Normally, insulin is secreted almost exclusively in a pulsatile fashion, in amounts closely related to the intake of meals. The pulses of insulin coupled with the presence of glucose, provides the necessary two signals to the liver for proper carbohydrate metabolism, whereas in comparison, continuous insulin infusion does not.
In fact, continuous exposure to insulin and glucagon in a non-pulsed fashion is known to decrease the hormones’ metabolic effectiveness on splanchnic glucose production in humans. Down-regulation at the cellular level partially explains the decreased action of steady-state levels, while pulsatile hormone (insulin) secretion allows recovery of receptor affinity or receptor numbers. APS insulin administration with its tailored peaks of insulin, enhances the suppression of gluconeogenesis and reduce endogenous hepatic glucose production (EHGP).
For induction and maintenance of insulin-dependent enzymes essential for glucose metabolism (e.g. hepatic glucokinase, phosphofructokinase, and pyruvate kinase), the hepatocytes require a defined pulsed insulin levels of 200-500 μU/ml in the portal vein, concomitant with high glucose levels (bimolecular signal). In non-diabetic subjects, portal insulin concentrations are twofold to tenfold greater than those in the peripheral circulation. During the first pass through the liver, 50% of the insulin is removed, strongly insinuating that the liver is the principal metabolic target organ of the gastrointestinal tract and the pancreas. APS provides this bimolecular signal using the bionic eye infusion device to provide tailored pulses of insulin delivered at specific pressures.
The insulin retained by the hepatocytes may itself be essential for the long-term effects of insulin on hepatic glucose metabolism as well as growth and de novo enzyme synthesis. Following oral glucose intake, the liver accounts for an equal or greater portion of total net glucose uptake compared to the periphery.
Insulin exerts pivotal control of glucose levels through its ability to regulate HGP directly or indirectly. The traditional subcutaneous (S.C.) insulin administration regimens used by diabetic patients, including Continuous Subcutaneous Insulin Infusion pumps (CSII); a) fail to mimic the pulsatile nature of natural insulin secretion and b) do not reach high enough insulin concentrations at the hepatocyte level (e.g., 10 U regular insulin injected S.C. produce a peak systemic circulation concentration of 30-40 μU/ml and an even lower portal vein concentration of 15-20 μU/ml).
The relative deficiency of insulin at the hepatocyte level leads to an impaired capacity to process incoming dietary glucose by the diabetic. Since the liver is obviously the target organ of the pancreas, it must be concluded that the primary purpose of giving insulin to the diabetic patient should not be to control blood glucose level (“control theory”) but rather the normalization of hepatic metabolism. Furthermore, these same hepatic enzymes are found in all glucose-utilizing bodily systems, suggesting a synchronous effect by insulin and glucose. APS corrects this deficiency.
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