Marshall B. Block

Sequential Changes in Beta-Cell Function in Insulin-Treated Diabetic Patients Assessed by C-Peptide Immunoreactivity

Abstract Assessment of beta-cell function in insulin-treated diabetes is hampered by the presence of circulating insulin antibodies, which interfere with the commonly used insulin immunoassay. The development of an immunoassay for C-peptide has enabled beta-cell secretory products, in addition to insulin, to be monitored in the circulation of such patients. Using this assay, we studied the progressive changes in beta-cell secretion in three insulin-treated diabetic patients with hyperglycemia and ketonemia. Serum C-peptide immunoreactivity increased during the remission phase of the diabetic state, suggesting that the improvement in carbohydrate tolerance was due to renewed beta-cell secretion. Eventual clinical relapse was associated with decreasing serum C-peptide immunoreactivity. These results confirm the long held clinical impression that the cause of the remission phase in diabetes is usually resumption of beta-cell secretory activity. (N Engl J Med 288:1144–1148, 1973)

Proinsulin and C-Peptide in Blood

Proinsulin-like components (proinsulin and its intermediate forms, PLC) and C-peptide have been identified as secretory products of the pancreatic beta cells in addition to insulin. Because a specific human proinsulin antiserum is not yet available, serum PLC can be measured with an insulin or C-peptide antiserum and a human proinsulin standard after separation of insulin and C-peptide by gel filtration. Assay of unextracted serum with these two immunoassay systems measures total insulin immunoreactivity (insulin + PLC) and C-peptide immunoreactivity (C-peptide + PLC), respectively. Fasting PLC in normal subjects ranged between 0.05 and 0.4 ng./ml. After oral glucose, PLC levels rose more slowly than insulin and peaked at a later time. In relation to insulin, the percentage PLC was high in the basal state and two to four hours after glucose. The serum PLC concentration has also been measured in a variety of disease states including obesity, acromegaly, myotonic dystrophy, uremia, myxedema and Cushings syndrome. However, the most frequent and marked abnormality in its level has been found in patients with islet cell tumors. Equimolar amounts of C-peptide and insulin were found in serum of subjects with a wide range of insulin values. Thus the C-peptide level can be used as an indicator of beta cell secretory function. This application is especially useful in diabetic patients who develop circulating insulin antibodies in response to exogenous bovine or porcine insulin therapy. Measurement of serum C-peptide and proinsulin in these subjects has shown varying degrees of beta cell failure as well as marked fluctuations in secretory capacity in individual patients with progression of their disease. Preliminary results have indicated the immunological heterogeneity of other circulating peptide hormones and have shown that they may be synthesized and stored in a form different from the secreted molecule. The discovery of proinsulin has thus opened up new and exciting areas which may have wide application in endocrinology.

Clinical Significance of Circulating Proinsulin and C-Peptide

Publisher Summary This chapter discusses the clinical significance of circulating pro-insulin and c-peptide. Till 1967, it was believed that the two chains of insulin were synthesized separately and then joined by means of two disulfide bonds at a post-ribosomal site. However, studies by Steiner and his colleagues using slices of a pancreatic islet cell tumor demonstrated the presence of a large molecular weight, single chain precursor molecule, which was named pro-insulin. This protein consists of the insulin A and B chains linked by an additional polypeptide segment of approximately 30 to 35 amino acids, depending on the species. The enzymes involved in the transformation of pro-insulin to insulin are probably localized in the granules or their membranes, and the conversion process takes place as the granules mature and move toward the plasma membrane of the cell. These pro-teolytic enzymes cleave pro-insulin at specific sites where two pairs of basic amino acids join the connecting peptide (C-peptide) to the insulin chains. The major products of this reaction are insulin and the C-peptide.

Are Abnormalities in Insulin Secretion Responsible for Reactive Hypoglycemia

Seventy patients with reactive hypoglycemia strictly defined by criteria which interpret the low blood glucose value in relationship to clinical and physiologic parameters, were studied to determine if abnormalities in insulin secretion could be demonstrated. These patients were separated into four groups: alimentary (N = 5), diabetic (N = 16), hormonal (N = 5), and idiopathic (N = 44). The findings in these patients were compared to normal control subjects and to weight- and disease-matched patient controls. All of the patients with hormonal and most patients with idiopathic reactive hypoglycemia (thirty-two of forty-four) demonstrated delayed insulin secretion regardless of the control group used for comparison. Diabetic reactive hypoglycemic patients exhibited delayed insulin secretion when compared to normal controls but not when compared to weight-matched diabetic controls. Excessive insulin secretion was consistently found only in the patients with the alimentary variety of reactive hypoglycemia. Using weight- and diseasematched control groups, no abnormalities in insulin secretion could be found to account for the hypoglycemia in the diabetic reactive hypoglycemic patients and some idiopathic reactive hypoglycemic (nine of forty-four) patients. These results help to explain the inconsistent findings of previous investigators and suggest that reactive hypoglycemia is a syndrome having multiple etiologies.

“Masked” 21-hydroxylase deficiency of the adrenal presenting with gynecomastia and bilateral testicular masses

An infertile 27 year old man with precocious puberty is described. He presented in adulthood with unilateral and then bilateral gynecomastia, and subsequently testicular tumors developed. An early diagnosis of congenital adrenal hyperplasia would have avoided unnecessary surgery. Initial detailed metabolic evaluation led to the erroneous diagnosis of 11-hydroxylase deficiency because of the presence of an unusual steroid (21-desoxycortisol) in serum which was falsely reported as an increased 11-desoxycortisol (compound S). The observed low urinary pregnanetriol measurements would have supported this diagnosis. Subsequent specific measurements of 21-desoxycortisol established its presence in the serum and its major metabolite, tetrahydro-21-desoxycortisol, in the urine. The unique features in this case of 21-hydroxylase deficiency alert the physician to its unusual clinical presentation and the pitfalls that may be encountered when evaluating adrenal steroidogenesis.

Anaphylactoid reaction to technetium-99m sulfur colloid stabilized with gelatin. Report of a case.

Adverse reactions to technetium-991n (Tc-99m) sulfur colloid stabilized with gelatin have been reported in the radiologic literature (1). Lancet, in a recent editorial extolling the virtues of Tc-99m sulfur colloid (2), made no mention of the adverse effects of this material which is widely nsed in liver and spleen scanning. We would like to draw attention to a patient who experienced an anaphylactoid reaction to Tc-99m sulfur colloid stabilized with gelatin, in order to alert the medical profession