Ralph A. De Fronzo

NIDDM subjects are characterized by impaired glucose tolerance and insulin resistance with respect to glucose metabolism. To examine whether the defect in glucose utilization extends to amino acid metabolism, 6 NIDDM subjects (64 ± 4 yr of age; ideal body weight of 107 ± 3%) and 7 control subjects (58 ± 4 yr of age; ideal body weight of 105 ± 2%) were studied with the euglycemic insulin clamp technique, in combination with [1-14C]leucine and indirect calorimetry. All subjects participated in two studies. In study 1, after 3 h of tracer equilibration, a 3-h insulin clamp (40 mU · m−2 · min−1) was performed to define the effect of insulin on leucine kinetics and glucose metabolism. In study 2, subjects received a repeat 3-h insulin clamp, and a balanced amino acid solution was infused to increase the plasma amino acid concentrations ∼ 2-fold to examine the effect of combined physiological hyperinsulinemia-hyperaminoacidemia on the rate of leucine and glucose disposal. Insulin-mediated total body glucose uptake was significantly reduced in NIDDM during both study 1 (5.6 ± 0.4 vs. 6.9 ± 0.6 mg · kg−1 · min−1 P < 0.01) and study 2 (5.2 ± 0.4 vs. 6.8 ± 0.6, P < 0.01). Basal plasma leucine (120 ± 10 vs. 123 ± 11 μM) and α-ketoisocaproic acid concentrations (28 ± 3 vs. 25 ± 2 μM) were similar in NIDDM and control subjects, respectively. In contrast, the basal plasma glucose concentration (8.9 ± 0.8 vs. 4.7 ± 0.2 μM) and the HbA1c (8.5 ± 0.2 vs. 5.7 ± 0.2%) were significantly increased in NIDDM (P < 0.01). In the postabsorptive state, endogenous leucine flux, leucine oxidation, and nonoxidative leucine disposal were similar in NIDDM and control subjects. When insulin was infused without amino acids (study 1), the decrement in plasma leucine (53 ± 5 vs. 48 ± 4 μM), endogenous leucine flux (13 ± 2 vs. 11 ± 1 μmol · m−2 · min−1), leucine oxidation (1.6 ± 0.2 vs. 1.3 ± 0.1 μmol · m−2 · min−1), and nonoxidative leucine disposal (10 ± 1 vs. 8 ± 1 μmol · m−2 · min−1) was comparable in both groups. During combined insulin and amino acid infusion (study 2), plasma leucine concentration (185 ± 20 vs. 190 ± 15 μM) rose similarly in NIDDM and control subjects. In NIDDM, the increment in leucine oxidation (9.0 ± 0.7 vs. 8.5 ± 0.6 μmol · m−2 · min−1) and nonoxidative leucine disposal (9.3 ± 0.7 vs. 10.5 ± 0.9 μmol · m−2 · min−1) was similar to that observed in control subjects; the decrement in endogenous leucine flux (22.3 ± 2.1 vs. 20.2 ±1.9 μmol · m−2 · min−1) was comparable in both groups. We conclude that 1) insulin-mediated glucose disposal is significantly impaired in NIDDM and 2) the effect of insulin on endogenous leucine flux (protein degradation), nonoxidative leucine disposal (protein synthesis), and leucine oxidation is similar in NIDDM and control subjects. These results indicate a clear-cut dissociation between the effect of insulin on glucose and protein metabolism in NIDDM.

Hyperinsulinemia

Glucose clamp technique

Basal (medicine)

Carbohydrate Metabolism

10.2337/diab.42.12.1868

Cite

Citations (79)

Beta Adrenergic Control of Extrarenal Potassium Disposal

The Nephron journals/Nephron journals (1986)

Margaret J. Bia David Lu Karen Tyler Ralph A. De Fronzo

Beta adrenergic control of extrarenal potassium disposal was evaluated by examining the effects of physiologic doses of beta adrenergic agonists and antagonists on potassium tolerance in acutely nephrectomized rats. Following an acute intravenous potassium load (0.17 mEq/100 g over 60 min), the plasma potassium concentration rose significantly less in animals concomitantly treated with epinephrine at a dose that raises plasma epinephrine concentration to levels found during surgical stress (maximum plasma K 2.2 vs. 2.9 mEq/l in controls receiving KCl alone; p < 0.005). Similar results were observed with the selective beta-2 agonists salbutamol and terbutaline. Conversely, the rise in plasma potassium concentration was significantly greater in rats treated with low-dose propranolol (beta-1 +beta-2 blockade) and with butoxamine (beta-2 blockade) compared to control animals. In contrast, the selective beta-1 blocking agent metoprolol had no effect on potassium tolerance. Alterations in potassium tolerance following the administration of various beta adrenergic agonists and antagonists could not be explained by changes in plasma insulin, renin, or glucose concentration or by differences in the acid-base or hemodynamic status of the animals. The data suggest that beta adrenergic control of extrarenal potassium disposal occurs with physiologic stimulation or blockade of the beta-2 receptor site.

Plasma renin activity

Terbutaline

BETA (programming language)

Sotalol

10.1159/000183809

Cite

Citations (28)

Glucose and Insulin Metabolism in Uremia

The Nephron journals/Nephron journals (1992)

Robert H. Mak Ralph A. De Fronzo

Review Articles| December 11 2008 Glucose and Insulin Metabolism in Uremia Subject Area: Nephrology Robert H.K. Mak; Robert H.K. Mak aDivision of Nephrology, Children's Hospital of Los Angeles University of Southern California, School of Medicine, Los Angeles, Calif; Search for other works by this author on: This Site PubMed Google Scholar Ralph A. De Fronzo Ralph A. De Fronzo bDivision of Diabetes, University of Texas Health Science Center at San Antonio, Tex., USA Search for other works by this author on: This Site PubMed Google Scholar Nephron (1992) 61 (4): 377–382. https://doi.org/10.1159/000186953 Article history Accepted: January 28 1992 Published Online: December 11 2008 Content Tools Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Robert H.K. Mak, Ralph A. De Fronzo; Glucose and Insulin Metabolism in Uremia. Nephron 1 April 1992; 61 (4): 377–382. https://doi.org/10.1159/000186953 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsNephron Search Advanced Search This content is only available via PDF. 1992Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Article PDF first page preview Close Modal You do not currently have access to this content.

Icon

10.1159/000186953

Cite

Citations (221)

New Insights on the Interactions Between Insulin Clearance and the Main Glucose Homeostasis Mechanisms

Roberto Bizzotto Domenico Tricò Andrea Natali Amalia Gastaldelli Elza Muscelli

Objective Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.e., at fixed ISR levels) and to analyze its associations with relevant physiologic factors. Research Design and Methods We estimated standardized EIC (EICISR) by mathematical modelling in 9 different studies with insulin and glucose infusions (N=2067). EICISR association with various traits was analyzed by stepwise multivariable regression, in studies with euglycemic clamp and OGTT (N=1410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N=1555). Results Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EICISR, ~4 times more influential than insulin-resistance related hypersecretion. EICISR independently associates positively with M/I, fasting and mean OGTT glucose or type 2 diabetes, and β-cell glucose sensitivity, and negatively with African American or Hispanic race, female sex, and female age. With oral glucose ingestion, an ISR-independent ~10% EIC reduction is necessary to explain the observed insulin concentration profiles. Conclusions Based on EICISR, we posit the existence of two adaptive processes involving insulin clearance: the first reduces EICISR with insulin resistance (not with higher BMI per se) and is more relevant than the concomitant hypersecretion; the second reduces EICISR with β-cell dysfunction. These processes are dysregulated in type 2 diabetes. Finally, oral glucose ingestion per se reduces insulin clearance.

Homeostasis

Glucose clamp technique

Carbohydrate Metabolism

10.2337/figshare.14785062

Cite

Citations (1)

Grasso corporeo totale e grasso regionale: rapporti con il metabolismo "in vivo" del glucosio in donne obese e non obese.

Enzo Bonora S. Del Prato Riccardo C. Bonadonna G. Gulli Anna Solini

Source

Cite

Citations (0)

Failure of glucagon to stimulate hepatic glycogenolysis in well-nourished patients with mild cirrhosis

Metabolism (1994)

Alexander S. Petrides Ralph A. De Fronzo

Glycogenolysis

Basal (medicine)

10.1016/0026-0495(94)90161-9

Cite

Citations (34)

New Insights on the Interactions Between Insulin Clearance and the Main Glucose Homeostasis Mechanisms

Roberto Bizzotto Domenico Tricò Andrea Natali Amalia Gastaldelli Elza Muscelli

Objective Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.e., at fixed ISR levels) and to analyze its associations with relevant physiologic factors. Research Design and Methods We estimated standardized EIC (EICISR) by mathematical modelling in 9 different studies with insulin and glucose infusions (N=2067). EICISR association with various traits was analyzed by stepwise multivariable regression, in studies with euglycemic clamp and OGTT (N=1410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N=1555). Results Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EICISR, ~4 times more influential than insulin-resistance related hypersecretion. EICISR independently associates positively with M/I, fasting and mean OGTT glucose or type 2 diabetes, and β-cell glucose sensitivity, and negatively with African American or Hispanic race, female sex, and female age. With oral glucose ingestion, an ISR-independent ~10% EIC reduction is necessary to explain the observed insulin concentration profiles. Conclusions Based on EICISR, we posit the existence of two adaptive processes involving insulin clearance: the first reduces EICISR with insulin resistance (not with higher BMI per se) and is more relevant than the concomitant hypersecretion; the second reduces EICISR with β-cell dysfunction. These processes are dysregulated in type 2 diabetes. Finally, oral glucose ingestion per se reduces insulin clearance.

Homeostasis

Glucose clamp technique

Carbohydrate Metabolism

10.2337/figshare.14785062.v1

Cite

Citations (0)

Book Reviews

The Nephron journals/Nephron journals (1992)

Robert H. Mak Ralph A. De Fronzo R. A. P. Koene D. Kampf Kai‐Uwe Eckardt

10.1159/000186982

Cite

Citations (0)