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Variability of Directly Measured First-Pass Hepatic Insulin Extraction and Its Association With Insulin Sensitivity and Plasma Insulin

Published on Aug 1, 2018in Diabetes7.20
· DOI :10.2337/db17-1520
Isaac Asare-Bediako2
Estimated H-index: 2
(Cedars-Sinai Medical Center),
Rebecca L. Paszkiewicz4
Estimated H-index: 4
(Cedars-Sinai Medical Center)
+ 5 AuthorsRichard N. Bergman103
Estimated H-index: 103
(Cedars-Sinai Medical Center)
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Abstract
Although the β-cells secrete insulin, the liver, with its first-pass insulin extraction (FPE), regulates the amount of insulin allowed into circulation for action on target tissues. The metabolic clearance rate of insulin, of which FPE is the dominant component, is a major determinant of insulin sensitivity (SI). We studied the intricate relationship among FPE, SI, and fasting insulin. We used a direct method of measuring FPE, the paired portal/peripheral infusion protocol, where insulin is infused stepwise through either the portal vein or a peripheral vein in healthy young dogs ( n = 12). FPE is calculated as the difference in clearance rates (slope of infusion rate vs. steady insulin plot) between the paired experiments. Significant correlations were found between FPE and clamp-assessed SI ( r s = 0.74), FPE and fasting insulin ( r s = −0.64), and SI and fasting insulin ( r s = −0.67). We also found a wide variance in FPE (22.4–77.2%; mean ± SD 50.4 ± 19.1) that is reflected in the variability of plasma insulin (48.1 ± 30.9 pmol/L) and SI (9.4 ± 5.8 × 10 4 dL · kg −1 · min −1 · [pmol/L] −1 ). FPE could be the nexus of regulation of both plasma insulin and SI.
  • References (50)
  • Citations (3)
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References50
Newest
Published on Oct 1, 2017in Diabetes7.20
Francesca Piccinini3
Estimated H-index: 3
(Cedars-Sinai Medical Center),
David Polidori25
Estimated H-index: 25
(Janssen Pharmaceutica)
+ 1 AuthorsRichard N. Bergman103
Estimated H-index: 103
(Cedars-Sinai Medical Center)
African Americans (AAs) tend to have higher plasma insulin concentrations than European Americans (EAs); the increased insulin concentrations have been attributed to increased secretion and/or decreased insulin clearance by liver or other tissues. This work characterizes the contributions of hepatic versus extrahepatic insulin degradation related to ethnic differences between AAs and EAs. By using a recently developed mathematical model that uses insulin and C-peptide measurements from the insul...
Published on Jun 1, 2016in Cell Metabolism22.41
Paul M. Titchenell8
Estimated H-index: 8
(UPenn: University of Pennsylvania),
William J. Quinn18
Estimated H-index: 18
(UPenn: University of Pennsylvania)
+ 8 AuthorsJoshua D. Rabinowitz71
Estimated H-index: 71
(Princeton University)
Summary During insulin-resistant states such as type II diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production (HGP) yet promotes lipid synthesis. This metabolic state has been termed "selective insulin resistance" to indicate a defect in one arm of the insulin-signaling cascade, potentially downstream of Akt. Here we demonstrate that Akt-dependent activation of mTORC1 and inhibition of Foxo1 are required and sufficient for de novo lipogenesis, suggesting that hepatic ins...
Published on May 1, 2014in Obesity3.97
Marilyn Ader28
Estimated H-index: 28
(Cedars-Sinai Medical Center),
Darko Stefanovski17
Estimated H-index: 17
(Cedars-Sinai Medical Center)
+ 20 AuthorsHsu Ir1
Estimated H-index: 1
(Cedars-Sinai Medical Center)
Objective Insulin resistance is a powerful risk factor for Type 2 diabetes and a constellation of chronic diseases, and is most commonly associated with obesity. We examined if factors other than obesity are more substantial predictors of insulin sensitivity under baseline, nonstimulated conditions. Methods Metabolic assessment was performed in healthy dogs (n = 90). Whole-body sensitivity from euglycemic clamps (SICLAMP) was the primary outcome variable, and was measured independently by IVGTT ...
Published on Apr 1, 2014in Obesity3.97
Mark O. Goodarzi48
Estimated H-index: 48
(Cedars-Sinai Medical Center),
Carl D. Langefeld75
Estimated H-index: 75
(Wake Forest University)
+ 18 AuthorsThomas A. Buchanan70
Estimated H-index: 70
(SC: University of Southern California)
Objective We describe the GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium, along with heritability estimates and genetic and environmental correlations of insulin sensitivity and metabolic clearance rate of insulin (MCRI).
Published on Aug 1, 2012in Diabetologia7.11
Xiaosen Guo55
Estimated H-index: 55
(Cedars-Sinai Medical Center),
Jinrui Cui18
Estimated H-index: 18
(Cedars-Sinai Medical Center)
+ 10 AuthorsWilla A. Hsueh68
Estimated H-index: 68
(Houston Methodist Hospital)
Aims/hypothesis We have previously documented a high heritability of insulin clearance in a Hispanic cohort. Here, our goal was to confirm the high heritability in a second cohort and search for genetic loci contributing to insulin clearance.
Published on Nov 1, 2009in Journal of Molecular Medicine
Natalia Rudovich18
Estimated H-index: 18
(Charité),
O Pivovarova12
Estimated H-index: 12
(Charité)
+ 6 AuthorsAndreas F.H. Pfeiffer67
Estimated H-index: 67
(Charité)
Insulin-degrading enzyme (IDE) is the ubiquitously expressed major enzyme responsible for insulin degradation. Insulin-degrading enzyme gene is located on chromosome region 10q23-q25 and exhibits a well-replicated peak of linkage with type 2 diabetes (T2DM). Several genetic association studies examined IDE gene as a susceptibility gene for T2DM with controversial results. However, pathophysiological mechanisms involved have remained elusive. We verified associations of two IDE polymorphisms (rs1...
Published on Apr 1, 2009
Giuseppe d'Annunzio20
Estimated H-index: 20
(Istituto Giannina Gaslini),
Vanelli M1
Estimated H-index: 1
(Istituto Giannina Gaslini)
+ 4 AuthorsRenata Lorini33
Estimated H-index: 33
(Istituto Giannina Gaslini)
Background and aim: To establish normal values of insulin resistance, secretion and sensitivity us- ing respectively HOMA-IR, HOMA-β% and QUICKI indexes in healthy Italian children and adolescents, based on fasting samples. Methods: We determined HOMA-IR, HOMA-β% and QUICKI at baseline in 142 healthy subjects from Pediatric Centres, aged 2.7 to 19 years (10.6±3.8, Mean±SD), with different Tan- ner's pubertal Stages (TS). None had hypo/hyperglycemia (fasting plasma glucose ranging from 3.6 to 5.6...
Published on Feb 1, 2009in Obesity3.97
Clifton Bogardus76
Estimated H-index: 76
(NIH: National Institutes of Health)
The environment is largely responsible for differences in BMI between populations; genetics is largely responsible for differences in BMI within populations. Evidences in support of the environmental effect are many. The prevalence of obesity differs greatly between countries, even among developed countries (1). On a smaller scale, differences in the “built environment” within a city are associated with differences in BMI. In New York City a greater density of bus and subway stops and greater va...
Cited By3
Newest
Published on Jun 26, 2019in Endocrine Reviews15.17
Jonathan D. Douros2
Estimated H-index: 2
(Duke University),
Jenny Tong32
Estimated H-index: 32
(Duke University),
David D’Alessio9
Estimated H-index: 9
(Duke University)
Published on May 1, 2019in Metabolism-clinical and Experimental6.51
Richard N. Bergman103
Estimated H-index: 103
(Cedars-Sinai Medical Center),
Francesca Piccinini3
Estimated H-index: 3
(Cedars-Sinai Medical Center)
+ 1 AuthorsMarilyn Ader28
Estimated H-index: 28
(Cedars-Sinai Medical Center)
Abstract Malfunction of the liver is a central factor in metabolic disease. Glucose production by liver is complex and controlled via indirect mechanisms; insulin regulates adipose tissue lipolysis, and free fatty acids in turn regulate liver glucose output. This latter concept is confirmed by studies in L-Akt-Foxo1 knockout mice. The adipocyte is a likely locus of hepatic insulin resistance. Also, kidneys play a role in regulating glucose production; denervated kidneys abrogate the effect of fa...
Published on Sep 1, 2019in Diabetes7.20
Richard N. Bergman103
Estimated H-index: 103
(Cedars-Sinai Medical Center),
Francesca Piccinini3
Estimated H-index: 3
(Cedars-Sinai Medical Center)
+ 2 AuthorsMarilyn Ader28
Estimated H-index: 28
(Cedars-Sinai Medical Center)
There is wide variance among individuals in the fraction of insulin cleared by the liver (20% to 80%). Hepatic insulin clearance is 67% lower in African Americans than European Americans. Clearance is also lower in African American children 7–13 years of age. Lower hepatic insulin clearance will result in peripheral hyperinsulinemia: this exacerbates insulin resistance, which stresses the β-cells, possibly resulting in their ultimate failure and onset of type 2 diabetes. We hypothesize that lowe...
Published on May 1, 2019in Physiology6.38
Sonia M. Najjar31
Estimated H-index: 31
(OU: Ohio University),
Germán Perdomo13
Estimated H-index: 13
(UBU: University of Burgos),
Germán Perdomo2
Estimated H-index: 2
(UBU: University of Burgos)
Upon its secretion from pancreatic β-cells, insulin reaches the liver through the portal circulation to exert its action and eventually undergo clearance in the hepatocytes. In addition to insulin ...
Published on Nov 1, 2018in Diabetes7.20
Kirstine N. Bojsen-Møller19
Estimated H-index: 19
(UCPH: University of Copenhagen),
Anne-Marie Lundsgaard9
Estimated H-index: 9
(UCPH: University of Copenhagen)
+ 2 AuthorsJens J. Holst148
Estimated H-index: 148
(UCPH: University of Copenhagen)
Hyperinsulinemia is the hallmark of insulin resistance in obesity, and the relative importance of insulin clearance, insulin resistance, and insulin hypersecretion has been widely debated. On the basis of recent experimental evidence, we summarize existing evidence to suggest hepatic insulin clearance as a major and immediate regulator of systemic insulin concentrations responding within days to altered dietary energy and, in particular, carbohydrate intake. Hepatic insulin clearance seems to be...
View next paperHepatic and Extrahepatic Insulin Clearance Are Differentially Regulated: Results From a Novel Model-Based Analysis of Intravenous Glucose Tolerance Data