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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 7 2338-2342
Copyright © 1998 by The Endocrine Society

From the Clinical Research Centers

Free Fatty Acids and Insulin Resistance during Pregnancy1

Eyal Sivan, Carol J. Homko, Paul G. Whittaker, E. Albert Reece, Xinhua Chen and Guenther Boden

Departments of Obstetrics/Gynecology (E.S., C.J.H., P.G.W., E.A.R.) and Medicine (X.C., G.B.), Temple University Hospital, Philadelphia, Pennsylvania 19140

Address all correspondence and requests for reprints to: Guenther Boden, M.D., Temple University Hospital, 3401 North Broad Street, Philadelphia, Pennsylvania 19140.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The purpose of this study was to determine whether elevation of plasma free fatty acids (FFA) in early pregnancy would cause alterations in insulin-stimulated glucose disposal similar to those occurring in late gestation. Seven glucose-tolerant women underwent 4-h euglycemic hyperinsulinemic (1 mU/kg·min) clamping during the early second trimester of pregnancy (14–17 weeks) on 2 consecutive days, receiving either lipid (Liposyn II; 1.5 mL/min) and heparin (0.4 U/kg·min; L/H) or saline/glycerol (2.25 g/h; S/G) infusions. Rates of total body glucose disposal (6,6-2H2 glucose) and of carbohydrate and fat oxidation (indirect calorimetry) were determined at hourly intervals. Blood glucose was clamped at about 85 mg/dL. Plasma FFA increased from 290 ± 50 to 1000 ± 139 µmol/L during L/H infusion and decreased from 351 ± 60 to 35 ± 11 µmol/L during S/G infusion. L/H infusion inhibited insulin stimulation of total body glucose disposal by 28% compared with S/G infusion (from 6.7 ± 0.7 to 4.9 ± 0.6 mg/kg·min; P < 0.01). L/H infusion increased fat oxidation from 0.73 ± 0.04 to 1.26 ± 0.2 mg/kg·min (P < 0.05) and decreased carbohydrate oxidation from 2.0 ± 0.2 to 1.6 ± 0.2 mg/kg·min (P < 0.05). Endogenous glucose production decreased equally by approximately 70% during L/H and S/G infusions. These data showed that elevating plasma FFA levels during early pregnancy inhibits total body glucose uptake and oxidation. We conclude that elevation of plasma FFA can contribute to the peripheral insulin resistance commonly observed during late pregnancy.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INSULIN sensitivity is normal or increases during early gestation (<20 weeks gestation), but decreases progressively during late pregnancy (1). Longitudinal studies have shown that insulin-stimulated glucose disposal declined by about 50% in lean (1) and by about 40% in obese women (2) at the end of the third trimester of pregnancy. The reason for this deterioration in insulin sensitivity is not well understood, although it has been generally assumed to be the result of rising blood levels of diabetogenic hormones, including human placental lactogen and estrogens (1, 3). However, there are reasons to believe that plasma free fatty acids (FFA) may play a role in the development of insulin resistance during late pregnancy. First, levels of plasma FFA have been shown to be elevated in late pregnancy (4, 5). Second, raising plasma FFA levels in pregnant rabbits has been shown to induce insulin resistance, whereas lowering FFA levels improved insulin action (6, 7). Third, studies in human subjects have demonstrated that physiological elevation of plasma FFA inhibited insulin-stimulated glucose uptake dose dependently in normal men (8) and in patients with type II diabetes (9). However, no studies have been performed to examine this issue in pregnancy. The purpose of this study was, therefore, to determine whether elevations of plasma FFA in early gestation (when insulin sensitivity is normal) would produce deterioration of insulin sensitivity comparable to that commonly seen in late gestation.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Seven healthy pregnant women were studied. The subjects’ ages, weights, heights, body mass indexes (BMIs), and body compositions are shown in Table 1Go. Three of the women were lean (BMI, <27.3), and four subjects were overweight (BMI, >27.3). None of the subjects had a family history of diabetes or other endocrine disorders, and none was taking any medication. All subjects were seen by a dietitian before the studies to standardize their food intake. Their diet contained a minimum of 250 g carbohydrate (CHO) for at least 2 days before the studies. Before the study, all subjects underwent a 3-h oral glucose tolerance test. The results were within the normal range based on the criteria of Carpenter and Coustan (10). The studies were approved by the Temple University Hospital institutional review board, and informed consent was obtained from each subject before the study.


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  		Table 1. Study subjects (n = 7)

 
Experimental design

All subjects were studied during the early second trimester (16 ± 1 weeks) on 2 consecutive days at the General Clinical Research Center at Temple University Hospital. Women were randomly assigned to receive either a lipid/heparin (L/H) infusion or a saline/glycerol (S/G) infusion to prevent a potential "order effect." Previous studies in the nonpregnant state have shown that the effect of elevated FFA on CHO metabolism lasts approximately 3 h; therefore, the studies could be completed on 2 consecutive days without influencing study results (8). L/H was infused to increase plasma levels of FFA, and the S/G infusion served as a control. The addition of glycerol to the saline infusion was needed to control for the presence of glycerol in the lipid solution. The amount of glycerol used in the control studies was matched to the amount of glycerol present in the Liposyn solution. During the studies, the subjects were reclining in bed. A short polyethylene catheter was inserted into an antecubital vein for infusion of test substances. Another catheter was placed into a contralateral forearm vein for blood sampling. This arm was kept at approximately 70 C with a heating blanket to arterialize venous blood (11). After an overnight fast (at ~0800 h), a 4-h euglycemic-hyperinsulinemic clamp was performed with the infusion of stable isotopes (for measurement of glucose turnover) and indirect calorimetry (for estimation of rates of CHO and fat oxidation). After completion of each study day, women were fed a late lunch and dinner.

Euglycemic hyperinsulinemic clamps

Regular human insulin (Humulin R, Eli Lilly Co., Indianapolis, IN) was infused iv at a rate of 1 mU/kg·min for 4 h starting at 0 min. Glucose concentrations were maintained at about 85 mg/dL by a variable rate infusion with 20% glucose, as previously described (12).

Infusions

During L/H infusions, Liposyn II (Abbott Laboratories, North Chicago, IL), a 20% triglyceride emulsion (10% safflower, 10% soy bean oil, and 2.5 g glycerol/100 mL) plus heparin (0.4 U/kg·min) were infused at a rate of 1.5 mL/min for 4 h. During S/G infusions, glycerol was infused at a rate of 2.25 g/h to simulate the infusion of glycerol contained in Liposyn II.

Glucose turnover

Glucose turnover was determined using the stable isotope 6,6-2H2 glucose as previously described (13) on both study days. Data from our pilot study demonstrated that complete washout of the tracer was achieved between consecutive studies (baseline enrichment was similar between the two studies). Briefly, the tracer was infused iv for 5.5 h (-90 to 240 min) starting with a bolus of 5.3 mg/kg followed by a continuous infusion of 0.05 mg/kg·min. To assure isotope equilibration, the tracer infusion was started 90 min before initiation of the clamp. To avoid changes in the isotope enrichment of plasma glucose during the hyperinsulinemia, 6,6-2H2 glucose was added to the unlabeled glucose, which was infused at a variable rate to maintain euglycemia (14). Blood was drawn at 60-min intervals for determination of 6,6-2H2 glucose enrichment, which was determined with a gas chromatograph-mass spectrometer (model 5890, Hewlett-Packard, Palo Atlo, CA). The penta-acetyl derivative of glucose was measured by the electron impact mode at 70 eV. Ions were measured at m/e 200 and 202, respectively. Rates of total body glucose appearance (GRa) and disappearance (GRd) were calculated using Steele’s equation (15).

Indirect calorimetry

Respiratory gas exchange rates were determined, as previously described (16), before and at 30-min intervals during the clamp with a metabolic measurement cart (Beckman Instruments, Palo Alto, CA). Rates of protein oxidation were estimated from urinary nitrogen excretion after correction for changes in the urea nitrogen pool size (17). Rates of protein oxidation were used to determine the nonprotein respiratory quotient. Rates of CHO and fat oxidation were determined with the tables of Lusk, which are based on a nonprotein respiratory quotient of 0.707 for 100% fat oxidation and 1.00 for 100% CHO oxidation.

Body composition

Body composition was assessed using a portable bioelectrical impedance meter (RJL Systems, Clinton Township, MO). Total body water was calculated using the equation of Lukaski et al., which was derived from pregnant women and validated against the deuterium-labeled water technique (18).

Fetal assessment

Fetal well-being was assessed every 30 min throughout the insulin infusions in both studies by ultrasound determinations of fetal heart rate. None of the women participating in this study developed any medical complications, and all delivered healthy babies.

Endogenous glucose production (EGP)

Most (>75%) of the EGP comes from the liver, whereas the kidneys at times may produce small amounts of glucose (19). EGP was calculated as the difference between the isotopically determined GRa and the glucose infusion rates (GIR) needed to maintain euglycemia during insulin infusion (EGP = GRa - GIR).

Analytical procedure

Plasma glucose was measured with a glucose analyzer (Beckman Instruments). Plasma free insulin was determined by RIA after polyethylene glycol precipitation using an antiserum with minimal (<0.2%) cross-reactivity with proinsulin (Linco Research, St. Charles, MO). Blood samples for FFA and glycerol determinations were collected in prechilled tubes containing ethylenediamine tetraacetate and Paroxon (Sigma Chemical Co., St. Louis, MO), a lipoprotein lipase inhibitor (0.275 mg/mL blood). Plasma FFA were measured enzymatically.

Statistical analysis

All data were expressed as the mean ± SEM. Statistical significance was set at P < 0.05 and was assessed using ANOVA with repeated measures and Student’s two-tailed paired or unpaired t test where applicable.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Plasma insulin, glucose, FFA, and glycerol levels (Fig. 1Go)

In both studies, insulin infusion raised plasma insulin concentrations from approximately 4.5 to about 70 µU/mL. Plasma glucose was clamped at about 85 mg/dL (coefficient of variation, 8.5%). During the L/H infusions, plasma FFA increased from 290 ± 50 µmol/L before to 1000 ± 139 µmol/L at the end of the clamp. During the S/G infusions, plasma FFA concentrations decreased from 351 ± 60 µmol/L at baseline to 35 ± 11 µmol/L at study end. The two FFA concentration curves were significantly different from each other (overall comparison of groups by ANOVA with repeated measures, P < 0.05). This difference became apparent at the first measurement at 60 min (Fig. 1Go, panel 3). It should be noted that the rise in FFA reached a plateau only after 180 min of infusion. In previous studies in nonpregnant subjects, plasma FFA rose faster because a bolus of heparin was given at the start of the infusion (8, 9).



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  		Figure 1. Euglycemic hyperinsulinemic clamps with L/H (•) or S/G ({blacksquare}) infusions. Serum glucose (top), serum insulin (middle), and FFA (bottom) concentrations in seven healthy pregnant women in the early second trimester. Shown are the mean ± SE. *, P < 0.05; **, P < 0.01 (comparing L/H with S/G).

 
The plasma glycerol concentration was 88 ± 14 µmol/L at baseline on both study days. Plasma glycerol levels increased to 674 ± 145 and 203 ± 22 µmol/L (P = 0.009), respectively, when L/H and S/G were infused.

Effect of lipid on GRd (Fig. 2Go)

The increase in GRd was nearly identical during the first 2 h of L/H and S/G infusions. Thereafter, however, the two curves diverged, so that during the last hour of the study GRd was about 28% lower during L/H than during S/G infusion (5.0 ± 1.4 vs. 6.5 ± 1.1 mg/kg·min; P = 0.02).



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  		Figure 2. GRd during euglycemic hyperinsulinemic clamps with L/H (•) or S/G ({blacksquare}) infusion. **, P < 0.01, comparing L/H with S/G.

 
Effect of lipid on CHO and fat oxidation (Fig. 3Go)

During L/H infusion, fat oxidation rose from 0.7 ± 0.04 at 0 min to 1.3 ± 0.2 mg/kg·min at 240 min (P < 0.05). During S/G infusion, fat oxidation decreased from 0.8 ± 0.2 at 0 min to 0.6 ± 0.1 mg/kg·min at 240 min (P < 0.05). The difference between the two studies became statistically significant (P < 0.05) at the first measurement at 60 min (Fig. 3Go, panel 1) and at each time point thereafter.



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  		Figure 3. Euglycemic hyperinsulinemic clamps with L/H (•) or S/G ({blacksquare}) infusions. Rates of fat (top) and CHO (middle) oxidation. In the bottom panel, CHO oxidation was normalized by setting baseline values (0 min) at 100%. *, P < 0.05, comparing L/H with S/G.

 
During the L/H infusion, CHO oxidation declined significantly from 2.0 ± 0.2 mg/kg·min at baseline to 1.6 ± 0.2 mg/kg·min at 240 min (P < 0.05). In contrast, during the S/G infusions, CHO oxidation increased from 1.5 ± 0.3 to 2.2 ± 0.2 mg/kg·min at 4 h of insulin infusion (P < 0.05; see Fig. 3Go, panel 2). To better illustrate these directional changes, CHO oxidation was normalized with basal values (0 min) set at 100%. As shown (Fig. 3Go, panel 3), the difference between L/H and S/G infusions became statistically significant (P < 0.05) at the first measurement at 60 min.

EGP (Fig. 4Go)

Basal EGP did not differ significantly between the L/H and S/G infusion groups when comparing individual time points or for the overall comparison of the curves. EGP was equally suppressed by hyperinsulinemia in both infusion groups (from 1.25 ± 0.06 to 0.37 ± 0.17 mg/kg·min with L/H and from 1.25 ± 0.10 to 0.41 ± 0.26 mg/kg·min with S/G at 240 min; -71%; P < 0.05).



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  		Figure 4. EGP during euglycemic hyperinsulinemic clamps with L/H (open bar) or S/G (hatched bar) infusions.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Effect of lipid on GRd

This is the first study to demonstrate that a physiological increase in plasma FFA inhibited insulin-stimulated glucose uptake by approximately 30% (at 4 h) in healthy women during early pregnancy. This degree of insulin resistance was virtually identical to that observed in nonpregnant subjects tested under the same euglycemic-hyperinsulinemic clamp conditions (8). As in these nonpregnant subjects, 3–4 h of hyperinsulinemia and high plasma FFA levels were required for the insulin resistance to develop (8). A defect in glucose transport and/or phosphorylation has been postulated as the most likely cause for the FFA-mediated reduction in insulin-stimulated glucose uptake (20). On the other hand, the insulin resistance produced by fat infusion during early pregnancy (this study) was somewhat less than that reported to occur during late pregnancy (~30% vs. 40–50%) (1, 2). Hence, our results and those from previous studies are compatible with the idea that the rise in plasma FFA commonly observed during late pregnancy may account for some, but not all, of the insulin resistance that develops during this period. Although unlikely, a direct effect of heparin (present in the L/H infusions but not in the S/G control infusions) cannot be completely excluded. Increases in plasma FFA may be due to the lipolytic action of placental hormones, notably human placental lactogen (hPL), which reach very high blood levels during late gestation (21, 22). On the other hand, it is well known that hPL and other gestational hormones (i.e. estrogens) have diabetogenic actions that are unrelated to the release of FFA (23). This may explain why raising plasma FFA levels in our studies did not produce the same degree of insulin resistance that has been observed in normal women during the third trimester of pregnancy (1, 2).

Glycerol levels were significantly higher in the L/H group despite the fact that an equivalent amount of glycerol was added to the control infusions. This increase in glycerol levels was presumably due to the intravascular lipolytic effect of heparin. However, the reduction in the rate of glucose disposal in the lipid/heparin group was unrelated to this finding, because previous studies in our laboratory have demonstrated that glycerol has no direct effect on peripheral insulin resistance (G. Boden, unpublished data).

Effect of lipid on CHO and fat oxidation

Fat oxidation increased whereas CHO oxidation decreased by 60 min after initiation of the lipid infusion (+46% and -20%, respectively). This effect of lipid is consistent with the observed switch from CHO to fat oxidation previously observed in late gestation. This phenomenon has been termed accelerated starvation by Freinkel (22).

It should be noted, however, that the FFA-induced increase in fat oxidation was not responsible for the increase in insulin resistance, as the inhibition of fat oxidation preceded by several hours the inhibition of insulin-stimulated glucose uptake. Similar results have been reported for nonpregnant normal and diabetic subjects (9, 24).

Effect of FFA on EGP

EGP was equally suppressed (by ~70%) by insulin in the L/H studies and in the S/G controls, indicating that FFA had no net effect on EGP. Although there are no previous data for pregnant females, increased plasma FFA levels have been reported to inhibit insulin suppression of EGP either modestly or not at all in nonpregnant individuals (for review, see Ref. 24). The best explanation of these somewhat contradictory results is that, on the one hand, FFA are very likely to stimulate hepatic gluconeogenesis (25, 26), which would tend to increase EGP. On the other hand, they stimulate insulin secretion, which would tend to decrease EGP (27). Glucagon, which is known to stimulate endogenous glucose production, is not affected by elevations of FFA as previously shown (20) and, therefore, is unlikely to affect the observed results.

Physiological relevance

Pregnancy has been characterized as a hyperlipidemic state. A number of investigators have shown that levels of FFA are elevated in late gestation compared to those during the nonpregnant state. In addition, it has been demonstrated that the placental hormones, specifically hPL, stimulate FFA release from adipose tissue (25). Both hPL and FFA levels decrease precipitously immediately after delivery. The increase in FFA during pregnancy may contribute to the increase in insulin resistance observed during pregnancy. Although the levels of FFA induced in our study were slightly higher than those normally observed in late gestation, an important relationship between FFA levels and insulin resistance has been demonstrated. The development of insulin resistance during late pregnancy is a normal physiological adaptation that shifts maternal energy metabolism from CHO to lipid oxidation and thus spares glucose for the growing fetus (22).

Women with gestational diabetes mellitus demonstrate an increase in insulin resistance beyond that observed in the normal pregnant state. Interestingly, these women have also been shown to have levels of FFA that exceed those of pregnant nondiabetic controls (26). Our data support the idea that FFA play a role in the pathogenesis of insulin resistance and gestational diabetes.


   Acknowledgments
 
We thank the nurses of the General Clinical Research Center for assistance with the clinical studies, Karen Davis and Maria Mozzoli for technical assistance, and Constance Harris for typing the manuscript. We also thank Peter Stein (University of Medicine and Dentistry of New Jersey, Stratford, NJ) for use of the gas chromatography-mass spectrometry facilities.


   Footnotes
 
1 This work was supported by NIH Grants RO1-AG-07988 (to G.B.), RO1-AA-10221 (to G.B.), RR-349 (to the General Clinical Research Center), a mentor-based doctoral fellowship grant from the American Diabetes Association (to G.B.), and Grant 6-FY94-0300 from the March of Dimes (to E.A.R.). Back

Received December 3, 1997.

Revised February 2, 1998.

Accepted March 23, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Catalano PM, Tyzibir ED, Roman NM, Amini SB, Sims EAH. 1991 Longitudinal changes in insulin resistance in non-obese pregnant women. Am J Obstet Gynecol. 165:1667–1772.[Medline]
  2. Sivan E, Chen XC, Homko CJ, Reece EA, Boden G. 1997 A longitudinal study of carbohydrate metabolism in healthy, obese pregnant women. Diabetes Care. 20:1470–1475.[Abstract]
  3. Desoyne G, Schweditsch O, Pfeiffer KP, Zechner R, Kostner GM. 1987 Correlation of hormones with lipid and lipoprotein levels during normal pregnancy and postpartum. J Clin Endocrinol Metab. 64:704–712.[Abstract/Free Full Text]
  4. Phelps RL, Metzger BE, Freinkel N. 1981 Carbohydrate metabolism in pregnancy. XVII. Diurnal profiles of plasma glucose, insulin, free fatty acids, triglycerides, cholesterol, and individual amino acids in late normal pregnancy. Am J Obstet Gynecol. 140:730–736.[Medline]
  5. Hubel CA, McLaughlin MK, Evans RW, Hauth BA, Sims CJ, Roberts JM. 1996 Fasting serum triglycerides, free fatty acids, and malondialdehyde are increased in preeclampsia, are positively correlated, and decrease within 48 hours postpartum. Am J Obstet Gynecol. 174:975–982.[CrossRef][Medline]
  6. Hauguel S, Gilbert M, Girard J. 1987 Pregnancy-induced insulin resistance in liver and skeletal muscles of the conscious rabbit. Am J Physiol 252:E165–E169.
  7. Gilbert M, Basile S, Baudelin A, Pere AMC. 1993 Lowering plasma free fatty acid levels improves insulin action in conscious pregnant rabbits. Am J Physiol 264:E576–E582.
  8. Boden G, Jadali F, White J, et al. 1991 Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. J Clin Invest. 88:960–966.
  9. Boden G, Chen X. 1995 Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes. J Clin Invest. 96:1261–1268.
  10. Carpenter MW, Coustan DR. 1982 Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol. 144:768–773.[Medline]
  11. Abumrad NN, Rabin D, Diamond MP, Lacy WW. 1981 Use of a heated superficial hand vein as an alternative site for the measurement of amino acid concentrations and for the study of glucose and alanine kinetics in man. Metabolism. 30:936–940.[CrossRef][Medline]
  12. Boden G, DeSantis R, Chen X, Morris M, Badoza F. 1993 Glucose metabolism and leg blood flow after pancreas/kidney transplantation. J Clin Endocrinol Metab. 76:1229–1233.[Abstract]
  13. Boden G, Chen X, DeSantis R, White J, Mozzoli M. 1993 Effects of ethanol on carbohydrate metabolism in the elderly. Diabetes. 42:28–34.[Abstract]
  14. Molina JM, Baron AD, Edelman SV, Brechtel G, Wallace P, Olefsky JM. 1990 Use of a variable tracer infusion method to determine glucose turnover in humans. Am J Physiol 258:E16–E23.
  15. Steele R, Wall JS, DeBodo RC, Altszuler N. 1956 Measurement of size and turnover rate of body glucose pool by the isotope dilution method. Am J Physiol. 187:15–24.[Abstract/Free Full Text]
  16. Owen OE, Trapp VE, Reichard Jr GA, Mozzoli MA, Smith R, Boden G. 1980 Effects of therapy of the nature and quantity of fuels oxidized during diabetic ketoacidosis. Diabetes. 29:365–372.[Medline]
  17. Tappy L, Owen OE, Boden G. 1988 Effect of hyperinsulinemia on urea pool size and substrate oxidation rates. Diabetes. 37:1212–1216.[Abstract]
  18. Lukaski HC, Siders W, Nielsen EJ, Hall CB. 1994 Total body water in pregnancy: assessment by using bioelectrical impedance. Am J Clin Nutr. 59:578–585.[Abstract/Free Full Text]
  19. Stumvoll M, Chintalapudi U, Perriello G, Welle S, Gutierez O, Gerich J. 1995 Uptake and release of glucose by human kidney. J Clin Invest. 96:2528–2533.
  20. Boden G, Chen X, Ruiz J, White JV, Rossetti L. 1994 Mechanisms of fatty-acid induced inhibition of glucose uptake. J Clin Invest. 93:2438–2446.
  21. Montelongo A, Lasuncion A, Pallardo LF, Herrera E. 1992 Longitudinal study of plasma lipoproteins and hormones during pregnancy in normal and diabetic women. Diabetes. 41:1651–1659.[Abstract]
  22. Freinkel N. 1980 Banting lecture 1980: of pregnancy and progeny. Diabetes. 29:1023–1035.[Abstract]
  23. Turtle JR, Kipnis DM. 1967 The lipolytic action of human placental lactogen in isolated fat cells. Biochim Biophys Acta. 144:583–593.[Medline]
  24. Boden G. 1997 Perspectives in diabetes: Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes. 46:3–10.[Abstract]
  25. Williamsson JR, Kreisberg RA, Felts PW. 1996 Mechanism for the stimulation of gluconeogensis by fatty acids in perfused rat liver. Proc Natl Acad Sci USA. 6:247–254.
  26. Morand C, Remesy C, Demigne C. 1993 Fatty acids are potent modulators of lactate utilization in isolated hepatocytes from fed rats. Am J Physiol 264:E816–E823.
  27. Boden G, Chen X, Rosner J, Barton M. 1995 Effects of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes. 44:1239–1242.[Abstract]



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