The importance of the liver in insulin replacement therapy in insulin-deficient diabetes.

Abstract

In this issue, Wang et al. (1) present data comparing subcutaneously (SC) administered hepatic targeted proinsulin-transferrin fusion protein compared with regular recombinant insulin. Their data demonstrate both primary hepatic insulin effects in insulin-deficient mice: inhibition of hepatic glucose production during fasting and stimulation of glycogen deposition during feeding. This study focuses needed attention on the role of the liver in insulin replacement therapy. Physiologically, 100% of endogenous insulin flows from the pancreas to the liver (Fig. 1 A ) via the pancreatic and portal veins. The pancreas releases insulin in quantal bursts every 4–5 min (2), with the liver retaining a major fraction of the pancreatic insulin (3). Insulin is always in portal blood, and during fasting insulin inhibits hepatic glucose release by inhibiting either glycogenolysis or gluconeogenesis. During a meal, insulin stimulates glucose storage by the liver as glycogen. The insulin released from the liver acts on adipose and muscle tissue to stimulate glucose uptake. These actions of insulin at the three main insulin-sensitive tissues maintain blood glucose levels within a narrow range of approximately 80−120 mg/dL. Figure 1 A : Normal metabolism: in response to insulin, the liver continuously micromanages glucose. B : Current insulin therapies: insufficient hepatic delivery. C : Preferred form of insulin therapies: hepatic and peripheral insulin in a single dose. Type 1 diabetic patients receive lifesaving insulin SC with meals and a once- or twice-per-day basal injection in an effort to mimic the normal peripheral blood insulin pattern. However, …