The Physiologic Replacement of Insulin

The use of insulin as an injected therapeutic agent for the treatment of diabetes has been one of the outstanding successes of modern medicine. The therapy has, however, had its associated problems, not least because injection of insulin does not lead to normal diurnal concentrations of insulin in the blood. This is especially true at meal times when absorption from subcutaneous tissue is too slow to mimic the normal rapid increments of insulin in the blood. In the neutral solutions used for therapy, insulin is mostly assembled as zinc-containing hexamers and this self-association, which under normal physiological circumstances functions to facilitate proinsulin transport, conversion and intracellular storage, may limit the rate of absorption. We now report that it is possible, by single amino-acid substitutions, to make insulins which are essentially monomeric at pharmaceutical concentrations (0.6 mM) and which have largely preserved their biological activity. These monomeric insulins are absorbed two to three times faster after subcutaneous injection than the present rapid-acting insulins. They are therefore capable of giving diabetic patients a more physiological plasma insulin profile at the time of meal consumption.

To evaluate the effect of strict glycemic control of insulin-dependent diabetes mellitus (IDDM) on the plasma glucose threshold initiating counterregulatory hormone responses to hypoglycemia, we used the glucose clamp technique to produce a standardized gradual glucose decline from 90 to 40 mg/dl in seven young IDDM patients before and after 2-6 mo of intensified insulin therapy. Before intensive therapy [hemoglobin A1 (HbA1) 9.6 +/- 1.1%], epinephrine responses were triggered at a higher plasma glucose level (67 +/- 4 mg/dl) than in normal control subjects (56 +/- 1 mg/dl, P less than .05), and clinical symptoms of hypoglycemia appeared at glucose levels of 50-60 mg/dl. After intensive therapy (HbA1 7.1 +/- 0.7%), the glucose threshold for epinephrine release consistently declined to values (46 +/- 2 mg/dl) below normal (P less than .01). Furthermore, epinephrine concentrations were markedly reduced at each hypoglycemic level, and a greater hypoglycemic stimulus was required to elicit symptoms. The glucose threshold stimulating release of growth hormone also significantly declined after intensive therapy. We conclude that strict glycemic control of IDDM lowers the plasma glucose level required to generate epinephrine release during hypoglycemia. This may diminish patient recognition of moderate hypoglycemia and increase the risk of severe hypoglycemia in intensively treated IDDM.

The large and variable hepatic extraction of insulin is a major obstacle to our ability to quantitate insulin secretion accurately in human subjects. The evidence that C-peptide is secreted from the beta cell in equimolar concentration with insulin, but not extracted by the liver to any significant degree, has provided a firm scientific basis for the use of peripheral C-peptide concentrations as a semiquantitative marker of beta cell secretory activity in a variety of clinical situations. Thus, plasma C-peptide has proved to be extremely valuable in the study of the natural history of type 1 diabetes, to monitor insulin secretion in patients with insulin antibodies, and as an adjunct in the investigation of patients with hypoglycemic disorders. The use of the peripheral C-peptide concentration to accurately quantitate the rate of insulin secretion is more controversial. This is mainly because understanding of the kinetics and metabolism of C-peptide under different conditions is incomplete. Unfortunately, sufficient quantities of human C-peptide are not available to allow the experimental validation of the mathematical formulae that have been proposed for the calculation of insulin secretion from peripheral C-peptide concentrations. Until it is possible to perform such experiments, the accuracy of studies that have derived insulin secretion rates from peripheral C-peptide levels will remain uncertain. The assumption that the peripheral C-peptide:insulin molar ratio can be used as a reflection of hepatic insulin extraction has not been experimentally validated. The marked difference in the plasma half-lives of insulin and C-peptide complicates the interpretation of changes in their ratios.(ABSTRACT TRUNCATED AT 250 WORDS)