 attock MB, Morrish NJ, Viberti GC, Keen H, Fitzgerald AP, Jackson G. Prospective study of microalbuminuria as predictor of mortality in NIDDM. Diabetes 1992; 41: Mattock MB, Keen H, Viberti GC, EI-Gohari MR, Murrells TJ, Scott GS, et al. Coronary heart disease and urinary albumin excretion rate in type 2 (noninsulin-dependent) diabetic patients. Diabetologia 1988; 31: Kikhava R, Haneda M, Togawa M, Koya D, Ebata K, Arimura T, et al. Microalbuminuria associated with a rise in blood pressure in non-insulin-dependent diabetes. J Diabet Comp11989; 3: Torffvit 0, Agardh E, Agardh CD. Albuminuria and sociated medical risk factors: a cross-sectional study III 451 type 2 (non-insulin-dependent) diabetic patients. J Diabet Compl 1991; 5: Gall MA, Rossing P, Vaag A, Bech K, Dejgaard A, Lauritzen M, et al. Prevalence of micro- and macroalbuminuria, arterial hypertension, retinopathy and large vessel disease in European type 2 (noninsulin-dependent) diabetic patients. Diabetologia 1991; 34: Schnack C, Scheithauer W, Gisinger C, Winkler J, Schernthauer G. Prevalence of microalbuminuria in maturity onset primarily non-insulin-requiring diabetes mellitus: effect ofdisease duration, glycemic control and mean systolic blood pressure. J Diabet Compl 1987; 1: Faber OK, Binder C. C-peptide response to glucagon: a test for the residual cell function in diabetes mellitus. Diabetes 1977; 26: Hother-Nielsen 0, Faber 0, Serensen NS Beck Nielsen H. Classification of newly diagnosed diabetic patients as insulin requiring or non-insulin-requiring based on clinical and biochemical variables. Diabet Care 1988; 11: Mogensen CE, Chachati A, Cristensen CK, Close CF, Deckert T, Hommel E, et al. Microalbuminuria: an early marker of renal involvement in diabetes. Uremia Invest 1986; 9: Banauch D, Brumer W, Ebeling W, Metz H, Rindfrey H, Lang H. Eine glucose-dehydrogenase fur die glucosebestimmung in korperflussigheiten. Z Klin Chem Klin Biochem 1975; 13: Svendsen PA, Christiansen JS, Soegaard U, Welinder BS, Nerup J. Rapid changes in chromatographically determined hemoglobin Ale induced by short-term changes in glucose concentration. Diabetologia 1980; 19: Technicon method No. SD FMG. Jaffe reaction in a SMA autoanalyzer. Tarrytown, NJ: Technicon Instruments Corporation, Darnsgaard EM, Mogensen CEo Microalbuminuria in elderly hyperglycaemic patients and controls. Diabet Med 1986; 3: Andersen AR, Christiansen JS, Andersen JK, Kreiner S. Diabetic nephropathy in type 1 diabetes: an epidemiological study. Diabetologia 1983; 25: Marshall SM, Alberti KGMM. Comparison of the prevalence and associated features of abnormal albumin excretion in insulin-dependent and noninsulin-dependent diabetes. Q J Med 1989; 261: Zanette G, Bonaa E, Donadon W, Muggeo M. Prevalence of proteinuria in type 2 diabetes mellitus and its relationships with other chronic vascular complications. European Association for the Study of Diabetes, 27th Annual Meeting, Dublin, September 1991 [Abstract 39]. Diabetologia 1991; 34 (suppl 2) 20 Cheta D, Stoica GH, Dumitrescu C Percium R Ionescu T, Cheta N, et al. Is microa'ibuminuria different problem for type 1 and type 2 diabetes mellitus? Med Int 1987; 25: Accepted for publication 23 September 1993