Metabolic Clearance Rate Of Insulin Research Articles

Effects of massive obesity on insulin sensitivity and insulin clearance and the metabolic response to insulin as assessed by the euglycemic clamp technique

Insulin sensitivity was studied in nine nondiabetic massively obese patients (one male and eight females ages 39.0 ± 2.7 years, body mass index 47.1 ± 1) by the euglycemic clamp technique (40 mU/m 2/min) and compared to seven lean control subjects (three males and three females, ages 34.8 ± 2.5 years, body mass index 23 ± 1.1). Fasting plasma glucose, immunoreactive insulin, and C-peptide concentrations were higher in the massively obese patients than in the controls ( P < 0.025). Following exogenous insulin infusion, immunoreactive glucagon and C-peptide concentrations decreased similarly in the massively obese patients and controls, indicating normal sensitivity of the alpha and beta cell to insulin. Glucose uptake (M) expressed either as mg · min −1 of fat free mass was significantly reduced in the massively obese patients compared to the controls ( P < 0.001). Similarly, the M I ratio (glucose uptake per unit of insulin) was significantly reduced in the massively obese patients ( P < 0.001). Free fatty acids and glycerol concentrations measured in the fasting state were significantly elevated in the massively obese patients (free fatty acids 678 ± 51 v 467 ± 55 μmol/L, P < 0.05; glycerol 97 ± 9 v 59 ± 11 μmol/L, P < 0.02). The effects of insulin on antilipolysis was assessed by measuring the reductions in free fatty acids and glycerol concentration during the glucose clamp study. Although the absolute levels remained higher in the massively obese patients, inhibition of lipolysis was similar in both groups. Alanine, lactate, and 3-hydroxybutyrate displayed similar responses in the massively obese patients and controls during the study. The metabolic clearance rate of insulin (MCR 1) was significantly lower in the massively obese patients compared to the controls when expressed per kg of total body weight but not when calculated per kg of fat free mass. In conclusion, massively obese patients showed marked insulin insensitivity on glucose disposal reflecting primarily muscle insensitivity to insulin action. In contrast to decreased glucose disposal, other metabolic effects of insulin were not markedly impaired. The antilipolytic, antiketogenic, and inhibitory effects on insulin and glucagon production remained essentially intact.

Insulin sensitivity and exogenous insulin clearance in Graves' disease. Measurement by the glucose clamp technique and continuous indirect calorimetry.

Insulin sensitivity was measured in a group of seven thyrotoxic patients and in a group of seven normal subjects by means of the glucose clamp technique. Infusion of insulin at a rate of 0.80 +/- 0.05 mU/kg X min in the hyperthyroid patients and of 0.55 +/- 0.04 mU/kg X min in the control group was performed to obtain a steady-state plasma insulin concentration of approximately 50 microU/ml. Substrate oxidation rates were measured in the postabsorptive state and during the 2 h of the clamp by means of continuous indirect calorimetry. In the postabsorptive state, hyperthyroid patients presented a preferential oxidation of lipids. During the period 60-120 min of the clamp, mean plasma glucose (92 +/- 2 versus 93 +/- 2 mg/dl), insulin (50 +/- 5 versus 58 +/- 3 microU/ml), and total glucose metabolism (5.8 +/- 0.7 versus 6.1 +/- 0.3 mg/kg X min) were similar in the hyperthyroid patients and the control subjects. The rate of glucose oxidation was higher in hyperthyroid patients than in control subjects (4.3 +/- 0.5 versus 2.2 +/- 0.2 mg/kg X min, P less than 0.001), while that of lipid oxidation was similar in both groups (0.6 +/- 0.2 versus control 0.7 +/- 0.1 mg/kg X min). The calculated metabolic clearance rate of insulin was markedly higher in the hyperthyroid patients (1144 +/- 132 ml/min) than in the normal subjects (812 +/- 56 ml/min, P less than 0.025). It is concluded that insulin sensitivity is not altered in the thyrotoxic state. The major route of insulin-stimulated glucose disposal in the hyperthyroid patients appears to be glucose oxidation.

Insulin-mediated glucose metabolism is related to liver structure and microsomal function.

The role of the liver in glucose metabolism was investigated in 24 consecutive patients undergoing diagnostic liver biopsy by comparing hepatic morphometry and microsomal enzyme activity in vivo (antipyrine) with fasting blood glucose (BG) and immunoreactive insulin (IRI) levels and with the metabolic clearance rate of insulin and the insulin sensitivity index. The patients had elevated BG and IRI levels and reduced insulin-mediated glucose metabolism, insulin sensitivity index, and microsomal enzyme activity as compared with controls. The insulin metabolic clearance rate did not diverge among the groups. Patients with fatty liver had a high BG associated with a reduced glucose disposal rate, whereas fasting IRI did not diverge when compared with other liver patients. Glucose disposal rate was related to the amount of unaltered liver (r2 = 0.640; p less than 0.001) and antipyrine metabolism (r = 0.631; p less than 0.01) and inversely related to the amount of fat (r2 = 0.585; p less than 0.01). The findings demonstrate that insulin-mediated glucose metabolism is related to liver structure and microsomal function. Accumulation of fat in the liver seems to be a major factor associated with reduced insulin sensitivity and glucose tolerance.

Kinetic models for plasma disappearance of insulin in normal subjects.

Three theoretical kinetic models for plasma disappearance of insulin were examined in six normal men. The models allowed for the existence of non-saturable and/or saturable mechanisms. Constant infusion of porcine insulin at different rates was used to achieve different levels of steady state plasma insulin concentrations, while normoglycaemia was secured by a glucose clamp technique. Appropriate validation procedures demonstrated that one of the three models was superior to the others in describing the relationship between the exogenous insulin infusion rate Iex and the steady state plasma insulin concentration C: Iex = -Iend + k2 X C/(k3 + C), where Iend is the endogenous post-hepatic insulin delivery rate. Thus, only saturable mechanism(s) could be demonstrated. The median value of k2 (the maximal insulin disappearance rate) and k3 (the plasma insulin concentration at which the insulin disappearance rate is half maximal) were 7.31 nmol X min.-1 and 3.89 nmol X 1-1. The median value of k2/k3 (the clearance rate of insulin for infinitesimal plasma insulin concentrations) was 25.0 ml X kg-1 X min.-1. Thus, at physiological levels of plasma insulin concentrations the metabolic clearance rate of insulin is higher than insulin clearance estimates previously reported in studies based on the assumption of first order kinetics.

Insulin secretion and action in the hyperthyroid rat.

To gain insight into the mechanism of the altered carbohydrate metabolism in thyrotoxicosis, intravenous glucose tolerance tests (IVGTT) and pancreatic suppression tests (PST) were performed in hyperthyroid rats (0.1 mg/kg T4 X 5 days) to assess insulin secretion and action in vivo. Thyroid hormone injections significantly increased T4 levels (182.8 nM +/- 11.6 (SEM) versus 50.2 +/- 6.4; P less than 0.001) and baseline glucose concentrations (9.3 mM +/- 0.2 versus 7.1 +/- 0.2; P less than 0.001). Body weights, basal insulin concentrations, glucose concentrations during IVGTT, glucose disappearance rates and steady state plasma glucose levels (SSPG) were normal. Insulin concentrations during the glucose tolerance test and during the PST were significantly decreased. The metabolic clearance rate of insulin (ml/min/kg +/- SEM) was significantly (P less than 0.01) increased (54.4 +/- 3.5 versus 41.6 +/- 2.3) in the hyperthyroid rats. If the different baseline glucose values were subtracted from the glucose concentrations achieved during the 2 tests, both the glucose disappearance rate and the fall in SSPG levels were significantly enhanced in the T4-injected animals. Thus, in the hyperthyroid rat, insulin secretion is decreased, the clearance of insulin is increased and insulin sensitivity is either normal or possibly enhanced.

The metabolic clearance of insulin and the feedback inhibition of insulin secretion are altered with aging.

Elevated basal and stimulated insulin levels have been previously demonstrated in elderly human subjects. To see whether these elevated insulin levels are due to alterations in either the metabolic clearance rate (MCR) for insulin or the feedback inhibition of insulin secretion, we have studied 14 elderly and 19 nonelderly subjects, mean age 70 +/- 2 and 35 +/- 2 yr, respectively. Fasting serum insulin and C-peptide levels were elevated in the elderly compared with the nonelderly, 17 +/- 2 versus 11 +/- 1 microU/ml, P less than 0.01 and 0.95 +/- 0.12 versus 0.47 +/- 0.07 pmol/ml, P less than 0.001. Euglycemic hyperinsulinemia created by insulin infusion rates of 15, 40, and 1200 mU/m2/min with glucose held constant resulted in steady-state serum insulin levels of 65 +/- 4, 109 +/- 8, and 11,316 +/- 890 versus 34 +/- 2, 96 +/- 5, and 11,083 +/- 1079 microU/ml in the elderly and nonelderly subjects, respectively. The MCR of insulin was decreased by 46% in the elderly compared with the nonelderly (10.1 +/- 0.7 versus 18.7 +/- 1.4 ml/kg/min) at the insulin infusion rate of 15 mU/m2/min with no difference observed between the two groups at the higher insulin infusions. Steady-state suppression of C-peptide by exogenous insulin was similar, 73 +/- 2% versus 72 +/- 2% and 70 +/- 3% versus 64 +/- 5% in the nonelderly and elderly groups during the 15 and 40 mU/m2/min insulin infusions, respectively. However, 50% suppression was achieved within 30 min in the nonelderly group compared with 70 min in the elderly group during the low-dose infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of parathyroid hormone in the glucose intolerance of chronic renal failure.

Evidence has accumulated suggesting that the state of secondary hyperparathyroidism and the elevated blood levels of parathyroid hormone (PTH) in uremia participate in the genesis of many uremic manifestations. The present study examined the role of PTH in glucose intolerance of chronic renal failure (CRF). Intravenous glucose tolerance tests (IVGTT) and euglycemic and hyperglycemic clamp studies were performed in dogs with CRF with (NPX) and without parathyroid glands (NPX-PTX). There were no significant differences among the plasma concentrations of electrolytes, degree of CRF, and its duration. The serum levels of PTH were elevated in NPX and undetectable in NPX-PTX. The NPX dogs displayed glucose intolerance after CRF and blood glucose concentrations during IVGTT were significantly (P less than 0.01) higher than corresponding values before CRF. In contrast, blood glucose levels after IVGTT in NPX-PTX before and after CRF were not different. K-g rate fell after CRF from 2.86 +/- 0.48 to 1.23 +/- 0.18%/min (P less than 0.01) in NPX but remained unchanged in NPX-PTX (from 2.41 +/- 0.43 to 2.86 +/- 0.86%/min) dogs. Blood insulin levels after IVGTT in NPX-PTX were more than twice higher than in NPX animals (P less than 0.01) and for any given level of blood glucose concentration, the insulin levels were higher in NPX-PTX than NPX dogs. Clamp studies showed that the total amount of glucose utilized was significantly lower (P less than 0.025) in NPX (6.64 +/- 1.13 mg/kg X min) than in NPX-PTX (10.74 +/- 1.1 mg/kg X min) dogs. The early, late, and total insulin responses were significantly (P less than 0.025) greater in the NPX-PTX than NPX animals. The values for the total response were 143 +/- 28 vs. 71 +/- 10 microU/ml, P less than 0.01. There was no significant difference in the ratio of glucose metabolized to the total insulin response, a measure of tissue sensitivity to insulin, between the two groups. The glucose metabolized to total insulin response ratio in NPX (5.12 +/- 0.76 mg/kg X min per microU/ml) and NPX-PTX (5.18 +/- 0.57 mg/kg X min per microU/ml) dogs was not different but significantly (P less than 0.01) lower than in normal animals (9.98 +/- 1.26 mg/kg X min per microU/ml). The metabolic clearance rate of insulin was significantly (P less than 0.02) reduced in both NPX (12.1 +/- 0.7 ml/kg X min) and NPX-PTX (12.1 +/- 0.9 ml/kg X min) dogs, as compared with normal animals (17.4 +/- 1.8 ml/kg X min). The basal hepatic glucose production was similar in both groups of animals and nor different from normal dogs; both the time course and the magnitude of suppression of hepatic glucose production by insulin were similar in both in groups. There were no differences in the binding affinity, binding sites concentration, and binding capacity of monocytes to insulin among NPX, NPX-PTX, and normal dogs. The data show that (a) glucose intolerance does not develop with CRF in the absence of PTH, (b) PTH does not affect metabolic clearance of insulin or tissue resistance to insulin in CRF, and (c) the normalization of metabolism in CRF in the absence of PTH is due to increased insulin secretion. The results indicate that excess PTH in CRF interferes with the ability of the beta-cells to augment insulin secretion appropriately in response to the insulin-resistant state.

Measurement using tracers of steady-state turnover and metabolic clearance of insulin in dogs.

In nine conscious dogs, the steady-state metabolic clearance rate (MCR) and the systemic appearance rate (Ra) of insulin were determined by the tracer dilution method. [3H-PheB1]insulin ([3H]insulin) was infused as a tracer from time 0 at a constant rate. After tracer equilibration was attained, unlabeled porcine insulin was infused at variable constant rates (10.6-279 mU/min) with somatostatin (0.3 microgram . kg-1 . min-1) to suppress endogenous insulin secretion. Glucose was infused to prevent hypoglycemia. Tritiated and immunoreactive insulin (IRI) concentrations were determined in plasma samples after extraction on a C-18 reverse-phase column. Tracer-determined basal Ra of insulin was 2.39 +/- (SE) 0.61 mU/min. The calculated steady-state Ra of insulin for plasma IRI from 20 to 2,300 microU/ml showed good agreement with insulin infusion rates. The mean ratio of these rates was 0.973 +/- 0.018. The MCR of insulin under basal conditions was 29.9 +/- 3.4 ml . kg-1 . min-1, and it decreased with increasing insulin concentrations. It is concluded that 1) insulin turnover rates can be measured accurately using [3H]insulin as a tracer and 2) insulin kinetics are nonlinear.

HYPERINSULINAEMIA AND INSULIN RESISTANCE OF CIRRHOSIS: THE IMPORTANCE OF INSULIN HYPERSECRETION

The mechanism for the hyperinsulinaemia in cirrhosis was investigated using two different approaches. In the first study, the metabolic clearance rate of insulin was measured at steady state in 13 cirrhotic and 13 weight-matched control subjects. With comparable insulin infusion rates (1.00 +/- 0.19 versus 1.07 +/- 0.15 mU/kg/min), steady-state plasma insulin concentrations (104 +/- 25 versus 87 +/- 12 microU/ml; P greater than 0.5) and MCRIRI (13.6 +/- 1.6 versus 15.4 +/- 2.0 ml/kg/min; P greater than 0.5) were similar. In the second study, fasting and oral glucose stimulated C-peptide/insulin ratios were compared in 16 cirrhotic and 18 weight matched control subjects. Although fasting glucose levels were significantly higher in the cirrhotic groups, all values were in the normal range (5.5 +/- 0.3 versus 4.8 +/- 0.1 mmol/l, P less than 0.02). However, fasting insulin (0.171 +/- 0.02 versus 0.068 +/- 0.004 nmol/l) and C-peptide (1.02 +/- 0.13 versus 0.42 +/- 0.02 nmol/l) were strikingly higher (P less than 0.001) in cirrhotic subjects. On the other hand, fasting C-peptide/insulin ratios were not statistically different in the two groups (6.18 +/- 0.52 versus 6.77 +/- 0.46; P greater than 0.3). This suggests that beta cell hypersecretion was the principal cause of the fasting hyperinsulinaemia, rather than decreased insulin hepatic extraction. Following the glucose load in 13 of the control and seven of the cirrhotic group, the C-peptide/insulin ratio fell in both groups but was significantly lower in the cirrhotic compared to control subjects at 30, 60 and 120 min, consistent with possible impairment of hepatic insulin extraction.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of biosynthetic human proinsulin on carbohydrate metabolism.

Large quantities of biosynthetic human proinsulin have recently become available through recombinant DNA technology. Since the in vivo effects of human proinsulin have not been studied in man, we compared the dose-response relationship for stimulation of glucose disposal and suppression of hepatic glucose output by proinsulin and insulin. Ten normal subjects were studied using the euglycemic glucose clamp technique. The human proinsulin and insulin infusion rates were chosen to achieve steady-state proinsulin levels 10-fold higher than insulin levels on a molar basis, based on previous observations that porcine proinsulin has approximately 10% the potency of insulin. Proinsulin infusion rates of 2.75, 7.5, 22.5, and 45 micrograms/m2/min were compared with insulin infusion rates of 0.63, 1.67, 5, and 10 micrograms/m2/min. Primed, continuous infusions of insulin yielded steady-state levels within 25 min, whereas proinsulin levels did not reach a steady state for 120-180 min. The metabolic clearance rate of insulin was 11-12 ml/kg/min at the lower infusion rates but fell to 8.4 ml/kg/min at the highest infusion rate. The metabolic clearance rate of proinsulin was 3.0-3.5 ml/kg/min at all infusion rates. Dose-response analysis demonstrated that proinsulin-mediated glucose disposal was approximately 8% that of insulin. In contrast, proinsulin-mediated suppression of hepatic glucose output was approximately 12% that seen with insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

The euglycemic clamp technique in patients with liver cirrhosis.

Tissue sensitivity to insulin and insulin metabolic clearance rate were assessed by means of the euglycemic clamp technique in 11 controls and 11 patients with liver cirrhosis. The method was carried out using an artificial endocrine pancreas. The amount of glucose infused to keep euglycemia, as well as the ratio of glucose infused to steady-state insulin level, were significantly lower in cirrhotics as compared to controls (p less than 0.001). The metabolic clearance rate of insulin did not show significant differences between the two groups. Our results confirm that a marked insulin resistance is present in cirrhotics, as previously shown by means of different techniques.

Physiological significance of altered insulin metabolism in the conscious rat during lactation.

Uptake of radioactively labelled insulin by the mammary gland of the rat increased 12-fold in lactation compared with non-lactating controls. This uptake was decreased by the presence of unlabelled insulin, indicating that it occurred via insulin receptors. The plasma half-life of insulin is decreased in lactation from 9.4 min to 4.8 min, and the metabolic clearance rate for insulin increased from 7.26 to 13.03 ml/kg body wt. per min. The basal insulin and glucose concentrations in the plasma were decreased in lactation. Infusion of insulin at a dose which led to a small physiological rise in plasma insulin concentration increased lipogenic rates in the mammary gland by 100% without causing marked hypoglycaemia. It is concluded that the lactating mammary gland is a highly insulin-sensitive tissue and that the lower plasma insulin during lactation occurs primarily as a result of this sensitivity increasing extraction of glucose by the gland and thus producing a decrease in the plasma glucose concentration. It is suggested that a secondary result of the fall in plasma insulin concentration is the preferential direction of substrates (glucose and non-esterified fatty acids) towards the lactating mammary gland and away from adipose tissue and the liver.

Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans

To examine the fate of insulin across the liver bed, biosynthetic human insulin was infused in increasing amounts in six healthy men. Trapping of insulin by the liver was determined by means of the hepatic venous catheter technique. To minimize any possible error in the estimation of insulin removal as a result of endogenous insulin, pancreatic insulin secretion was suppressed by intravenous administration of somatostatin (500 μg/h). Infusion rates of human insulin were 30, 60, and 150 pmol/m 2 · min (corresponding to 0.25, 0.5, and 1.25 U/m 2 · h) for 70 minutes each. Steady-state insulin levels were within the physiologic range, ie, 69 ± 2, 135 ± 3, and 342 ± 10 pmol/L, respectively. Euglycemia was maintained throughout the study by a variable glucose infusion. The output of C-peptide from the splanchnic bed was reduced by somatostatin by about 90%, indicating that endogenous insulin production only minimally contributed to total insulin levels achieved during infusion of exogenous human insulin. Fractional extraction of insulin by the liver (63 ± 6%, 71 ± 4%, and 74 ± 5%) and hepatic insulin clearance (201 ± 19, 235 ± 23, and 245 ± 29 mL/m 2 · min) did not differ significantly during the three insulin infusion studies. The hepatic uptake of insulin rose with increasing insulin infusion rates, constituting 40% to 60% of total-body insulin removal. No change in the total metabolic clearance rate of insulin was observed between the groups (451 ± 8 mL/m 2 · min). To study the extraction rate of C-peptide by the liver, porcine C-peptide was also infused at the same increasing rates. The failure to detect any concentration gradient of the porcine C-peptide across the splanchnic bed indicates that C-peptide is not extracted by the liver in humans. The results obtained in both studies validate our previously reported data on endogenous secretion and hepatic handling of insulin derived from calculations of splanchnic output of C-peptide and insulin.

Post-hepatic insulin secretion in the fetal lamb.

Post-hepatic insulin secretion was measured in six chronically catheterized fetal lambs (fetal weight 2.8 +/- 0.3 kg, mean +/- S.E.M.) and the results were compared with those obtained in nine prematurely delivered newborn lambs (birth weight 3.1 +/- 0.3 kg and postnatal age 1.3 +/- 0.2 days). The fetal and neonatal lambs received either a 0.45% saline or a glucose infusion respectively, which resulted in a 2-fold increase in the plasma glucose concentration. [131I]insulin was infused for 110 min to determine the rate of insulin secretion during a steady state of plasma glucose concentration. Post-hepatic insulin secretion and the metabolic clearance rate were calculated. With the 2-fold rise in plasma glucose concentration, the post-hepatic insulin secretion rate increased significantly in the newborn lamb and in three out of four fetuses. The plasma insulin concentration increased significantly in the fetus (11 +/- 4.0 to 35 +/- 8 microU/ml, P less than 0.05) during glucose stimulation as a result of decreased metabolic clearance rate of insulin (10.6 +/- 1.9 to 6.3 +/- 1.8 ml . kg-1 . min-1) and an increase in post-hepatic insulin secretion rate. In spite of an increase in post-hepatic insulin secretion rate, the increase in plasma insulin concentration in the newborn lamb was not significant because of large variation in the values obtained. The data suggest that pancreatic beta-cells in the newborn and in the fetal lamb are equally responsive to a 2-fold increase in plasma glucose concentration.

Hyperinsulinemia of obesity is due to decreased clearance of insulin.

The hyperinsulinemia of obesity could result from a decrease in the metabolic clearance rate of insulin (MCR-I), an increase in the secretory rate of insulin (SR-I), or a combination of both these processes. Because C-peptide and insulin are secreted in an equimolar ratio, the plasma concentrations of C-peptide (C) and insulin (I) are inversely proportional to their rates of metabolic clearance (C/I = MCR-I/MCR-C). We obtained 24-h integrated concentrations (IC) of insulin (IC-I) and C-peptide (IC-C) in 23 obese and 45 nonobese subjects over a period of normal activity and food intake. The IC-I was 69% higher in the obese subjects (P less than 0.0001). A 13% increase in the IC-C (P = 0.04), with a constant rate of C-peptide clearance, indicates a proportionate increase in SR-I. A 33% decrease in the IC-C/IC-I in the obese group (P less than 0.005) reflects a decrease in MCR-I; hence, 75% of the hyperinsulinemia is due to a decrease in the clearance of insulin. Because peripheral MCR-I (pMCR-I) is similar in obese and nonobese subjects, the decrease in MCR-I may be due to a decrease in the hepatic clearance of insulin. This conclusion was supported by our comparison of 24-h IC-C/IC-I ratios in the obese and nonobese subjects. Whereas the 24-h IC-C/IC-I of the nonobese resembled the fasting state, the 24-h IC-C/IC-I of the obese resembled the postprandial state, when insulin removal by the liver is known to be suppressed. These data are consistent with a decreased 24-h hepatic MCR-I (hMCR-I) as the cause of the hyperinsulinemia of obesity.

Insulin sensitivity in hyperthyroidism: measurement by the glucose clamp technique.

Sensitivity to porcine insulin has been compared in overnight fasted hyperthyroid and control subjects using a euglycaemic clamp technique. Basal values for blood glucose, lactate, pyruvate, alanine, serum insulin and C-peptide were similar in the two groups, whilst blood glycerol (hyperthyroid 0.11 +/- 0.02 (mean +/- S.E.) vs. control 0.06 +/- 0.01 mmol/l, P less than 0.01) and blood 3-hydroxybutyrate (0.28 [0.03-0.79, range ]vs 0.09 [0.01-0.29 ]mmol/l, P less than 0.05) were increased in hyperthyroidism. During the 2 hour insulin infusion (0.05 U/kg/h), serum insulin plateaued at the same level (44 +/- 4 vs 44 +/- 1 mU/l) and insulin metabolic clearance rates were similar (1.21 +/- 0.10 vs 1.25 +/- 0.03 l/min). Serum C-peptide levels also decreased by similar amounts (40 +/- 8 vs 47 +/- 6%). The amount of glucose infused to maintain euglycaemia was identical during the second hour of insulin infusion (290 +/- 50 vs 330 +/- 30 mg/kg) as were the increments in lactate and pyruvate concentrations. Blood glycerol values decreased in both groups although values in hyperthyroid patients remained significantly higher than in controls. 3-Hydroxybutyrate concentrations fell to similar values in the two groups. These findings suggest that insulin-stimulated glucose metabolism and inhibition of ketogenesis are normal in hyperthyroidism.

Plasma insulin and insulin kinetics in growing sheep. Influence of age and diet

This study was carried out to clarify the nutritional control of insulin metabolism in growing sheep fed a control or an experimental diet low in crude protein and high in propionic acid used as a feed additive. Daily variations in blood insulin and the disappearance from the circulation of unlabelled injected insulin were investigated. These data were used to calculate the metabolic clearance rate of insulin and insulin secretion. At 23 kg of body weight (BW), blood insulin showed an increase in the control group at 10 a.m. (i.e. 2 h after feeding) and a large peak in the experimental group at 3 p.m. At 33-kg BW, blood insulin in both groups showed a peak at 10 a.m. and a moderate increase at 3 p.m. Mean plasma insulin throughout the day (except at 3 p.m.) rose with increasing BW. It was lower in the experimental than in the control group. Injected insulin disappeared rapidly from the circulation; its half-life was constant (13 min). In both groups, the insulin level along the disappearance curve was higher at 33-kg BW than at 23-kg BW, and insulin metabolic clearance rate decreased. Except at 3 p.m., the mean insulin secretion rate over the day was lower in the control group at 33-kg BW than at 23-kg BW. Feeding the experimental diet increased the insulin level along the disappearance curve. In young animals, it decreased insulin metabolic clearance rate and diminished mean insulin secretion rate over the day, except at 3 p.m. when the insulin secretion rate increased. In old animals, the experimental diet did not significantly change the kinetic parameters of insulin metabolism.

Mechanisms of insulin resistance following injury.

To assess the mechanisms of insulin resistance following injury, we examined the relationship between insulin levels and glucose disposal in nine nonseptic, multiple trauma patients (average age 32 years, Injury Severity Score 22) five to 13 days postinjury. Fourteen age-matched normals served as controls. Using a modification of the euglycemic insulin clamp technique, insulin was infused in 35 two-hour studies using at least one of four infusions rates (0.5, 1.0, 2.0 or 5.0 mU/kg min). Basal glucose levels were maintained by a variable infusion of 20% dextrose using bedside glucose monitoring and a servo-control algorithm. The amount of glucose infused reflected glucose disposal (M, mg/kg.min). Tracer doses of (6,6,2D2) glucose were administered in selected subjects to determine endogenous glucose production. At plasma insulin concentrations less than 100 microU/ml, responses in both groups were similar. However, maximal glucose disposal rates were significantly less in the patients than in the controls (9.17 +/- 0.87 mg/kg . min vs. 14.3 +/- 0.78, mean +/- SEM, p less than 0.01). Insulin clearance rates in the patients were almost twice that seen in controls. To further characterize this decrease in insulin responsiveness, we studied six additional patients and 12 controls following the acute elevation of glucose 125 mg/dl above basal (hyperglycemic glucose clamp). In spite of exaggerated endogenous insulin production in the patients (80-200 microU/ml vs. 30--70 in controls), M was significantly lower (6.23 +/- 0.59 vs. 9.46 +/- 0.79, p less than 0.02). In conclusion, this study demonstrated that (1) the maximal rate of glucose disposal is reduced in trauma patients; (2) the metabolic clearance rate of insulin in the injured patients is almost twice normal and; (3) insulin resistance following injury appears to occur in peripheral tissues, probably skeletal muscle, and is consistent with a postreceptor defect.

The effect of ageing on insulin sensitivity and insulin secretion in non-obese healthy subjects.

Abstract. The relationship of age to insulin sensitivity was studied in 74 non-obese healthy subjects with normal fasting plasma glucose concentration, ranging in age from 17 to 65 years. Glucose tolerance and early as well as late insulin responses were characterized by means of a 2 h glucose infusion test (12 mg/kg/min) primed by an initial injection of 0.33 g/kg body weight glucose. Glucose tolerance did not markedly differ between young (&lt; 30 years; n = 31) and middle-aged subjects (31–45 years; n = 29) but deteriorated significantly in the elder group (&gt; 45 years; n = 14). Early and late insulin responses to glucose were not appreciably altered during ageing in this selected healthy population. For the determination of insulin sensitivity a 1 h priming dose-constant infusion technique (two 30 min periods of 8 and 16 mU/kg, insulin 'MC-Actrapid', initiated by a start injection of 1 and 2 mU/kg, respectively) was used. The percent decrease of plasma glucose, FFA and glycerol levels serves as a measure of the whole body sensitivity to exogenous insulin. Under condition of identical steady-state insulin levels the decrease in plasma glucose was significantly reduced in elderly (24 ± 5%) vs young (34 ± 2%) subjects (P &lt; 0.05). However, a marked sensitivity to the antilipolytic effect of insulin was demonstrated in elderly subjects considered to be resistant to its glucose-lowering action. There was no evidence that disappeared time and metabolic clearance rate of insulin were altered with advancing age. In conclusion, the impaired insulin sensitivity to glucose metabolism seems to be the primary factor responsible for the deterioration of glucose tolerance with advancing age.

The effects of exercise on plasma insulin.

The decrease of plasma insulin levels after physical training is explained mainly by a decreased insulin secretion, but also to a significant degree by an increased peripheral insulin metabolic clearance rate in several peripheral tissues and increased insulin uptake in the liver. The peripheral tissues demonstrate an increased insulin sensitivity, but this seems to be due to factors after the insulin receptor level. An increased turnover of insulin at the receptor level might be postulated. The explanation for the decrease of insulin secretion has been studied extensively. A decreased cortisol secretion might be a primary factor in physical training, followed by lower insulin levels. Autonomic nervous system adaptations could also be involved in the form of an increased alpha-adrenergic activity. Another alternative is that the effect is mediated via an influence of physical training on a gut "incretin" factor, facilitating insulin secretion, Finally, it might be considered that the increased insulin sensitivity of muscle following physical training is regulating insulin secretion via feedback mechanisms to the beta cell. Recent demonstrations of inhibited glucose uptake in the liver after exercise facilitates an explanation along these lines.