Anders Frøland

Microalbuminuria and Potential Confounders: A review and some observations on variability of urinary albumin excretion

U rinary albumin excretion rate (UAER) is the main parameter used in diabetic patients for the clinical evaluation of early renal disease (1-3); likewise, it is a key to other complications (3-5). The parameter is not only related to diagnosis, but it is also important to early intervention, e.g., optimized diabetes care (6), and more specifically, to early antihypertensive treatment (6-10). Several review articles summarize trials documenting that treatment with angiotensin-converting enzyme (ACE) inhibitors (and other antihypertensive agents) in microalbuminuric insulindependent diabetes mellitus (IDDM) and relatively young non-insulin-dependent diabetes mellitus (NIDDM) patients decreases albuminuria and is likely to postpone the decline in glomerular nitration rate (7-9). Optimal diabetic control may be difficult to achieve in some patients with microalbuminuria (11), and the trials in the microalbuminuric patients with this treatment modality do not provide totally coherent results (11-13). However, new data on the microalbuminuric patients in the Diabetes Control and Complications Trial (DCCT) documented a positive effect of intensified treatment (12), but good metabolic control may be problematic in some of these patients, who generally have higher HbAlc values compared with matched normoalbuminuric patients (14). With respect to primary prevention of mi-

Correlations Between Fasting Plasma C-Peptide, Glucagon-Stimulated Plasma C-Peptide, and Urinary C-Peptide in Insulin-Treated Diabetics

This study correlated fasting plasma C-peptide (CP), plasma CP 6 min after stimulation with 1 mg glucagon i.v., and the mean of three 24-h urinary excretions of C-peptide (UCP)/creatinine in 132 insulin-treated diabetics. Patients were divided into three groups: group 1, stimulated CP < 0.06 nM (n = 51); group 2, stimulated CP 0.067−0.60 nM (n = 48); and group 3, stimulated CP > 0.60 nM (n = 33). In all patients fasting CP was closely correlated to stimulated CP (r = .988, P < .001), whereas the correlations between UCP and both fasting CP (r = .904, P < .001) and stimulated CP r = .902, P < .001) were slightly less pronounced. The associations between UCP and both fasting CP (r = .716, P < .001) and stimulated CP (r = .731, P < .001) were modest in group 2, and even more so in group 3 (r = .557, P < .001 and r = .641, P < .001, respectively). In conclusion, fasting CP is closely correlated to glucagon-stimulated CP in insulin-treated diabetics and can probably be used equally well in the assessment of β-cell function. The associations between UCP and both fasting and glucagon-stimulated CP are less pronounced, especially in patients with well-preserved β-cell function.

Predischarge maximal exercise test identifies risk for cardiac death in patients with acute myocardial infarction

A maximal exercise test was performed in 54 patients with acute myocardial infarction (AMI) before discharge and in 49 age-matched control subjects. The long-term prognosis was assessed after an average follow-up of 7.6 years in AMI patients and 5.8 years in control subjects. The maximal work capacity and systolic blood pressure increase in AMI patients was 59% that of control subjects (p less than 0.001). Seventeen AMI patients had significant ST-segment shifts, 13 with ST depression and 4 with ST elevation. In AMI patients experiencing a cardiac death during follow-up the maximal work capacity and systolic blood pressure increase were significantly lower than in survivors and those who died from noncardiac reasons (p less than 0.01; p less than 0.05), with no difference between these groups in the number of patients with ST-segment shifts. The average maximal work capacity of control subjects was 143 watts. A maximal work capacity half this (less than or equal to 72 watts) predicted long-term mortality in AMI patients (p less than 0.001). In addition a low increase in systolic blood pressure (less than 30 mm Hg) also predicted long-term mortality (p less than 0.005), whereas ST shifts were of no significant value. In this study maximal work capacity turned out to be the best single exercise variable for identifying groups of AMI patients with very low and relative high risk of cardiac death. When all 3 exercise variables were combined, the predischarge maximal exercise test was of great value in identifying AMI patients at low risk for cardiac death (predictive value of a negative test: 95%).

Urinary Albumin Excretion in a Population Based Cohort

In order to compare a 1‐h daytime urine specimen collection with a timed overnight collection, as well as different ways of expressing urinary albumin excretion: (urinary albumin excretion rate (UAE), urinary albumin concentration (UAC), and urinary albumin creatinine ratio (UACR)), a population of 922 people of whom 35 had diabetes was examined. The median age was 47 (range 26–65) years. The results of the different ways of collecting urine specimens and the different expressions of urinary albumin excretion were related to known cardiovascular risk factors. The daytime collection showed higher values of urinary albumin excretion than the overnight collections. Systolic blood pressure was an important risk factor correlated to UAE and UACR in the day as well as the overnight collection, followed by HbA1c in the total group and by BMI in the non‐diabetic group. UAC showed significant relation to triglycerides and HDL‐cholesterol. In conclusion, urinary albumin in a 1‐h daytime collection showed a similar correlation to cardiovascular risk factors as the excretion of albumin in overnight collected urine. Follow‐up studies are needed to compare day collections of urine as predictors of cardiovascular disease and early death with overnight collections.

Use of Hospital Services by Elderly Diabetics: The Frederica Study of Diabetic and Fasting Hyperglycaemic Patients Aged 60–74 Years

The use of hospital services was studied in 228 patients with known diabetes (KD) (52 insulin treated, 101 diet plus oral hypoglycaemic agents (OHAs), 66 diet treated and 9 without treatment) and 87 subjects with fasting hyperglycaemia (FH) found by screening of a well‐defined population aged 60–74 years. Ninety per cent were NIDDM as evaluated by a high C‐peptide response on glucagon stimulation. Information about all admissions during the year before ascertainment was obtained from the complete regional computerized hospital registration system.

Reproducibility of beta-cell function estimates in non-insulin-dependent diabetes mellitus.

We evaluated the reproducibility of different estimates of endogenous insulin secretion in 30 patients with non-insulin-dependent diabetes mellitus (NIDDM). Fasting blood glucose concentration was similar on the 2 days of study. The coefficients of variation of fasting plasma C-peptide, plasma Cpeptide 6 min after the injection of 1 mg i.v. glucagon, and the increment in plasma C-peptide after glucagon were 16.0, 14.8 and 24.1%, respectively. The coefficients of variation of the corresponding plasma insulin values were 19.2, 24.8, and 34.8%, respectively. The coefficient of variation of 24-h urinary C-peptide excretion was 22.1%. Because fasting plasma C-peptide correlated closely with plasma C-peptide 6 min after giucagon (test 1: r = .70, P < .01; test 2: r = .76, P < .01), it seems that these two values can be used equally well as assessment of (3-cell function in NIDDM. In conclusion, fasting plasma insulin, fasting plasma C-peptide, and plasma C-peptide 6 min after glucagon stimulation showed a similar and acceptable degree of reproducibility. Plasma insulin 6 min after glucagon and increments in plasma insulin and C-peptide, as well as urinary C-peptide, seem to be less reproducible.

Prevalence of Fasting Hyperglycemia and Known Non-Insulin-Dependent Diabetes Mellitus Classified by Plasma C-Peptide: Fredericia Survey of Subjects 60–74 Yr Old

A Danish population of 5699 individuals (60–74 yr old) was screened by fasting blood glucose (FBG) and interviewed about known diabetes. The distribution of FBG in individuals not known to have diabetes showed no sex difference or significant variation with age. Fasting hyperglycemia (FH), defined as FBG ≥ 7 mM in subjects without a history of diabetes, was found in 1.7% of men and women. Known diabetes (KD) had a prevalence of 3.9 and 5.0% in men and women, respectively. The prevalence rates of FH and KD increased significantly with age. In the two subgroups, plasma C-peptide was measured after overnight fasting and subsequently 6 min after an intravenous injection of glucagon. Based on the distribution of the C-peptide concentrations in non-insulin-treated KD subjects, lower limits for non-insulin-dependent diabetes mellitus (NIDDM) of 0.30 pmol/ml for fasting C-peptide and 0.60 pmol/ml for stimulated C-peptide were arbitrarily chosen. According to these cutoff points, only 38.5% of KD subjects treated with insulin had insulin-dependent diabetes mellitus, corresponding to 9.3% of all KD subjects. After exclusion of these patients, the prevalence of recognized NIDDM was 3.5% in men and 4.5% in women. All FH subjects except one had C-peptide values in the NIDDM interval. A close agreement between fasting and glucagon-stimulated C-peptide was seen. In epidemiological studies with an expected high prevalence of NIDDM, we propose to use fasting C-peptide for classification of patients with insulin-treated diabetes.

Over-mortality as related to age and gender in patients with established non-insulin-dependent diabetes mellitus.

In 1981-1982, 5699 persons representing 92.9% of the total population aged 60-74 years living in Fredericia, Denmark, were interviewed about a possible history of diabetes and had a fasting blood glucose measured. A total of 236 gave a positive history of diabetes; 88 had one fasting blood glucose of 7 mmol/L or more. For each of these probands, an age- and gender-matched control person with normal fasting blood glucose and no history of diabetes was selected randomly. Of the 236, 91.5% had NIDDM as judged by glucagon-stimulated C-peptide tests. At the end of December 1995, the participants were traced through the National Register and their status (alive or dead) was determined. The date of death was confirmed. The median observation time from screening and inclusion in the study till death or the end of the observation period in December 1995 was 12.81 years, the maximum was 14.91, and the 25th and 75th percentile values were 6.36 and 13.94 years, respectively. At the end of 1995, 165 (74.4%) of 228 persons with known diabetes at the time of ascertainment had died opposed to 90 (40.4%) of the 223 nondiabetic control persons. The difference is statistically highly significant (p < 0.00001, log-rank test). Within the first 5 years of observation, 42.9% of diabetic men died and only 22.5% of non-diabetic men. This percentage of deaths in diabetic men was found already in the 60-64 year age interval (46.2%). The mortality rate for the non-diabetic population seems to increase later. After 13 years of observation, 74 (81.3%) of 91 men with known diabetes had died, in the age-matched control men, 50 (56.2%) of 89 (p = 0.00006). Ninety-one (66.4%) of 137 diabetic women had died: 40 (29.9%) of 134 control women (p < 0.00001). The difference between mortality in diabetic men and women, and between nondiabetic men and women is highly significant (p = 0.00285 and 0.00001, respectively). The over-mortality of established diabetic persons decreases with age. In the age group 60-74 years, the over-mortality is about 2.5 without gender difference.

Sensitivity and reproducibility of urinary C-peptide as estimate of islet B-cell function in insulin-treated diabetes

The aims of the present study were to evaluate the ability of urinary C‐peptide determination to demonstrate presence of residual insulin secretion, and to evaluate the reproducibility of urinary C‐peptide excretion in 125 insulin‐treated diabetic patients. C‐peptide was determined in two consecutive 24‐h urine specimens and related to plasma C‐peptide 6 min after the intravenous injection of 1 mg glucagon. The detection limit of C‐peptide in plasma was defined analytically (≤0.02 nmol 1−1) and from pancreatectomized patients (≤0.06 nmol I−1), and in urine only analytically (≤0.1 nmol I−1). If the analytical detection limit of plasma C‐peptide was used as indicator of residual insulin secretion, islet B‐cell function was preserved in all patients. In patients with stimulated plasma C‐peptide levels from 0.02‐<0.06 nmol I−1 no increase was found in plasma C‐peptide values after stimulation with glucagon. This unresponsiveness of islet B‐cells is in good agreement with the existence of a biological detection limit of C‐peptide in plasma of 0.06 nmol I‐1. Using this biological plasma C‐peptide detection limit, 49 of 125 patients were without residual insulin secretion. In contrast to this, only 7 patients were diagnosed as C‐peptide non‐secretors using the analytical detection limit of urinary C‐peptide. Eighty‐four per cent of patients considered to have Type 1 (insulin‐dependent) diabetes with a duration of diabetes of more than 15 years had detectable C‐peptide in the urine. Only 16% of such patients had stimulated plasma C‐peptide levels above the biological detection limit. The biological detection limit of plasma C‐peptide of 0.06 nmol I−1 corresponded to a urinary C‐peptide concentration of 0.3 nmol I‐1. This value may represent a biological detection limit of C‐peptide in urine. The coefficients of variation of urinary C‐peptide expressed as nmol I−1, nmol mmol‐urinary‐creatinine−1 24 h−1 and nmol 24 h−1 were 39 %, 41 %, and 45 %, respectively. In conclusion, determination of C‐peptide in 24 h urine samples is much more sensitive as an indicator of residual insulin secretion than determination of C‐peptide in plasma using the analytical detection limit of C‐peptide in urine and the biological detection limit of C‐peptide in plasma. The final destruction of islet B‐cells may proceed more slowly than previously anticipated in Type 1 diabetes. The reproducibility of urinary C‐peptide is low.

Reduced glomerular filtration rate and cardiovascular damage in diabetes: a key role for abnormal albuminuria

There is general agreement that a fall rate in glomerular filtration rate (GFR) is the principal endpoint in diabetics with renal disease, and that abnormal albuminuria (including microalbuminuria) is an important intermediate end-point. The relative roles of blood pressure (BP) elevation and abnormal albuminuria in the prediction and genesis of renal disease are a matter of debate, and are further analysed in this paper. New studies show that neither genetic predisposition to hypertension (parental BP) nor parental abnormal albuminuria can be used to predict renal disease in patients with type 1 (insulin-dependent) diabetes. However, parental predisposition to proteinuria seems to be important to certain types of patients with type 2 (non-insulin-dependent) diabetes. Cross-sectional as well as follow-up studies document that GFR is generally well preserved in microalbuminuria (in both type 1 and type 2 patients), while the transition to clinical proteinuria is associated with a decline in GFR. Thus, prevention of overt proteinuria is important in clinical trials in microalbuminuric patients. In type 1 diabetes clear ultrastructural changes have been documented with microalbuminuria and a good correlation between abnormal albuminuria and structural damage is seen. Structural damage in normo- and microalbuminuric patients correlates poorly with BP. New studies in type 1 diabetes document that microalbuminuria (but not elevated BP) predicts not only clinical diabetic nephropathy but also end-stage renal failure and mortality. In type 2 diabetes microalbuminuria is the strongest predictor of mortality, whereas BP elevation is not a predictor. Several studies now document that antihypertensive treatment, especially with inhibitors of angiotensin converting enzyme, is able to reverse or reduce abnormal albuminuria, even in non-hypertensive type 1 patients, and possibly preserve GFR. Therefore, microalbuminuria may be the main indicator for starting antihypertensive treatment in these patients. With respect to organ damage in the retina, abnormal albuminuria is an important indicator of the risk of severe diabetic retinopathy. BP elevation seems not to be an initiating factor, but rather aggravates established retinopathy. Left ventricular hypertrophy has a stronger correlation with BP elevation than normoalbuminuria, suggesting that left ventricular hypertrophy is at least partially a phenomenon secondary to elevated BP in diabetic patients with abnormal albuminuria. Generally, abnormal albuminuria is a strong indicator of cardiovascular renal damage in diabetic patients and in most organs is a stronger factor than elevated BP.