First-pass hepatic extraction and metabolic effects of insulin and insulin analogues

Chap, Z.; Ishida, Toshihiko; Chou, Jesse; Hartley, Craig J.; Entman, Mark L.; Brandenburg, Dietrich; Jones, Richard H.; Field, James B.

doi:10.1152/ajpendo.1987.252.2.e209

Cited by 30 publications

(28 citation statements)

References 19 publications

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“…The increased exposure of the liver to the hormone results from its secretion into a limited vascular pool and the fact that the liver extracts 50–60% of the insulin to which it is exposed (24). In contrast, when insulin is administered subcutaneously, the normal portal-peripheral insulin gradient is lost so that the peripheral tissues are comparatively hyperinsulinemic while the liver is comparatively hypoinsulinemic (25,26).…”

Section: Discussionmentioning

confidence: 99%

Novel PEGylated Basal Insulin LY2605541 Has a Preferential Hepatic Effect on Glucose Metabolism

et al. 2014

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The impact of the novel basal insulin LY2605541 (LY) on hepatic and nonhepatic glucose uptake (non-HGU) was evaluated. Conscious dogs underwent euglycemic clamps with tracer and hepatic balance measurements. Clamp period infusions were peripheral venous regular insulin (0.1 nmol ⋅ kg−1 ⋅ h−1 [control], n = 6) or LY (bolus [nmol/kg], continuous [nmol ⋅ kg−1 ⋅ h−1]: 0.5, 0.5 [n = 6]; 0.375, 0.375 [n = 5]; 0.25, 0.25 [n = 4]), somatostatin, and glucose, as well as intraportal glucagon (basal). During the clamp, the dogs switched from net hepatic glucose output to uptake (rates reached 2.1 ± 1.2, 0.9 ± 2.1, 8.6 ± 2.3, and 6.0 ± 1.1 µmol ⋅ kg−1 ⋅ min−1 within 5 h in control, LY0.25, LY0.375, and LY0.5, respectively). Non-HGU in LY increased less than in control; the ratio of change from basal in non-HGU to change in net hepatic glucose balance, calculated when glucose infusion rates (GIRs) were ~20 µmol ⋅ kg-1 ⋅ min−1 in all groups, was higher in control (1.17 ± 0.38) versus LY0.25 (0.39 ± 0.33), LY0.375 (−0.01 ± 0.13), and LY0.5 (−0.09 ± 0.07). Likewise, the change from baseline in glucose Rd-to-Ra ratio was greatest in control (1.4 ± 0.3 vs. 0.6 ± 0.4, 0.5 ± 0.2, and 0.6 ± 0.2 in LY0.25, LY0.375, and LY0.5, respectively). In contrast to exogenously administered human insulin, LY demonstrated preferential hepatic effects, similar to endogenously secreted insulin. Therefore, the analog might reduce complications associated with current insulin therapy.

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Section: Discussionmentioning

confidence: 99%

Novel PEGylated Basal Insulin LY2605541 Has a Preferential Hepatic Effect on Glucose Metabolism

et al. 2014

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“…In normal physiology, insulin is secreted from pancreatic β cells into the portal circulation 64. Hepatocytes are thus normally exposed to three to four times greater insulin concentrations than peripheral tissues such as muscle and adipose tissue.…”

Section: Hepatoselective Hypothesismentioning

confidence: 99%

Weight‐sparing effect of insulin detemir: a consequence of central nervous system‐mediated reduced energy intake?

Russell‐Jones

Danne

Hermansen

et al. 2015

Diabetes Obesity Metabolism

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Insulin therapy is often associated with adverse weight gain. This is attributable, at least in part, to changes in energy balance and insulin's anabolic effects. Adverse weight gain increases the risk of poor macrovascular outcomes in people with diabetes and should therefore be mitigated if possible. Clinical studies have shown that insulin detemir, a basal insulin analogue, exerts a unique weight‐sparing effect compared with other basal insulins. To understand this property, several hypotheses have been proposed. These explore the interplay of efferent and afferent signals between the muscles, brain, liver, renal and adipose tissues in response to insulin detemir and comparator basal insulins. The following models have been proposed: insulin detemir may reduce food intake through direct or indirect effects on the central nervous system (CNS); it may have favourable actions on hepatic glucose metabolism through a selective effect on the liver, or it may influence fluid homeostasis through renal effects. Studies have consistently shown that insulin detemir reduces energy intake, and moreover, it is clear that this shift in energy balance is not a consequence of reduced hypoglycaemia. CNS effects may be mediated by direct action, by indirect stimulation by peripheral mediators and/or via a more physiological counter‐regulatory response to insulin through restoration of the hepatic–peripheral insulin gradient. Although the precise mechanism remains unclear, it is likely that the weight‐sparing effect of insulin detemir can be explained by a combination of mechanisms. The evidence for each hypothesis is considered in this review.

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“…The liver extracts up to 60% of the insulin delivered to it with the remainder dispersed into the systemic circulation [1]. In consequence, hepatocytes are exposed to insulin concentrations that are three to four times higher than the other major targets for insulin (adipose tissue and muscle).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of insulin detemir and neutral protamine Hagedorn (NPH) insulin on hepatic glucose production and peripheral glucose uptake during hypoglycaemia in type 1 diabetes

et al. 2009

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Aims/hypothesis We compared the symptoms of hypoglycaemia induced by insulin detemir (NN304) (B29Lys(ε-tetradecanoyl),desB30 human insulin) and equally effective doses of neutral protamine Hagedorn (NPH) insulin in relation to possible differential effects on hepatic glucose production and peripheral glucose uptake. Methods After overnight intravenous infusion of soluble human insulin 18 participants with type 1 diabetes received subcutaneous injections of NPH insulin or insulin detemir (0.5 U/kg body weight) on separate occasions in random order. During the ensuing gradual development of hypoglycaemia cognitive function and levels of counter-regulatory hormones were measured and rates of endogenous glucose production and peripheral glucose uptake continuously evaluated using a primed constant infusion of [6,6-2 H 2 ] glucose. The study was terminated when plasma glucose concentration had fallen to 2.4 mmol/l or had reached a minimum at a higher concentration. Results During the development of hypoglycaemia no difference between the two insulin preparations was observed in symptoms or hormonal responses. Significant differences were seen in rates of glucose flux. At and below plasma glucose concentrations of 3.5 mmol/l suppression of endogenous glucose production was greater with insulin detemir than with NPH insulin, whereas stimulation of peripheral glucose uptake was greater with NPH insulin than with insulin detemir. Conclusions/interpretation In participants with type 1 diabetes subcutaneously injected insulin detemir exhibits relative hepatoselectivity compared with NPH insulin, but symptoms of hypoglycaemia and hormonal counterregulation are similar.

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First-pass hepatic extraction and metabolic effects of insulin and insulin analogues

Cited by 30 publications

References 19 publications

Novel PEGylated Basal Insulin LY2605541 Has a Preferential Hepatic Effect on Glucose Metabolism

Novel PEGylated Basal Insulin LY2605541 Has a Preferential Hepatic Effect on Glucose Metabolism

Weight‐sparing effect of insulin detemir: a consequence of central nervous system‐mediated reduced energy intake?

Differential effects of insulin detemir and neutral protamine Hagedorn (NPH) insulin on hepatic glucose production and peripheral glucose uptake during hypoglycaemia in type 1 diabetes

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