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IMMUNOLOGIC & GENETIC TESTING IN DIABETES

GENETIC
IMMUNOLOGIC

THE ROLE OF GLUCOSE MANAGEMENT IN DIABETES

NON & MINIMALLY INVASIVE GLUCOSE ANALYSIS

Monitoring of Patients with Diabetes

KETONES

GLYCATED PROTEINS

TESTING FOR MICRO ALBUMINURIA

Guidelines & Recommendations for Laboratory Analysis in the Diagnosis & Management of Diabetes Mellitus

INSULIN & PRECURSORS, LEPTIN & AMYLIN:
IS THERE A ROLE?

Marion Parrott, MD
American Diabetes Association
Alexandria, VA

    1. Miscellaneous potentially important analytes

Recommendations: There is no role for routine testing for insulin or pro-insulin levels in most patients with diabetes. In most patients, differentiation between type 1 and type 2 diabetes may be made based on the clinical presentation and subsequent course. There is no role for measurement of insulin levels in the diagnosis of the metabolic syndrome, as knowledge of this value does not alter the management of these patients. These assays are useful primarily for research purposes, and in rare instances to resolve diagnostic dilemmas.

Insulin and precursors

In the last several years, interest has increased in the possibility that measurements of the concentration of plasma insulin and its precursors might be of clinical benefit. In particular, evidence has been published that increases in insulin and/or proinsulin concentrations in nondiabetic individuals predict the development of coronary heart disease (CHD). Although this possibility may be scientifically valid, its clinical utility is questionable. Increased concentrations of insulin and proinsulin in nondiabetic individuals are surrogate markers of resistance to insulin-mediated glucose disposal, and can identify individuals at risk to develop Syndrome X, or the insulin resistance syndrome. However, important as these changes may be in identifying such individuals, it is not clear that they are responsible for the increased risk of CHD. Consequently, it seems of greater clinical utility to quantify the consequences of the insulin resistance and hyperinsulinemia (or hyperproinsulinemia) rather than the hormone levels themselves, i.e., measuring blood pressure, degree of glucose tolerance, and plasma triglyceride and HDL cholesterol concentrations. It is these changes that should be the focus of clinical interventions, not plasma insulin or proinsulin concentrations.

Attention has also been directed to the clinical utility of measuring insulin or proinsulin concentrations as helping to choose the anithyperglycemic agent that might be best used as initial therapy in patients with type 2 diabetes. This issue is based upon the notion that the lower the pre-treatment insulin concentration, the more appropriate might be insulin, or an insulin secretagogue, as the drug of choice to initiate treatment. Alternatively, the higher the baseline insulin concentration, the more reasonable it might be to begin therapy with a thiazolidenedione compound or metformin. While this line of reasoning may have some intellectual appeal, there is no evidence that measurement of plasma insulin, or proinsulin concentrations, will lead to more efficacious treatment of patients with type 2 diabetes.

In contrast to the above considerations, determining plasma insulin and proinsulin concentrations is mandatory in the diagnosis of fasting hypoglycemia. The diagnosis of an islet cell tumor is based on the persistence of inappropriately elevated plasma insulin concentrations in the face of a falling glucose concentration. In addition, an increase in the ratio of fasting proinsulin to insulin in patients with difficulty in maintaining euglycemia strongly suggests the presence of an islet cell tumor. The absence of these associated changes in glucose, insulin, and proinsulin concentrations in an individual with fasting hypoglycemia makes the diagnosis of an islet cell tumor most unlikely, and should focus attention on alternative explanations for the inability to maintain fasting euglycemia.

Finally, measurement of the C-peptide response to intravenous glucagon can aid in the rare instance in which it is difficult to differentiate between the diagnosis of type 1 versus type 2 diabetes. However, even in this instance, the therapeutic response to drug therapy will provide useful information, and measurement of C-peptide is not clinically necessary. In rare instances, it may be helpful to measure c-peptide levels prior to discontinuation of insulin, for example, in an obese adolescent presenting with diabetic ketoacidosis, who may have type 2 diabetes and be able to be safely managed with an oral agent after resolution of glucotoxicity.

  1. Insulin antibodies
  2. Given sufficiently sensitive techniques, insulin antibodies can be detected in any patient being treated with exogenous insulin. In the vast majority of instances, the titer of insulin antibodies is low, and their presence is of no clinical significance. Very low levels are seen in patients treated exclusively with human recombinant insulin. However, on occasion the titer of insulin antibodies in the circulation can be quite high, associated with dramatic resistance to the ability of exogenous insulin to lower plasma glucose concentration. This clinical situation is quite rare, usually occurs in insulin-treated patients with type 2 diabetes, and the cause and effect relationships between the magnitude of the increase in insulin antibodies and the degree of insulin resistance is unclear. There are several therapeutic approaches to treating patients with this clinical problem, and a quantitative estimate of the level of circulating insulin antibodies does not appear to be of significant benefit in dealing with this issue.

  3. Amylin
  4. Recommendation: Assays for amylin are not clinically useful in the management of diabetes. These studies should be confined to the research setting.

    Amylin is a 37-amino acid pancreatic peptide first described in 1987. Amylin is co-secreted and co-located with insulin by the pancreatic beta cells in response to nutrient intake. Amylin appears to help regulate glucose metabolism by delaying gastric emptying and decreasing glucagon production. It has been suggested that amylin deficiency may account for some of the difficulty in achieving glycemic control in patients with type 1 diabetes. Amylin deficiency may also occur in insulinopenic type 2 patients. Trials of an amylin analog, pramlintide, are currently underway. At the present time, there is no clinical utility in measuring amylin.

  5. Leptin

Aside from rare instances of leptin deficiency, plasma leptin concentrations seem to vary directly with adiposity and plasma insulin concentrations. At this stage of knowledge, the only situation in which knowing the leptin concentration would be in suspected cases of leptin deficiency, characterized by early onset, massive obesity.

    1. Monitoring
    1. Lipids

Recommendations: All adults with diabetes should receive annual lipid profiles. Individuals at low risk, i.e. LDL < 100 and HDL>35 for men and>45 for women, may be screened less frequently. Since many patients with diabetes are candidates for lipid lowering therapy, more frequent measurements may be required until control is obtained.

Coronary heart disease is the major cause of morbidity and mortality in patients with type 2 diabetes, and attempts to rectify this situation must emphasize the diagnosis and treatment of dyslipidemia when present. Consequently, measurement of lipids is an important clinical practice recommnedation for people with diabetes, especially type 2, althought type 1 patients are also at increased risk for cardiovascular disease. As this topic is covered in detail elsewhere ( Davidódoes your organization have something on lipids??), only brief mention of it is made here.

Small, dense LDL particles, hypertriglyceridemia, and low HDL levels characterize diabetic dyslipidemia. Generally speaking, diabetic patients can have lipid profiles measured in the same manner as the general population of patients appropriate for lipid screening.

The clinical evaluation of patients with type 2 diabetes should include the quantification of plasma cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, and triglyceride concentrations. In most cases, this can be accomplished by the usual clinical laboratory approach of directly measuring total plasma cholesterol and triglyceride concentrations, precipitating HDL and measuring the cholesterol concentration of the precipitate, and calculating the LDL cholesterol concentration. This approach is satisfactory under most conditions, but is inadequate if the plasma triglyceride concentrations are >400 mg/dL. In this situation, ultracentrifugation separation and measurement of the cholesterol and triglyceride concentrations in the specific lipoprotein fractions will be necessary to insure accurate quantification of LDL and HDL cholesterol concentrations.