Constant Insulin Infusion Research Articles

Prospective evaluation of insulin resistance and lipid metabolism in women receiving oral contraceptives.

It has been suggested that normal women receiving oral contraceptives (OC) may develop a series of metabolic side-effects which relate to the risk of cardiovascular disease. These metabolic disturbances include changes in glucose and insulin metabolism, raised serum lipid and lipoprotein concentrations and elevated blood pressure. All these changes indicate that OC might cause insulin resistance. We have prospectively examined the effect of OC on insulin resistance and lipid metabolism including Lp(a) values. The study group comprised 13 normally menstruating Chinese women. The study subjects were given a combined triphasic oral contraceptive which was administered on a 21-day on, 7-day off medication cyclic regimen, the first pill being administered on day 5 from the beginning of menses. The metabolic investigations were carried out during luteal phase before OC and again the third week of the third month of OC administration. Metabolic evaluation including insulin secretion and insulin-mediated glucose uptake were evaluated by oral glucose tolerance test and the modification of insulin suppression test. Fasting triglyceride, cholesterol, HDL-cholesterol and Lp(a) concentrations were also measured. The plasma glucose and insulin responses during a 75-g oral glucose challenge increased significantly (P < 0.05 and P < 0.03, respectively). The steady-state plasma glucose (SSPG) concentrations achieved during constant infusion of glucose, insulin and somatostatin increased significantly after 3 cycles of OC administration (glucose 7.5 +/- 0.8 vs 12.4 +/- 0.7 mmol/l, P < 0.001) while the steady-state plasma insulin (SSPI) concentrations were relatively similar (410 +/- 14 vs 391 +/- 7 pmol/l, NS). Plasma triglyceride levels increased significantly (0.81 +/- 0.12 vs 1.09 +/- 0.19 mmol/l, P < 0.03) following OC administration. Fasting plasma cholesterol, HDL cholesterol and calculated LDL cholesterol concentrations did not change as compared with baseline values, nor did the ratio of total cholesterol to HDL cholesterol. The Lp(a) concentrations did not change during the administration of OC (81 +/- 25 vs 71 +/- 21 mg/l, NS). These data indicated that intake of OC for 3 cycles induced glucose intolerance, hyperinsulinaemia and insulin resistance in normal menstruating Chinese women. These changes occurred in association with elevated plasma triglyceride concentrations and no alteration in Lp(a) or other lipid values.

Patients with type 1 diabetes lack vasoconstrictor response in skin microcirculation during insulin-induced hypoglycemia.

Disturbed hemodynamic reactions to insulin-induced hypoglycemia have been documented in diabetic patients and considered related to hyperinsulinemia and impairment of autonomic nervous functions. In the present study we investigated the effect on skin microcirculation of insulin-induced hypoglycemia obtained during moderate hyperinsulinemia, in 7 men with type 1 diabetes and in 8 healthy age- and sex-matched controls. The patients had all normal cardiovascular reflexes as assessed by respiratory sinus arrhythmia and Valsalva ratio. The skin microcirculation of the left fourth finger nailfold was investigated by laser Doppler fluxmetry, and the skin temperature within the same area was measured by a thermistor. Hypoglycemia was induced by a constant insulin infusion of Actrapid Human, 0.034 U kg-1 h-1 during 120 min. Plasma adrenaline, noradrenaline and pancreatic polypeptide increased significantly in both groups during hypoglycemia and the insulin levels never exceeded 50 mUl-1. A close to identical arterial hypoglycemia was obtained in the two groups 60 min after onset of insulin infusion. During hypoglycemia the control subjects revealed a significant decrease in laser Doppler flux (p < 0.025), while it was unchanged in the diabetic patients. Simultaneously, the skin temperature decreased (p < 0.05) in the controls, but was unchanged in the diabetic patients. The present study indicates that type 1 diabetic patients with normal cardiovascular reflexes have an abolished vasoconstrictor response in skin microcirculation of fingers during insulin-induced hypoglycemia, despite the fact that neurogenic and neuroglucopenic symptoms developed in these patients during hypoglycemia.

Insulin resistance and hyperinsulinemia in individuals with small, dense low density lipoprotein particles.

Subjects characterized by a predominance of small LDL particles (pattern B) have changes in plasma triglyceride (TG) and HDL-cholesterol concentrations consistent with the presence of resistance to insulin-mediated glucose uptake. To pursue this issue, plasma glucose and insulin responses to oral glucose, insulin-mediated glucose disposal, and lipoprotein concentrations were measured in subjects categorized on the basis of LDL peak diameter measured by gradient gel electrophoresis. Subjects with pattern B had higher (P < 0.05-0.001) total integrated plasma glucose (20.7 +/- 1.0 mmol/liter.h) and insulin (1,743 +/- 293 pmol/liter.h) responses to oral glucose compared with glucose (16.3 +/- 0.4 and 19.2 +/- 0.8 mmol/liter.h) and insulin (856 +/- 60 and 1,222 +/- 168 pmol/liter.h) responses in those with either pattern A or an intermediate pattern. Pattern B individuals were shown to be more insulin resistant on the basis of higher steady state plasma glucose concentrations (SSPG, 10.4 +/- 1.0, P < 0.002, vs. 7.5 +/- 0.7 and 6.0 +/- 0.4 mmol/liter) after a constant infusion of somatostatin, glucose, and insulin than those with either the intermediate or pattern A subclass. Pattern B subjects also had higher concentrations of (P < 0.001) TG (1.98 +/- 0.15 vs. 1.33 +/- 0.17 and 0.77 +/- 0.05 mmol/liter) and lower (P < 0.01-0.001) HDL cholesterol (1.12 +/- 0.06 vs. 1.34 +/- 0.05 vs. 1.45 +/- 0.05 mmol/liter) than those with either the intermediate or pattern A. Finally, significant (P < 0.001) correlation coefficients existed between LDL diameter and SSPG (r = -0.44); glucose (r = -0.41) and insulin (r = -0.38) responses; TG (r = -0.65) and HDL-cholesterol (r = 0.42) concentrations; and systolic (r = -0.34) and diastolic (r = -0.34) blood pressure. Thus, pattern B subjects are insulin resistant, have higher glucose, insulin, and TG, lower HDL-cholesterol levels, and higher blood pressure than those with pattern A or intermediate.

Day-to-day variation of the glycemic response in subjects with insulin-dependent diabetes with standardized premeal blood glucose and prandial insulin concentrations

To study the day-to-day variation in the glycemic response to a starch-rich meal in subjects with insulin-dependent diabetes mellitus (IDDM), eight young subjects with IDDM were served test meals of 100 g white bread on 3 separate days. They had achieved normoglycemia 2 h before the test meals by means of a glucose clamp and a constant insulin infusion was provided during the study period. Mean areas under the response curves of blood glucose to the three meals (above basal) were not different: 1067 +/- 93, 1028 +/- 91, and 970 +/- 42 mmol/L x 180 min (NS) and no difference in insulin concentrations was found. The mean (+/- 95% confidence interval) of blood glucose area under the response curves for one test meal was 1067 +/- 230 mmol/L x 180 min and for the test meal repeated three times was 1021 +/- 133 mmol/L x 180 min. Intra- and interperson components of variance were 26% and 74%, respectively, of the total variance of blood glucose areas.

Dose-dependency of the glycemic response to starch-rich meals in insulin-dependent diabetic subjects: Studies at constant insulinemia

The study objective was to determine the dose-response relationship of postprandial blood glucose response areas to the amount of starch ingested in insulin-dependent diabetic (IDDM) subjects. Three test meals were served in random order with a 7-day interval to seven IDDM subjects attending the outpatient clinic at Aarhus Kommunehospital. Mixed meals of 23, 46, and 69 g parboiled white rice (raw weight) containing approximately 20, 40, and 60 g available carbohydrate were served cooked on three separate days. The patients had achieved normoglycemic blood glucose levels 2 hours before meal intake by means of an artificial pancreas (Biostator, Miles Laboratories, Elkhart, IN), which also provided constant insulin infusion during the study periods (0 to 180 minutes). A clear-cut dose-response relationship between the amount of starch ingested and postprandial peak blood glucose values ( r = .96) as well as glucose response areas ( r = .99) was found. Glucose response areas to meals containing 20, 40, and 60 g carbohydrate differed significantly ( P < .01), attaining 291 ± 77, 643 ± 75, and 878 ± 99 mmol/L × 180 minutes, respectively. Glucosuria accounted for 0.6 and 1.6 g (NS) after 20 and 40 g carbohydrate, whereas 5.0 glucose ( P < .05) was detected following 60 g carbohydrate. Similar mean serum free insulin levels (range, 102 to 150 pmol/L) during the three study periods were found.

Local skin-fold thickness as a clinical predictor of depot size during basal rate infusion of insulin.

To determine the influence of local adiposity on insulin depot size during CSII at basal rate. In 27 diabetic patients, a constant infusion of 125I-labeled Actrapid insulin was given, with U-40 insulin at a rate of 1.12 IU/h in 20 patients, and U-100 at a rate of 1 IU/h in 7 patients. After 16 h of infusion, the steady-state depot size was measured by external counting, and the local skin fold was measured with a Harpenden skin-fold caliper. U-40 insulin infusion resulted in a steady-state depot size of 5.1 U (2.1-10.9 U), and a corresponding skin-fold thickness of 17.8 mm (5-34 mm). A positive correlation was found between depot size and skin-fold thickness. A similar correlation was observed with U-100 insulin. During basal rate CSII, large variations in local skin-fold thickness create large variations in the steady-state depot size, which is partly predictable just by lifting the skin fold.

Insulin resistance, hyperinsulinemia, and dyslipidemia in nonobese individuals with a family history of hypertension.

Various facets of glucose, insulin, and lipid metabolism were compared in 76 normal volunteers--38 with and 38 without a family history of hypertension. The two groups were comparable in terms of age, gender distribution, and degree of obesity (both generalized and abdominal). Although the plasma glucose response to oral glucose was similar in both groups, glucose-stimulated insulin concentrations were significantly greater in volunteers with a family history of hypertension (P < .001). Furthermore, the steady state plasma glucose concentration during a constant infusion of glucose, insulin and somatostatin was significantly greater in subjects with a family history of hypertension (8.1 +/- 0.6 v 6.2 +/- 0.6 mmol/L, P < .001). Since the steady-state plasma insulin levels during the infusion were similar, these results indicate that normotensive individuals with a family history of hypertension are relatively insulin resistant. Finally, plasma very low density lipoprotein (VLDL) triglyceride and VLDL cholesterol were higher in those with a family history of hypertension, as was the ratio of total to high density lipoprotein cholesterol. Thus, normotensive individuals with a family history of high blood pressure are insulin resistant, hyperinsulinemic and dyslipidemic when compared to a matched group of healthy volunteers without a family history of hypertension.

Hypoglycemic thresholds for cognitive dysfunction in IDDM.

Fourteen poorly controlled insulin-dependent diabetes mellitus (IDDM) patients (HbA1c 11 +/- 0.5%) with a mean +/- SE duration of disease of 15 +/- 2 yr were studied to evaluate the hypoglycemic threshold for cognitive dysfunction under insulin-induced hypoglycemia. The P300 event-related potential, a measure of cognitive function, and reaction time (RT) in response to visual stimuli under euglycemic conditions and at plasma glucose concentrations of 3.5 and 2.5 mM (63 and 45 mg/dl, respectively) during a constant insulin infusion were recorded. Baseline P300 latency was similar to that of a nondiabetic control group, but baseline RT was greater in the IDDM group. There was no increase in P300 latency or RT under euglycemic clamp conditions or at a plasma glucose level of 3.5 mM (63 mg/dl). However, when plasma glucose was lowered to 2.5 mM (45 mg/dl), there was an increase in P300 latency and a prolongation of RT. As plasma glucose returned to baseline, P300 latency and RT remained prolonged. After administration of intravenous glucose and a meal, P300 latency and RT returned to baseline. P140, an event-related potential reflecting sensory processes, was not altered. Because P300 latency changes paralleled RT changes, hypoglycemia appears to slow decision-making processes in IDDM. This study revealed that 1) baseline P300 latency is not elevated in poorly controlled IDDM patients, suggesting no cumulative cognitive dysfunction.

Mechanism of intrahippocampal neostigmine-induced hyperglycemia in fed rats.

We previously reported that the injection of neostigmine, an acetylcholine esterase inhibitor, into the dorsal hippocampus produced hepatic venous plasma hyperglycemia associated with an increase of epinephrine and glucagon in anesthetized fed rats. To evaluate the relative contribution of these glucoregulatory hormones and the nervous system to the net hyperglycemic response, we unilaterally injected neostigmine (5 x 10(-8) mol) into the dorsal hippocampus in the following groups of rats: intact rats with bilateral adrenalectomy to eliminate the action of epinephrine, and rats receiving a constant infusion of somatostatin and insulin to prevent the glucagon response and to maintain the basal insulin level. Hepatic venous plasma levels of glucose, immunoreactive glucagon, immunoreactive insulin, epinephrine, and norepinephrine were determined. The area under the glucose curve during the 120-min period following the injection of neostigmine was compared between groups. The areas under the glucose curve for rats receiving somatostatin and insulin, adrenalectomy rats, and adrenalectomy rats receiving somatostatin and insulin were, respectively, 82, 31, and 61% of that for intact rats. The fashion of hippocampal stimulated hyperglycemia with neostigmine was similar to that after injection of neostigmine into the third cerebral ventricle. Therefore, we investigated hyperglycemia in rats with lesions of ventromedial hypothalamus and found that the response to hippocampal neostigmine was significantly inhibited by the hypothalamic lesion. These findings suggest that the glucoregulatory hippocampal activity evoked by neostigmine may be transmitted to peripheral organs via the ventromedial hypothalamus.

Insulin Clearance During Hypoglycemia in Patients with Insulin-Dependent Diabetes Mellitus

Eight male patients with insulin-dependent diabetes mellitus (IDDM) without residual beta-cell function were studied on two occasions in random order. In one experiment hypoglycemia was induced by a constant rate iv infusion of insulin (0.034 U/kg/h) during 150 minutes. At the other occasion an identical infusion of insulin was given, but this time euglycemia was maintained by a variable iv infusion of glucose. Plasma levels of free insulin were almost identical during the two experiments indicating that insulin clearance is not influenced by hypoglycemia in patients with IDDM.

Preprandial blood glucose values and glycemic responses in insulin-dependent diabetes mellitus at constant insulinemia

The influence of preprandial blood glucose (PPBG) concentration on glycemic responses was studied in seven subjects with insulin-dependent diabetes who, by means of the artificial pancreas, had achieved PPBG concentrations of 6, 9, and 17 mmol/L. A test meal of 50 g parboiled rice was given at the three different occasions and a constant insulin infusion was provided during the observation periods. The mean postprandial-blood-glucose-response area (above basal) differed significantly at the three blood glucose concentrations of 6, 9, and 17 mmol/L, reaching 1371, 621, and 179 mmol/L x 240 min, respectively (P less than 0.01). A negative correlation between the PPBG concentrations and the glycemic responses to the test meal was found (r = 0.94; P less than 0.001). The fasting insulin concentration at a PPBG concentration of 17 mmol/L was lower than at a PPBG concentration of 6 and 9 mmol/L. In conclusion, the glycemic responses to a carbohydrate meal are inversely correlated to the PPBG concentration in insulin-dependent diabetic subjects.

Fetal catecholamine responses to maternal hypoglycemia

The present studies were designed to determine the fetal catecholamine and metabolic responses to insulin-induced maternal hypoglycemia. Maternal hypoglycemia was induced by a primed constant infusion of insulin and glucose administered to pregnant ewes to maintain maternal glucose at 20-25 mg/dl. Maternal and fetal samples for measurement of catecholamine, glucose, and free fatty acid levels and arterial blood gas analysis were collected before insulin infusion and at intervals thereafter for 6 h. Maternal and fetal plasma catecholamine levels increased significantly in response to hypoglycemia (analysis of variance, P less than 0.01). Fetal insulin and glucagon levels did not change despite a 50% reduction in fetal whole blood glucose concentration. Fetal free fatty acid levels increased significantly during hypoglycemia (P less than 0.05). There were no significant changes in maternal or fetal heart rate, blood pressure, or arterial blood gases during hypoglycemia. These results suggest that the fetus is capable of responding to hypoglycemia with an increase in catecholamine and free fatty acid levels. These results are consistent with the interpretation that the fetus is able to mobilize alternative energy substrates in response to maternal insulin-induced hypoglycemia.

D-[U-11C]glucose uptake and metabolism in the brain of insulin-dependent diabetic subjects

We used D-[U-11C]glucose to evaluate transport and metabolism of glucose in the brain in eight nondiabetic and six insulin-dependent diabetes mellitus (IDDM) subjects. IDDM subjects were treated by continuous subcutaneous insulin infusion. Blood glucose was regulated by a Biostator-controlled glucose infusion during a constant insulin infusion. D-[U-11C]-glucose was injected for positron emission tomography studies during normoglycemia as well as during moderate hypoglycemia [arterial plasma glucose 2.74 +/- 0.14 in nondiabetic and 2.80 +/- 0.26 mmol/l (means +/- SE) in IDDM subjects]. Levels of free insulin were constant and similar in both groups. The tracer data were analyzed using a three-compartment model with a fixed correction for 11CO2 egression. During normoglycemia the influx rate constant (k1) and blood-brain glucose flux did not differ between the two groups. During hypoglycemia k1 increased significantly and similarly in both groups (from 0.061 +/- 0.007 to 0.090 +/- 0.006 in nondiabetic and from 0.061 +/- 0.006 to 0.093 +/- 0.013 ml.g-1.min-1 in IDDM subjects). During normoglycemia the tracer-calculated metabolism of glucose was higher in the whole brain in the nondiabetic than in the diabetic subjects (22.0 +/- 1.9 vs. 15.6 +/- 1.1 mumol.100 g-1.min-1, P less than 0.01). During hypoglycemia tracer-calculated metabolism was decreased by 40% in nondiabetic subjects and by 28% in diabetic subjects. The results indicate that uptake of glucose is normal, but some aspect of glucose metabolism is abnormal in a group of well-controlled IDDM subjects.

Effect of Plasma Amino Acid Replacement on Glucagon and Substrate Responses to Insulin-Induced Hypoglycemia in Humans

A defective glucagon response impairs glucose recovery from insulin-induced hypoglycemia in some insulin-dependent (type I) diabetic patients. Our objective was to determine whether the glucagon response to insulin-induced hypoglycemia could be stimulated in nondiabetic humans. Because insulin reduces plasma amino acid concentrations, and amino acids are known to stimulate glucagon secretion, we investigated the effect of amino acid replacement during insulin infusion on the glucagon response to hypoglycemia in six healthy nondiabetic subjects. In two separate studies, blood glucose was clamped at the postabsorptive level during a constant infusion of insulin (0.05 U.kg-1.h-1) for 3 h. Blood glucose was then reduced to 45 mg/dl over 20 min. Hormone and substrate concentrations during recovery from hypoglycemia were monitored for 2 h. In the control study, normal saline was infused, and in the other study, an amino acid mixture was infused to prevent the insulin-induced fall in plasma amino acids. Amino acid replacement did not change the basal glucagon levels but resulted in a more robust glucagon response to hypoglycemia (from 184 +/- 24 to 292 +/- 36 pg/ml) than in the control study (from 176 +/- 30 to an average 229 +/- 32 pg/ml, P less than 0.01). Plasma concentrations of epinephrine, norepinephrine, cortisol, and growth hormones increased during hypoglycemia, but the magnitude of the response was not different between the control and amino acid-replacement studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of baroreflex by varying insulin and glucose in conscious dogs

We developed a conscious, chronically instrumented canine preparation (n = 5 dogs) in which insulin concentration was precisely controlled to study the effects of controlled variations of plasma insulin and glucose concentrations on cardiac responses to bilateral carotid occlusion and dobutamine. Endogenous insulin secretion was reduced to negligible levels using alloxan and then replaced by continuous, constant intravenous insulin infusion at a rate (0.625 +/- 0.115 U/h) sufficient to maintain fasting normoglycemia (85 +/- 9 mg/100 ml); plasma immunoreactive insulin (IRI) in this basal "normal insulin, normal glucose" (NI,NG) condition was 0.362 +/- 0.45 ng/ml (NS vs. prealloxan fasting concentration). A fivefold increase of IRI from NI,NG levels with normoglycemia maintained (5 x NI,NG) reduced (P less than 0.05) the maximal first time derivative of left ventricular pressure (LV dP/dtmax) from 3,010 +/- 62 to 2,398 +/- 91 (SE) mmHg/s but had no effect on LV dP/dtmax when plasma glucose was elevated to 298 +/- 25 mg/100 ml (5 x NI,HG). The LV dP/dtmax increase during bilateral carotid occlusion (BCO) in the NI,NG state of 124 +/- 17 mmHg/s was significantly reduced (P less than 0.05) in the 5 x NI,HG state to 58 +/- 18 mmHg/s but was not altered in the 5 x NI,NG state. Reduction of plasma insulin to one-fifth of the normal fasting level had no effect on basal cardiac function or the responses to BCO. There were no other statistically significant effects of insulin or glucose concentration on cardiovascular responses to BCO or to infusion of dobutamine. Our data indicate that physiologically realistic variations in plasma IRI and glucose concentrations interact and may modulate cardiovascular responses to changes in autonomic nervous activity, even though previously reported effects of pharmacological doses of insulin were not observed.

A Comparison of Brain Glucose Metabolism in Diabetes as Measured by Positron Emission Tomography or by Arteriovenous Techniques

[U-11-C]-glucose and positron emission tomography was used to evaluate transport and oxidative metabolism of glucose in the brain of non-diabetic and insulin dependent diabetic (IDDM) subjects. These results were compared with results obtained by the Fick principle. Blood glucose was regulated by a Biostator controlled glucose infusion during a constant insulin infusion. [U-11-C]-glucose was injected during normoglycemia as well as during moderate hypoglycemia. The tracer data were analysed using a three compartment model with a fixed correction for [11-C]-CO2 egress. During normoglycemia the influx rate constant (k1) and blood brain glucose flux of the two groups were similar. During hypoglycemia k1 increased significantly and to the same extent in both groups. During normoglycemia the tracer calculated metabolism of glucose was higher in the brain of non-diabetic than of diabetic subjects. When measured by the Fick principle the net uptake of glucose was broadly the same for the groups. During normoglycemia the molar ratio of O2 to glucose uptake was, however, lower in IDDM than in non-diabetic subjects (4.67 vs 5.50, P less than 0.05, Wilcoxon test). A significant release of lactate and pyruvate was seen in IDDM but not in non-diabetic subjects. The results imply that a larger fraction of glucose is non-oxidatively metabolized in IDDM than in non-diabetic subjects.

Insulin transport across capillaries is rate limiting for insulin action in dogs.

This study examined the relationship between transcapillary insulin transport and insulin action in vivo. During euglycemic clamps (n = 7) in normal conscious dogs we simultaneously measured plasma and thoracic duct lymph insulin and glucose utilization (Rd). Clamps consisted of an activation phase with constant insulin infusion (0.6 mU/kg per min) and a deactivation phase. [14C]Inulin was infused as a passively transported control substance. While [14C]inulin reached an equilibrium between plasma and lymph, steady-state (ss) plasma insulin was higher than lymph (P less than 0.05) and the ratio of 3:2 was maintained during basal, activation, and deactivation phases: 18 +/- 2 vs. 12 +/- 1, 51 +/- 2 vs. 32 +/- 1, and 18 +/- 3 vs. 13 +/- 1 microU/ml. In addition, it took longer for lymph insulin to reach ss than plasma insulin during activation and deactivation: 11 +/- 2 vs. 31 +/- 5 and 8 +/- 2 vs. 32 +/- 6 min (P less than 0.02). Rd increased from 2.6 +/- 0.1 to a ss of 6.6 +/- 0.4 mg/kg per min within 50 +/- 8 min. There was a remarkable similarity in the dynamics of insulin in lymph and Rd: the time to reach ss for Rd was not different from lymph insulin (P greater than 0.1), and the relative increases of the two measurements were similar, 164 +/- 45% and 189 +/- 29% (P greater than 0.05). While there was only a modest correlation (r = 0.78, P less than 0.01) between Rd and plasma insulin, the dynamic changes of lymph insulin and Rd showed a strong correlation (r = 0.95, P less than 0.01). The intimate relationship between lymph insulin and Rd suggests that the transcapillary insulin transport is primarily responsible for the delay in Rd. Thus, transcapillary transport may be rate limiting for insulin action, and if altered, it could be an important component of insulin resistance in obesity and diabetes mellitus.

Early morning hyperglycemia in insulin-dependent diabetes: acute and sustained effects of cholinergic blockade.

Nocturnal release of GH has been shown to be related to the early morning rise in plasma glucose (PG) seen in insulin-dependent diabetes mellitus (IDDM). We have studied the effects of suppression of nocturnal GH release during a single night (acute study) and after nightly suppression for 1 week (chronic study). Changes in plasma glucose and counter-regulatory hormone concentrations were monitored in six IDDM patients during a constant overnight insulin infusion alone, after addition of the anticholinergic agent pirenzepine to cause acute GH suppression, and again on the seventh night of such treatment. In control experiments (infusion of insulin alone; 0.075 mU/kg.min) PG increased from (mean +/- SEM) 5.6 +/- 0.6 mmol/L at 2400 h to 11.1 +/- 1.3 mmol/L at 0900 h (P = 0.0024). Addition of pirenzepine (100 mg at 2200 h and again at 2400 h) in the acute study resulted in a PG change from 5.6 +/- 0.3 mmol/L at 2400 h to 8.4 +/- 1.4 mmol/L at 0900 h (P = 0.17). After pirenzepine administration at the same dose for 7 nights, PG increased from 4.7 +/- 0.6 mmol/L at 2400 h to 6.8 +/- 1.2 mmol/L at 0900 h (P = 0.11). Increases in PG during the study period were significantly less after chronic treatment than after acute treatment compared with changes on control nights. The nocturnal release of GH, which was demonstrated in all patients during the control nights, was suppressed in all patients during the acute study and in four of six patients during the chronic studies. We conclude that initial reduction of the early morning rise of PG in IDDM is associated with acute suppression of nocturnal GH release, and that the more significant sustained effect of anticholinergic GH suppression on the rise of PG may be associated with additional indirect effects on insulin clearance.

NO IMPROVEMENT OF PANCREAS TRANSPLANT ENDOCRINE FUNCTION BY EXOGENOUS INSULIN INFUSION (ISLET REST) IN THE POSTOPERATIVE PERIOD

The concept of islet exhaustion maintains that exposure of pancreatic islets to hyperglycemia and other stresses leads to islet dysfunction and irreparable damage. The process of pancreatic transplantation places many stresses on islets (e.g., counter-regulatory hormones, steroids, cyclosporine toxicity). As practiced by some centers, it may be important to administer exogenous insulin in the postoperative period to provide islet rest. Using a porcine pancreas transplant model that simulates clinical transplantation, we studied 2 groups: 1 group (n = 8) received constant insulin infusion for 7 days after transplantation; the control group (n = 5) received vehicle only. The islets in the insulin infusion group were rested as evidenced by a significantly decreased mean C-peptide level (0.27 +/- 0.04 ng/ml) as compared to the control group (0.66 +/- 0.08 ng/ml) (P less than 0.05). After insulin infusion was discontinued, intravenous glucose tolerance testing found insulin, C-peptide and glucagon responses were not different between groups. Glucose clearance was also comparable; K values were -1.79 and -1.60 in the insulin infusion and control groups, respectively. In conclusion, islet rest by insulin infusion for 7 postoperative days did not improve subsequent pancreas transplant endocrine function.

Effect of euglycemic hyperinsulinemia on neonatal canine hepatic and muscle metabolism.

The effects of euglycemic hyperinsulinemia on hepatic and muscle metabolism were determined in the fasted newborn dog during the first day of life. Hyperinsulinemia was sustained with a primed constant infusion of insulin whereas euglycemia was maintained with an intravenous infusion of 10% glucose using the insulin clamp technique. Euglycemic hyperinsulinemia caused an increase of glucose utilization from 43.9 +/- 3.7 to 66.5 +/- 5.4 mumol/kg/min (p less than 0.001) and reduced endogenous glucose production to 44.4 +/- 5.4% of basal values obtained before the induction of hyperinsulinemia. Hepatic tissue glycogen, triglycerides, or intermediates were not altered by hyperinsulinemia nor was the incorporation of [3H]glucose into glycogen. However, the hepatic cytoplasmic redox state was more oxidized, and the incorporation of [3H]glucose into triglycerides was higher among hyperinsulinemic pups. Pups who demonstrated incomplete suppression of endogenous glucose production had metabolite perturbation suggestive of ongoing gluconeogenesis. Despite very few changes in hepatic tissue metabolite levels, pups subjected to hyperinsulinemia demonstrated a linear uptake of 2-deoxyglucose into hepatic tissue as a function of circulating insulin levels during hyperinsulinemia. Muscle tissue demonstrated no alterations of tissue metabolites, glycogen, or triglycerides levels or precursor incorporation into these storage pools. Nonetheless, 2-deoxyglucose incorporation into neonatal muscle tissue was a significant linear function of plasma insulin concentration. Total tissue 2-deoxyglucose uptake was lower in muscle tissue than in hepatic tissue (245 +/- 19 versus 514 +/- 20 dpm/g/min) (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)