Comparison of insulin-mediated and glucose-mediated glucose disposal in patients with insulin-dependent diabetes mellitus and in nondiabetic subjects

To determine whether glucose-mediated as well as insulin-mediated regulation of glucose utilization and glucose production is impaired in patients with insulin-dependent diabetes mellitus (IDDM), six nonobese, diabetic patients and seven age-, sex-, and weight-matched nondiabetic subjects were studied. Despite slightly higher free insulin concentrations in the diabetic patients than in the nondiabetic subjects during 0.2 mU/kg X min (22 +/- 3 versus 15 +/- 2 microU/ml) and 1.0 mU/kg X min (98 +/- 10 versus 75 microU/ml) insulin infusions, glucose utilization at plasma glucose concentrations of 95, 135, and 175 mg/dl was lower in the diabetic patients than in the nondiabetic subjects. The increment in glucose utilization per increment in plasma glucose (i.e., slope) in the diabetic and nondiabetic subjects, respectively, did not differ significantly during either the 0.2 (1.7 +/- 1.3 versus 1.4 +/- 0.5 dl/kg X min) or 1.0 (4.4 +/- 1.1 versus 6.2 +/- 1.0 dl/kg X min) mU/kg X min insulin infusions, although they tended to be higher in the nondiabetic subjects during the latter infusion. Thus, although stimulation of glucose utilization by insulin is impaired in patients with IDDM, the ability of an increase in glucose concentration to increase glucose utilization does not appear to differ from that present in nondiabetic subjects, at insulin concentrations in the low physiologic range. Whether differences exist in the high physiologic range remains to be determined.     

The effect of graded doses of insulin on peripheral glucose uptake and lactate release in cancer cachexia

With the euglycemic clamp technique, we evaluated the effects of graded doses of insulin on glucose turnover rates and forearm lactate balance in five weight-losing patients with cancer before surgery and five age- and weight-matched healthy volunteers (control subjects). Insulin was infused sequentially at increasing rates of 0.5 (low physiologic), 1.0 (high physiologic), and 4.0 (supraphysiologic) mU/kg.min for 120 minutes each. Concurrently, rates of glucose appearance and disappearance were derived from [3-3H] glucose infusion. The mean postabsorptive rate of glucose appearance in patients (2.9 +/- 0.1 mg/kg.min) was significantly higher (p less than 0.02) than that of control subjects (1.98 +/- 0.16 mg/kg.min). Complete suppression of endogenous glucose production occurred at high physiologic insulin concentrations. With progressive insulin infusion, the rate of glucose disappearance increased to 3.6 +/- 1.2, 8.7 +/- 0.8, and 13.7 +/- 1.1 mg/kg/min in control subjects and 2.9 +/- 0.4, 5.3 +/- 0.3, and 10.9 +/- 0.9 mg/kg.min in patients, significantly different from that of control subjects (p less than 0.05) during the intermediate (high physiologic) insulin infusion. A comparable slight increase in arterial plasma lactate concentration was observed in both groups with progressive hyperinsulinemia. Baseline peripheral lactate flux was identical in patients (-272 +/- 56 nmol/100 gm.min) and in controls (-271 +/- 57 nmol/100 gm.min). Progressive physiologic hyperinsulinemia resulted in significantly (p less than 0.05) augmented peripheral lactate efflux in patients (-824 +/- 181 nmol/100 gm.min) compared with control subjects (-287 +/- 64 nmol/100 gm.min). Supraphysiologic insulin abolished this increased lactate efflux in patients. Postabsorptive rates of endogenous glucose appearance in weight-losing patients with cancer were elevated, but complete suppression was achieved with insulin concentrations in the physiologic range. Total body glucose use was diminished in these patients, consistent with a state of insulin resistance. This impaired insulin action on peripheral glucose use was associated with an increase in peripheral lactate release in patients.     

The insulin sensitivity index. Correlation in dogs between values determined from the intravenous glucose tolerance test and the euglycemic glucose clamp

We previously proposed the insulin sensitivity index, Sl, as an absolute measure of whole body tissue sensitivity to insulin. Sl is defined, in the physiologic range of insulin action, as the effect of insulin to augment glucose's ability to reduce its own plasma level. This parameter can be determined from the frequently sampled intravenous glucose tolerance test (IVGTT) by using a digital computer to find the coefficients of a minimal mathematical model of glucose kinetics. In the present study we compared, in normal dogs, Sl determined from the IVGTT to an analogous parameter [Sl(clamp)] calculated from the euglycemic glucose clamp (EGC). Fifteen pairs of experiments (1 IVGTT and 1 EGC) were performed on 12 animals. IVGTTs: After glucose injection (0.3 g/kg), frequent blood samples were taken over the subsequent 3 h. KG ranged from 1.7 to 4.7%/min, and integrated insulin from 0.4 to 5.9 (mU/ml) min for 0-60 min. Sl varied over a nine-fold range from 1.0 to 9.1 X 10(-4) (min-1)/(microU/ml), with a mean of 4.3 +/- 0.7 X 10(-4). Fractional glucose disappearance rate independent of insulin (p1) was 4.3 +/- 0.5%/min. EGCs: Low-rate insulin infusion (8 mU/min from 1 to 150 min) elevated plasma insulin (INS) from 15 +/- 4 to 43 +/- 10 microU/ml. Glucose was infused (GINF) at 119 +/- 20 mg/min to maintain euglycemia. Moderate insulin infusion (40 mU/min: 151-300 min) further elevated plasma insulin (to 176 +/- 37 microU/ml) and the requisite glucose infusion (to 372 +/- 36 mg/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of anti-insulin receptor antibodies on in vivo insulin metabolism

The effects of anti-insulin receptor antibodies (AIRA) on receptor binding and insulin metabolism were studied in two patients with the type B, severe insulin resistance syndrome. Insulin binding was determined using rat hepatocytes in primary culture and the patient's own red blood cells. Plasma and urinary insulin concentrations and metabolic clearance rates (MCR) were determined in the two patients and in four normal controls in response to infusions of insulin for 60-120 min at rates ranging from 1 to 925 mU/kg/min. In patient 1, basal insulin concentration was 1400 microU/ml. After infusion of 1, 10, and 925 mU/kg/min of insulin it rose to 3800, 5500, and 225,000 microU/ml, respectively. Respective MCRs were 19, 110, and 186 ml/min. In patient 2, basal insulin concentration was 440 microU/ml. After infusion of 1, 10, and 100 mU/kg/min of insulin it rose to 720, 2500, and 18,800 microU/ml, respectively. Respective MCRs were 193, 262, and 294 ml/min. In controls, basal insulin concentration was 4 +/- 0.3 microU/ml. After infusion of 1 and 10 mU/kg/min of insulin, it rose to 82 +/- 17 and 1288 +/- 50 microU/ml. Respective MCRs were 950 and 630 ml/min. These data showed that, in patients with AIRA: (1) insulin metabolism took place at the same rate but at higher insulin concentrations than in normal controls, and (2) MCR increased with rising insulin concentration but remained subnormal even at the highest insulin concentrations. In contrast, MCR in normal controls decreased with increasing insulin concentrations. The data suggest that prevention of insulin binding prevents insulin metabolism at physiologic insulin concentrations and that supraphysiologically elevated insulin concentrations are needed to activate nonreceptor mechanisms.     

Effect of chronic diabetes on myocardial fuel metabolism and insulin sensitivity

To assess the effect of chronic insulin-deficient diabetes on myocardial fuel substrate metabolism in vivo, we measured the myocardial balance of glucose, free fatty acids (FFAs), and amino acids in nine postabsorptive conscious dogs 4-6 wk after treatment with streptozocin. The acute effect of insulin on the myocardial balance of these same substrates was measured in six dogs by use of the euglycemic insulin clamp technique. To further examine the effect of insulin on heart amino acid balance, we studied three additional dogs given a constant infusion of amino acids during the insulin clamp to blunt the insulin-induced hypoaminoacidemia. In these dogs, the fasting plasma glucose concentration was markedly elevated (258 +/- 3 mg/dl). In the basal period, there was no significant glucose uptake by the heart [arterial vs. coronary sinus concentration difference (delta) = 1.0 +/- 2.0 mg/dl]; furthermore, physiologic hyperinsulinemia did not stimulate glucose uptake (delta = 2.0 +/- 2.5 mg/dl). Postabsorptively, arterial FFAs were elevated (1550 +/- 320 microM) in diabetic animals, and there was a significant net extraction of FFAs by the heart (net uptake 26 +/- 9 mumol/min; extraction ratio 30 +/- 8%). During the insulin clamp, arterial FFAs declined (645 +/- 240 microM), as did heart FFA uptake (11 +/- 6 mumol/min), and the net extraction ratio for FFAs was unchanged (30 +/- 7%). Similarly, the arterial branched-chain amino acid (BCAA) concentration was elevated in the postabsorptive state, and there was a significant myocardial uptake of these amino acids and of alanine.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Reversal of abnormal glucose production after pancreatic resection by pancreatic polypeptide administration in man

Pancreatic polypeptide (PP) deficiency has been associated with impaired hepatic sensitivity to insulin and pancreatogenic diabetes in chronic pancreatitis. Since pancreatic resection might also result in PP deficiency, hepatic responses to insulin infusion (0.25 mU/kg/min) were determined by the euglycemic glucose clamp technique in 10 patients who had previously undergone pancreatic resection for trauma and in eight healthy control subjects. Six resection patients (RES-PP) demonstrated deficient PP levels, with a mean increase of plasma immunoreactive PP of 20 +/- 7 pg/ml above basal rate after a test meal compared with 232 +/- 82 pg/ml in control subjects (p less than 0.01) and 353 +/- 133 pg/ml in four other patients undergoing resection with normal levels of immunoreactive PP (RES + PP) (p less than 0.03). Three identical insulin infusion studies were performed in each subject, the second of which was performed during the final 2 hours of an 8-hour infusion of bovine PP (2.0 pmol/kg/min). Whereas hepatic glucose production (HGP) in control subjects fell 74% +/- 4% from a basal rate of 2.0 +/- 0.1 mg/kg/min to a 60- to 120-minute value of 0.5 +/- 0.1 mg/kg/min during insulin infusion, HGP was suppressed only 58% +/- 5% in RES-PP subjects, from 1.9 +/- 0.1 to 0.8 +/- 0.1 mg/kg/min (p less than 0.05 vs controls). Intravenous infusion of PP corrected the hepatic resistance to insulin seen in the PP-deficient group. During PP infusion, HGP was suppressed 74% +/- 5% in RES-PP subjects, from 2.1 +/- 0.2 to 0.5 +/- 0.1 mg/kg/min (p less than 0.04 compared with initial study). PP infusion produced no significant change in glucose metabolism in control and RES + PP subjects. Overall glucose disposal rates were not altered by PP infusion in any group. These findings support a role of PP as a glucoregulatory hormone and suggest that PP deficiency may serve as a reversible pathophysiologic factor in the abnormal glucose metabolism seen after pancreatic resection.     

Direct and indirect effects of insulin to inhibit hepatic glucose output in obese subjects

The effects of small increases in plasma insulin on hepatic glucose production are incompletely understood. To partially elucidate this issue we have studied seven obese subjects with the euglycemic clamp technique with a low-dose insulin infusion rate of 15 mU X m-2 X min-1 over 3 h. Basal insulin levels were 24 +/- 7 microU/ml and increased to steady-state levels of 35 +/- 3 microU/ml during insulin infusion. Endogenous insulin secretion, quantitated by C-peptide measurements, decreased by 58% of the basal value after peripheral insulin infusion. Based on C-peptide measurements and the contribution of the peripheral insulin infusion to the circulating insulin concentrations, calculated portal insulin levels either decreased or remained unchanged during the clamp studies. Basal glucagon levels were 165 +/- 18 and did not change during the insulin infusion. The basal glucose disposal rate was 86 +/- 2 mg X m-2 X min-1 and did not increase significantly during the clamp studies. In contrast, hepatic glucose output (HGO) was suppressed by 82 +/- 5% of the basal value. In summary, in a group of insulin-resistant obese subjects, glucose-clamp studies were performed at peripheral insulin levels of 35 +/- 3 microU/ml; glucose disposal did not increase, whereas HGO was suppressed by 82%. At the same time, glucagon levels remained constant and estimated portal insulin levels either decreased or remained unchanged. These findings suggest that insulin can suppress HGO through indirect extrahepatic actions.     

Insulin action during pregnancy. Studies with the euglycemic clamp technique

To assess the mechanisms responsible for the insulin resistance associated with both normal human pregnancy and gestational-onset diabetes, we have measured exogenous glucose disposal using sequential insulin infusions with the euglycemic glucose clamp technique and erythrocyte insulin binding. Three groups of women were studied: nonpregnant women with normal glucose tolerance (N = 7, mean age 32.9 +/- 2.1 yr), pregnant women with normal glucose tolerance (N = 5, mean age 24.8 +/- 3.5 yr), and pregnant women with gestational-onset diabetes (N = 5, mean age 34.6 +/- 2.6 yr). Despite normal plasma glucose levels obtained during a 100-g oral glucose tolerance test, plasma insulin levels were significantly elevated in the pregnant women compared with the nonpregnant control subjects, suggesting a state of insulin resistance. Insulin binding to erythrocytes was similar in all three groups (maximum specific binding being 5.0 +/- 0.6%, 5.5 +/- 1.1%, and 6.0 +/- 0.7% in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively). In vivo peripheral insulin action was measured using the euglycemic glucose clamp technique during an insulin infusion of 40 mU/m2 X min, with blood glucose clamped at a concentration of 75 mg/dl using a variable glucose infusion. Glucose infusion rates were 213 +/- 11 mg/m2 X min, 143 +/- 23 mg/m2 X min, and 57 +/- 18 mg/m2 X min in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively. This demonstrates that pregnant subjects display a state of insulin resistance, and that this appears to be more marked in gestational-onset diabetic subjects. To further define the possible mechanism of insulin resistance during pregnancy, the insulin infusion rate was increased to 240 mU/m2 X min and further euglycemic clamp measurements performed. Glucose infusion rates were 372 +/- 11 mg/m2 X min, 270 +/- 31 mg/m2 X min, and 157 +/- 26 mg/m2 X min, in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively. This demonstrates a shift to the right of the dose-response curve of insulin action and suggests that the insulin resistance of pregnancy may include a decrease in presumed "maximum" insulin responsivity. In four subjects, studies were repeated in the postpartum period, and these demonstrated that the insulin resistance of pregnancy is ameliorated shortly after delivery. These studies suggest that the insulin resistance of pregnancy results from a target cell defect in insulin action beyond the initial step of insulin binding to cellular receptors, a postreceptor (or postbinding) defect in insulin action.     

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.     

Somatostatin does not increase insulin-stimulated glucose uptake in humans

Somatostatin (SRIF) has been widely used in the study of in vivo carbohydrate metabolism to suppress pancreatic hormone secretion and thereby interrupt the glucoregulatory feedback loops between insulin, glucagon, and glucose. A critical assumption in the use of SRIF is that it has no effect on hepatic or peripheral glucose metabolism other than those mediated through the inhibition of hormone secretion. To assess whether doses of SRIF commonly used in human investigation have any effect on insulin-stimulated glucose disposal rates, we measured the rate in 6 normal subjects (mean fasting serum glucose level, 93 +/- 2 mg/dl) during euglycemic (approximately equal to 85 mg/dl) hyperinsulinemic (40 mU X m-2 X min-1) clamp studies both with and without the concomitant infusion of SRIF (600 micrograms/hr). The steady-state insulin levels achieved were 85 +/- 6 microU/ml and 74 +/- 8 microU/ml with and without SRIF, respectively (difference not significant). Glucose disposal rates between 120 and 180 min of the clamp were 7.11 +/- 0.10 and 7.35 +/- 0.10 mg X kg-1 X min-1 with and without SRIF, respectively (difference not significant). We concluded that in doses commonly used in human investigation, SRIF does not increase glucose disposal.     

Effects of insulin and amino acids on glucose and leucine metabolism in CAPD patients

This study investigates the basal and insulin-stimulated glucose metabolism, substrate utilization, and protein turnover in eight patients maintained on continuous ambulatory peritoneal dialysis (CAPD) (mean age 39+/-5 yr, body mass index [BMI] 108+/-6) and 14 control subjects (mean age 33+/-4 yr, BMI 103+/-3). Euglycemic insulin clamp studies (180 min) were performed in combination with continuous indirect calorimetry and 1-14C leucine infusion (study I). Postabsorptive glucose oxidation was higher (1.75+/-0.18 versus 1.42+/-0.14 mg/kg per min) and lipid oxidation was lower (0.43+/-0.09 versus 0.61+/-0.12 mg/kg per min) in CAPD patients than in control subjects (P<0.05 versus control subjects). During the last 60 min of euglycemic hyperinsulinemia, the total rate of glucose metabolism was similar in CAPD and control subjects (6.33+/-0.51 versus 6.54+/-0.62 mg/kg per min). Both insulin-stimulated glucose oxidation (2.53+/-0.27 versus 2.64+/-0.37 mg/kg per min) and glucose storage (3.70+/-0.48 versus 3.90+/-0.58 mg/kg per min) were similar in CAPD and control subjects. Basal leucine flux (an index of endogenous proteolysis) was significantly lower in CAPD patients than in control subjects (1.21+/-0.15 versus 1.65+/-0.07 micromol/kg per min). Leucine oxidation (0.13+/-0.02 versus 0.26+/-0.02 micromol/kg per min) and nonoxidative leucine disposal (an index of protein synthesis) (1.09+/-0.16 versus 1.35+/-0.05 micromol/kg per min) were also reduced in CAPD compared with control subjects (P<0.01 versus control subjects). In response to insulin (study I), endogenous leucine flux decreased to 0.83+/-0.08 and 1.05+/-0.05 micromol/kg per min in CAPD and control subjects, respectively (all P<0.01 versus basal). Leucine oxidation declined to 0.06+/-0.01 and to 0.19+/-0.02 micromol/kg per min in CAPD and control subjects, respectively (P<0.01 versus basal). A second insulin clamp was performed in combination with an intravenous amino acid infusion (study II). During insulin plus amino acid administration, nonoxidative leucine disposal rose to 1.23+/-0.17 and 1.42+/-0.09 micromol/kg per min in CAPD and control subjects, respectively (both P<0.05 versus basal, P = NS versus control subjects), and leucine balance, an index of the net amino acid flux into protein, become positive in both groups (0.30+/-0.05 versus 0.40+/-0.07 micromol/kg per min in CAPD and control subjects, respectively) (both P<0.01 versus basal, P = NS versus control subjects). In summary, in CAPD patients: (1) basal glucose oxidation is increased; (2) basal lipid oxidation is decreased; (3) insulin-mediated glucose oxidation and storage are normal; (4) basal leucine flux is reduced; (5) the antiproteolitic action of insulin is normal; and (6) the anabolic response to insulin plus amino acid administration is normal. Uremic patients maintained on CAPD treatment show a preferential utilization of glucose as postabsorptive energy substrate; however, their anabolic response to substrate administration and the sensitivity to insulin are normal.     

Influence of hyperglycemia on glucose uptake and hepatic glucose production in non-dialyzed uremic patients

To determine whether the deranged glucose metabolism in uremia, in addition to insulin resistance can be attributed also to reduced glucose-induced glucose uptake, a two-step sequential hyperglycemic clamp (plasma glucose: 120 and 300 mg/dl) was performed in 6 non-dialyzed uremic and 8 healthy subjects. A constant infusion of somatostatin (300 micrograms/h) and soluble insulin (0.2 mU/kg/min) resulted in peripheral serum insulin slightly higher than basal in both uremics (16 +/- 3 and 22 +/- 3 microU/ml; step 1 and 2, respectively) and controls (20 +/- 2 and 22 +/- 1 microU/ml). The glucose-induced glucose uptake (3-3H-glucose) assessed as the difference between step 2 and 1 glucose disposal at the final 30 min of each step was markedly reduced in uremics (3.2 +/- 0.5 mg/kg/min) compared to healthy subjects (5.7 +/- 0.8 mg/kg/min; p less than 0.03). However, the percentage increment in glucose uptake from step 1 to step 2 hyperglycemia was comparable in the two groups (134 +/- 27 and 148 +/- 17%). Modest hyperglycemia (120 mg/dl) and slightly raised insulinemia resulted in comparable suppression of the endogenous (hepatic) glucose production (EGP) in healthy (1.6 +/- 0.2 mg/kg/min) and uremic subjects (1.5 +/- 0.3 mg/kg/min). In controls, pronounced hyperglycemia (300 mg/dl) further reduced EGP (0.6 +/- 0.3 mg/kg/min; p less than 0.01) while EGP in uremics on the contrary tended to rise (2.0 +/- 0.4 mg/kg/min; p = 0.09), thus indicating an abnormal reaction of the liver.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gliclazide therapy is associated with potentiation of postbinding insulin action in obese, non-insulin-dependent diabetic subjects

Six obese, non-insulin-dependent diabetic subjects were studied before and 3 mo after treatment with the sulfonylurea gliclazide, 40-80 mg b.i.d. Fasting plasma glucose fell significantly from 13.4 +/- 1.6 (SEM) to 8.6 +/- 1.2 mmol/L, accompanied by a significant reduction from 40.6 +/- 3.7 to 29.8 +/- 2.8 mM X h of the plasma glucose response to 75 g oral glucose. Fasting plasma insulin showed a nonsignificant increase from 24.8 +/- 2.0 to 31.3 +/- 2.3 mU/L. The percent specific binding of tracer 125I-insulin to erythrocytes and monocytes did not change significantly (from 9.8 +/- 1.7 to 8.5 +/- 0.7 for erythrocytes and 1.7 +/- 0.3 to 1.6 +/- 0.4 for monocytes). Glucose utilization was measured at three levels of insulin infusion (40, 100, and 300 mU/kg/h) by the euglycemic clamp technique. Overall there was a significant (P less than 0.05) increase in the disappearance rate (Rd) and metabolic clearance rate (MCRg) for glucose at the two higher insulin infusion rates (MCRg: 3.3 +/- 0.7 to 5.1 +/- 0.7 and 5.9 +/- 0.9 to 7.9 +/- 0.9 ml/kg/min), but not at the lowest infusion rate (MCRg: 3.6 +/- 0.8 to 3.3 +/- 0.6). Thus, the chronic hypoglycemic effect of gliclazide in obese diabetic subjects was associated with an improvement in insulin-mediated glucose utilization at high plasma insulin concentrations. This enhanced effect of insulin after gliclazide treatment was not accompanied by increased monocyte or erythrocyte insulin binding, which suggests that it was due to potentiation of postbinding insulin-sensitive pathways.     

Occurrence of dawn phenomenon without change in insulin clearance in patients with insulin-dependent diabetes mellitus

To assess the possible role of increased insulin clearance in the pathogenesis of the dawn phenomenon, we compared plasma free-insulin concentrations, free-insulin clearance rates, and plasma glucose concentrations in eight subjects with insulin-dependent diabetes mellitus (IDDM) during infusion of insulin from midnight to 0800 h (0.15 mU . kg-1 . min-1) with a Biostator and a Harvard pump. During infusion of insulin with the Biostator, plasma free insulin decreased 40% (from 14 +/- 1 to 9 +/- 1 microU/ml, P less than .01), insulin clearance increased 54% (from 11 +/- 1 to 17 +/- 2 ml/min, P less than .05), and plasma glucose increased from 101 +/- 4 to 217 +/- 27 mg/dl, P less than .01. During infusion of insulin with the Harvard pump, neither plasma free insulin (14 +/- vs. 13 +/- 1 microU/ml) nor free-insulin clearance (12 +/- 2 vs. 13 +/- 2 ml/min) changed significantly, but plasma glucose increased from 100 +/- 3 to 167 +/- 21 mg/dl, P less than .01. The increases in plasma glucose during infusion of insulin with the Biostator and the Harvard pump were not significantly different (t = 1.44, P = .19). When insulin was delivered directly into test tubes with the Biostator and the Harvard pump, insulin concentrations in the test tubes decreased 46% over 8 h (P less than .05) with the Biostator, whereas no decrease was observed with the Harvard pump.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus

We have studied the effects of 3 wk of continuous subcutaneous insulin infusion (CSII) on endogenous insulin secretion and action in a group of 14 type II diabetic subjects with a mean (+/-SEM) fasting glucose level of 286 +/- 17 mg/dl. Normal basal and postprandial glucose levels were achieved during insulin therapy at the expense of marked peripheral hyperinsulinemia. During the week of posttreatment evaluation, the subjects maintained a mean fasting glucose level of 155 +/- 11 mg/dl off insulin therapy, indicating a persistent improvement in carbohydrate homeostasis. Adipocyte insulin binding and in vivo insulin dose-response curves for glucose disposal using the euglycemic clamp technique were measured before and after therapy to assess the effect on receptor and postreceptor insulin action. Adipocyte insulin binding did not change. The insulin dose-response curve for overall glucose disposal remained right-shifted compared with age-matched controls, but the mean maximal glucose disposal rate increased by 74% from 160 +/- 14 to 278 +/- 18 mg/m2/min (P less than 0.0005). The effect of insulin treatment on basal hepatic glucose output was also assessed; the mean rate was initially elevated at 159 +/- 8 mg/m2/min but fell to 90 +/- 5 mg/m2/min in the posttreatment period (P less than 0.001), a value similar to that in control subjects. Endogenous insulin secretion was assessed in detail and found to be improved after exogenous insulin therapy. Mean 24-h integrated serum insulin and C-peptide concentrations were increased from 21,377 +/- 2766 to 35,584 +/- 4549 microU/ml/min (P less than 0.01) and from 1653 +/- 215 to 2112 +/- 188 pmol/ml/min (P less than 0.05), respectively, despite lower glycemia. Second-phase insulin response to an intravenous (i.v.) glucose challenge was enhanced from 170 +/- 53 to 1022 +/- 376 microU/ml/min (P less than 0.025), although first-phase response remained minimal. Finally, the mean insulin and C-peptide responses to an i.v. glucagon pulse were unchanged in the posttreatment period, but when glucose levels were increased by exogenous glucose infusion to approximate the levels observed before therapy and the glucagon pulse repeated, responses were markedly enhanced. Simple and multivariate correlation analysis showed that only measures of basal hepatic glucose output and the magnitude of the postbinding defect in the untreated state could be related to the respective fasting glucose levels in individual subjects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Evidence that carotid bodies play an important role in glucoregulation in vivo

The carotid bodies are sensitive to glucose in vitro and can be stimulated to cause hyperglycemia in vivo. The aim of this study was to determine if the carotid bodies are involved in basal glucoregulation or the counterregulatory response to an insulin-induced decrement in arterial glucose in vivo. Dogs were surgically prepared >16 days before the experiment. The carotid bodies and their associated nerves were removed (carotid body resected [CBR]) or left intact (Sham), and infusion and sampling catheters were implanted. Removal of carotid bodies was verified by the absence of a ventilatory response to NaCN. Experiments were performed in 18-h fasted conscious dogs and consisted of a tracer ([3-3H]glucose) equilibration period (-120 to -40 min), a basal period (-40 to 0 min), and an insulin infusion (1 mU x kg(-1) x min(-1)) period (0-150 min) during which glucose was infused as needed to clamp at mildly hypoglycemic (65 mg/dl) or euglycemic (105 mg/dl) levels. Basal (8 microU/ml) and clamp (40 microU/ml) insulin levels were similar in both groups. Basal arterial glucagon was reduced in CBR compared with Sham (30 + 2 vs. 40 +/- 2 pg/ml) and remained reduced in CBR during hypoglycemia (peak levels of 36 +/- 3 vs. 52 +/- 7 pg/ml). Cortisol levels were not significantly different between the 2 groups in the basal state, but were reduced during the hypoglycemic clamp in CBR. Catecholamine levels were not significantly different between the 2 groups in the basal and hypoglycemic periods. The glucose infusion rate required to clamp glucose at 65 mg/dl was 2.5-fold greater in CBR compared with Sham (4.0 +/- 0.4 vs. 1.6 +/- 0.4 mg x kg(-1) x min(-1)). Basal endogenous glucose appearance (R(a)) was equal in CBR and Sham (2.5 +/- 0.1 vs. 2.5 +/- 0.2 mg x kg(-1) x min(-1)). During the hypoglycemic clamp, insulin suppressed R(a) in CBR but not Sham (1.1 +/- 0.2 vs. 2.5 +/- 0.2 mg x kg(-1) x min(-1) during the last 30 min of the clamp), reflecting impaired counterregulation. Glucose disappearance (R(d)) in the basal state was similar in CBR and Sham, whereas it was elevated in CBR during the hypoglycemic clamp (4.8 +/- 0.1 vs. 3.9 +/- 0.1 mg x kg(-1) x min(-1) during the last 30 min of the clamp). R(d) was also elevated in euglycemic clamp studies, indicating an effect of carotid body resection independent of hypoglycemia. There were no other measured systematic endocrine or metabolic effects of carotid body resection during euglycemic clamps. In conclusion, we found that the carotid bodies (or receptors anatomically close by) play an important role in the insulin-induced counterregulatory response to mild hypoglycemia.     

Effects of chronic beta receptor stimulation on glucose metabolism

The acute administration of a beta receptor-stimulating agent profoundly affects insulin-mediated glucose metabolism; however, little is known about the impact of chronic beta receptor stimulation on glucose metabolism and insulin sensitivity. We therefore investigated the effect of the chronic administration of a beta-2-agonist, terbutaline sulfate (TS), on glucose metabolism in 7 healthy, normal-weight, male volunteers between the ages of 21 and 30 yr. Studies were performed using the euglycemic, hyperinsulinemic (1.0 mU/min X kg) clamp technique before and after the oral administration of 5 mg of TS three times a day for 1 and 2 wk. Basal endogenous glucose production (EGP) (2.54 +/- 0.11 versus 2.64 +/- 0.14 mg/min X kg) and basal glucose oxidation (1.87 +/- 0.16 versus 2.0 +/- 0.2 mg/min X kg) were unchanged by the chronic administration of TS. However, insulin-stimulated total glucose metabolism increased by 29% (7.0 +/- 0.47 versus 9.05 +/- 0.67 mg/min X kg; P less than 0.02). Insulin-stimulated, nonoxidative glucose disposal increased by 45% (3.62 +/- 0.42 versus 5.26 +/- 0.48 mg/min X kg; P less than 0.01), while insulin-stimulated glucose oxidation did not change significantly (3.38 +/- 0.15 versus 3.79 +/- 0.22 mg/min X kg). EGP was completely suppressed under both conditions. Mean basal plasma insulin concentration (41 +/- 9 versus 49 +/- 15 pmol/L) and insulin clearance during the clamp procedure was unchanged (477 +/- 45 versus 474 +/- 37 ml/min X m2). We conclude that chronic beta receptor stimulation with TS improves insulin-stimulated glucose disposal in man, mostly by improving nonoxidative glucose disposal, i.e., "glucose storage."(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucose turnover and adipose tissue lipolysis are insulin-resistant in healthy relatives of type 2 diabetes patients: is cellular insulin resistance a secondary phenomenon?

To elucidate potential mechanisms for insulin resistance occurring early in the development of type 2 diabetes, we studied 10 young healthy individuals, each with two first-degree relatives with type 2 diabetes, and 10 control subjects without known type 2 diabetic relatives. They were pairwise matched for age (35 +/- 1 vs. 35 +/- 1 years), BMI (23.6 +/- 0.6 vs. 23.1 +/- 0.4 kg/m2), and sex (four men, six women). Glucose turnover was assessed during a euglycemic clamp at two insulin levels (low approximately 20 mU/l; high approximately 90 mU/l), and abdominal subcutaneous adipose tissue (SAT) lipolysis and blood flow were concomitantly studied with microdialysis and 133Xe clearance. HbA1c was higher in patients with type 2 diabetic relatives than in control subjects (4.8 +/- 0.1 vs. 4.5 +/- 0.1%, P < 0.02), but fasting glucose, insulin, and C-peptide levels were similar. During the clamp, the insulin sensitivity index for glucose disposal was lower (P < 0.03) in relatives than in control subjects (low 12.0 +/- 1.6 vs. 18.1 +/- 1.4; high 9.4 +/- 0.8 vs. 12.9 +/- 0.6 [100 x mg x l x kg(-1) x mU(-1) x min(-1)]). This difference was partially attributed to slightly higher clamp insulin levels in the relatives (P < 0.03), suggesting an impaired rate for insulin clearance. SAT lipolysis measured as in situ glycerol release did not differ under basal conditions (2.0 +/- 0.2 vs. 2.1 +/- 0.2 micromol x kg(-1) x min(-1)), but the suppression during the insulin infusion was less marked in relatives than in control subjects (glycerol release: low 0.92 +/- 0.09 vs. 0.68 +/- 0.16; high 0.71 +/- 0.10 vs. 0.34 +/- 0.10 micromol x kg(-1) x min(-1); P < 0.03). Plasma nonesterified fatty acids also tended to be higher in relatives than in control subjects during the insulin infusion (NS). In contrast, in vitro experiments with isolated subcutaneous adipocytes displayed similar effects of insulin in relatives and control subjects with respect to both glucose uptake and antilipolysis. In conclusion, insulin action in vivo on both lipolysis and glucose uptake is impaired early in the development of type 2 diabetes. Since this impairment was not found in isolated adipocytes, it may be suggested that neural or hormonal perturbations precede cellular insulin resistance in type 2 diabetes.     

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)