Pulsatile Portal Vein Insulin Delivery Enhances Hepatic Insulin Action and Signaling

Abstract

Insulin is secreted as discrete insulin secretory bursts at ∼5-min intervals into the hepatic portal vein, these pulses being attenuated early in the development of type 1 and type 2 diabetes mellitus (T2DM). Intraportal insulin infusions (pulsatile, constant, or reproducing that in T2DM) indicated that the pattern of pulsatile insulin secretion delivered via the portal vein is important for hepatic insulin action and, therefore, presumably for hepatic insulin signaling. To test this, we examined hepatic insulin signaling in rat livers exposed to the same three patterns of portal vein insulin delivery by use of sequential liver biopsies in anesthetized rats. Intraportal delivery of insulin in a constant versus pulsatile pattern led to delayed and impaired activation of hepatic insulin receptor substrate (IRS)-1 and IRS-2 signaling, impaired activation of downstream insulin signaling effector molecules AKT and Foxo1, and decreased expression of glucokinase (Gck). We further established that hepatic Gck expression is decreased in the HIP rat model of T2DM, a defect that correlated with a progressive defect of pulsatile insulin secretion. We conclude that the physiological pulsatile pattern of insulin delivery is important in hepatic insulin signaling and glycemic control. Hepatic insulin resistance in diabetes is likely in part due to impaired pulsatile insulin secretion.

Fucosylated Chondroitin Sulfate from Sea Cucumber in Combination with Rosiglitazone Improved Glucose Metabolism in the Liver of the Insulin-Resistant Mice

“…35) Thus IR and IRS-2 genes are essential for insulin signaling. In this study, CHS treatment alone increased IR and IRS-2 mRNA expression levels by 62.6% and 47.7% respectively in the liver of the HFSD mice (Fig.…”

Beta-cell hubs maintain Ca2+ oscillations in human and mouse islet simulations

“…Multiple animal models of diabetes have also demonstrated that the impaired insulin secretion characteristic of this disease, is due, in part, to dysfunctional Ca 2+ oscillations, 13-18 with studies on human β-cells corroborating this finding. 19-21 These Ca 2+ oscillations drive pulsatile insulin release 22 – a secretory pattern that enhances hepatic insulin action, 23 protects against insulin resistance, 24 and is lost in T2DM. 25-28 To understand how these Ca 2+ oscillations become defective in T2DM, it is important to first understand how an islet generates and maintains these oscillations.…”

Low Level Pro-inflammatory Cytokines Decrease Connexin36 Gap Junction Coupling in Mouse and Human Islets through Nitric Oxide-mediated Protein Kinase Cδ

“…An initial pulse of [Ca 2ϩ ] i stimulates a pulse of insulin (first phase insulin release) and subsequent [Ca 2ϩ ] i oscillations stimulate prolonged insulin secretion (13). These dynamics have been shown to be important for hepatic insulin signaling (14). Pro-inflammatory cytokines have been shown to disrupt [Ca 2ϩ ] oscillations (10), which has been attributed to altered endoplasmic reticulum uptake (15) and can impact [Ca 2ϩ ] i dynamics.…”