A RNA transcript (Heg) in mononuclear cells is negatively correlated with CD14 mRNA and TSH receptor autoantibodies.

During a study of gene expression of foxp3 in blood mononuclear cells we observed a DNA product of an unknown RNA fragment. The area of this peak correlated with CD14 mRNA in a small group of subjects. The sequence was localized to chromosome 1. We tested the hypothesis that gene expression of the poly A(-) transcript (designated Heg) in mononuclear cells was correlated with CD14 mRNA in normal subjects and with CD14 mRNA and TSH receptor autoantibodies in patients with acute and untreated Graves' disease. mRNA was expressed in amol/microg DNA. The main study groups were: (i) normal subjects; (ii) patients with early and untreated Graves' disease; and (iii) patients with Graves' disease studied after treatment. In 18 normal subjects and in 20 patients with treated Graves' disease CD14 mRNA was negatively correlated with Heg (P < 0.001). In 17 untreated patients with Graves' disease Heg and thyroid receptor autoantibodies were negatively correlated (P < 0.009). Incubation studies with mononuclear cells showed that the addition of a fragment of the central part of Heg (949 bases) to mononuclear cells decreased CD14 mRNA markedly to zero or nearly zero (P < 0.001). This response was not specific in the sense that siRNA and lipopolysaccharide also decreased CD14 mRNA, probably due to activation of the CD14/Toll-like receptor complex. Single-stranded RNA is likely to increase interferon production. Due to the anti-inflammatory effect Heg may also inhibit the early phase of TSH receptor autoantibody production.

Plasma catecholamines in long-term diabetics with and without neuropathy and in hypophysectomized subjects.

Employing a precise and sensitive double-isotope derivative technique, plasma catecholamine concentration (PCA) was measured in four groups of subjects: (a) long-term diabetics with neuropathy, (b) long-term diabetics without neuropathy, (c) hypophysectomized long-term diabetics with neuropathy, and (d) nondiabetic control subjects. Blood samples were obtained from subjects in the supine and in the standing position. In nondiabetic control subjects, PCA (mainly noradrenaline) increased from 0.26 ng/ml in the supine positon to 0.69 and 0.72 ng/ml 5 and 10 min after assuming the standing position. By plotting this increase in PCA on the y axis in a coordinate system vs. increase in pulse rate, PCA was divided into two components: one of these depended on the rise in pulse rate on standing (called CAH) and the other corresponded to the intercept on the y axis where rise in pulse rate equals zero (CAP).Long-term diabetics with neuropathy showed a significant reduction in PCA in both the supine and the standing position. Further analysis demonstrated that CAP was considerably reduced whereas CAH was normal. Long-term diabetics without neuropahty showed normal PCA values.Surprisingly, hypophysectomized diabetics with neuropathy exhibited mean PCA values in both the supine and the standing position which were similar to those found in the nondiabetic subjects and considerably elevated compared with the findings in the nonoperated, long-term diabetics with neuropathy. Further analysis in terms of CAP and CAH demonstrated, however, that CAP was just as abnormally reduced in the hypophysectomized as it was in the nonoperated patients whereas CAH was considerably increased. In contrast to the findings in the nonoperated diabetics with neuropathy, the hypophysectomized diabetic patients with neuropathy demonstrated a negative correlation between rise in PCA and blood pressure on standing indicating that the increase in PCA was at least partially a compensatory phenomenon in the interest of the maintenance of a normal level of blood pressure. An increased sympathetic tone (vasoconstriction) is believed to be at least partially responsible for the increased capillary resistance and decreased capillary permeability occuring after hypophysectomy.

Whole body clearance of norepinephrine. The significance of arterial sampling and of surgical stress.

The whole body clearance of norepinephrine (NE) was measured in seven patients pre- and postoperatively. L[(3)H]NE was infused intravenously for 90 min and steady-state concentrations of L[(3)H]NE were measured at 75 and 90 min in both arterial and peripheral venous blood. Preoperatively, in the resting supine position, the clearance values based on arterial and venous sampling averaged 1.4 and 2.5 liter/min, respectively (P < 0.02). The difference in clearance values was due to a peripheral uptake of NE averaging 45%. The mean plasma NE increased from 1.70 nmol/liter preoperatively to 5.20 nmol/liter postoperatively (P < 0.02). The plasma appearance rate of NE averaged 2.4 nmol/min before surgery and it increased to 9.5 nmol/min postoperatively (P < 0.02). The plasma clearance of NE averaged 1.4 and 1.6 liter/min pre- and postoperatively, respectively (not significantly different). Our study demonstrates that the calculation of plasma NE clearance based on venous sampling results in values that are too high. Furthermore, such values may be influenced by individual variations in the peripheral uptake of NE, since we found no correlation between clearance values based on venous and arterial sampling. The increase in plasma NE postoperatively was due to an increase in the plasma appearance rate of NE because the clearance rate did not change.

The relationship between endogenous serum insulin concentration and glucose uptake in the forearm muscles of nondiabetics.

IN A SERIES OF EXPERIMENTS ON THE HUMAN FOREARM, PREPARATION DESIGNED TO EXAMINE THE EFFECTS OF VARIATIONS IN IMMUNOLOGICALLY DETERMINED ENDOGENOUS SERUM INSULIN LEVELS AND OF BLOOD GLUCOSE CONCENTRATIONS ON MUSCULAR GLUCOSE UPTAKE, THE FOLLOWING RESULTS WERE OBTAINED: (a) A highly significant correlation between muscular glucose uptake and simultaneous arterial serum insulin concentration. (b) No correlation between glucose uptake and simultaneous arterial blood glucose concentration during hyperglycemia. (c) A maximal insulin effect on muscular glucose uptake at arterial serum insulin concentrations at about 200 muU/ml. This observation is, however, based on only a few experiments.

Plasma catecholamines and carbohydrate metabolism in patients with acute myocardial infarction.

Blood glucose, glucose tolerance, serum insulin, free fatty acids in serum, plasma noradrenaline, and plasma adrenaline were measured in 10 patients with acute myocardial infarction (AMI) as well as in healthy subjects. Both noradrenaline and adrenaline in plasma were elevated in patients with AMI, the level being fairly constant in the individual patients and dependent on their degree of illness. In the fasting state, blood glucose, serum insulin, and free fatty acids were elevated in patients with AMI. Plasma noradrenaline showed a highly significant correlation with the fasting blood glucose concentration, but not with serum insulin or free fatty acids. The concentration of free fatty acids in serum could be predicted only if both plasma noradrenaline and the basal insulin concentration were known. Intravenous glucose tolerance was reduced in patients with AMI, especially in patients with high plasma noradrenaline and a low initial rise in insulin. There was a significant negative correlation between the initial rise in insulin expressed in percentage of the basal insulin concentration and the plasma noradrenaline level. The statistical effects of serum insulin and plasma noradrenaline on the glucose tolerance could not be separated from each other. The decline in free fatty acids after intravenous injection of glucose showed a negative correlation with plasma noradrenaline and a positive correlation with the initial rise in insulin. Plasma adrenaline did not correlate with any of the metabolic parameters mentioned above. The plasma noradrenaline concentration was elevated to such a degree in patients with AMI that the observed changes in metabolism might have been caused directly by the circulating noradrenaline. During the glucose tolerance tests, the effects of noradrenaline was probably carried out indirectly via a suppression of insulin secretion. It is conceivable that any effect of plasma noradrenaline on the basal insulin secretion was neutralized by the fasting hyperglycemia.

Hemodynamics in diabetic orthostatic hypotension.

Hemodynamic variables (blood pressure, cardiac output, heart rate, plasma volume, splanchnic blood flow, and peripheral subcutaneous blood flow) and plasma concentrations of norepinephrine, epinephrine, and renin were measured in the supine position and after 30 min of quiet standing. This was done in normal subjects (n = 7) and in juvenile-onset diabetic patients without neuropathy (n = 8), with slight neuropathy (decreased beat-to-beat variation in heart rate during hyperventilation) (n = 8), and with severe neuropathy including orthostatic hypotension (n = 7). Blood pressure decreased precipitously in the standing position in the diabetics with orthostatic hypotension, whereas moderate decreases were found in the other three groups. Upon standing, heart rate rose and cardiac output and plasma volume decreased similarly in the four groups. The increases in total peripheral resistance, splanchnic vascular resistance and subcutaneous vascular resistance were all significantly lower (P less than 0.025) in the patients with orthostatic hypotension compared with the other three groups. The increase in plasma norepinephrine concentrations in the patients with orthostatic hypotension was significantly lower (P less than 0.025) than in the patients without neuropathy, whereas plasma renin responses to standing were similar in the four groups. We conclude that in diabetic hypoadrenergic orthostatic hypotension the basic pathophysiological defect is lack of ability to increase vascular resistance, probably due to impaired sympathetic activity in the autonomic nerves innervating resistance vessels; cardiac output and plasma volume responses to standing are similar to those found in normal subjects and in diabetics without neuropathy.

Decreased norepinephrine concentration in normal tissue neighboring a malignant tumor.

We observed in five adenocarcinomas that norepinephrine as well as nerve fibers were absent from tumor tissue. The number of nerve fibers in normal tissue neighboring the tumor was normal. In contrast, norepinephrine concentration was decreased in normal tissue immediately surrounding tumor and increased in a stepwise fashion with the distance from tumor. Since there is evidence that some catecholamines possess antitumor activity, we suggest that depletion of catecholamines and perhaps other neurotransmitters in normal tissue neighboring a tumor may be of importance for invasion and accelerated malignant growth.

Analysis of prostaglandins formed from endogenous and exogenous arachidonic acid in homogenates of human reproductive tissues.

Isotope-labelled arachidonic acid has been used to study in vitro formation of prostaglandins and other products in mammalian tissue. Quantitative conclusions about cyclooxygenase activity have been drawn from such studies. However, arachidonic acid is present in all tissues, free and esterified, and therefore it can be expected that endogenous arachidonate would interfere with transformation of the radioactive exogenous substrate. (1-14C)-labelled arachidonate was, therefore, incubated with homogenates of various human tissues (amnion, chrorion, placenta and myometrium), and the two molecular forms, 12C and 14C, of arachidonic acid as well as of prostaglandin E2 and prostaglandin F2 alpha were quantitated, before and after 30 min of incubation, using gas chromatography-mass spectrometry with multiple ion detection. The results demonstrate a substantial release of arachidonic acid into the medium during incubation. There was no correlation between either the initial concentration of [12C]arachidonic acid and initial concentration of [12C]prostaglandin E2 or the percent increase of those compounds during incubation. The net formation of [12C]prostaglandin E2 and [14C]prostaglandin E2 from endogenous and exogenous precursor, respectively, were also very different. The study shows that by simply incubating (1-14C)-labelled arachidonic acid in tissue homogenates and measuring the amount of radioactivity transformed into various prostaglandins only qualitative conclusions can be drawn.

Norepinephrine, epinephrine, and dopamine contents of the cardiovascular system in long-term diabetics.

Norepinephrine, epinephrine, and dopamine concentrations were studied in the cardiovscular system of postmortem material obtained from six long-term diabetics and six control subjects. Norepinephrine concentration was considerably reduced in the cardiovascular system of the diabetic patients. The mean norepinephrine concentration in the apex of the heart, the radial artery, the posterior tibial artery, and the femoral artery in the diabetics averaged 6, 9, 12, and 20 per cent, respectively, of the corresponding mean values in the controls. Epinephrine was present in the cardiovascular system in the controls but in small amounts in comparision with norepinephrine. There was no correlation between the epinephrine and the norepinephrine concentrations in the tissue. In the diabetics the epinephrine concentration in the heart and in the arteries did not differ from the values obtained in the controls. The dopamine concentration averaged 11 per cent of the norepinephrine concentration in the cardiovascular system in the controls. There was a strong correlation between tissue concentrations of dopamine and of norepinephrine. In the diabetics the dopamine concentration was reduced, but relatively less than that of norepinephrine, and constituted 53 per cent of the norepinephrine concentration. It is suggested that the depletion of the norepinephrine stores in the heart in diabetic patients may in part be responsible for their reduced survival rate in acute myocardial infarction.

The effect of metabolic control on hemodynamics in short-term insulin-dependent diabetic patients.

Hemodynamics variables (heart rate, arterial blood pressure, cardiac output, hepato-splanchnic blood flow, forearm blood flow, and plasma catecholamines) were measured during good (median blood glucose 4.7 mmol/L) and poor (median blood glucose 16.3 mmol/L) metabolic control in eight young, short-term, insulin-dependent diabetic patients. The measurements were performed twice within 2 wk, in random order. Continuous subcutaneous insulin infusion (CSII) was applied for 1 wk in order to obtain good control. All eight patients had elevated cardiac output (median 9%) and forearm blood flow (median 34%) during poor compared with good metabolic control, P less than 0.01. In contrast, hepato-splanchnic blood flow was lower (median 12%) during poor compared with good metabolic control, P less than 0.05. Heart rate remained unchanged, while mean arterial blood pressure was slightly higher during poor control, P less than 0.05. Five of six patients had elevated plasma noradrenaline concentration during poor metabolic control. Due to the small number of patients investigated, no valid conclusion regarding the activity of the sympathoadrenal system can be drawn. Our study suggests that both increased cardiac output and reduced hepato-splanchnic blood flow (redistribution) contribute to the elevated blood flow previously demonstrated in various other organs and tissues in diabetic patients during poor metabolic control.

Central hemodynamic changes after ingestion of a meal in patients with coronary artery disease.

Thirty-six patients with coronary artery disease participated in a controlled trial of the influence of food intake on central hemodynamic parameters determined noninvasively by radionuclide cardiography. Stroke volume increased considerably (23%) and heart rate was slightly higher (8%) half an hour after the meal, whereas the elevated cardiac output two hours postprandially could be ascribed entirely to relative tachycardia. No significant hemodynamic changes occurred in the patients who fasted. That the left ventricular ejection fraction was increased postprandially (3% to 4%) indicated that food intake had positive inotropic as well as chronotropic effects on the ischemic heart, even in heart failure. Afterload reduction and increased sympathetic nervous activity contribute to the changes, but the primary mechanism may be a change in resistance and blood flow in the intestinal vascular bed involved in digestion.

Determinants of coronary sinus noradrenaline in patients with ischaemic heart disease: coronary sinus catecholamine concentration in relation to arterial catecholamine concentration, pulmonary artery oxygen saturation and left ventricular end-diastolic pressure.

Arterial and coronary sinus noradrenaline (NA) and adrenaline (A) concentrations, cardiac output, pulmonary artery oxygen saturation (PAO2), coronary sinus oxygen saturation, left ventricular end-diastolic pressure (LVEDP), and arterial pressure were examined in 21 patients with ischaemic heart disease at rest and during exercise before and after intravenous propranolol. The heart had a net uptake of A and a net release of NA. It can be estimated that at least 50% of NA in the coronary sinus derived from the heart. NA in the coronary sinus and in the arterial blood originated therefore, at least partially, in different tissues. The NA concentration showed close correlation with PAO2, but not with cardiac index or arterial blood pressure. Multiple regression analysis also revealed a relationship between LVEDP and arterial and coronary sinus NA independent of PAO2. A very close correlation between arterial and coronary sinus NA (r = 0.93, P less than 0.001) indicates that they are largely controlled by the same factors.

Effects of nonselective and beta-1-selective blockade on glucose metabolism and hormone responses during insulin-induced hypoglycemia in normal man.

The effects of nonselective beta-blockade (propranolol) and beta-1-selective blockade (atenolol) on glucose metabolism during insulin-induced hypoglycemia were studied in eight normal subjects during constant infusion of 3-[3H]glucose. Propranolol and to a lesser extent atenolol prolonged the hypoglycemic response to insulin. After maximal hypoglycemia a significant increase in glucose uptake rate was seen after propranolol and a corresponding trend was found in the atenolol experiments. The two beta-blockers did not influence glucose production rate after insulin administration. FFA concentration declined rapidly after insulin. Propranolol delayed the subsequent normalization of FFA whereas atenolol had no significant effect. Propranolol increased epinephrine and GH responses to hypoglycemia, whereas atenolol had no effect. Neither of the two beta-blockers influenced the concentrations of glucagon, norepinephrine, and PRL. It is concluded that nonselective beta-blockade prolongs the hypoglycemic response to insulin through an increased tissue uptake of glucose which is not counteracted by an increased glucose production. It is suggested that nonselective beta-blockade increases muscle glucose uptake by lowering FFA concentrations. beta-Blocker inhibition of the antiinsulin effect of epinephrine on glucose uptake in muscle can, however, not be excluded.

Effect of ketone body infusion on plasma catecholamine and substrate concentrations during acute hypoglycemia in man.

Experimental studies have shown that ketone body infusion inhibits the catecholamine response to hypoglycemia. We have studied six men during insulin-induced hypoglycemia who were concomitantly infused with saline or 3-hydroxybutyrate at dose rates of 4 and 13 mg/kg.min. The mean blood concentrations of 3-hydroxybutyrate increased to about 0.45 and 3 mmol/liter, respectively. The results show that the glucose response to insulin; hypoglycemic symptoms; and the adrenaline, noradrenaline, and cortisol responses to hypoglycemia were not influenced by ketone infusion at any dose rate.

Twenty-four-hour energy expenditure: the role of body composition, thyroid status, sympathetic activity, and family membership.

The present study assessed the possible familial effect in 71 healthy Caucasian siblings on each of the variables determining the inter-individual variations in energy expenditure (EE) measured under standardized conditions. We found that the 24-h EE measured in respiration chambers of 71 siblings from 32 different families was positively correlated with fat-free mass, which explained 82% of the variation between subjects (P < 0.00001). An additional 10% of the total variation was explained by differences in spontaneous physical activity (P < 0.00001), fat mass (P < 0.00001), plasma concentration of free T3 (P < 0.003), and norepinephrine (P < 0.002), whereas plasma values of epinephrine and androgen hormones did not correlate with 24-h EE. After adjustment for gender, there was a familial aggregation of both 24-h and sleeping EE, as indicated by intraclass correlation coefficients (r) of 0.44 (P < 0.02) and 0.58 (P < 0.01), respectively. The familial effect on gender-adjusted 24-h EE was explained mainly by a familial resemblance of fat-free mass (ri = 0.48; P < 0.015) and fat mass (ri = 0.40; P < 0.03), whereas spontaneous physical activity and plasma concentrations of T2 and norepinephrine did not correlate in families. It is concluded that the familial aggregation of EE in Caucasians is mediated mainly through familial resemblance of body composition; even though plasma concentrations of free T3 and norepinephrine, independent of body composition, explain an additional proportion of the variation in EE, they do not contribute to the familial correlation.

The contribution of body composition, substrates, and hormones to the variability in energy expenditure and substrate utilization in premenopausal women.

Twenty-four-hour energy expenditure and substrate use were measured by indirect calorimetry in respiration chambers on a fixed physical program and related to body composition and plasma concentrations of various substrates and thermogenic hormones. Fifty premenopausal women with a wide range of body weight were examined in the follicular menstrual phase under weight stable conditions. Most of the variance in the sleeping energy expenditure (82%) was accounted for by two covariates, lean body mass (75%, P less than 0.0001), and fat mass (7%, P less than 0.0001). An additional 6% of the variance in sleeping energy expenditure was accounted for by plasma androstenedione concentration (4%, P = 0.0005) and by free T3 index (2%, P = 0.03). Thus physiological variation among individuals in plasma androstenedione concentration may result in a difference in energy expenditure of 908 kJ/day and the corresponding variation in free T3 index may result in a difference between individuals of 594 kJ/day. Fifty four percent of the variation in carbohydrate oxidation rates was accounted for by 24-h energy balance, and by plasma concentrations of insulin, nonesterified fatty acids, and estradiol. Waist circumference, plasma nonesterified fatty acids, and estradiol concentrations explained 49% of the variance in 24-h lipid oxidation. An obese subgroup of women (n = 27) had significantly higher 24-h energy expenditure, lipid, and carbohydrate oxidation rates than an age-matched normal weight group (n = 16), but the entire group difference in energy expenditure was explained by differences in body composition. We conclude that physiological variations in plasma androstenedione and T3 concentrations contribute to the interindividual variance in energy expenditure of women, and their role is not different in obese women. A positive energy balance and increased insulin action may be mediators of the higher carbohydrate oxidation in obesity, whereas an increased substrate availability seems to bring about the increased lipid oxidation.

Twenty-four-hour respiratory quotient: the role of diet and familial resemblance.

Body weight and obesity show familial resemblance that could be the result of familial correlation of fat oxidation, low levels of which have been implicated in the etiology of weight gain and obesity. We studied the familial correlation of both 24-h respiratory quotient (RQ), an index of the ratio of fat to carbohydrate oxidation, and the possible influence of dietary macronutrient composition expressed by the food quotient (FQ), i.e. the theoretical RQ produced by the diet. We measured the habitual FQ of the 7 days diet by weighed food records, followed by measurement of 24-h RQ in respiration chambers in 71 healthy Caucasian siblings from 31 families. After adjustment for age, gender, and 24-h energy balance, 24-h RQ correlated in families as indicated by an intraclass correlation coefficient (r(i)) of 0.31 (P = 0.03). FQ, adjusted for age and gender, was also a familial trait for the two days immediately preceding diet (r(i) = 0.32, P < 0.01). The familial effect on 24-h RQ, adjusted for age, gender, and 24-h energy balance, remained after adjustment for the FQ of the two days preceding diet (r(i) = 0.27, P < 0.05) and was reduced but not abolished after further adjustment for fasting plasma insulin plus free fatty acids (r(i) = 0.24, P < 0.09). By a correlation analysis aimed at separating familial and individual nonfamilial factors influencing both 24-h RQ and FQ, we found a great but insignificant familial (etaF = 0.49, P < 0.18) and a somewhat lower, but significant individual nonfamilial correlation (etaNF = 0.35, P < 0.03). We conclude that substrate oxidation rates measured by RQ exhibit familial correlation after proper adjustment for confounders such as energy balance, gender, and age, and that this effect could not be fully explained by preceding diet composition, fasting plasma insulin, and free fatty acids. Further RQ and the habitual dietary composition shared familial and nonfamilial factors.

Interaction between beta-adrenergic receptor stimulation and nitric oxide release on tissue perfusion and metabolism.

Nitric oxide (NO) may be an important modulator of sympathetic tone. We used im and sc microdialysis in humans to characterize the interaction of NO synthase inhibition and adrenoreceptor stimulation on tissue perfusion, metabolism, and norepinephrine release. Microdialysis probes were perfused with L- or D-nitro-L-arginine-methyl-ester (100 micromol/L) followed by incremental doses of isoproterenol, epinephrine, or nitroprusside. Blood flow was estimated based on the ethanol dilution technique. In muscle, the increase in blood flow with isoproterenol was abolished by L-NAME. The ethanol ratio was 0.03 +/- 0.011 with D-NAME and 0.075 +/- 0.014 with L-NAME during isoproterenol treatment (1 micromol/L). The effect was less pronounced in adipose tissue. The vasodilatory effect of nitroprusside was similar with D- and L-NAME. L-NAME augmented isoproterenol- and epinephrine-induced glycerol release. Dialysate glycerol during 1 micromol/L isoproterenol was 47 +/- 6.7 micromol/L with D-NAME and 72 +/- 15 micromol/L with L-NAME. In skeletal muscle, dialysate norepinephrine during 1 micromol/L isoproterenol treatment was 0.73 +/- 0.17 and 1.3 +/- 0.15 nmol/L with D- and L-NAME, respectively. We conclude that NO synthase inhibition attenuates beta(2)-adrenoreceptor-mediated vasodilation and enhances beta-adrenoreceptor-mediated lipolysis. These effects are in part mediated through an increase in interstitial norepinephrine concentrations. The data are consistent with the idea that in humans, NO is important in modulating and ameliorating sympathetic effects in peripheral tissues.

Insulin secretion, insulin action and non-insulin-dependent glucose uptake in pancreas transplant recipients.

To assess individual factors responsible of overall glucose tolerance after successful pancreas transplantation, an i.v. glucose tolerance test, with frequent blood sampling and tolbutamide administration to elicit a second insulin response was used to estimate insulin sensitivity (SI) and glucose effectiveness (SG) with Bergman's minimal model. Insulin secretion was calculated from the combined insulin-C-peptide kinetics method. These parameters were quantified in identically immunosupressed transplants: ISPx, four segmental pancreas recipients with impaired glucose tolerance; TSPx, five segmental pancrease recipients with normal glucose tolerance; WPx, five whole pancreas recipients with normal glucose tolerance; and in two controls groups, Kx, eight nondiabetic kidney recipients, and Ns, eight normal subjects. All participants had normal fasting plasma glucose and normal glycosylated hemoglobin A1C levels. The glucose tolerance KG value was significantly reduced only in ISPx compared with Ns (P < 0.05). SI was reduced by 60% in ISPx, WPx, and Kx compared with normal subjects (P < 0.05), whereas SI was reduced by 30% in TSPx compared with normal controls (P = NS). The reduction in SG was the same in all pancreas transplanted groups, as compared to Kx and Ns (by 33% and 40%, respectively, P < 0.05). The first-phase insulin secretion (0-5 min) was markedly reduced in ISPx and TSPx compared with Ns (by 76% and 50%), to Kx (by 84% and 66%) and to WPx (by 73% and 45%), respectively (P < 0.05), but similar to Ns in WPx. The overall incremental insulin secretion was reduced in ISPx compared with Ns, WPx, and Kx (by 38%, 62%, and 73%, respectively, P < 0.05) and reduced in TSPx compared to WPx and Kx (by 47% and 67%, respectively, P < 0.05) Ns secreted 43% of the total amount of insulin during the first phase the corresponding value was only 13% in ISPx vs. 24% in TSPx, 24% in Kx, and 25% in WPx, respectively (P < 0.05). In conclusion, after pancreas transplantation, the overall glucose tolerance is determined by the net effect of reductions in insulin sensitivity and glucose effectiveness and in the adaptability of the beta-cells to ensure sufficient insulin secretion. beta-cell function was impaired in both the whole pancreas and segmental transplant recipients, and the failure to increase insulin secretion sufficiently leads to glucose intolerance.

Pancreatic endocrine function in recipients of segmental and whole pancreas transplantation.

To determine potential abnormalities in beta-cell function after pancreas transplantation, the secretory capacity of the pancreatic grafts was assessed by measuring the glucose-potentiating effect on arginine-induced insulin secretion in recipients of cadaveric segmental (SPx; n = 8) and whole organ pancreas grafts (WPx; n = 6) and compared to that in nondiabetic kidney transplant recipients (Kx; n = 6) and normal controls (Ns; n = 7). alpha-Cell adaptation to increasing hyperglycemia and the glucagon response to arginine stimulation were also studied. The secretory capacity of the beta-cell to arginine-induced (5 g L-arginine) insulin secretion was measured at fasting plasma glucose and 15 and 30 mmol/L glucose. Insulin secretion was evaluated by the calculation of insulin secretion rates. Insulin sensitivity was markedly reduced in all three transplanted groups compared to that in normal subjects (P < 0.05). The prestimulation insulin secretion rate and maximal insulin secretion rate in response to hyperglycemia and arginine were significantly lower in SPx than in WPx, Kx, or Ns (P < 0.05). The incremental amount of insulin secreted in response to arginine was reduced by 40-70% in SPx depending on glycemia compared to that in all other groups (P < 0.05), among which there were no statistical differences. Both SPx and WPx demonstrated suppression of glucagon release in response to graded hyperglycemia, but failure to adequately suppress arginine-induced glucagon release. In conclusion, recipients of cadaveric segmental pancreas grafts display a markedly reduced maximal insulin secretory reserve capacity. This impairment was primarily due to an insufficient beta-cell mass. Taking the concomitant insulin resistance into account, recipients of a cadaver whole organ pancreas graft had an impaired insulin secretory reserve capacity as well.