Pulsatile portal vein insulin delivery enhances hepatic insulin action and signaling.
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.
Larry Hillblom Islet Research Center, Division of Endocrinology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Aleksey V
AV
Matveyenko
David
D
Liuwantara
Tatyana
T
Gurlo
David
D
Kirakossian
Chiara
C
Dalla Man
Claudio
C
Cobelli
Morris F
MF
White
Kyle D
KD
Copps
Elena
E
Volpi
Satoshi
S
Fujita
Peter C
PC
Butler
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004285:Dogs; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005941:Glucokinase / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D008099:Liver / Q000502:physiology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011169:Portal Vein; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D000071161:Forkhead Box Protein O1
D001786:Blood Glucose; D051858:Forkhead Transcription Factors; D005941:Glucokinase; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D009419:Nerve Tissue Proteins; D051057:Proto-Oncogene Proteins c-akt; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1