Original Article
Effects of Pancreas Transplantation on Postprandial Glucose Metabolism
N Engl J Med 1991; 325:1278-1283October 31, 1991
- Abstract
- Abstract
Background.
Because a pancreas allograft is placed in the pelvis, pancreas transplantation abolishes the normal gradient between portal-vein and peripheral-vein insulin concentrations and causes systemic hyperinsulinemia. Whether pancreas transplantation restores carbohydrate metabolism to normal is not known.
Methods.
We studied seven patients with insulin-dependent diabetes mellitus after pancreas—kidney transplantation, seven nondiabetic patients after kidney transplantation (to control for immunosuppression), and eight normal subjects. Measurements were made after an overnight fast and after ingestion of a mixed meal.
Results.
Although plasma glucose concentrations did not differ in the two transplant groups, plasma insulin concentrations were significantly higher in the diabetic pancreas—kidney recipients than in the nondiabetic kidney recipients, both before the meal (mean ±SE 102±15 vs. 53±6 pmol per liter; P<0.05) and afterward (123±22 vs. 61±6 nmol per liter per six hours; P<0.05). Plasma C-peptide concentrations were the same in both groups, indicating that hyperinsulinemia was due to decreased insulin clearance rather than increased insulin secretion. Despite drainage of the venous effluent from the transplanted pancreas into the systemic circulation, the values for splanchnic clearance of ingested glucose, suppression of hepatic glucose release, incorporation of carbon dioxide into glucose, stimulation of glucose oxidation, glucose uptake, and forearm glucose clearance were all similar in the transplant groups and differed minimally from the values in the normal group. The similar rates of glucose uptake in the presence of higher systemic insulin concentrations indicated that the extrahepatic tissues of the diabetic pancreas—kidney recipients were insulin-resistant.
Conclusions.
Despite systemic delivery of insulin, pancreas—kidney transplantation in patients with diabetes results in carbohydrate metabolism similar to that in nondiabetic subjects receiving the same immunosuppressive agents after kidney transplantation. (N Engl J Med 1991; 325:1278–83.)
Media in This Article
Figure 1
Mean (±SE) Plasma Glucose, Insulin, C-Peptide, and Glucagon Concentrations before and after a Mixed Meal in Diabetic Recipients of Pancreas—Kidney Transplants (■), Nondiabetic Kidney-Transplant Recipients (
), and Normal Subjects (○). The meal was ingested at time 0.Figure 2
Mean (±SE) Rate of Appearance of Ingested Glucose in the Systemic Circulation, Rate of Hepatic Glucose Release, and Rate of Incorporation of Carbon Dioxide (CO2) into Glucose before and after a Mixed Meal in Diabetic Recipients of Pancreas-Kidney Transplants (■), Nondiabetic Kidney-Transplant Recipients (), and Normal Subjects (○).Article Activity
- Article
PANCREAS transplantation offers a means of normalizing plasma glucose concentrations in patients with insulin-dependent diabetes mellitus (IDDM) and therefore the possibility of delaying or preventing the long-term complications of the disease. However, it is not known whether pancreas transplantation, in addition to lowering glucose concentrations, also restores hepatic and extrahepatic glucose metabolism to normal. In normal subjects, the pancreatic venous effluent drains into the portal venous system and the liver extracts approximately 50 percent of the insulin presented to it.1 , 2 Current surgical procedures drain the venous effluent of the transplanted pancreas into the systemic circulation.3 Unfortunately, this method abolishes the normal gradient between the portal and peripheral venous systems, thereby inducing systemic hyperinsulinemia.4 5 6
Whether long-term systemic delivery of insulin has deleterious effects on carbohydrate metabolism in humans is not known. If rapid increases in portal-vein insulin concentrations are required for normal postprandial regulation of glycogen synthesis, glycogenolysis, and gluconeogenesis, then systemic insulin delivery could impair the hepatic response to carbohydrate ingestion. On the other hand, if glucose rather than insulin is the primary regulator of hepatic glucose metabolism,6 7 8 9 10 11 and if extrahepatic insulin resistance produced by chronic systemic hyperinsulinemia12 13 14 15 16 appropriately compensates for the higher concentrations of circulating insulin, then systemic insulin delivery may not alter the relative contribution of hepatic and extrahepatic tissues to carbohydrate tolerance.17
We undertook the present study to determine whether the delivery of insulin to the portal vein is essential for normal carbohydrate metabolism in humans. To answer this question, we compared the pattern of carbohydrate metabolism in patients with IDDM after successful pancreas—kidney transplantation (i.e., persons in whom pancreatic venous effluent drains into the systemic circulation) with that in nondiabetic patients receiving the same antirejection therapy after successful kidney transplantation. The results in both groups were compared with those in normal subjects to determine whether long-term anti-rejection therapy itself impairs carbohydrate metabolism.
Methods
Subjects
We studied seven patients with IDDM who had functioning pancreas—kidney transplants, none of whom had received any exogenous insulin since they underwent transplantation, seven nondiabetic patients with functioning kidney transplants, and eight normal subjects. The three groups of subjects were matched for age, sex, weight, and body-mass index; the two groups of transplant recipients were also matched for renal function, as well as for the type and extent of antirejection therapy (Table 1Table 1
Characteristics of the Three Study Groups.*), with the exception of one patient in the pancreas—kidney transplant group, who was receiving cyclophosphamide (50 mg per day) instead of azathioprine.The concentrations of glycosylated hemoglobin were normal in all subjects. The mean (±SD) duration of diabetes in the pancreas-kidney recipients at the time of transplantation was 22±3 months. The pancreas was placed in the pelvis, with its arterial blood supplied from one iliac artery, its venous drainage directed into the ipsilateral iliac vein, and its excretory duct connected to the urinary bladder.
The protocol was approved by the institutional review board of the Mayo Clinic, and all subjects gave written informed consent for the study.
Experimental Design
The subjects were admitted to the clinical research center on the evening before the study. They were fed a standard meal between 5:30 and 6:30 p.m. and then fasted overnight. On the morning of the study, the subjects remained in bed and supine. An 18-gauge catheter (Cathalon, Criticon, Tampa, Fla.) was placed in a forearm vein for infusion of radioisotopes. An ipsilateral hand vein was cannulated retrogradely with an 18-gauge catheter and kept at 50°C to allow sampling of arterialized venous blood.18 In six subjects from each group, a contralateral deep antecubital vein was cannulated retrogradely with an 18-gauge catheter to allow sampling of deep venous blood. In the other subjects, cannulation of the deep antecubital vein could not be accomplished for technical reasons.
At 7 a.m., primed, continuous intravenous infusion of [6–3H]glucose (New England Nuclear, Boston) and bicarbonate Radio-labeled with carbon-14 (Research Products International, Mount Prospect, Ill.) was begun to measure glucose turnover and the rate of incorporation of carbon dioxide into glucose. The isotopes were purchased in sterile form, verified as being pyrogen-free, and confirmed as being more than 99 percent pure.19 At 9 a.m., a solid mixed meal was given and consumed within 15 minutes. The meal, to which 100 μCi of [2–3H]glucose had been added, consisted of gelatin, a two-egg omelette (472 kcal; 45 percent carbohydrate, 40 percent fat, and 16 percent protein), and a caffeine-free, noncaloric beverage.20 Blood samples were obtained at regular intervals both before and after the meal. Forearm blood flow was measured with an electrocapacitance plethysmograph (UFI, Morro Bay, Calif.).21 Oxygen consumption and carbon dioxide production were measured with a Horizon metabolic cart (Beckman Instruments, Anaheim, Calif.).22 Breath samples were collected into 2 ml of solution containing 0.5 mM Hyamine (Packard Instruments, Downers Grove, Ill.) for measurement of the [14C]carbon dioxide specific activity in the samples.23 Urine samples were obtained just before the meal and at the end of the study for the measurement of nitrogen excretion.
Analytic Techniques
Samples of arterialized venous blood and forearm deep venous blood were placed on ice and centrifuged at 4°C, after which the plasma was separated and stored at 20°C until assayed. Plasma glucose was measured with a glucose oxidase method (Yellow Springs Instruments, Yellow Springs, Ohio). Plasma concentrations of insulin, C peptide, and glucagon were measured by radioimmunoassay as previously described,24 25 26 except that Jaspan G15 antibody was used in the glucagon assay. The specific activities of [6–3H]glucose and [2–3H]glucose were determined by selective enzymatic detritiation of [2–3H]glucose with a modification27 of the method of Issekutz.28 Glycosylated hemoglobin was measured by affinity chromatography (Glyc-Affin, IsoLab, Akron, Ohio).
Calculation of Glucose Turnover
The rates of glucose appearance and disappearance were calculated with the equations of Steele et al.,29 as modified by de Bodo et al.30 The rate of appearance of the glucose from the meal in the systemic circulation was determined by measuring the systemically infused tracer (i.e., [6–3H]glucose) to quantitate the rate of appearance of the labeled ingested glucose ([2–3H]glucose) and therefore the rate of appearance of the unlabeled ingested glucose. Glucose entering the systemic circulation after a meal is the sum of that derived from the ingested carbohydrate and that released by the liver. Therefore, the rate of hepatic glucose release can be calculated by subtracting the rate of appearance of the ingested glucose from the total rate of glucose appearance. Splanchnic glucose uptake was calculated by subtracting the amount of the ingested glucose that reached the systemic circulation from the amount ingested.17 , 20 , 21 , 31 Glucose released by the liver is derived from either glycogenolysis or gluconeogenesis. [l4C]bicarbonate can serve as a qualitative index of gluconeogenesis, since carbon dioxide is incorporated into oxaloacetate by the action of pyruvate carboxylase.20 , 32 , 33 In these experiments, the percentage of glucose derived from bicarbonate was calculated by dividing the specific activity of [l4C]glucose in plasma by the specific activity of [14C]carbon dioxide in the breath.20 The percentage of glucose derived from bicarbonate was multiplied by the isotopically determined total appearance rate of glucose to calculate the rate of incorporation of carbon dioxide into glucose. The assumptions and limitations in the use of the rate of incorporation of carbon dioxide into glucose as a qualitative indicator of gluconeogenesis have been discussed elsewhere.20 , 32 , 33 Glucose uptake by the forearm (which primarily reflects glucose uptake by muscle) was determined by multiplying the forearm blood flow by the difference in glucose concentration between arterial and venous blood.21 The rates of glucose and lipid oxidation were calculated from the measured rates of oxygen consumption, carbon dioxide production, and nitrogen excretion with the equations of Consolazio et al.34 as described by Frayn.35
Statistical Analysis
Results are reported as means ±SE. The responses after ingestion of the meal were calculated as integrated responses for the six hours after ingestion. Statistical analyses were performed with Student's unpaired t-test. The results in the patients with pancreas—kidney transplants were compared with those in the patients with kidney transplants to determine whether pancreas transplantation restored glucose metabolism to a pattern similar to that in nondiabetic transplant recipients given the same immunosuppressive agents. The results in the two transplant groups were compared with those in the normal group to determine whether antirejection therapy alone impaired carbohydrate metabolism. P values of less than 0.05 were considered to indicate statistical significance.
Results
Plasma Glucose, Insulin, C-Peptide, and Glucagon Concentrations
The mean plasma glucose concentrations were similar in all three study groups before ingestion of the meal (Fig. 1Figure 1
Mean (±SE) Plasma Glucose, Insulin, C-Peptide, and Glucagon Concentrations before and after a Mixed Meal in Diabetic Recipients of Pancreas—Kidney Transplants (■), Nondiabetic Kidney-Transplant Recipients (), and Normal Subjects (○). The meal was ingested at time 0.); the concentrations measured after the meal were slightly but not significantly higher in the pancreas—kidney transplant group than in the kidney transplant group (2.4±0.1 vs. 2.3±0.1 mmol per liter per six hours; P = 0.45). In contrast, the plasma insulin concentrations were significantly higher in the pancreas—kidney transplant group than in the kidney transplant group both before (Fig. 1, insert) and after the meal (102±15 vs. 53±6 pmol per liter and 123±22 vs. 61±6 nmol per liter per six hours, respectively; P<0.05). However, the plasma C-peptide concentrations of the two groups (Fig. 1) did not differ significantly, either before (pancreas—kidney vs. kidney, 0.06±0.1 vs. 0.06±0.01 nmol per liter) or after (582±72 vs. 594±98 nmol per liter per six hours) the meal, indicating that the hyperinsulinemia in the pancreas—kidney transplant group was due to decreased insulin clearance rather than increased insulin secretion. Plasma glucagon concentrations were comparable in the two transplant groups both before and after the meal (Fig. 1).Whereas fasting plasma glucose concentrations were the same (Fig. 1), postprandial glycemic excursion was greater in the transplant groups than in the group of normal subjects (2.1±0.1 mmol per liter per six hours; P<0.02). The plasma insulin concentrations were higher both before and after the meal in the transplant groups than in the normal group (35±6 and 40±7 nmol per liter per six hours, respectively; P<0.05) (Fig. 1). The fasting and postprandial glucagon concentrations in the two transplant groups tended to be higher than those in the normal group (P = 0.06 to 0.08) (Fig. 1).
Appearance of Ingested Glucose, Hepatic Glucose Release, and Rate of Incorporation of [14C]Carbon Dioxide into Glucose
Of the 50 g of ingested glucose, the amount appearing in the systemic circulation was 36.7±0.9 g in the pancreas—kidney transplant group, 36.9±2.1 g in the kidney-transplant group, and 33.0±l.3 g in the normal group. The degree of postprandial suppression of hepatic glucose release and the rate of incorporation of [l4C]carbon dioxide into glucose also were similar in all three groups (Fig. 2Figure 2
Mean (±SE) Rate of Appearance of Ingested Glucose in the Systemic Circulation, Rate of Hepatic Glucose Release, and Rate of Incorporation of Carbon Dioxide (CO2) into Glucose before and after a Mixed Meal in Diabetic Recipients of Pancreas-Kidney Transplants (■), Nondiabetic Kidney-Transplant Recipients (), and Normal Subjects (○).).Disappearance of Glucose and Forearm Glucose Uptake
The rate of total-body glucose disappearance was comparable in all groups both before and after the meal (Fig. 3Figure 3
Mean (±SE) Total Rate of Disappearance of Glucose from the Systemic Circulation and Rate of Forearm Glucose Uptake before and after a Mixed Meal in Diabetic Recipients of Pancreas—Kidney Transplants (■), Nondiabetic Kidney-Transplant Recipients (), and Normal Subjects (○).). Forearm glucose uptake, which primarily reflects glucose uptake by insulin-dependent tissues (i.e., muscle), was slightly but not significantly lower after the meal in the pancreas—kidney transplant group than in the kidney-transplant group (552±137 vs. 780±143 μmol per 100 ml of forearm volume per six hours) (Fig. 3). Forearm glucose uptake in both transplant groups did not differ from that in the normal group (569±101 μmol per 100 ml of forearm volume per six hours) (Fig. 3).Carbohydrate and Lipid Oxidation
The rates and temporal patterns of change of carbohydrate and lipid oxidation were equal in all three groups before ingestion of the meal (Fig. 4Figure 4
Mean (±SE) Rates of Carbohydrate and Lipid Oxidation before and after a Mixed Meal in Diabetic Recipients of Pancreas—Kidney Transplants (■), Nondiabetic Kidney-Transplant Recipients (), and Normal Subjects (○).). The increment in carbohydrate oxidation and the decrement in lipid oxidation after the meal also did not differ among the groups.Discussion
The liver has a central role in the maintenance of carbohydrate tolerance in healthy persons. During fasting, the rate of release of glucose by the liver closely approximates the rate of glucose uptake by extrahepatic tissues.18 After carbohydrates are ingested, hepatic glucose output decreases and the liver extracts glucose as it passes from the gut to the systemic circulation.20 , 21 , 31 These two processes are regulated by the insulin and glucose concentrations to which the liver is exposed. Since insulin is secreted into the portal vein and since portal-vein insulin concentrations rapidly increase after meals, the delivery of insulin to the peripheral circulation could impair the ability of the liver to respond to carbohydrate ingestion. The results in our subjects, in conjunction with those of previous studies in dogs,17 suggest that this assumption is incorrect. The postprandial suppression of hepatic glucose release, the rate of incorporation of carbon dioxide into glucose (a qualitative index of gluconeogenesis), and the splanchnic uptake of ingested glucose were all normal after pancreas transplantation. If anything, suppression of hepatic glucose release tended to be slightly greater in the pancreas—kidney transplant (diabetic) group than in either of the other two groups.
Several factors may account for this apparent paradox. First, studies both in vitro7 and in vivo8 9 10 11 have suggested that once "adequate" amounts of insulin are present, glucose rather than insulin is the primary regulator of glycogen synthesis, glycogenolysis, and gluconeogenesis. Second, the normal gradient between portal-vein and peripheral-vein insulin concentrations is approximately 2:1.1 , 2 Because of the lack of initial hepatic insulin clearance, the systemic insulin concentrations in pancreas-transplant recipients increase rapidly after transplantation to levels that probably approximate those present moments earlier in the portal veins of the nondiabetic subjects.1 , 2 Thus, the duration of relative hypoinsulinemia in the portal vein is probably brief. Third, even in the presence of euglycemia, the liver is sensitive to small changes in the insulin level, with maximal suppression of hepatic glucose output occurring when the insulin concentration approaches 300 pmol per liter.18 Once maximally effective insulin levels have been achieved, a delay in insulin delivery or a difference between portal-vein and peripheral-vein insulin concentrations would become moot. Finally, the lack of immediate insulin delivery to the portal vein may cause subtle abnormalities in hepatic carbohydrate metabolism that were not detected in our study.
By definition, the diabetic group (the pancreas—kidney transplant recipients) had extrahepatic insulin resistance, since despite higher insulin concentrations they had the same rates of glucose uptake as the two nondiabetic groups. These results are consistent with the recent study of Luzi et al.,36 in which insulin action, assessed with the hyperinsulinemic—euglycemic clamp technique, was impaired in patients with IDDM after they underwent pancreas transplantation. However, insulin secretion, as reflected by plasma C-peptide concentrations, was identical in both our transplant groups. Thus, there is no evidence that systemic insulin delivery will hasten beta-cell "exhaustion" by increasing insulin requirements. Furthermore, since virtually every facet of carbohydrate metabolism was normal in the pancreas—kidney transplant recipients, insulin resistance, rather than reflecting a deleterious outcome, appears to represent an appropriate adaptation to chronic systemic hyperinsulinemia.
It is important to note that the two transplant groups were matched for their degree of renal function. Whereas insulin is cleared by multiple tissues, C peptide is cleared almost exclusively by the kidney.37 It is likely that the mild impairment of renal function in the two transplant groups led to a decrease in C-peptide clearance,38 accounting for the disproportionate increase in concentrations of C peptide relative to the increase in insulin concentrations. However, it is also possible that prednisone contributed to hyperinsulinemia by inducing insulin resistance.36 This was most readily apparent when the insulin concentrations in the kidney recipients were compared with those in the normal subjects. Glucocorticoids can oppose insulin action both directly, by antagonizing insulin-induced stimulation of glucose uptake and suppression of hepatic glucose release,39 and indirectly, by enhancing glucagon secretion.40 Taken together, these data suggest that whether the proximal cause of hyperinsulinemia is decreased insulin clearance (e.g., after pancreas transplantation with peripheral venous drainage) or antagonism of insulin action (e.g., after glucocorticoid administration), hepatic and extrahepatic tissues have the capacity to adapt appropriately to the prevailing insulin concentrations.
In summary, systemic delivery of insulin associated with pancreas transplantation in humans results in higher plasma insulin concentrations than are found in nondiabetic kidney-transplant recipients given the same immunosuppressive agents. The higher plasma insulin concentrations are due to decreased first-pass hepatic clearance rather than to increased insulin secretion. Despite systemic hyperinsulinemia and a lack of insulin delivery to the portal circulation, the postprandial pattern of glucose metabolism in diabetic subjects after pancreas transplantation does not differ from that in nondiabetic subjects receiving the same immunosuppressive agents. Although systemic insulin delivery does not appear to impair carbohydrate metabolism, it remains to be determined whether it has other deleterious effects, such as increasing the risk of atherosclerotic vascular disease.41
Supported by grants (DK-29953, DK-39994, and RR-00585) from the U.S. Public Health Service and by the Mayo Foundation.
We are indebted to Ms. J. King, Mr. T. Madson, and Ms. D. Nash for technical assistance, to Ms. P. Geerdes for assistance in recruiting the patients and scheduling the studies, to Ms. J. Ashenmacher for assistance in the preparation of the manuscript, and to the staff of the clinical research center for assistance in conducting the studies.
Source Information
From the Department of Medicine, University of Minnesota, Minneapolis (P.R.), and the Department of Medicine, Mayo Clinic (H.K., M.H., J.V., R.R.), Rochester, Minn. Address reprint requests to Dr. Rizza at Endocrinology and Internal Medicine, Mayo Clinic, Rochester, MN 55905.
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Full Text
