Sulfated Insulin in Mild, Moderate, Severe and Insulin-resistant Diabetes Mellitus

Abstract

Moloney and co-workers prepared sulfated insulin and

Sulfated beef insulin treatment elicits CD8+ T cells that may abrogate immunologic insulin resistance in type I diabetes.

“…Certain of these modifications are situated in regions of the A-and B-chain that we have shown contribute to the formation of three immunodominant conformational epitopes of insulin recognized by human T cells (9). SBI is much less immunogenic both in vivo (23)(24)(25) and in vitro (this report) than either BI or PI. Addition of many negatively charged groups to insulin may alter its tertiary conformation, kinetics, and pathway of processing by an APC, or the capacity of a processed fragment(s) either to bind to HLA-D region encoded class II antigens or to be recognized with sufficient avidity by helper T cell antigen receptors.…”

“…Sulfation of insulin adds sulfate groups (average of six out of a possible eight per molecule) to side chains of threonine, serine, and tyrosine residues (23,24). Certain of these modifications are situated in regions of the A-and B-chain that we have shown contribute to the formation of three immunodominant conformational epitopes of insulin recognized by human T cells (9).…”

Intravenous Infusions of Sulfated Insulin Normalize Plasma Glucose Levels in Pancreatectomized Dogs

“…Six of the dogs were pancreatectomized as previously described, 12 at which time two silicone rubber catheters were placed as detailed previously. 15 Catheters were placed (1) into an external jugular vein and (2) into the portal vein either via the splenic or a mesenteric vein, the former for blood sampling and the latter for exogenous insulin infusion.…”

“…17 In the postprandial period, insulin infusion was accelerated above basal rates and for time durations in keeping with reducing the postprandial glycemic excursion to approximate the normal response without hypoglycemia, similar to methods detailed previously. 12 Insulin solutions were prepared as follows. Porcine SI 100 U/ml (Connaught Laboratories Ltd., Toronto, Ontario, Canada) was diluted in buffered bacteriostatic water containing 1% benzyl alcohol and 10 mM TRIS-HCI to a final concentration of 0.5 U/ml and pH adjusted to 7.6.…”

“…P revious long-term studies with intravenous insulin infusion in diabetic dogs resulted in good glycemic control only when the reservoirs were changed or flushed every 3-4 days. 12 Purified porcine insulins readily self-associate when exposed to various materials 3 and such aggregation is accelerated by motion. 4 Such aggregates include high-molecular-weight polymers of insulin and have reduced biologic activity.…”