Low-dose Insulin Infusion Research Articles

Bis(maltolato)oxovanadium(IV) attenuates hyperinsulinemia and hypertension in spontaneously hypertensive rats.

We previously reported that bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium complex, decreased plasma insulin concentrations in nondiabetic rats without affecting plasma glucose levels (McNeill JH, Yuen VG, Hoveyda HR, Orvig C: Bis(maltolato)oxovanadium(IV) is a potent insulin mimic. J Med Chem 35:1489-1491, 1992). In this study, chronic oral BMOV treatment was started in 6-week-old spontaneously hypertensive (SH) rats and their Wistar-Kyoto (WKY) controls, and the effects of the drug on insulin sensitivity, plasma insulin, and blood pressure (BP) were studied. BMOV (0.35-0.45 mmol.kg-1.day-1) caused a sustained reduction in plasma insulin (198 +/- 6 vs. untreated 366 +/- 13.2 pM, P < 0.0001) and systolic BP (149 +/- 3 vs. untreated 184 +/- 3 mmHg, P < 0.0001) in SH rats. No changes were seen in WKY rats (plasma insulin: treated 228 +/- 4.8 vs. untreated 222.6 +/- 3.6 pM, P > 0.05; BP: treated 134 +/- 3 vs. untreated 134 +/- 5 mmHg, P > 0.05). At 13 weeks of age, euglycemic clamps were performed in fasted, conscious, mobile rats. During low-dose insulin infusions (14 pmol.kg-1.min-1) with concomitant somatostatin administration, neither hepatic glucose output nor total body glucose uptake differed between the untreated SH and WKY rats. Insulin sensitivity, expressed as steady-state glucose clearance per unit of plasma insulin, was higher in the untreated SH compared with the untreated WKY rats (2.1 +/- 0.2 vs. 1.2 +/- 0.1 ml.kg-1.h-1.pM-1, P < 0.002). BMOV further enhanced insulin sensitivity in SH rats (3.6 +/- 0.4, P < 0.002 vs. untreated SH rats).(ABSTRACT TRUNCATED AT 250 WORDS)

Vanadyl sulfate prevents fructose-induced hyperinsulinemia and hypertension in rats.

To determine whether insulin resistance and hyperinsulinemia are causally related to fructose-induced hypertension, we used vanadyl sulfate, a drug that improves insulin sensitivity in rats. Chronic oral vanadyl treatment was initiated in 6-week-old male Sprague-Dawley rats. One week after vanadyl was started, rats were fed either normal rat chow or a fructose-enriched diet. Plasma glucose and insulin levels and systolic blood pressure were measured weekly for 4 weeks. Fructose feeding induced hyperinsulinemia (fructose-fed, 366.6 +/- 8.4 versus control, 276 +/- 10.8 pmol/L, P < .001) and increased blood pressure (fructose-fed, 160 +/- 3.0 versus control, 124 +/- 3.0 mm Hg, P < .001). Vanadyl (0.4 to 0.6 mmol/kg per day) prevented the rise in plasma insulin (treated, 211.2 +/- 6.0 pmol/L, P < .001) and blood pressure (treated, 127 +/- 3.0 mm Hg, P < .001) in the fructose-fed rats without a change in plasma glucose. No change in blood pressure was seen in the control group. After 4 weeks, euglycemic clamps were performed on 20-hour fasted, conscious, mobile rats. Low-dose porcine insulin infusion (14 pmol/kg per minute) with concomitant somatostatin infusion resulted in similar steady-state plasma glucose and insulin levels in the various groups. Hepatic glucose production was suppressed and similar among various groups under clamp conditions. Insulin sensitivity index (micromoles of glucose per kilogram per hour per picomole per liter of insulin) was reduced in the fructose-fed rats compared with controls (fructose-fed, 0.9 +/- 0.4 versus control, 5.4 +/- 1.2, P < .002).(ABSTRACT TRUNCATED AT 250 WORDS)

Skeletal muscle blood flow independently modulates insulin-mediated glucose uptake

Insulin-mediated glucose uptake (IMGU) occurs principally in skeletal muscle. To directly examine whether skeletal muscle perfusion (F) can directly and independently modulate IMGU, we combined the hyperinsulinemic euglycemic clamp and leg balance techniques [leg glucose uptake (LGU) = arteriovenous glucose difference (delta AVG) x F]. Young (< 40 yr) healthy lean subjects were studied during euglycemic hyperinsulinemia of approximately 23 microU/ml (group I, n = 8) and approximately 950 microU/ml (group II, n = 6). Femoral delta AVG and leg F were measured, and LGU was calculated at baseline after approximately 200 min of steady-state hyperinsulinemia alone and during a superimposed intrafemoral artery infusion of methacholine hydrochloride designed to increase leg F two- to threefold. In groups I and II, insulin raised the delta AVG approximately 4- and 14-fold, respectively (P < 0.0001). Leg F was unchanged during the low-dose insulin infusion (group I) but increased 112 +/- 35% in group II (P < 0.001). During methacholine infusion the delta AVG narrowed 35.9 +/- 6.8% (P < 0.01) and 20.5 +/- 4.8% (P < 0.05) in groups I and II, respectively. Leg F rose 224 +/- 30% (P < 0.01) and 79 +/- 13% (P < 0.05) above the flow rate achieved with insulin alone. Thus, during methacholine flow modulation, LGU increased 116 +/- 36% (P < 0.01) and 47 +/- 11% (P < 0.05) in groups I and II, respectively. In conclusion, skeletal muscle perfusion during hyperinsulinemia can act as an independent determinant of IMGU.

Effects of insulin on the counterregulatory response to equivalent hypoglycemia in normal females.

The aim of this study was to determine if insulin could augment the counterregulatory response to equivalent hypoglycemia in normal females similarly to males. Experiments were carried out in nine normal lean overnight-fasted female subjects. Insulin was infused in two separate randomized protocols so that steady-state levels of 794 +/- 62 (low) and 3,620 +/- 476 pM (high) were obtained. Despite an identical plasma glucose level (2.8 +/- 0.1 mM), epinephrine (5.7 +/- 0.9 vs. 3.9 +/- 0.6 nM), norepinephrine (2.7 +/- 0.4 vs. 1.8 +/- 0.3 nM), cortisol (918 +/- 55 vs. 826 nM), and growth hormone (35.8 +/- 3.7 vs. 28.4 +/- 2.7 micrograms/l) were increased (P < 0.05) during high compared with low insulin infusion, respectively. Glucagon and pancreatic polypeptide levels increased significantly but were not different during the two insulin infusions. Hepatic glucose production was increased during the high-compared with low-dose infusions (9.5 +/- 1.1 vs. 5.1 +/- 2.2 mumol.kg-1 x min-1; P < 0.05). Lipolysis, as indicated by the blood glycerol level, increased significantly during high- compared with low-dose insulin infusions (121 +/- 29 vs. 65 +/- 13 microM; P < 0.05). The hormonal and metabolic responses to hypoglycemia were significantly different in females compared with previous results in males.(ABSTRACT TRUNCATED AT 250 WORDS)

Correction: Treatment of diabetic ketoacidosis in dogs by continuous low-dose intravenous infusion of insulin

Correction: Treatment of diabetic ketoacidosis in dogs by continuous low-dose intravenous infusion of insulin

Gender differences in counterregulation to hypoglycaemia

To investigate the effect of gender on catecholamine responses to hypoglycaemia, single-step euglycaemic-hypoglycaemic clamps have been performed in 14 healthy men and 17 women. Adrenaline responses were 44% lower in females (p < 0.01) and noradrenaline 17% lower (p = 0.08). In response to low-dose intravenous insulin infusion (0.3 mU.kg-1.min-1), plasma glucose fall and counterregulation in seven men and seven women had a different course (p < 0.001), with different glucose kinetics. In men, endogenous glucose output recovered quickly to levels that exceeded basal; in women suppression of endogenous glucose output was more prolonged, without rates ever exceeding basal (p < 0.05). Peripheral glucose uptake was stimulated in men only. The hormones of acute glucose counterregulation (catecholamines and glucagon) did not differ between the sexes during this challenge, the catecholamine response in the women being supported by the continuous fall in plasma glucose. These results suggest that: 1) catecholamine responses to moderately controlled hypoglycaemia are diminished in women, and 2) peripheral insulin sensitivity in men is enhanced over that of women but hepatic sensitivity to insulin may be greater in women.

Treatment of diabetic ketoacidosis in dogs by continuous low-dose intravenous infusion of insulin

Summary: In a prospective clinical trial, low-dose, continuous, iv infusion of insulin (dosage, 2.2 U/kg of body weight, q 24 h) was used to treat 21 dogs with diabetic ketoacidosis. Mean (± sd) blood glucose concentration at the onset of treatment was 550 ± 150 mg/dl and after 6 hours, was 350 ± 106 mg/dl, with a mean decline of 34 ± 16 mg/dl/h. By 12 hours, mean blood glucose was 246 ± 85 mg/dl, with a mean decline of 28 ± 14 mg/dl/h during the second 6 hours of treatment. Mean duration of treatment required to reach a blood glucose concentration ≤ 250 mg/dl was 10 ± 4 hours, with a range of 4 to 24 hours. Ketonuria was observed for 26 ± 14 hours (range, 6 to 12 hours). Hypoglycemia developed in 3 of 21 dogs during treatment, but responded to iv administration of a glucose solution and to a reduction in rate of insulin delivery. Potassium supplementation was required in 15 of 21 dogs. Mean bicarbonate concentration was 11.6 ± 3.4 mEq/L before treatment and was 18.2 ± 0.7 mEq/L after 24 hours. Fifteen of 21 dogs (71%) survived to be discharged. Mean duration of treatment with the insulin infusion was 50 ± 30 hours (range, 7 to 124 hours). In this series of dogs, continuous, low-dose, iv infusion of insulin provided a gradual and consistent reduction in blood glucose concentration while ketoacidosis, electrolyte balance, and dehydration were corrected. Although hypoglycemia, hypokalemia, hypophosphatemia, and cerebral edema remain potential complications of any treatment for diabetic ketoacidosis, this protocol appears to provide a safe and effective treatment method.

Insulin-like growth factor-binding protein-1 response to insulin during suppression of endogenous insulin secretion

Insulin-like growth factor-binding protein-1 (IGFBP-1) is one of several related proteins that bind and modulate the actions of IGFs. The liver is the primary source of IGFBP-1, and insulin is a major regulator of hepatic IGFBP-1 production. We report five sets of investigations that further define the characteristics of hepatic IGFBP-1 response to insulin. In normal subjects, a continuous high-dose insulin infusion caused a rapid decrease in plasma IGFBP-1 concentrations, with a rate of 0.24 ± 0.04 μg/L·min −1 and a t 1 2 of 89 ± 4 minutes. Conversely, a 3-hour somatostatin (SRIF) infusion caused a 4.5-fold increase in plasma IGFBP-1 levels. SRIF plus low-dose insulin infusion (to inhibit break-through insulin secretion) resulted in a plateau in IGFBP-1 concentrations at 5 to 8 hours, with a t 1 2 to achieve steady state of 60 to 75 minutes. Under similar conditions, a stepped increase in plasma glucose level from 5 to 9 mmol/L had no effect on the rate of IGFBP-1 increase in plasma, indicating that an acute increase in glucose concentration within a physiologic range has no independent inhibitory effect on IGFBP-1 production in the presence of a nonsuppressive insulin level. Using SRIF plus sequential graded insulin infusions, the threshold peripheral (=portal) plasma insulin concentration for IGFBP-1 suppression was between 65 and 172 pmol/L. Subjects with insulin-dependent diabetes mellitus (IDDM) showed a similar dose-response pattern, suggesting that insulin regulation of IGFBP-1 may be normal in IDDM. The rapid and sensitive response of IGFBP-1 to insulin is consistent with its postulated role to modulate IGF bioaction in relation to substrate availability. Moreover, measurement of plasma IGFBP-1 concentrations may serve as a useful marker of hepatic insulin sensitivity.

Lowering of triglycerides by gemfibrozil affects neither the glucoregulatory nor antilipolytic effect of insulin in Type 2 (non-insulin-dependent) diabetic patients

Hypertriglyceridaemia and insulin resistance are closely associated but it is unknown whether hypertriglyceridaemia per se contributes to insulin resistance. In the present study we examined whether gemfibrozil, by lowering triglyceride levels, improves the glucoregulatory and antilipolytic action of insulin in Type 2 (non-insulin-dependent) diabetes mellitus. Twenty patients were randomly allocated to receive either placebo or gemfibrozil 1200 mg daily for 12 weeks in a double-blind study. Very low density lipoprotein triglyceride levels decreased in the gemfibrozil group by 42 +/- 12% (p < 0.01). Gemfibrozil had no effect on the diurnal concentration of non-esterified fatty acids (NEFA). At the randomization HbA1c levels were comparable (7.6 +/- 0.3 vs 7.8 +/- 0.2%, NS) and increased slightly both in the gemfibrozil (8.2 +/- 0.4%, p < 0.05) and placebo groups (8.0 +/- 0.3%, NS). Pre- and post-treatment diurnal glucose and insulin concentrations remained unchanged. Basal pre- and post-treatment hepatic glucose production rates were comparable in both groups and similarly suppressed by insulin. Rate of whole body glucose disposal during a low-dose insulin infusion (serum insulin -90 pmol/l) (pre- vs post-gemfibrozil 11.9 +/- 1.1 vs 11.1 +/- 0.7, pre- vs post-placebo 9.9 +/- 1.1 vs 10.8 +/- 0.8 mumol.kg-1.min-1, NS for both) and a high-dose insulin infusion (serum insulin approximately 500 pmol/l) (16.2 +/- 1.7 vs 17.7 +/- 2.7, 17.1 +/- 4.2 vs 17.4 +/- 2.9 mumol.kg-1 x min-1, respectively, NS for both) remained unchanged. Basal pre- and post-treatment NEFA turnover rates were comparable in both groups and similarly suppressed by insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Euglycaemic diabetic ketoacidosis: does it exist?

The original criteria described for euglycaemic ketoacidosis (initial blood glucose less than 16.7 mmol/l and plasma bicarbonate equal to or less than 10 mmol/l) were identified in 23 of 722 consecutive episodes (3.2%) of diabetic ketoacidosis. True euglycaemic ketoacidosis (initial blood glucose 10 mmol/l or less) was rare, occurring in 0.8-1.1% of all episodes depending on the defining plasma bicarbonate concentration. Management of euglycaemic ketoacidosis with low-dose continuous intravenous infusion of insulin together with adequate fluid replacement was effective. The clinical and biochemical data did not support the concept of euglycaemic ketoacidosis as a separate entity. The importance of ketone testing rather than glucose testing in the diagnosis of ketoacidosis is, however, emphasized. The importance of adequate insulin and fluid therapy in those few episodes where blood glucose is normal or near normal at presentation is also highlighted.

Impaired stimulation of gluconeogenesis during prolonged hypoglycemia in intensively treated insulin-dependent diabetic subjects.

Defective glucose counterregulation commonly seen in intensively treated insulin-dependent diabetes (IDDM) is mediated in part by a failure of compensatory stimulation of hepatic glucose production. Since the response of the liver to insulin-induced hypoglycemia normally involves activation of gluconeogenesis, we measured [14C]alanine conversion to [14C]glucose (a qualitative index of gluconeogenesis) and glucose production (using [3-3H]glucose) in seven intensively treated type I diabetic subjects (hemoglobin-A1, 7.1 +/- 0.4%) during low dose infusion of insulin (0.3 mU/kg.min for 210 min). IDDM patients received insulin overnight to maintain euglycemia before study. Although insulin levels rose to a similar extent as those in normal control subjects (n = 6), the fall in plasma glucose was markedly greater in IDDM (2.5 +/- 0.2 vs. 3.64 +/- 0.2 mM in controls; P < 0.01). The glucagon response was totally lost in IDDM, and epinephrine release was delayed and slightly reduced compared to that in control subjects. In contrast to that in normal subjects, hepatic glucose production in the IDDM subjects remained persistently suppressed by about 60% throughout the study. The conversion of alanine and lactate to glucose remained virtually unchanged in the IDDM, whereas in controls it increased 2-fold above baseline during the last hour of the study. Our data suggest that the failure of gluconeogenesis to increase during hypoglycemia is an important factor contributing to the defective hepatic response observed in the intensively treated type I diabetic subjects.

Effects of morbid obesity on insulin clearance and insulin sensitivity in several aspects of metabolism as assessed by low-dose insulin infusion

Obesity is associated with impaired insulin action in glucose disposal, but not necessarily in other aspects of intermediary metabolism or insulin clearance. Sixteen morbidly obese and 14 normal-weight subjects (body mass index, 51.2 ± 11.5 v 22.1 ± 2.2 kg · m −2; mean ± SD) were studied with sequential, low-dose, incremental insulin infusion with estimation of glucose turnover. In obese patients, basal plasma insulin was higher (10.5 ± 3.8 v 2.4 ± 3.0 mU · L −1, P < .001) and remained elevated throughout infusion (F = 492, P < .001), as did C-peptide (F = 22.7, P < .001). Metabolic clearance rate for insulin (MCR I) at the highest infusion rate was similar (1,048 ± 425 v 1,018 ± 357 mL · m −2 · min −1, NS). Basal hepatic glucose production in obese subjects was less than in normal-weight subjects (270 ± 108 v 444 ± 68 μmol · m −2 · min −1, P < .01), as was the basal metabolic clearance rate for glucose (MCR G, 77 ± 26 v 108 ± 31 mL · m −2 · min −1, P < .05). Insulin infusion caused blood glucose to decrease less in the obese patients (1.4 ± 0.5 v 1.9 ± 0.5 mmol · L −1, P < .05); hepatic glucose production was appropriately suppressed in them by hyperinsulinemia, but their insulin-mediated glucose disposal was reduced (1.67 [0.79] v 4.45 [2.13] mL · m −2 · min −1/mU · L −1, P < .01). Concentrations of nonesterified fatty acids (NEFA), glycerol, and ketones were evevated throughout the insulin infusions in obese patients, despite the higher insulin concentrations. Dose-response calculations suggested insulin resistance at physiological insulin concentrations in obesity for glucose, NEFA, glycerol, and ketones.

Incomplete suppression of hepatic glucose production in non-insulin dependent diabetes mellitus measured with [6,6-2H2]glucose enriched glucose infusion during hyperinsulinaemic euglycaemic clamps.

We have minimized methodological errors in the isotope dilution technique by using stable isotope, [6,6-2H2]glucose, thus avoiding the problem of contamination of tritiated glucose tracers and, by maintaining a constant plasma tracer enrichment have reduced error due to mixing transients. Using these modifications we have calculated hepatic glucose production in 20 patients with non-insulin-dependent diabetes mellitus during low (1 mU kg-1 min-1) and high (8 mU kg-1 min-1) dose insulin infusions. Mean fasting hepatic glucose production was 14.2 +/- 0.8 mumol kg-1 min-1. This suppressed by only 68% to 4.6 +/- 0.8 mumol kg-1 min-1 during the low-dose insulin infusion (plasma insulin 0.85 +/- 0.05 nmol l-1) and did not suppress further during the high-dose insulin infusion (plasma insulin 14.55 +/- 0.83 nmol l-1). Hepatic glucose production was significantly higher than zero throughout the study. Thus, we have found that minimization of known errors in the isotope dilution technique results in physiologically plausible and significantly positive values for hepatic glucose production indicating that the liver is resistant to insulin in patients with non-insulin-dependent diabetes mellitus.

Impaired adrenergic response to prolonged exercise in type I diabetes

Patients with type I diabetes mellitus commonly experience hypoglycemia related to physical activity. We investigated the metabolic and hormonal response to exercise in type I diabetics, normal controls, and controls exercising under hypoglycemic conditions. All subjects exercised for 60 minutes at 60% to 65% of their V o 2 max while insulin concentrations were clamped at balal or hyperinsulinemic levels. With low-dose insulin infusion, despite similar free insulin levels, diabetics had a greater decrease in plasma glucose concentrations during exercise than controls. Nevertheless, the increments of epinephrine (E) and norepinephrine (NE) during exercise tended to be less in the diabetic subjects. Circulating levels of free fatty acids (FFA) were lower in diabetics, especially during early recovery from exercise. To better compare responses, a group of normal controls exercised during an infusion of insulin, which resulted in a similar decrease in plasma glucose to that of exercising diabetics. While exercising during a similar degree of hypoglycemia, diabetics had a significantly smaller increment of E and NE compared with controls. Increments of glucagon (GL) and growth hormone (GH) were not different. These studies suggest that there is a subnormal catecholamine response to exercise under hypoglycemic conditions in some patients with type I diabetes. The hypoglycemia during and after exercise in these individuals is probably the result of multiple factors, including relative hyperinsulinemia, decreased increment in catecholamines, and decreased availability of FFA.

A High Concentration of Circulating Insulin Suppresses the Glucagon Response to Hypoglycemia in Normal Man*

In an attempt to clarify whether circulating insulin per se exerts an inhibitory effect on the hormonal responses to hypoglycemia, with special emphasis on glucagon secretion, nine healthy volunteers were exposed to low dose (244 pmol/kg.h) and high dose (1034 pmol/kg.h) iv insulin infusions for 3 h on two separate occasions. A close to identical arterial hypoglycemia of about 3.4 mmo/L was obtained in both tests by glucose clamping during the high dose test. The corresponding glucose concentration in the venous blood was significantly lower in the high dose test (2.5 +/- 0.1 vs. 3.0 +/- 0.1 mmol/L; P less than 0.01), while the plasma free insulin level was 4 times higher in the high dose test (897 +/- 50 vs. 208 +/- 14 pmol/L). Plasma glucagon was elevated in both experiments, but its rise was reduced during the high dose test after 1 h, yielding an incremental area under the glucagon curve that was significantly smaller than that obtained during the low dose test (213 +/- 70 vs. 348 +/- 81 ng/L.h; P less than 0.05). The plasma adrenaline, noradrenaline, GH, C-peptide, pancreatic polypeptide, and somatostatin profiles were similar in the two tests. We conclude that an inhibitory effect of circulating insulin on the glucagon response to hypoglycemia can be demonstrated in normal man during an infusion of insulin yielding a plasma concentration of about 900 pmol/L. The responses of other hormones studied are not significantly influenced by the circulating insulin level.

Impaired Glucose Tolerance is Characterized by Multiple Abnormalities in the Regulation of Intermediary Metabolism

The responses of circulating intermediary metabolites to a low-dose sequential insulin infusion (basal, 0.005, 0.01, and 0.05 U kg-1 h-1) were assessed in eight non-obese men with Impaired Glucose Tolerance (IGT), and in eight healthy control subjects with normal glucose tolerance matched for age, gender, and body mass index. Fasting hyperinsulinaemia was observed in the subjects with IGT (7.4 +/- 1.0 vs 2.9 +/- 0.3 mU I-1, p less than 0.001). While there was no significant difference (p greater than 0.1) in fasting venous glucose levels between the groups, fasting concentrations of lactate (p less than 0.02), alanine (p less than 0.01), and glycerol (p less than 0.05) were significantly elevated in the subjects with IGT. During the incremental insulin infusion, overall concentrations of glucose (p less than 0.05), lactate (p less than 0.05), alanine (p less than 0.05), glycerol (p less than 0.05), immunoreactive insulin (p less than 0.001), and C-peptide (p less than 0.01) were significantly higher in the subjects with IGT. Linear dose-response relationships (p less than 0.005) for circulating immunoreactive insulin (log) vs metabolite concentrations were demonstrated by analysis of variance for glucose, non-esterified fatty acids (NEFA), glycerol, and total ketone bodies. For glucose, glycerol, and NEFA, group dose-response regression lines for the subjects with IGT were displaced significantly to the right (p less than 0.001 for each) of those for the normal control subjects, implying insulin insensitivity. In addition to the recognized defect in glucose homeostasis, these results indicate impaired regulation of multiple aspects of intermediary metabolism including lipolysis in IGT.

Impaired Glucose Tolerance in Obesity is Associated with Insensitivity to Insulin in Multiple Aspects of Metabolism as Assessed by a Low Dose Incremental Insulin Infusion Technique

To determine whether Impaired Glucose Tolerance gives rise to additional defects in insulin action in lipid and ketone metabolism, thirty-two obese subjects were studied by low-dose incremental insulin infusion. Sixteen had Impaired Glucose Tolerance and 16 had normal glucose tolerance. Body mass index was 36.9-80.9 kg m-2 and was similar in each group. In patients with Impaired Glucose Tolerance, plasma insulin was higher in the fasted state (logarithmic mean 14.5 (9.8-21.6) (-SD(-)+SD) vs 9.6 (6.4-14.5) mU l-1, p less than 0.01) and during the infusion (p less than 0.001). The metabolic clearance rate for insulin at the highest infusion rate was lower (14.2 +/- 0.8 (+/- SE) vs 18.9 +/- 2.1 ml kg-1 min-1, p less than 0.05) in these subjects. Basal hepatic glucose production was higher in subjects with Impaired Glucose Tolerance (6.3 +/- 0.4 vs 4.5 +/- 0.6 mol kg-1 min-1, p less than 0.02) and remained elevated during infusion (p less than 0.01). Glucose disposal per unit circulating insulin at the maximal infusion rate was approximately half in subjects with Impaired Glucose Tolerance (0.022 +/- 0.010 vs 0.047 +/- 0.017 ml kg-1 min-1 mU-1 l, p less than 0.01). When simultaneous insulin and metabolite concentrations during the infusion are plotted as dose-response relationships, a difference in relative sensitivity to insulin in Impaired Glucose Tolerance over subjects with normal glucose tolerance is suggested for non-esterified fatty acids 0.72 (95% CI 0.62-0.84) and glycerol 1.85 (1.37-2.49).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin Effects on Glucose and Potassium Metabolismin Vivo: Evidence for Selective Insulin Resistance in Humans

The effects of insulin on in vivo glucose use and potassium uptake in healthy humans are well documented. However, the interrelationship between these two processes is not fully defined. In order to characterize it, we have used the euglycemic clamp technique on six normal volunteers, two patients with acanthosis nigricans and insulin resistance (AN), and one patient with idiopathic nonazotemic hyperkalemia (HK). In the basal state, all patients had normal fasting blood sugar, the AN patients had fasting hyperinsulinemia (600% of controls), and the HK patient had an elevated plasma potassium level of 5.1 mmol/L (n = 4.2 +/- 0.2 mmol/L). During low dose (1 mU/kg.min), and high dose (10 mU/kg.min) insulin infusions, normals used glucose at a rate of 220 +/- 10 and 470 +/- 20 mg/M2.min, respectively. The HK patient had a normal glucose use at both infusion rates, but the AN patients had a 20% decrease of glucose use compared to normals at the two infusion rates. In normal patients, plasma potassium fell by 0.7 and 1.4 mmol/L at the end of the two infusion periods, respectively. AN patients had a similar fall in potassium, but the HK patient displayed no change in plasma potassium levels during a low dose insulin infusion, and only a 0.6 mmol/L drop during the high dose insulin infusion. These results indicate that: 1) patients with AN are resistant to insulin action on glucose use, 2) AN patients have a normal response to insulin on potassium uptake, 3) HK is a patient with normal response to insulin on glucose use, and 4) this patient is resistant to insulin action on potassium uptake. 1) we have demonstrated the independence of insulin action on glucose and potassium uptake in vivo, 2) we documented the existence of selective insulin resistance in the above patients, 3) we speculate, that in patients with a normal response to insulin on one parameter of its actions, and subnormal response on another parameter, a postreceptor defect rather than a receptor abnormality must exist.

Effect of physiologic hyperinsulinemia on glucose and lipid metabolism in cirrhosis.

Insulin secretion and insulin sensitivity were evaluated in eight clinically stable cirrhotic patients and in 12 controls. OGTT was normal in cirrhotics but plasma insulin response was increased approximately twofold compared with controls. Subjects received a three-step (0.1, 0.5, 1.0 mU/kg.min) euglycemic insulin clamp with indirect calorimetry, [6-3H]-glucose, and [1-14C]-palmitate. During the two highest insulin infusion steps glucose uptake was impaired (3.33 +/- 0.31 vs. 5.06 +/- 0.40 mg/kg.min, P less than 0.01, and 6.09 +/- 0.50 vs. 7.95 +/- 0.52 mg/kg.min, P less than 0.01). Stimulation of glucose oxidation by insulin was normal; in contrast, nonoxidative glucose disposal (i.e., glycogen synthesis) was markedly reduced. Fasting (r = -0.553, P less than 0.01) and glucose-stimulated (r = -0.592, P less than 0.01) plasma insulin concentration correlated inversely with the severity of insulin resistance. Basal hepatic glucose production was normal in cirrhotics and suppressed normally with insulin. In postabsorptive state, plasma FFA conc (933 +/- 42 vs. 711 +/- 44 mumol/liter, P less than 0.01) and FFA turnover (9.08 +/- 1.20 vs. 6.03 +/- 0.53 mumol/kg.min, P less than 0.01) were elevated in cirrhotics despite basal hyperinsulinemia; basal FFA oxidation was similar in cirrhotic and control subjects. With low-dose insulin infusion, plasma FFA oxidation and turnover failed to suppress normally in cirrhotics. During the two higher insulin infusion steps, all parameters of FFA metabolism suppressed normally. In summary, stable cirrhotic patients with normal glucose tolerance exhibit marked insulin resistance secondary to the impaired nonoxidative glucose disposal. Our results suggest that chronic hyperinsulinism may be responsible for the insulin resistance observed in cirrhosis.

Insulin resistance in multiple aspects of intermediary metabolism in myotonic dystrophy

The responses of circulating intermediary metabolites to a low-dose incremental insulin infusion (basal, 0.005, 0.01, and 0.05 U · kg −1 · h −1) were examined in eight ambulant subjects with the multisystem disorder, myotonic dystrophy. Eight healthy subjects matched for age, gender, and body mass index served as controls. Oral glucose tolerance (75 g) was normal in all subjects. Basal (postabsorptive) hyperinsulinemia was observed in the subjects with myotonic dystrophy (8.4 ± 2.0 v 2.3 ± 0.2 mU/L, P < .01) with increased basal C-peptide levels. Basal blood glycerol (0.09 ± 0.02 v 0.05 ± 0.01 mmol/L, P < .05), lactate (1.14 ± 0.12 v 0.77 ± 0.07 mmol/L, P < .02), and pyruvate (0.08 ± 0.01 v 0.05 ± 0.01 mmol/L, P < .02) were also elevated in these subjects. During the incremental insulin infusion, circulating insulin (F = 8.2, P < .02) and C-peptide (F = 5.1, P < .05) levels were significantly higher in the myotonic subjects. Despite the hyperinsulinemia, circulating concentrations of lactate (F = 9.8, P < .01), pyruvate (7.8, P < .02), and glycerol (F = 7.5, P < .02) were also higher in the subjects with myotonic dystrophy, providing prima facie evidence of insulin resistance in the regulation of these metabolites. During the highest insulin rate, isotopically determined metabolic clearance rate of glucose was significantly lower in the myotonic subjects (3.6 ± 0.4 v 5.5 ± 0.7 mL · kg −1 · min −1, P < .05), indicating impaired peripheral glucose metabolism. ANOVA confirmed parallel, linear dose-response relationships ( P < .005) for plasma insulin (log) and glucose, glycerol, nonesterified fatty acids (NEFA), and total ketone bodies (TKB). For glucose ( P < .001), glycerol ( P < .001), and NEFA ( P < .001), the group regression lines for the subjects with myotonic dystrophy lay parallel to those for the control subjects, but with a significant rightward displacement indicative of insulin resistance. No significant displacement was observed between the group regression lines for TKB. These results indicate that myotonic dystrophy is characterized by insulin resistance in the regulation of multiple aspects of carbohydrate metabolism (glucose, lactate, and pyruvate) and lipolysis (NEFA and glycerol).