The hepatic extraction of insulin in normal man was evaluated by kinetic analysis of peripheral insulin behavior in the plasma following stimulation of endogenous insulin secretion. Prehepatic insulin production was determined by deconvolution of plasma connecting peptide behavior (C-peptide) and hepatic extraction of the secreted insulin determined with a three-compartment model for hepatic, vascular, and extravascular plasma spaces. Three dosages of oral glucose (10, 25, and 100 g) administered to normal volunteers resulted in 1.8 +/- 0.5, 2.7 +/- 1.1, and 7.2 +/- 1.6 U endogenous insulin secretion, respectively. Total hepatic exposure to insulin exceeded the endogenous secretion due to recycling to the liver from the systemic circulation. Decreasing insulin extraction by the liver (67-53-42%) in the presence of increasing insulin exposure (2.6-4.4-13.2 U) was observed during the dose-response to glucose. The rates of hepatic insulin extraction observed with arginine (58 +/- 9% with 3.2 U), and a normal meal (50 +/- 9% with 7.6 U) were intermediate between the extremes seen with the 10- and 100-g glucose challenge. These results quantitate hepatic exposure of insulin in man during differing stimuli of endogenous insulin secretion, and demonstrate reduced fractional hepatic extraction with increasing insulin exposure.

Successful implantation of an artificial pancreas requires the infusion of insulin into an appropriate anatomic site. Three sites being actively investigated include (1) intravenous (i.V.), (2) intraperitoneal (i.p.), and (3) subcutaneous (s.c). This study compared the rate, magnitude, and duration of insulin absorption from these three absorption sites as assessed by the appearance of “free” insulin into the plasma of 10 insulin-dependent diabetic subjects. The biologic effectiveness of insulin was assessed by the suppression of plasma glucose concentration following a 750-calorie meal. Our results suggest that i.v. delivered insulin provides the most rapid increase in plasma free insulin concentration, followed by the i.p. and s.c. routes, respectively. In contrast, the elevation of plasma free insulin concentration was most prolonged with the s.c. route, followed by i.p. and i.v. routes, respectively. Compared with the i.v. and s.c. routes of insulin delivery, only 50% of the i.p. delivered insulin appeared in the plasma. The onset of the biologic activity of the insulin delivered by the three different routes during the 4½-h observation period was most rapid for the i.v. and least rapid for the s.c. route. These results suggest that all three routes may be appropriate sites for delivery of insulin from an artificial pancreas. However, because of the difference in absorption kinetics and the onset of biologic effectiveness of the delivered insulin, different quantities and timing of insulin delivery may be needed.

Segmentation of small anatomic structures in noisy magnetic resonance (MR) images is inherently challenging because the edge information is contained in the same high-frequency image component as the noise. The authors overcame this obstacle in the analysis of the sural nerve in the ankle by processing images to reduce noise and extracting edges with an edge detection algorithm less sensitive to noise. Anatomic accuracy of the segmentation was confirmed by a neuroradiologist. A nerve hydration coefficient was determined from the signal intensity of the nerve in these segmented images. These semiautomated measurements of hydration agreed closely with those obtained with a previously described manual method (n = 44, P = .76). Each image in the study was analyzed identically, with no modification of the computer algorithm parameters. The data suggest that this robust method may be useful in a multicenter evaluation of diabetes treatment protocols.

Brittle diabetes is a subset of insulin-dependent diabetes mellitus for which multiple causes have been suggested. In its most severe form, brittle diabetes is incapacitating, preventing gainful employment and a normal lifestyle. Although some brittle diabetic individuals will significantly improve by intensive insulin therapy and education, many others remain unable to function normally because of recurrent episodes of hyperglycemia and hypoglycemia. We studied 30 incapacitated brittle diabetic subjects and developed an efficient algorithmic approach to determine the etiology of brittleness. Central to our diagnostic algorithm was the glucose response to 0.1 U/kg insulin administered subcutaneously and intravenously. If this response was normal, then psychosocial evaluations were completed, including psycholinguistic and health psychological testing. Other parameters affecting blood glucose concentration were also assessed, such as gastric motility, counterregulatory hormones, and, most important, patient compliance with prescribed regimens. However, if an "abnormal" glucose response to the insulin challenge tests was observed, the location of the insulin resistance was identified as being subcutaneous, intravascular, or at the peripheral tissue. Using our diagnostic algorithm, the identification of the etiology of brittleness in 29 of the 30 referred patients was possible. Thus, the purpose of an algorithmic approach to diagnosis is not only to avoid unnecessary testing, but also to determine the correct etiology of the brittle diabetes to determine appropriate therapy.