A. Michael Albisser

Nonaggregating Insulin Solutions for Long-Term Glucose Control in Experimental and Human Diabetes

A physiologic additive for dissolving insulin crystals for parenteral application has been found. Insulin crystals are relatively insoluble in simple aqueous solutions. They will dissolve, however, in highly acidic solutions, but these are not suitable for parenteral use. Both neutral and acid pH insulin solutions have a tendency for the dissolved hormone to reaggregate. Notwithstanding possible changes in biologic activity, such formed aggregates must be prevented because they interfere with the flow in portable insulin delivery devices and result in the loss of glycemic control. The addition of 1.5% autologous serum to the aqueous diluent for insulin has eliminated these difficulties and increased by 37% the apparent biologic activity of insulin solutions prepared in this way. With this additive, continuous uninterrupted intravenous insulin infusion has provided near ideal blood glucose control in four pancreatectomized dogs for 5 mo and four patients with juvenile-onset diabetes for 18–23 days. Serum apparently contains factor(s) that promote the dissolution of insulin and prevent the formation of peptide aggregates in dilute solutions.

A Portable System for Continuous Intravenous Insulin Delivery: Characteristics and Results in Diabetic Patients

A portable insulin delivery system for clinical use has been developed, with the aim of improving glycemic control for prolonged periods for individuals with insulin-dependent diabetes. It weighs 1.5 kg and measures 8 × 11 × 20 cm. A plastic case contains two insulin reservoirs, two peristaltic pumps (flow variability ± 3%), a battery pack, and voltage regulator. Silastic tubes connect the reservoirs to an indwelling intravenous catheter inserted into the arm. The system is carried by a strap over the shoulder. One pump operates continuously, giving insulin at a “basal” rate, and the other is activated during meals to give a preprogrammed waveform of insulin, the latter controlled by a small bedside unit. Twelve insulin-dependent diabetic patients were infused with insulin by this system for 4–60 days (mean 18 days), for a total of 199 patient days. Insulin delivery rates were modified according to data obtained by intermittent glycemic monitoring, and on one and in some cases two days glycemia was continuously monitored (N = 10). With a basal infusion rate of 18 ± 2 mU/min (mean ± SEM), fasting glycemia was 99 ± 7 mg/dl. The mean insulin delivered with meals was 12 ± 2 U for breakfast, 9 ± 2 U for lunch, and 11 ± 2 U for dinner. Mean glycemia before lunch and supper was 102 ± 6 and 121 ± 11 mg/dl, respectively. The lowest mean glycemia occurred after lunch (88 ± 7 mg/dl) and the mean peak postprandial glycemia was 136 ± 8 mg/dl (2 h after supper). The range from lowest to highest observed value was 47–189 mg/dl. This system is capable of maintaining glycemia within the normal range for periods up to 60 days. Further refinement of the waveforms of insulin delivery may allow for total glycemic normalization. The future refinement of such a system will allow for longer-term studies addressing the relationship between glycemic control and complications.

The metabolic and hormonal adaptations of normal dogs to long-term exogenous sulfated insulin infusions.

Hyperinsulinism frequently accompanies glucose normalization in type I diabetes but the long-term consequences of this exaggerated hormonal state are not known. To study this condition, normal dogs received constant exogenous sulfated insulin infusions for prolonged periods up to 43 weeks. During the interval and inspite of prevailing postabsorptive and fasting hypoglycemia, overt resistance to the infused insulin or loss of sensitivity did not occur. In counterring the imposed fasting hyperinsulinemia and the resulting hypoglycemia, fasting pancreatic glucagon levels rose while the fasting levels of several glucogenic precursors (lactate, pyruvate, and alanine) decreased. Fasting free fatty acid (FFA) levels were suppressed, but beta-hydroxybutyrate (beta-OHB) levels were unchanged. Body weight did not change. Most remarkably, all changes measured in the fasting levels of the hormones and metabolites reverted to normal following the cessation of exogenous sulfated insulin infusion. In addition to the hormonal and metabolite adaptations invoked by chronic exogenous hyperinsulinism in the fasting state of these normal dogs, there were interesting responses to their usual mixed meals. Of particular interest in this regard were the plasma glucose, insulin, and FFA diurnal profiles. First of all, a definite and unusual postprandial glycemic excursion occurred. Second, insulin levels were elevated some sixfold, and rather unresponsive to the meal in general. Inspite of the depressed fasting FFA levels and the absence of a postprandial rise in insulinemia, FFA showed a distinct fall after the meal. Whether the sulfated insulins infused were of the bovine or porcine species of origin made no discernible difference.(ABSTRACT TRUNCATED AT 250 WORDS)