Comparison of the physiological relevance of systemic vs. portal insulin delivery to evaluate whole body glucose flux during an insulin clamp

Abstract

To understand the underlying pathology of metabolic diseases, such as diabetes, an accurate determination of whole body glucose flux needs to be made by a method that maintains key physiological features. One such feature is a positive differential in insulin concentration between the portal venous and systemic arterial circulation (P/S-IG). P/S-IG during the determination of the relative contribution of liver and extra-liver tissues/organs to whole body glucose flux during an insulin clamp with either systemic (SID) or portal (PID) insulin delivery was examined with insulin infusion rates of 1, 2, and 5 mU·kg(-1)·min(-1) under either euglycemic or hyperglycemic conditions in 6-h-fasted conscious normal rats. A P/S-IG was initially determined with endogenous insulin secretion to exist with a value of 2.07. During an insulin clamp, while inhibiting endogenous insulin secretion by somatostatin, P/S-IG remained at 2.2 with PID, whereas, P/S-IG disappeared completely with SID, which exhibited higher arterial and lower portal insulin levels compared with PID. Consequently, glucose disappearance rates and muscle glycogen synthetic rates were higher, but suppression of endogenous glucose production and liver glycogen synthetic rates were lower with SID compared with PID. When the insulin clamp was performed with SID at 2 and 5 mU·kg(-1)·min(-1) without managing endogenous insulin secretion under euglycemic but not hyperglycemic conditions, endogenous insulin secretion was completely suppressed with SID, and the P/S-IG disappeared. Thus, compared with PID, an insulin clamp with SID underestimates the contribution of liver in response to insulin to whole body glucose flux.

Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion

“…In contrast, fed rodents and fasted large animals respond to insulin by rapidly suppressing glycogenolysis (2,(7)(8)(9). In addition, Perry et al infused insulin into a peripheral vein at a rate (3 mU/kg/min) that has been shown to increase arterial levels 3-fold (17,18,51), but which would not have elevated insulin at the liver (26). Therefore, that study does not provide insight into the suppression of HGP due to inhibition of lipolysis in the context of an increase in insulin secretion (i.e., a rise in portal vein insulin delivery).…”

“…Thus, the route of insulin delivery can have a major impact on both the overall response of the liver and the mechanisms by which that response is achieved. Indeed, over a range of insulin doses, peripheral insulin infusion was not as effective at suppressing HGP as compared with direct infusion into the portal vein (26).…”

“…This was demonstrated in a recent rat study in which a low peripheral insulin infusion rate (resulting in only a 2-fold rise in arterial insulin) completely eliminated endogenous insulin secretion and reversed the normal insulin gradient between the liver and peripheral tissues (26). It is apparent, therefore, that when insulin is infused into a peripheral vein its direct effects on the liver are underemphasized, while its indirect effects are exaggerated.…”

“…Because of the loss of the normal hepatic/arterial insulin gradient (which occurs even without somatostatin infusion; see ref. 26), the liver is hypoinsulinemic under such basal conditions and euinsulinemic under the so-called hyperinsulinemic condition (5,26,27). Therefore, it is no surprise that insulin did not directly contribute to the suppression of HGP in many gold-standard clamp studies (11,17,18,28,29).…”

Tissue barriers and novel approaches to achieve hepatoselectivity of subcutaneously-injected insulin therapeutics

“…Liver hypoinsulinemia was reported in studies on rats, where it was shown that when arterial INS levels were clamped at twofold above basal levels during peripheral INS infusion, the portal vein INS concentration was still marked as "deficient," or below the basal level. 13 Peripheral IR mediated degradation and the short plasma T 1/2 (5 min) of INS may presumably attribute to observations in those early studies, which showed that only 1% of exogenous INS was delivered to the liver. 14 Therefore, in order to obtain sufficient INS concentrations in the liver, peripheral hyperinsulinemia is necessary.…”