Besides measurement of blood glucose or carbohydrate tolerance, certain other procedures are widely used or proposed for the detection of diabetes mellitus. The appearance of glucose in the urine has long been used both for detection and as a parameter of treatment. As a clue to diagnosis, urine glucose depends on hyperglycemia that exceeds the renal tubular threshold for glucose. This threshold is most often considered to be a venous plasma true glucose value of 180 mg/100 ml (1.0 mmol/L); (however, there is a range in the literature of 150-200 mg/100 ml). Of some interest regarding the threshold concept in diabetics is evidence that some diabetics (especially the elderly) possess unusually high thresholds (up to 300 mg/100 ml; 16.6 mmol/L). It has also been shown that arterial blood glucose levels are much better correlated with glucosuria than venous ones. Nevertheless, routine urine testing provides one method for practical continuous outpatient monitoring of therapy and for the prevention of ketoacidosis. This aspect provides another argument for more routine use of the full GTT, since glucosuria can be correlated with degree of hyperglycemia. Incidentally, many diabetic patients and many of those involved in mass surveys have a urine glucose test before breakfast, which is the least likely time to produce glucosuria.

The problem of causes of hyperglycemia not due to diabetes mellitus was discussed earlier. Renal threshold assumes importance in another way because of the condition known as “renal glucosuria.” This may be congenital or acquired; the acquired type may be idiopathic or secondary to certain diseases such as Fanconi’s syndrome, acute tubular necrosis, or renal rickets. In all these conditions there is glucosuria at lower blood glucose levels than normal renal threshold values. Some report that a significant number of patients with the nonfamilial idiopathic variety of renal glucosuria eventually develop overt diabetes mellitus, although others do not agree.

Glucosuria of pregnancy occurs in the last trimester. Reported incidence depends on the sensitivity of the testing methods used, ranging from 5%-35% or even 70%. The etiology seems to be a combination of increased glomerular filtration rate and temporarily decreased renal threshold. Lactosuria is even more common. Glucosuria without hyperglycemia occurs in 20% of patients with lead poisoning. This is due to a direct toxic effect on the renal tubule cells. Glucosuria of a transient nature has been reported in 24% of normal newborn infants. A study utilizing paper chromatography found galactosuria, usually in amounts too small for detection by routine techniques, to be even more common.

Mentioned here only for the sake of completeness are the two main types of urine glucose tests: the copper sulfate tests for reducing substances and the glucose oxidase enzyme papers. The merits, drawbacks, and technical aspects of these tests, as well as a general discussion of glucosuria.

Diabetic proteinuria

The earliest evidence of diabetic renal disease is glomerular basement membrane abnormality on renal biopsy using special stains or electron microscopy. This is present in nearly all type I patients by 2-5 years after onset. The structural changes initially produce increase in glomerular permeability that in turn results in increased urinary excretion of certain molecules (such as albumin and immunoglobulin-G) that are filtered by the glomeruli. Initially, the degree of abnormality is small enough that urinary albumin remains within reference range during at least the first 5 years after initial diagnosis of type I diabetes. Afterward, there is a variable number of years during which about 30% of patients (range, 12%-43%) increase urinary albumin above reference range but below threshold of detection (200-300 mg/L) by standard laboratory urinalysis dipstick protein tests. This “subclinical” state of selectively elevated albumin excretion rate (AER) is called “microalbuminuria”. This sequence also occurs in a substantial number of type II diabetics (about 30%, range 13%-59%). After a variable number of years, about 70% (range, 14%-100%) of type I patients gradually increase albumin excretion until it is “overt”; that is, detectable by routine laboratory protein dipstick screening methods. This eventually happens in at least 35%-40% (range, 2%-60%) of all type I diabetics, although about 40% never develop overt albuminuria. Progression from microalbuminuria to overt albuminuria in type II diabetics occurs in about 20%-25% of patients, with about 25% (range, 3%-40%) of all type II patients reaching this stage. Once overt albuminuria occurs, most type I diabetics eventually progress to renal failure (65%-75%, range, 50%-100%) unless death occurs from coronary heart disease or some other cause. Renal failure occurs in about 30% (range, 22%-40%) of all type I patients. Overall, diabetics comprised 30% of all patients in 1987 who had end-stage renal disease; of the diabetics, type I and II were represented in equal numbers (type I is more apt to progress to renal failure; but type II occurs nearly 10 times more frequently than type I). All these sometimes conflicting statistics are influenced by many factors, such as patient age at diagnosis, number of years followed, type of microalbumin test used, and patient racial group composition. African Americans, native Americans, and Hispanics have higher rates of progressive diabetic renal disease than Europeans. The rationale for detecting microalbuminuria is to find disease at a stage in which certain therapies might retard or even prevent further impairment. By the time overt albuminuria develops, there is no current way to prevent progression.

Microalbuminuria has been defined in several ways; there is not unanimous opinion which is the best screening method or “gold standard” method. Based on a Consensus Conference held in 1989, the following definitions currently appear to be most widely accepted: excretion rate, 30-300 mg/24 hrs or 20-200 µg/min; excretion ratio, 20-200 mg albumin/gm creatinine (0.4-2.8 mg/mmol creatinine). There is also controversy whether to employ overnight specimens, 24-hour specimens, early morning specimens, or random specimens. 24-hour specimens are generally considered “gold standard”; however, since albumin excretion increases in the upright position and during exercise, plus the problems of incomplete 24-hour collections, many investigators prefer overnight collection as a baseline. In general, timed collections are thought to be more accurate than untimed ones, and some studies obtained more accurate and reproducible results using an albumin/creatinine ratio, which would partially correct for differences in urine volume and concentration. Finally, several investigators advocate an early morning untimed specimen for screening purposes (microalbuminuria range, 20-30 mg/L). Impacting on all these techniques is a rather high percentage of variability (30%-45%) in day-to-day albumin excretion in diabetics with or without microalbuminuria. There is also significant assay technical variation that can be as high as 20%-40%, depending on the analytical method, the quantity of albumin, and the laboratory. Therefore, it is strongly recommended that at least 2 of 3 specimens be abnormal during a 6 month time period before diagnosing microalbuminuria.

Assay methods for microalbuminuria include quantitative immunoassay (ELISA or particle agglutination methods using nephelometry); qualitative “yes-no” agglutination slide immunoassay using anti-albumin antibodies (e.g., AlbuSure, 20mg/L detection level); and chemical methods (e.g., Microbumintest tablets). The quantitative assays are advantageous in establishing a baseline value and disclosing worsening of disease if it occurs. Of the qualitative screening tests, Microbumintest has been criticized by some for false positive results and some false negative results. AlbuSure is said to produce acceptable results. Other tests are available, but with insufficient evaluation data. With any method it is possible to obtain false positive results if the urine specimen is contaminated with blood. The specimen should be assayed fresh (i.e., within 12 hours); if not possible, it can be refrigerated (acceptable for 7 days) or a suitable preservative can be added. There are conflicting reports whether freezing lessens albumin content. Some albumin may adhere to the walls of glass collection bottles.

Finally, it must be remembered that various conditions other than diabetes (e.g., atherosclerosis, hypertension, infection, collagen diseases, glomerulonephritis) may increase urinary albumin as a component of ordinary proteinuria induced by either focal or diffuse acute or chronic renal damage. Theoretically, these conditions would cause detectable proteinuria on standard dipstick protein screening tests.

The American Diabetes Association (1989) recommends that urine microalbuminemia should be assayed yearly in all type II diabetics and yearly beginning 5 years after diagnosis in all type I diabetics (unless the patient has known diabetic progressive nephropathy).

Diagnosis of diabetic coma

Diabetic coma may occur without a history of diabetes or in circumstances where history is not available. Other major etiologies of coma must be considered; including insulin hypoglycemia, meningitis or cerebrovascular accident, shock, uremia and barbiturate overdose. A clear-cut, fast diagnosis of diabetic coma can be made with a test for plasma ketones (frequently called “acetone,” although acetone is not the only ketone substance). Anticoagulated blood is obtained, a portion is centrifuged for 2-3 minutes, and the plasma is tested for ketones. Diabetic acidosis severe enough to produce coma will be definitely positive (except for the rare cases of lactic acidosis or hyperosmolar coma). The other etiologies for coma will be negative, since they rarely produce the degree of acidosis found in diabetic coma. The presence of urinary glucose and ketones strongly suggests diabetes but may occur in other conditions. Such findings would not entirely rule out insulin overdose (always a consideration in a known diabetic), since the urine could have been produced before the overdose. An elevated blood glucose level also is strong evidence of diabetic coma, especially if the degree of elevation is marked. Other conditions that might combine coma with hyperglycemia (cerebrovascular accident, acute myocardial infarction) have only mild or moderate hyperglycemia in those instances where hyperglycemia is produced. Besides blood glucose determination, a simple empirical test to rule out hypoglycemia is to inject some glucose solution intravenously. Cerebral damage is investigated by cerebrospinal fluid examination or computerized tomography scan. Uremia is determined by means of the blood urea nitrogen (BUN) level, although other etiologies of coma besides primary renal disease may be associated with an elevated BUN level. Drug ingestion is established by careful history, analysis of stomach contents, and identification of the drug in blood samples (one anticoagulated and one clotted specimen are preferred) or urine samples. Shock is diagnosed on the basis of blood pressure; further laboratory investigation depends on the probable etiology.

Hyperosmolar nonketotic coma. Hyperosmolar nonketotic coma is uncommon but is being reported with increased frequency. The criterion for diagnosis is very high blood glucose level (usually well above 500 mg/100 ml; 28.0 mmol/L) without ketones in either plasma or urine. The patients usually become severely dehydrated. Plasma osmolality is high due to dehydration and hyperglycemia. Most patients are maturity-onset mild diabetics, but nondiabetics may be affected. Associated precipitating factors include infections, severe burns, high-dose corticosteroid therapy, and renal dialysis. Occasional cases have been reported due to phenytoin and to glucose administration during hypothermia.

Lactic acidosis syndrome. Lactic acidosis syndrome is rare and may have several etiologies. It used to be most frequently reported with phenformin therapy of diabetes but now is encountered as a nonketotic form of diabetic acidosis. The most common cause of elevated blood lactate levels is tissue hypoxia from shock. Arterial blood is said to be more reliable than venous for lactic acid determination. Tourniquet blood stagnation must be prevented, and the specimen must be kept in ice until analyzed.