Pulsatile Portal Vein Insulin Delivery Enhances Hepatic Insulin Action and Signaling

• Published in: Diabetes (New York, N.Y.) Vol. 61; no. 9; pp. 2269 - 2279
• Main Authors: MATVEYENKO, Aleksey V, LIUWANTARA, David, BUTLER, Peter C, GURLO, Tatyana, KIRAKOSSIAN, David, DALLA MAN, Chiara, COBELLI, Claudio, WHITE, Morris F, COPPS, Kyle D, VOLPI, Elena, FUJITA, Satoshi
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.09.2012
• Subjects: Analysis; Animals; Biological and medical sciences; Biopsy; Blood Glucose - metabolism; Catheters; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Dogs; Dosage and administration; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Forkhead Transcription Factors - metabolism; Glucagon; Glucokinase - metabolism; Glucose; Insulin; Insulin - administration & dosage; Insulin - metabolism; Insulin - physiology; Insulin Receptor Substrate Proteins - metabolism; Insulin resistance; Insulin Resistance - physiology; Insulin Secretion; Laboratories; Liver - physiology; Male; Medical sciences; Metabolism; Nerve Tissue Proteins - metabolism; Physiology; Portal Vein; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction - physiology; Veins & arteries; California; Los Angeles California; United States > US; Endocrinopathy; Signal transduction; Pancreatic hormone; Pulsatile; Diabetes mellitus; Portal vein; Insulin
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db11-1462

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.