Comparison of peripheral and portal venous insulin administration on postprandial metabolic responses in alloxan-diabetic dogs. Effects of identical preprogrammed complex insulin infusion waveforms.

The optimal route for insulin administration by insulin infusion devices has not been established. To assess the differences between the peripheral venous and portal venous routes of insulin administration on postprandial metabolic responses, six alloxan-diabetic dogs were studied on four occasions. On the first, the insulin infusion rates given by the Biostator for disposal of a mixed meal were recorded electronically. On two subsequent occasions, these insulin infusion profiles were administered by a peripheral vein. On an additional occasion, the identical insulin infusion profile was given via the portal vein. No differences were observed in basal or peak plasma glucose, insulin, glucagon, branched chain amino acids, and lactate concentrations between portal and peripheral venous insulin administration. Furthermore, no differences in isotopically ( [2-3H]glucose) determined rates of systemic glucose appearance and disappearance were observed between the two routes. Although preprandial plasma alanine concentrations were greater when insulin was infused via the portal vein, the postprandial increments did not differ from those observed during infusion of insulin by a peripheral vein. These studies suggest that under the current experimental conditions, there appears to be no difference in the disposition of a mixed meal, measured as net whole body glucose appearance and disappearance rates, when insulin is administered in an open-loop fashion via either a peripheral or the portal vein.

Considerations for the programming of an open-loop insulin infusion device from the biostator glucose controller.

To assess the feasibility of preprogramming an open-loop device with insulin flow rates generated by the Biostator Glucose Controller, comparisons were made in 10 juvenile-onset diabetic patients between meals of equal size and composition taken in the morning, at noon, and in the evening and a bedtime snack during a 24-h period of Biostator glucose control. Four additional diabetic patients had Biostator glucose control for 72 h. Similar amounts of insulin were infused for the meals taken at differing times of the day and, except for the morning meal, for the same meal on two successive days. The meal-related glycemic patterns expressed as mean indices of meal excursions (MIME) were similar for meals of identical size and composition during a single day and for the same meal taken on two consecutive days. Preliminary results using an open-loop device preprogrammed by the Biostator system, although encouraging, underscore the deficiency of the subcutaneous route viz. the delayed entry of insulin into the circulation in achieving normal glucose levels and patterns.

Prandial insulin requirements in insulin-dependent diabetics: effects of size, time of day, and sequence of meals.

To assess the effects of size, time of day, and sequence of meals on insulin requirements determined by an artificial endocrine pancreas, eight insulin-dependent diabetics ate meals of 12.5%, 25%, and 50% of total calories (30 Kcal/kg) at 0800, 1300, and 1800 on each of 3 separate days in a randomized order in one of two sequences in a three by three Latin square design. Plasma glucose and free insulin concentrations and amounts of insulin infused by the artificial endocrine pancreas were associated with meal size (P less than 0.001) but not with time of day of meal ingestion (analysis of variance). The sequence of meal ingestion did not alter integrated plasma glucose responses, but did influence the meal-related amounts of insulin infused. Thus, consideration should be given to meal size and sequence of meal ingestion but not time of day of meal ingestion when determining prandial iv insulin requirements.

Gastric inhibitory polypeptide in obesity and diabetes mellitus.

Gastric inhibitory polypeptide (GIP) concentrations may be influenced by obesity, diabetes, and glucagon deficiency and be under feedback inhibition by insulin. To assess these factors, insulin-dependent diabetic, totally pancreatectomized diabetic, and lean and obese noninsulin-dependent diabetic patients were studied twice, once during partial insulin withdrawal and again when euglycemia was achieved before and after mixed meal ingestion, using an artificial endocrine pancreas. The results were compared to those from weight-matched lean and obese nondiabetic subjects. No significant differences in postprandial GIP responses were found between lean and obese nondiabetic subjects. Despite basal and postprandial hyperglycemia, the GIP responses to the mixed meal were not significantly different between insulin-deficient (insulin-dependent and totally pancreatectomized) patients and lean nondiabetic subjects. In addition, there were no significant differences in postprandial GIP responses between insulin-dependent and totally pancreatectomized patients. In contrast, lean and obese noninsulin-dependent diabetic patients had reduced GIP responses compared to weight-matched nondiabetic subjects (mean +/- SE, 37.9 +/- 5.4 vs. 67.1 +/- 10.8 ng ml-1 240 min-1, respectively; P less than 0.05). This difference was entirely due to the reduced GIP responses in obese noninsulin-dependent diabetic patients compared to those in obese nondiabetic subjects (32.1 +/- 7.9 vs. 76.9 +/- 18.2 ng ml-1 240 min-1, respectively; P less than 0.05); the postprandial GIP responses were not significantly different between lean noninsulin-dependent diabetic patients and lean nondiabetic subjects. Insulin infusion by an artificial endocrine pancreas resulted in postprandial insulin and glucose profiles that approximated those of nondiabetics, but did not significantly alter GIP responses to the mixed meal (48.2 +/- 5.5 ng ml-1 240 min-1) in the 18 diabetic patients compared to results obtained with sc insulin treatment (42.2 +/- 5.2 ng ml-1 240 min-1). In conclusion, postprandial GIP responses are normal in obese nondiabetic subjects and insulin-deficient diabetic patients and are blunted in obese, but not in lean, noninsulin-dependent diabetic patients. In addition, GIP does not appear to be under feedback inhibition by insulin or influenced by glucagon deficiency in diabetes.

Effect of peripheral versus portal venous administration of insulin on postprandial hyperglycemia and glucose turnover in alloxan-diabetic dogs.

The effects of peripheral venous and portal venous delivery of insulin by a closed-loop insulin infusion device (Biostator GCIIS) on postprandial hyperglycemia and rates of glucose appearance, disappearance, and clearance were compared in alloxan-diabetic dogs. The amounts of insulin required and the peripheral venous plasma insulin concentrations achieved were not different for the two routes of insulin administration. No statistically significant differences in postprandial hyperglycemia or patterns of glucose disposal were observed between the two routes of insulin delivery. These studies indicate that in terms of hepatic versus extrahepatic disposal of glucose, there appears to be no practical advantage of portal venous over peripheral venous administration of insulin when a closed-loop insulin infusion device is used.

Glucose clamping using the Biostator GCIIS.

The Biostator GCIIS was used to clamp circulating glucose at hypoglycemic (42 +/- 1 mg/dl), euglycemic (86 +/- 2 mg/dl), and hyperglycemic (142 +/- 1 mg/dl) levels in normal subjects during a concomitant infusion of insulin (0.1 U/kg/h). Because of limitations in maximal glucose infusion (1 g/min) from the Biostator, a supplementary infusion of glucose was required to accomplish euglycemic and hyperglycemic clamps. The coefficients of variation of blood glucose were 7.06 +/- 1.3%, 5.9 +/- 0.5%, and 6.1 +/- 0.9 for 120 minutes of hypoglycemic, euglycemic, and hyperglycemic clamps, respectively. Despite the occasional interruption of blood flow in the double-lumen catheter and the occasional poor correlation between Biostator and reference glucose method, satisfactory glucose clamps could be maintained for 2 hours.

Effects of size, time of day and sequence of meal ingestion on carbohydrate tolerance in normal subjects.

The effects of size, time of day and sequence of meal ingestion were determined in healthy subjects using a Latin square design. Plasma glucose, insulin and gastric inhibitory polypeptide, but not glucagon, were correlated with meal size. Plasma glucose, but not insulin, gastric inhibitory polypeptide or glucagon, were greater later in the day. The progressive decline in carbohydrate tolerance from 08.00 to 18.00 h was associated with impaired insulin secretion estimated by C-peptide, and with impaired insulin action.