GASTROENTEROLOGY 1991;100:245-251

Insulin Resistance in Noncirrhotic Idiopathic Portal Hypertension ALEXANDER

S. PETRIDES,

CAROLINE

A. RIELY,

and RALPH A. DEFRONZO Division of Hepatology and Gastroenterology, Department of Internal Medicine, Heinrich-HeineUniversitlt, Diisseldorf, Germany

To explore further the pathogenesis of glucose intolerance and insulin resistance observed in patients with cirrhosis and portal hypertension, we studied a %-year-old woman with presinusoidal portal hypertension without cirrhosis due to nodular regenerative hyperplasia of the liver. After oral glucose ingestion, glucose tolerance remained normal; however, this occurred at the expense of a markedly hyperinsulinemic plasma response, suggesting the presence of insulin resistance. To examine this question more directly, we performed a stepwise euglycemic insulin clamp study in combination with an infusion of [6-3H]glucose and [l-‘4C]palmitate and indirect calorimetry. The ability of insulin to promote total body (primarily muscle) glucose uptake was markedly impaired, whereas its effect to suppress hepatic glucose production was normal compared with results obtained in nine healthy subjects. Moreover, insulin failed to normally suppress plasma free fatty acid turnover and oxidation in this patient. This informative case demonstrates that portal hypertension alone, without hepatic dysfunction from cirrhosis, is associated with impaired insulinmediated glucose and plasma free fatty acid metabolism and may also play a predominant role in the development of insulin resistance in many cirrhotic patients.

I

mpaired sensitivity to the action of insulin and the development of glucose intolerance and overt diabetes mellitus are features characteristic of patients with cirrhosis (1).The pathogenetic factor(s) leading to the defect in insulin-mediated glucose metabolism have yet to be clearly defined. A defect of glycogen synthesis in muscle tissue was recently identified as the major determinant of insulin resistance in cirrhosis (2,s). The question remains, however, whether impaired glucose metabolism is caused by the presence of liver disease per se (e.g., impaired liver function) or

by portosystemic shunting (e.g., by the action of hormones shunted around the liver). In most cirrhotic patients, both alterations are present and separating one contribution from the other is quite difficult. To examine whether portal hypertension per se is associated with alterations of carbohydrate and lipid metabolism, the effect of insulin on glucose [and also plasma free fatty acid (FFA)] metabolism was studied in a 3%year-old woman with presinusoidal portal hypertension caused by nodular regenerative hyperplasia of the liver in the absence of any measurable impairment of liver function. Materials

and Methods

Subjects The 35-year-old normal-weight patient had experienced two short episodes of jaundice at age 19 that resolved within a few days and never recurred. However, since that time she had diffuse abdominal pain without any symptoms of liver disease. The patient denied fever or pruritus, and her appetite was good. She denied alcohol or drug abuse and was never chronically on any medication. Liver function tests through the years have intermittently shown minimal elevated transaminase levels [maximum: serum glutamic pyruvic transaminase (SGPT), 117 U/L; serum glutamic oxaloacetic transaminase (SGOT), 121 U/L] and a mild increase of alkaline phosphatase (200 U/L). All other laboratory tests have shown normal results. Multiple biopsies over the years have been unrevealing, showing some increase in portal fibrosis but otherwise nonspecific findings. There was no history of acute or chronic hepatitis; results of hepatitis B serologies were negative. Tests for antinuclear antibodies (ANA) and antimitochondrial anti-

Abbreviations used in this paper: ANA, antinuclear antibodies: AMA, antimitocbondrial antibodies: HGP, hepatic glucose production. o 1991 by the American Gastroenterological Association 9016-5005/91/$3.00

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bodies (AMA) were negative. In 1982, endoscopy of upper gastrointestinal tract showed esophageal varices. The patient was well until 1984, when she suddenly experienced impressive ascites and edema. Because of this, administration of spironolactone was started in a dose of 150 mg/ day. Fluid retention resolved but she remained fatigued. On physical examination at presentation in 1985, the liver span was normal but the spleen was enlarged, felt three fingerbreadths below the left costal margin. There were no other signs of chronic liver disease. Abdominal ultrasound did not show any other abnormalities than splenomegaly. The liver biopsy specimen was read as suggesting vague nodularity but otherwise showing normal structure of liver parenchyma without fibrosis. There was no sign of alteration of the architecture of arterial or central venous vessels, but some sclerosis of small portal vessels was found. Ultrastructural findings on electron microscopy were nonspecific and did not demonstrate any primary pathogenic process. Altogether, histological results were interpreted as nodular regenerative hyperplasia of the liver. The hepatic wedge venous pressure gradient was normal, but the patient did have large varices (grade IV) on upper endoscopy. Since 1985, transaminase levels have been nearly normal or somewhat elevated (maximum for both, 80 U/L) and alkaline phosphatase levels have been either normal or slightly elevated (maximum, 199 U/L). All parameters of liver function such as albumin and bilirubin level and prothrombin time have been normal; other laboratory tests of renal function and electrolytes have showed results within normal limits. Studies in nine normal-weight, healthy volunteers (five men, four women; age, 48 k 3 years; range, 34-61 years) performed in our laboratory under identical conditions served as controls. None of the subjects had any history of diabetes or other major organ disease. Before participation, the nature, purpose, and risks of the studies were explained to all subjects, and their voluntary, informed, written consent was obtained. The experimental protocol was approved by the Human Investigation Committee of Yale University School of Medicine. Experimental

Protocol

Each subject participated in two studies performed with a l-week interval at the Clinical Research Center at Yale University School of Medicine. Study 1: oral glucose tolerance test. After a lo-l2hour overnight fast, a 75-g oral glucose load was administered, and plasma glucose, insulin, and FFA concentrations were measured over a period of 2 hours. Study 2: euglycemic hyperinsulinemic clamp study. Studies were performed with subjects in the recumbent position at 8 AM after a IO-12-hour overnight fast, as previously described (4). After the basal period, a stepwise (0.1, 0.5, and 1.0 mu. kg-’ . min-I), primed continuous infusion of crystalline porcine insulin (Lilly, Indianapolis, IN) was administered to acutely raise and maintain the plasma insulin concentration by approximately 5-10, 3040, and 70-80 kU/mL above the basal concentration. The three insulin steps lasted 100 minutes each. The plasma glucose concentration was held constant at the basal prein-

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fusion level by determining the plasma glucose concentration every 5 minutes and adjusting appropriately by infusing a 20% glucose solution based on the negative-feedback principle (4).

Tracer Application One hundred twenty minutes before beginning the insulin clamp studies, a bolus dose of n-[6-3H]glucose (25 FCi; New England Nuclear, Boston, MA) and [ l-‘4C]palmitate (2 l&i; New England Nuclear) was rapidly injected, and a constant infusion ([6-3H]glucose, 0.25 pCi/min; [1-“‘Clpalmitate, 0.1 $Zi/min) was begun and continued throughout the insulin clamp studies. The labeled FFA was supplied in toluene, and after drying under nitrogen it was resuspended in 25% human serum albumin. To prime the bicarbonate pool, a bolus injection of sodium [l-‘C]bicarbonate (3.7 pCi; New England Nuclear) was also given at the beginning of the study. During the basal period and during the last 20-30 minutes of each step of the insulin clamp, when substrate and isotopic steady-state conditions were achieved, plasma samples were drawn every 5 minutes for determination of tritiated glucose and ‘C-FFA specific activity. To test the effect of time on the rate of FFA turnover and oxidation, we recently performed experiments in which we could demonstrate that, under the present experimental conditions, isotopic steady state is achieved 60 minutes after beginning the insulin infusion (5).

Respiratory Gas Exchange

Measurements

For 60 minutes before the stepwise insulin clamp study and during the last 60 minutes of each step, continuous indirect calorimetry was performed as previously described (6). A transparent plastic ventilated hood was placed over the head of the subject and made airtight around the neck. A slight negative pressure was maintained in the hood to avoid loss of expired air. Ventilation was measured by a dry gas meter (American Meter Division, Singer Co., Philadelphia, PA). A constant fraction of the air flowing out of the hood was automatically collected for analysis. Carbon dioxide content was continuously measured by an infrared analyzer (Model CD 3A carbon dioxide analyzer; Applied Elektrochemistry, Sunnyvale, CA).

Expired Air Collection The rate of oxidation of plasma FFA was calculated from the specific activity of expired CO, during the 14Cpalmitate infusion (see below). Expired air samples were collected at 5-minute intervals during the last 20 minutes of the baseline and each clamp step, respectively, and were bubbled through a carbon dioxide trapping solution (hyamine hydroxide, absolute ethanol, 0.1% phenolphthalein; 3:5:1, vol:vol:vol). The solution was titrated to trap 1 mmol/CO, per 3 mL of solution. The ‘C-radioactivity was subsequently determined using a Packard (Packard Instruments, Downers Grove, IL) Tricarb Scintillation Counter, and the expired ‘CO, specific activities were calculated.

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Total 14C0, expired per minute was determined by multiplying the 14C0, specific activity by the total CO, production measured by indirect calorimetry.

Analytical Determinations Plasma glucose concentration was determined in duplicate by the glucose oxidase method on a Beckman glucose analyzer II (Beckman Instruments Inc., Fullerton, CA). The method for determination of plasma tritiated glucose specific activity has been published previously (7). Plasma insulin concentrations were measured by specific radioimmunoassays (8). Plasma FFA concentrations were measured by the microfluorometric method of Miles et al. (9). To determine Y-FFA specific activity, 1.5 mL of plasma was extracted with 10 mL of Doles solution. Free fatty acids were isolated from the lipid phase using 0.02N NaOH and reextracted after acidification with heptane. The heptane extraction was repeated three times, and 96% of the radioactivity was recovered in the heptane phase. The extracts were dissolved in Scintiverse scintillation liquid and counted in a Packard Tricarb Scintillation Counter.

Calculations Glucose metabolism. During the stepwise insulin studies, the glucose infusion rate was determined by calculating the mean value observed during selected time intervals. For data presentation, the mean of the last 60 minutes of each insulin-infusion step was used. Total glucose metabolism was calculated by adding the mean rate of endogenous glucose production during the last 60 minutes of each insulin-infusion step to the mean glucose infusion rate during the same period. In all studies, a steady-state plateau of tritiated glucose specific activity was achieved during the 26-minute period before starting the insulin clamp. Glucose production in the basal state was determined by dividing the [6-3H]glucose infusion rate by the steady-state plateau of [6-3H]glucose specific activity achieved during the last 36 minutes of the pm-insulin-infusion control period. After glucose/insulin administration, a non-steady-state condition in glucose specific activity exists. Hepatic glucose production was calculated by Steele’s equations in the derivative form (10); this permits the evaluation of continuous changes in the rates of glucose turnover. The value of 0.65 was used as the pool fraction in the present calculations (11). The determination of glucose turnover by the primed continuous infusion and pool-fraction technique has recently been validated for both steady- and non-steady-state conditions (12). The rate of endogenous glucose production was calculated by subtracting the glucose infusion rate from the rate of glucose appearance (Ra) as determined by the isotopic tracer technique. Negative numbers for HGP were assumed to be zero. Glucose oxidation was calculated from continuous calorimetric measurements during the last 46 minutes in the basal state and during the last 40 minutes of each insulininfusion step, as previously described (6). Nonoxidative

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glucose disposal was calculated by subtracting the rate of glucose oxidation from the rate of total body glucose uptake. Plasma free fatty acid metabolism. Plasma FFA concentrations and specific activities were constant during the last 30 minutes of the equilibration period and the last 40 minutes of each insulin clamp step. Therefore, steady-state conditions were assumed to calculate rates of FFA turnover. Palmitic acid accounts for about 36% of the total F’FA pool independently of the plasma concentration (13). Because palmitate is thought to be typical of other long-chain fatty acids (13,14), the fractional turnover of palmitate can be assumed to be similar to that of total FFA. Therefore, labeled palmitate can be used to trace the total FFA fraction when studying whole-body FFA turnover in humans. FFA turnover was calculated as the rate of infusion of palmitate divided by the steady-state plasma FFA specific activity and is expressed as kmol . kg-’ . min-‘. It should be noted that the present tracer [‘4C]palmitateinfusion protocol differed significantly from that used by previous investigators (15,16). To achieve a steady state of 14C0, specific activity in expired air more quickly, we administered a bolus of palmitate and primed the bicarbonate pool with a bolus of sodium [‘4C]bicarbonate (17). Steady state of plasma [14C]FFA and ‘*CO, specific activity was achieved during the last 36-40 minutes of each insulin clamp. We have therefore used steady-state kinetic in the calculation of both the rate of FFA turnover and the rate of FFA oxidation. The rate of oxidation of plasma FFA (in kmol . kg-’ . min-‘) in the basal state and during the euglycemic insulin clamping was calculated from the “C-radioactivity in expired CO, divided by the product of the plasma specific activity and a factor k, which takes into account the incomplete recovery of labeled 14C0, from the bicarbonate pool (15,17); i.e., (SA CO,) x VCO,/k x (SA [14C]FFA), where SA “CO2 is the specific activity of CO, in expired air, VCO, is the total CO, production, SA [‘YJFFA is the specific activity of [‘*C]FFA in plasma, and k = 0.81.

Results The patient’s history, clinical, laboratory, and histological findings confirmed the diagnosis of portal hypertension caused by nodular regenerative hyperplasia of the liver.

Glucose Metabolism Oral glucose tolerance test. The patient showed normal glucose tolerance; fasting as well as postglucase plasma levels of insulin were elevated compared with those of the control group (Figure 1). Plasma FFA levels were increased in the patient in the fasting state and were somewhat less suppressed than in control subjects after the oral glucose load (Figure 1). Plasma glucose and insulin concentrations in the basal state and during insulin clamping. Fasting plasma glucose levels were similar in the patient and the control group (81 vs. 89 2 4 mg/dL) and remained

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Plasma Glucose (mgldl)

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patient with portal hypertension than in control subjects (Figure 2). Because glucose oxidation was stimulated by insulin to a similar extent in the patient and in controls during 0.5 and 1.0 mU . kg-’ . min’ insulin infusions, a decrease in nonoxidative glucose disposal (0.5 mU . kg-’ . min’: 0.00 vs. 3.05 + 0.15 and 1 mU * kg-‘. min-‘: 1.71 vs. mg . kg-’ . min’; 5.29 + 0.20 mg . kg-’ . min-‘) accounted entirely for the defect in total body glucose uptake.

180r

Plosmo Insulin (uU/ml)

Plasma Free FattyAcid Metabolism

Plosmo FFA (w&/l) 1500

1000 n

TIME

-

PAT

-

CON

(min)

Figure 1. Plasma glucose, insulin, and FFA concentrations after an oral glucose load. Shaded area represents the range of the control group.

constant at the basal level during three-step insulin clamping in all participants with coefficients of variation (CV) of 4.4% and 3.7% + 0.5%, respectively. The patient with portal hypertension exhibited fasting hyperinsulinemia (12 vs. 7 2 1; range, 4-12 $J/mL), but the increments of plasma insulin levels during the three insulin clamp steps were nearly identical in all subjects (+5, +3O, and +7O pU/mL, respectively). Hepatic glucose production. The basal rate of hepatic glucose production (HGP) was slightly decreased in our patient compared with the control group (1.55 vs. 1.94 f 0.11; range, 1.64-2.71 mg * kg-’ * min-I). The liver of the patient was very sensitive to insulin; HGP was somewhat more suppressed than in controls at the two higher insulin infusion steps (75% vs. 50%, 100% vs. 93%, and 100% in both at the time of 1 mU . kg-’ . min-’ clamping, respectively). Total body glucose metabolism. In the basal state, the rate of glucose disposal equals the rate of glucose appearance (HGP); it was slightly reduced in the patient (see above). Glucose uptake remained unchanged during O.l-mU clamping in either of the subjects. During the two higher insulin infusions, whole-body glucose uptake was less stimulated in the

In the basal state, plasma FFA levels were elevated in the patient with noncirrhotic portal hypertension compared with controls (Figure 3). In response to low-dose insulin infusion, plasma FFA concentrations declined in both the patient and controls but were still higher in the patient (Figure 3). At the two higher insulin concentrations, circulating FFA levels were suppressed to a similar degree in the patient and in the control group (Figure 3). The FFA turnover rate mirrored the behavior of plasma FFA concentration (Figure 3). In the basal state, the rate of plasma FFA oxidation was increased in the patient and remained elevated throughout all three insulin-infusion steps (Figure 3). Discussion The regenerative by multiple than that etiology is

underlying disease in our patient, nodular hyperplasia of the liver, is characterized regenerative nodules of a diameter smaller of the lobule, without fibrosis (18). Its often unknown (19). The development of 12

TOTAL

r

BODY GLUCQSE 10 UPTAKE hg/kg*min)

-

PAT

-

CON

a64-

2-

0.5

CM fnsulin

Infusion

1.0

(mU/kg.min)

Figure 2. Total body glucose uptake during the hyperinsulinemic euglycemic clamp studies. Shaded area represents the range of the control group.

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-

PAT

-coN

Pkxma FFA Turnover hol/kgmin)

10

5

Plasma FFA

Oxidation hnol/kg.min)

4r 3 2 1

0.1 1.0 0.5 Insulin Infusion (mU/kg~min) Figure 3. Plasma FFA concentrations, turnover, and oxidation rates in the basal state and during the hyperinsulinemic euglycemic clamp studies. Shaded urea represents the range of the control group.

portal hypertension is partially caused by distortion of intrahepatic portal vessels by the nodules. As was true in this case, recognizing the disease is generally difficult. Results of several liver biopsies had not been revealing, showing normal histology and no damage to the liver parenchyma. The finding of presinusoidal portal hypertension (confirmed by a normal hepatic venous pressure gradient) with esophageal varices in the presence of slightly elevated transaminase levels and normal liver function test results finally helped to define the diagnosis. As is characteristic for this disease, elevation of alkaline phosphatase levels was documented (19). Cirrhotic patients with portal hypertension commonly have peripheral hyperinsulinemia (1,2,2 O-2 3). To examine the separate effect of portosystemic shunting on insulin metabolism, several studies have measured plasma glucose and insulin concentrations in cirrhotic patients with spontaneous portasystemic shunts in comparison with patients with idiopathic portasystemic shunts but without liver disease (20,21). These investigators failed to demonstrate a significant contribution of extrahepatic shunts to peripheral hyperinsulinemia and argued that parenchymal liver damage is responsible for the increased plasma insulin levels. In contrast, studies by Sonnenberg et al. (22) and Bosch et al. (23) have shown that arterial concentrations of insulin were higher than hepatic vein concentrations in patients with either spontane-

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ous or surgical portacaval shunts, demonstrating the important role of portosystemic shunting in increased peripheral hyperinsulinemia. The different results can be explained, at least partly, by the different degree of extrahepatic shunting. The study by Bosch et al. (23), as well as studies by Sikuler et al. (24) in a portal-hypertensive rat model, have documented that hyperinsulinemia in the presence of portal hypertension is caused, at least in part, by a reduced metabolic clearance rate of insulin, probably reflecting decreased hepatic blood flow. Whatever the cause of the hyperinsulinemia, to our knowledge no one has investigated the effect of insulin on glucose metabolism in either patients or experimental animals with portal hypertension and normal liver function. Our results demonstrate that the ability of insulin to promote whole-body glucose uptake was impaired under conditions of extrahepatic shunting due to presinusoidal portal hypertension. The patient did not exhibit any quantitatively significant damage of liver parenchyma or loss of liver function. Thus, portasystemic shunting per se is associated with peripheral hyperinsulinemia and insulin resistance. Because during euglycemic insulin clamping, peripheral tissues, primarily muscle, are responsible for the disposal of about 80%85% of the infused glucose load (6), it is obvious that muscle tissue represents the major site of insulin resistance in this patient. The observed reduction in total-body glucose uptake was entirely accounted for by a defect in nonoxidative glucose metabolism. In recent studies using nuclear magnetic resonance spectroscopy it has been demonstrated that glycogen synthesis accounts for more than 90%95% of nonoxidative glucose disposal (25). Thus, the insulin resistance in this patient with portal hypertension seems to involve a specific biochemical abnormality in the glycogen synthetic pathway in muscle. These findings of hyperinsulinemia and impaired glucose uptake caused by decreased nonoxidative glucose disposal of muscle tissue have also been observed in a number of other insulin-resistant states such as obesity (26), type II diabetes (27), hypertension (28), uremia (29), and cirrhosis (2). At present, it is generally assumed that the development of diabetes in cirrhosis is caused by the disease of the liver itself. However, as mentioned above, we and others have provided evidence that decreased insulin sensitivity of muscle tissue (i.e., a defect in glycogen synthesis) is responsible for the defect in insulin action in cirrhosis (2,3). It is conceivable, therefore, that extrahepatic factors contribute to the development of the insulin-resistant state. For example, it has been demonstrated that physiological hyperinsulinemia (as well as hyperglucagonemia) created for 72 hours in normal humans can induce insulin resistance (30-32) due to an impairment of insulin-

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mediated nonoxidative glucose disposal (30,~~). It is quite possible, therefore, that extrahepatic shunting in cirrhotic patients leads to increased peripheral plasma levels of insulin (and glucagon), which in turn could induce insulin resistance. That this sequence of events may indeed explain the defect in insulin action in cirrhotic patients (with portal hypertension) is supported by the results of the present study, in which a severe loss of insulin sensitivity is demonstrated in a patient with extrahepatic shunting but with no other organ disease such as cirrhosis, diabetes, uremia, hypertension, or obesity. It should be remembered that the ability of insulin to promote glucose uptake by peripheral (muscle) tissues can be antagonized not only by insulin and glucagon but also by other circulating substrates such as FFAs. More than 25 years ago, Randle et al. first introduced the “glucose fatty acid cycle,” demonstrating that enhanced FFA oxidation leads to a decrease in glucose utilization (33). In fact, this is precisely what was confirmed in vivo when a lipid emulsion was infused to elevate the plasma FFA concentration and to stimulate FFA oxidation; both nonoxidative glucose disposal (primarily glycogen formation) and oxidative glucose disposal were markedly impaired after insulin infusion (34). Because in our study insulin almost completely failed to suppress FFA oxidation during all insulin-infusion steps, it is conceivable that increased FFA oxidation is associated with an inhibition of glycogen formation and that this mechanism contributes, at least partly, to the observed defect in insulin-mediated glucose uptake in our patient with idiopathic portal hypertension. In summary, noncirrhotic portal hypertension with extrahepatic shunting in the presence of normal liver function is associated with peripheral hyperinsulinemia and insulin resistance. Whether hyperinsulinemia by itself (or in combination with hyperglucagonemia) or increased Randle cycle activity or another additional factor accounts for the insulin-resistant state remains to be established.

References 1. Petrides AS, DeFronzo RA. Glucose metabolism in cirrhosis: a review with some perspectives for the future. Diab Metab Rev 1990;5:691-709. 2. Petrides AS, Riely CA, Groop L, DeFronzo RA. The glucosefatty acid cycle does not explain the insulin resistance in cirrhosis (abstr). Gastroenterology 1987;92:1763A. 3. Kruszynska Y, Williams N, Perry M, Home P. The relationship between insulin sensitivity and skeletal muscle enzyme activities in hepatic cirrhosis. Hepatology 1988;8:1615-1619. 4. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol1979;237:E214-E223. 5. Groop LC, Bonadonna AC, Del Prato S, Ratheiser K, Zyck K, Ferrannini E, DeFronzo RA. Glucose and free fatty acid metab-

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olism in non-insulin-dependent diabetes mellitus. J Clin Invest 1989;84:205-213. 6. DeFronzo RA, Jacot E, Jequier E, Maeder E, Felber JP. The effect of insulin on the disposal of intravenous glucose: results from indirect calorimetry and hepatic and femoral venous catherization. Diabetes 1981;30:1000-1007. 7. Altzuler N, Barkai A, Bjerknes A, Gottlieb B, Steele R. Glucose turnover values in the dog obtained with various species of labelled glucose. Am J Physiol 1975;225:E1662-E1667. 8. Hales CN, Randle PJ. Immunoassay of insulin with insulin antibody precipitate. Biochem J 1963;88:137-146. 9. Miles JR, Glassock J, Aikens J, Gerich J, Haymond M. A microfluorometric method of free fatty acids in plasma. J Lipid Res 1983;24:96-99. 10. Steele R. Influence of glucose loading and of injected insulin on hepatic glucose output. Ann NY Acad Sci 1959;82:420-430. responses in normal and 11. Cowan JS, Hetenyi C. Glucoregulatory diabetic dogs recorded by a new tracer method. Metab Clin Exp 1971;20:360-372. 12. Radziuk J, Norwich KH, Vranic M. Measurements and validation of non-steady state turnover rates with application to the insulin and glucose system. Fed Proc 1974;33:1855-1864. L, Wahren J, Pernow B, Raf L. Uptake of individual 13. Hagenfeldt free fatty acids by skeletal muscle and liver in man. J Clin Invest 1972;51:2324-2330. of free fatty acids 14. Spitzer JJ, Gold M. Studies on the metabolism in diabetic and fating dogs. Ann Y Acad Sci 1965;131:235-249. 15. Issekutz B, Paul P, Miller HI, Bortz WM. Oxidation of plasma FFA in lean and obese humans. Metabolism 1967;17:62-72. in metabolic research. New York, Liss, 16. Wolfe RR. Tracers 1984:141-147. 17. Cobelli C, Mari A, Ferrannini E. Non-steady state: error analysis of Steele’s model and development for glucose kinetics. Am J Physiol 1987;252:E679-E689. 18. Steiner PE. Nodular regenerative hyperplasia of the liver. Amer J Path01 1959;35:943-953. J-P. Nodular regenera19. Rougier P, Degott C, Rueff B, Benhamou tive hyperplasia of the liver. Report of six cases and review of the literature. Gastroenterology 1978;75:169-172. S, Sugiura M, 20. Iwasaki Y, Sato H, Onkubo A, Sanjo T, Futagawa Tsuji S. Effect of spontaneous portal-systemic shunting on insulin metabolism. Gastroenterology 1979;76:685-690. 21. Smith-Laing G, Sherlock S, Faber OK. Effect of spontaneous portal-systemic shunting on insulin metabolism. Gastroenterology 1979;76:685-690. 22. Sonnenberg GE, Keller U, Burckhardt D, Gyr K. Ursachen der Hyperinsulinamie bei Patienten mit Lebercirrhose: portocavale Shunts oder verminderte Degradationsfahigkeit der Leber? Verh Dtsch Ges Inn Med 1980;86:771-775. R, Teres J, Rivera F, 23. Bosch J, Gomis R, Kravetz D, Casamitjana Rodes J. Role of spontaneous portal-systemic shunting in hyperinsulinism in cirrhosis. Am J Physiol 1984;247:G206G212. 24. Sikuler E, Polio J, Groszmann R, Hendler R. Glucagon and insulin metabolism in a portal-hypertensive rat model, Am J Physiol 1987;253:GllO-115. 25. Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin dependent diabetes mellitus by 13C nuclear magnetic resonance. N Engl J Med 1990;322:223-228. 26. DeFronzo RA. Insulin secretion, insulin resistance, and obesity. Int J Obes 1983;6(Suppl 1):73-82. 27. DeFronzo RA. The triumvarate: beta cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988;37:667-687. 28. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilaqua S. Insulin

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34. Thiebaud D, DeFronzo RA, Jacot E, Golay A, Acheson K, Maeder E, Jecquier E, Felber JP. Effect of long chain triglyceride infusion on glucose metabolism in man. Metabolism 1982;31: 1128-1136.

Received Address

November 30,1989. Accepted July 17,199O. requests for reprints to: Dr. Alexander S. Petrides,

Division of Hepatology and Gastroenterology, Department of Internal Medicine, Heinrich-Heine Universitat of Dusseldorf, Moorenstrasse 5,400O Dusseldorf 1, Germany. Dr. Riely’s present address is: College of Medicine, Department of Medicine, University of Tennessee, Memphis, Tennessee 38163. Dr. DeFronzo’s present address is: Division of Medicine, University of Texas, Health Antonio, San Antonio, Texas, 78284-7886.

of Diabetes, Department Science Center at San