Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity.

Caro, J F; Ittoop, O; Pories, W J; Meelheim, D; Flickinger, E G; Thomas, F; Jenquin, M; Silverman, J F; Khazanie, P G; Sinha, M K

doi:10.1172/jci112558

Cited by 215Metabolism, Diabetes, and CancerDiabetes, Cardiovascular Risks, and LipoproteinsGrowth Hormone and Insulin-like Growth Factors

Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity.

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Caro, J F, Ittoop, O, Pories, W J, Meelheim, D, Flickinger, E G, Thomas, F, Jenquin, M, Silverman, J F +2 more·1986·Journal of Clinical Investigation

DOI 10.1172/jci112558PMC PMC329556

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Abstract

We have developed a method to isolate insulin-responsive human hepatocytes from an intraoperative liver biopsy to study insulin action and resistance in man.Hepatocytes from obese patients with noninsulin-dependent diabetes were resistant to maximal insulin concentration, and those from obese controls to submax- imal insulin concentration in comparison to nonobese controls.Insulin binding per cell number was similar in all groups.How- ever, insulin binding per surface area was decreased in the two obese groups because their hepatocytes were larger.In addition, the pool of detergent-extractable receptor was further decreased in diabetics.Insulin receptors in all groups were unaltered as determined by affinity-labeling methods.However, insulin-stim- ulated insulin receptor kinase activity was decreased in diabetics.Thus, in obesity, decreased surface binding could explain re- sistance to submaximal insulin concentrations.In diabetes, di- minished insulin-stimulated protein kinase activity and decreased intracellular pool of receptors could provide an explanation for postinsulin-binding defect(s) of insulin action in human liver. Methods Materials. a-[ I 14C]Aminoisobutyric acid (51.6 mCi/mmol), carrier-freeNa 125I, [methoxyl-3H]inulin (186.4 mCi/g), 3-0-['4C] methyl-D-glucose (58.0 mCi/mmol), L-[U-_4C]leucine (300 mCi/mmol), and [I-_4C]acetic acid, sodium salt (56.0 mCi/mmol) were obtained from New England Nuclear, Boston, MA.Crude collagenase (type IV, lots 124F-6807, 25F-6806, 25F-68 17, 44F-68 12) and deoxyribonuclease were obtained from Sigma Chemical Co., St. Louis, MO; dispase was purchased from Boeh- ringer Mannheim Biochemicals, Indianapolis, IN; and soybean trypsin inhibitor from Worthington Biomedical Corp., Freehold, NJ.Fraction V bovine serum albumin (BSA) was obtained from Armour Pharma- ceutical, Co., Kankakee, IL, and it was further purified by charcoal treat- ment (23).Crystalline porcine insulin was kindly provided by Dr. Ronald Chance of Eli Lilly & Co., Indianapolis, IN.All other chemicals were reagent grade.Human subjects.11 morbidly obese patients with NIDDM and an equal number of morbidly obese patients without diabetes were studied.The clinical and biochemical data ofthese patients are presented in Table I.These patients were admitted to the hospital to undergo gastric bypass for the treatment of morbid obesity.We also studied a nonobese non- diabetic group composed of four subjects who had uncomplicated gallstone disease and were admitted for elective cholecystectomy, and five brain-dead organ donors.The biochemical data on the liver ofthese two clinically different subgroups of nonobese subjects were identical.Thus, they have been combined and referred to as the nonobese comparison group.The value ofthe organ donor's liver should be underscored because we have the entire liver from the donors.This tissue has been fundamentalInsulin Resistance in Liverfrom Noninsulin-dependent Diabetes 249

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Early studies found a modest 20-30% reduction in insulin binding to monocytes and adipocytes from type 2 diabetic patients, but this was not a consistent finding.
“Early studies have demonstrated a modest 20–30% reduction in insulin binding to monocytes and adipocytes from type 2 diabetic patients, but this has not been a consistent finding [1, 151–154].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [153]
Most but not all investigators found reduced insulin receptor tyrosine kinase activity in skeletal muscle from normal-weight and obese diabetic subjects that cannot be explained by receptor number or binding affinity.
“Most [1, 7, 152, 153, 156, 161] but not all [155] investigators have found a reduction in tyrosine kinase activity that cannot be explained by alterations in insulin receptor number or insulin receptor binding affinity.”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [153]
Insulin binding to solubilized receptors from skeletal muscle and liver is normal in obese and lean diabetic individuals.
“insulin binding to solubilized receptors obtained from skeletal muscle and liver has been shown to be normal in obese and lean diabetic individuals [152, 153, 155].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [153]

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Arner, P., Einarsson, K., Ewerth, S., & Livingston, J. N. (1986) · Journal of Clinical Investigation · doi:10.1172/jci112492 · Cited by 29 · see citing works
Insulin receptor kinase in human skeletal muscle from obese subjects with and without noninsulin dependent diabetes.
Caro, J. F., Sinha, M. K., Raju, S. M., Ittoop, O., Pories, W. J., Flickinger, E. G., Meelheim, D., & Dohm, G. L. (1987) · Journal of Clinical Investigation · doi:10.1172/jci112958 · Cited by 341 · see citing works
Self-citation

Authors: Caro, J. F., Ittoop, O., Pories, W. J., Meelheim, D., Flickinger, E. G., Thomas, F., Jenquin, M., Silverman, J. F., Khazanie, P. G., & Sinha, M. K.
Affiliations: East Carolina University (US)
ORCID: Pories, W J
Silverman, J F
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1986-07-01
Volume: 78
Issue: 1
Pages: 249-258
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci112558
PMC: PMC329556
OpenAlex: W2062299625
Cited by: 215
References: 74
Citations by year: 2026: 2 · 2024: 4 · 2023: 4 · 2022: 7 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 4 · 2017: 3 · 2016: 1 · 2015: 5 · 2013: 1 · 2012: 2
FWCI: 8.05
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (R01-AM3285-04)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Keywords: insulin resistance, type 2 diabetes, liver, hepatocytes, insulin receptor, insulin receptor kinase, insulin binding, obesity, insulin action, receptor internalization, insulin-stimulated glucose transport
MeSH terms: Biopsy, Cell Separation, Diabetes Mellitus, Electrophoresis, Polyacrylamide Gel, Humans, Insulin, Insulin Resistance, Kinetics, Liver, Obesity, Protein Kinases, Receptor, Insulin, Structure-Activity Relationship

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Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity.

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