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Intrahepatic Transplanted Islets in Humans Secrete Insulin in a Coordinate Pulsatile Manner Directly Into the Liver

¹ Larry Hillblom Islet Research Center, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California
² Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
³ Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota
⁴ Department of Surgery, University of Minnesota, Minneapolis, Minnesota

Address correspondence and reprint requests to Peter C. Butler, Larry Hillblom Islet Research Center, University of California Los Angeles David Geffen School of Medicine, 24-130 Warren Hall, 900 Veteran Ave., Los Angeles, CA 90095-7073. E-mail: pbutler{at}mednet.ucla.edu

Abbreviations: GCRC, general clinical research center

Intrahepatic islet transplantation is an experimental therapy for type 1 diabetes. In the present studies, we sought to address the following questions: 1) In humans, do intrahepatic transplanted islets reestablish coordinated puslatile insulin secretion? and 2) To what extent is insulin secreted by intrahepatic transplanted islets delivered to the hepatic sinusoids (therefore effectively restoring a portal mode of insulin delivery) versus delivered to the hepatic central vein (therefore effectively providing a systemic form of insulin delivery)? To address the first question, we examined insulin concentration profiles in the overnight fasting state and during a hyperglycemic clamp (150 mg/dl) in 10 recipients of islet transplants and 10 control subjects. To address the second question, we measured first-pass hepatic insulin clearance in two recipients of islet autografts after pancreatectomy for pancreatitis versus five control subjects by direct catheterization of the hepatic vein. We report that coordinate pulsatile insulin secretion is reestablished in islet transplant recipients and that glucose-mediated stimulation of insulin secretion is accomplished by amplification of insulin pulse mass. Direct hepatic catheterization studies revealed that intrahepatic islets in humans do deliver insulin directly to the hepatic sinusoid because 80% of the insulin is extracted during first pass. In conclusion, intrahepatic islet transplantation effectively restores the liver to pulsatile insulin delivery.

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