Benfluorex and blood glucose control in non insulin-dependent diabetic patients

Benfluorex has been reported to decrease blood glucose in different dismetabolic conditions, particularly in noninsulin-dependent diabetic (NIDD) patients, but the mechanism of this effect is poorly known. We evaluate fasting glucose production (3H-glucose infusion) and B-cell secretion (phi 1, phi 2 and glucose utilization SI) (minimal model technique) in 7 mild, diet treated, NIDDM patients after 6-week administration of benfluorex (450 mg/day) and placebo, in random sequence and double blind design. Body weight, HbA1c, plasma glucose profile, fasting plasma insulin, lactate, pyruvate, beta-OH-butyrate, total cholesterol, HDL-cholesterol and triglycerides were also measured at the end of each treatment. Mean values of body weight (71 +/- 4 vs 69 +/- 4 kg, p less than 0.01), HbA1c (8.3 +/- 0.2 vs 7.7 +/- 0.2%, p less than 0.01), fasting plasma glucose (137.0 +/- 6.5 vs 121.4 +/- 5.6 mg/dl, p less than 0.01), lactate (1.82 +/- 0.13 vs 1.22 +/- 0.11 mmol/l, p less than 0.0025) pyruvate (0.164 +/- 0.011 vs 0.095 +/- 0.010 mmol/l, p less than 0.0005), and beta-OH-butyrate (0.91 +/- 0.06 vs 0.66 +/- 0.04 mmol/l, p less than 0.005) were significantly lower after benfluorex than after placebo. phi 1, phi 2 and SI values were not significantly different in the two treatments. Fasting glucose production was significantly lower after benfluorex than after placebo: 2.46 +/- 1.57 vs 1.84 +/- 0.85 mg/kg.min, p less than 0.02. These results demonstrate that 6-week treatment with benfluorex produces a significant blood glucose lowering effect in mild NIDDM patients, mainly by decreasing glucose production.     

Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes

Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study. Metformin 0.5 g trice daily or placebo were given for 4 weeks. At the end of each period fasting and day-time postprandial values of plasma glucose, insulin, C-peptide and lactate were determined, and in vivo insulin action was assessed using the euglycemic clamp in combination with [3-3H]glucose tracer technique. Metformin treatment significantly reduced mean day-time plasma glucose levels (10.2 +/- 1.2 vs 11.4 +/- 1.2 mmol/l, P less than 0.01) without enhancing mean day-time plasma insulin (43 +/- 4 vs 50 +/- 7 mU/l, NS) or C-peptide levels (1.26 +/- 0.12 vs 1.38 +/- 0.18 nmol/l, NS). Fasting plasma lactate was unchanged (1.57 +/- 0.16 vs 1.44 +/- 0.11 mmol/l, NS), whereas mean day-time plasma lactate concentrations were slightly increased (1.78 +/- 0.11 vs 1.38 +/- 0.11 mmol/l, P less than 0.01). The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization (370 +/- 38 vs 313 +/- 33 mg.m-2.min-1, P less than 0.01), whereas insulin-mediated suppression of hepatic glucose production was unchanged. Also basal glucose clearance was improved (61.0 +/- 5.8 vs 50.6 +/- 2.8 ml.m-2.min-1, P less than 0.05), whereas basal hepatic glucose production was unchanged (81 +/- 6 vs 77 +/- 4 mg.m-2.min-1, NS). Conclusions: 1) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of physiologic and supraphysiologic hyperglycemia on early and late-phase insulin secretion in chronically dialyzed uremic patients

To test secretory capacity of the beta-cell to a glucose stimulus in uremic patients on chronic dialysis, three hyperglycemic clamps (plasma glucose increments: 1, 4.5 and 11 mmol/l) were performed in 8 uremic and 8 healthy subjects. Early-phase insulin and C-peptide responses (delta I and delta C) during the initial 6 min were consistently exaggerated at all three steps in uremic patients compared with controls (delta I. 16 +/- 4 vs 4 +/- 2, 41 +/- 11 vs 15 +/- 4 and 60 +/- 12 vs 24 +/- 5 mU/l; delta C. 0.39 +/- 0.13 vs 0.07 +/- 0.02, 0.40 +/- 0.13 vs 0.16 +/- 0.02 and 0.73 +/- 0.15 vs 0.29 +/- 0.04 nmol/l, p less than 0.05 in all cases). Similarly, late-phase insulin secretion defined as the insulin increment between 90 and 120 min after initiation of the glucose challenge was enhanced in uremic patients at the two highest glycemic steps (44 +/- 10 vs 16 +/- 2 and 123 +/- 29 vs 44 +/- 5 mU/l, both p less than 0.01). The raised late-phase insulin response allowed comparable glucose disposal in the two groups (uremic patients: 9.2 +/- 1.0 and 15.5 +/- 1.6 mg.kg-1.min-1. Controls: 9.0 +/- 1.3 and 19.9 +/- 2.4 mg.kg-1.min-1). The slopes of potentiation, i.e. the slopes of the regression lines expressing the relationship between changes in insulin increments and changes in glucose, were markedly steeper in uremic patients (0.45 +/- 0.09 and 0.66 +/- 0.20, early and late-phase respectively) than in controls (0.20 +/- 0.06 and 0.25 +/- 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)     

Time-dependent effect of hyperglycemia and hyperinsulinemia on oxidative and non-oxidative glucose metabolism in patients with NIDDM.

The present study was undertaken to compare the effect of hyperglycemia and euglycemia during identical hyperinsulinemic conditions on glucose metabolism in NIDDM subjects. Eight NIDDM subjects participated in a 4 h hyperglycemic (12.1 +/- 0.7 mmol/l), hyperinsulinemic (475 +/- 43 pmol/l) and in a 4 h euglycemic (5.5 +/- 0.5 mmol/l), hyperinsulinemic (468 +/- 36 pmol/l) insulin clamp in combination with indirect calorimetry and [3H]-3-glucose. Six non-diabetic subjects were studied during euglycemia (5.1 +/- 0.2 mmol/l) and hyperinsulinemia (474 +/- 35 pmol/l) and served as controls. In NIDDM patients the rate of insulin-stimulated glucose disposal was 57% greater during hyperglycemia compared with euglycemia throughout the 4 h clamp (p less than 0.01). The major part of the increase in glucose metabolism during hyperglycemia was due to an increase in the non-oxidative glucose metabolism (89%). Whereas glucose metabolism could not be normalized during the prolonged euglycemic hyperinsulinemic clamp in NIDDM patients (49.9 +/- 6.8 vs 57.5 +/- 5.4 mumol.(kgLBM)-1.min-1 in controls) the addition of hyperglycemia resulted in complete normalization of the glucose disposal rates (78.3 +/- 5.8 mumol.(kgLBM)-1.min-1). The effect of hyperglycemia was apparent already at 60 min of the clamp. The data thus suggest that glucose metabolism in NIDDM is insulin resistant, but that the defect in insulin-stimulated glucose uptake can be overcome by increasing the glucose concentration.     

Insulin resistance, but normal basal rates of glucose production in patients with newly diagnosed mild diabetes mellitus

Fasting hyperglycemia in Type II (non-insulin-dependent) diabetes has been suggested to be due to hepatic overproduction of glucose and reduced glucose clearance. We studied 22 patients (10 lean and 12 obese) with newly diagnosed mild diabetes mellitus (fasting plasma glucose less than 15 mmol/l, urine ketone bodies less than 1 mmol/l), and two age- and weight-matched groups of non-diabetic control subjects. Glucose turnover rates and sensitivity to insulin were determined using adjusted primed-continuous [3-3H]glucose infusion and the hyperinsulinemic euglycemic clamp technique. Insulin-stimulated glucose utilization was reduced in both diabetic groups (lean patients: 313 +/- 35 vs 531 +/- 22 mg.m-2.min-1, p less than 0.01; obese patients: 311 +/- 28 vs 453 +/- 26 mg.m-2.min-1, p less than 0.01). Basal plasma glucose concentrations decreased 0.43 +/- 0.05 mmol/l per h (p less than 0.01). Glucose production rates were smaller than glucose utilization rates (lean patients: 87 +/- 3 vs 94 +/- 3 mg.m-2.min-1, p less than 0.01; obese patients: 79 +/- 5 vs 88 +/- 5 mg.m-2.min-1, p less than 0.01), were not correlated to basal glucose or insulin concentrations, and were not different from normal (lean controls: 87 +/- 4 mg.m-2.min-1; obese controls: 80 +/- 5 mg.m-2.min-1). These results suggest that the basal state in the diabetic patients is a compensated condition where glucose turnover rates are maintained near normal despite defects in insulin sensitivity.     

How Does Glibenclamide Lower Plasma Glucose Concentration in Patients with Type 2 Diabetes?

Twelve patients with Type 2 diabetes and uncontrolled hyperglycaemia, never before treated with anti-diabetic drugs, were studied before and after several months of glibenclamide therapy. Fasting plasma glucose fell significantly (p less than 0.01) from 12.5 +/- 1.1 (mean +/- SE) to 8.3 +/- 0.4 mmol l-1 with glibenclamide therapy, as did glycosylated haemoglobin (from 12.0 +/- 0.9 to 8.4 +/- 0.7%). The improvement in blood glucose control was accompanied by an increase in postprandial plasma insulin concentration measured hourly from 0800 to 1600 h (p less than 0.001). Over the same period, plasma NEFA and lactate levels were significantly (p less than 0.001) lower after treatment with glibenclamide. Mean (+/- SE) insulin-mediated glucose metabolic clearance rate was evaluated during glucose clamp studies, and was significantly higher (p less than 0.001) after glibenclamide therapy at steady-state insulin levels of approximately 10 mU l-1 (53 +/- 3 vs 38 +/- 2 ml-2 min-1) and approximately 70 mU l-1 (78 +/- 9 vs 55 +/- 6 ml m-2 min-1). Hepatic glucose production was also lower following glibenclamide treatment at both the lower (56 +/- 5 vs 68 +/- 5 mg m-2 min-1) and higher 22 +/- 4 vs 32 +/- 6 mg m-2 min-1) insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sulfonylureas in insulin-dependent (type I) diabetes: evidence for an extrapancreatic effect in vivo

The effect of glibenclamide treatment on insulin-mediated glucose disposal was studied in eight C-peptide-negative type I diabetic patients. The patients were studied twice by the euglycemic insulin clamp technique. One of the two experiments was preceded by glibenclamide treatment at the dose of 5 mg, three times daily for 15 days; half of the patients had the first test before and the second test after sulfonylurea treatment, and vice versa. Insulin was infused for four periods of 2 h each sequentially at 0.5, 1.0, 2.0, and 5.0 mU kg-1 min-1; for each insulin infusion period, the steady state plasma free insulin levels were comparable with or without glibenclamide. The mean +/- SEM plasma glucose concentration was 88 +/- 2 mg/dl in both experiments. The insulin-mediated glucose disposal rate was greater with glibenclamide during the first insulin infusion period (which generated plasma free insulin levels within the physiological range) 2.68 +/- 0.32 mg kg-1 min-1 with glibenclamide vs. 1.97 +/- 0.20 mg kg-1 min-1 without glibenclamide (P less than 0.005). However, glucose disposal rates did not differ in the diabetic patients with or without glibenclamide treatment during the second, third, and fourth insulin infusion periods, which generated plasma free insulin levels in the supraphysiological range. These results provide evidence for an extrapancreatic effect of glibenclamide at low insulin concentrations during euglycemic clamping in patients with insulin-dependent diabetes mellitus. However, this effect was not reflected clinically in either an increased rate of hypoglycemic reactions or decreased insulin needs during the short term period of treatment.     

Lack of effects of angiotensin-converting enzyme (ACE)-inhibitors on glucose metabolism in type 1 diabetes

To evaluate the impact of ACE-inhibitors on insulin-mediated glucose uptake, glucose-induced glucose uptake, and hepatic glucose production, a sequential glucose clamp was performed in eight normotensive Type 1 diabetic patients after 3 weeks of enalapril therapy 20 mg day-1 and during control conditions. The experiments were carried out in random order. Mean arterial blood pressure was significantly reduced during ACE-inhibition (95 +/- 3 (+/- SE) vs 84 +/- 3 mmHg; p less than 0.02), while blood glucose control as assessed by HbA1c was unaltered (7.9 +/- 0.5 vs 7.6 +/- 0.5%). The night prior to the study normoglycaemia was maintained by a Biostator. A two-step hyperinsulinaemic euglycaemic clamp (insulin infusion rate 0.3 and 0.8 mU kg-1 min-1) was followed by a hyperinsulinaemic and hyperglycaemic clamp (insulin infusion rate 0.8 mU kg-1 min-1, plasma glucose 11 mmol l-1). Insulin concentrations were comparable with and without enalapril treatment. During the hyperinsulinaemic clamps isotopically determined glucose disposal was unchanged (low dose 2.5 +/- 0.3, high dose 4.3 +/- 0.7 vs 2.6 +/- 0.3 and 4.3 +/- 0.7 mg kg-1 min-1, enalapril vs control). Glucose-induced glucose disposal (9.2 +/- 1.2 vs 9.1 +/- 1.2 mg kg-1 min-1) was also similar, as were non-protein respiratory exchange ratios (indirect calorimetry). Glucose production was not changed by enalapril. In conclusion, treatment with enalapril has no significant effect on glucose metabolism in Type 1 diabetes.     

Inhibition of the rise in FFA by Acipimox partially prevents GH-induced insulin resistance in GH-deficient adults.

To test the hypothesis that GH-induced insulin resistance is mediated by an increase in FFA levels we assessed insulin sensitivity after inhibiting the increase in FFA by a nicotine acid derivative, Acipimox, in nine GH-deficient adults receiving GH replacement therapy. The patients received in a double blind fashion either Acipimox (500 mg) or placebo before a 2-h euglycemic (plasma glucose, 5.5 +/- 0.2 mmol/liter) hyperinsulinemic (serum insulin, 28.7 +/- 6.3 mU/liter) clamp in combination with indirect calorimetry and infusion of [3-(3)H]glucose. Acipimox decreased fasting FFA by 88% (P = 0.012) and basal lipid oxidation by 39% (P = 0.015) compared with placebo. In addition, the insulin-stimulated lipid oxidation was 31% (P = 0.0077) lower during Acipimox than during placebo. Acipimox increased insulin-stimulated total glucose uptake by 36% (P = 0.021) compared with placebo, which mainly was due to a 47% (P = 0.015) increase in glucose oxidation. GH induced insulin resistance is partially prevented by inhibition of lipolysis by Acipimox.     

Does overnight normalization of plasma glucose by insulin infusion affect assessment of glucose metabolism in Type 2 diabetes?

AIMS: In order to perform euglycaemic clamp studies in Type 2 diabetic patients, plasma glucose must be reduced to normal levels. This can be done either (i) acutely during the clamp study using high-dose insulin infusion, or (ii) slowly overnight preceding the clamp study using a low-dose insulin infusion. We assessed whether the choice of either of these methods to obtain euglycaemia biases subsequent assessment of glucose metabolism and insulin action. METHODS: We studied seven obese Type 2 diabetic patients twice: once with (+ ON) and once without (- ON) prior overnight insulin infusion. Glucose turnover rates were quantified by adjusted primed-constant 3-3H-glucose infusions, and insulin action was assessed in 4-h euglycaemic, hyperinsulinaemic (40 mU m-2 min-1) clamp studies using labelled glucose infusates (Hot-GINF). RESULTS: Basal plasma glucose levels (mean +/- sd) were 5.5 +/- 0.5 and 10.7 +/- 2.9 mmol/l in the + ON and - ON studies, respectively, and were clamped at -5.5 mmol/l. Basal rates of glucose production (GP) were similar in the + ON and - ON studies, 83 +/- 13 vs. 85 +/- 14 mg m-2 min-1 (NS), whereas basal rates of glucose disappearance (Rd) were lower in the + ON than in the - ON study, 84 +/- 8 vs. 91 +/- 11 mg m-2 min-1 (P = 0.02). During insulin infusion in the clamp period, rates of GP, 23 +/- 11 vs. 25 +/- 10 mg m-2 min-1, as well as rates of Rd, 133 +/- 32 vs. 139 +/- 37 mg m-2 min-1, were similar in the + ON and - ON studies, respectively (NS). CONCLUSIONS: Apart from basal rates of Rd, assessment of glucose turnover rates in euglycaemic clamp studies of Type 2 diabetic patients is not dependent on the method by which plasma glucose levels are lowered.     

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 less than .001) and remained elevated throughout infusion (F = 492, P less than .001), as did C-peptide (F = 22.7, P less than .001). Metabolic clearance rate for insulin (MCRI) 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 mumol.m-2.min-1, P less than .01), as was the basal metabolic clearance rate for glucose (MCRG, 77 +/- 26 v 108 +/- 31 mL.m-2.min-1, P less than .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 less than .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 less than .01). Concentrations of nonesterified fatty acids (NEFA), glycerol, and ketones were elevated throughout the insulin infusions in obese patients, despite the higher insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

A double blind study of the effect of acipimox on serum lipids, blood glucose control and insulin action in non-obese patients with type 2 diabetes mellitus.

Hyperlipidaemia, in particular raised concentrations of serum triglycerides, together with raised plasma non-esterified fatty acid concentrations, is common in patients with Type 2 (non-insulin-dependent) diabetes mellitus and may be associated with insulin insensitivity. Thirty non-obese Type 2 diabetic patients (15 controlled with diet alone and 15 with diet plus oral sulphonylurea therapy) were therefore recruited to take part in a double-blind, randomized, crossover comparison of acipimox (250 mg three times daily for 3 months) and placebo. Serum lipids, blood glucose control, insulin sensitivity, and glucose tolerance were measured before and after each treatment period. There was a significant decrease in serum triglycerides (2.05 +/- 1.08 vs 2.91 +/- 1.75: p < 0.005), cholesterol (5.66 +/- 1.02 vs 6.26 +/- 1.17: p = 0.0005), and apoprotein B (1.32 +/- 0.23 vs 1.44 +/- 0.25: p < 0.05) while HDL cholesterol and apoprotein A-1 concentrations were unchanged. There was no change in blood glucose control measured by fasting glucose, insulin, and HBA, concentrations, but there was a significant improvement in insulin action assessed by glucose-insulin infusion. Although plasma non-esterified fatty acid concentrations were lower during the oral glucose tolerance test after acipimox, there was no difference in either the peak or 2-h plasma glucose concentrations and the total area under the glucose curve did not change. Acipimox was well tolerated and no patients withdrew from the study for drug-related symptoms. Thus, acipimox effectively lowers serum cholesterol and triglycerides in patients with Type 2 diabetes without adversely altering blood glucose control, and appears to improve insulin sensitivity.     

Effects of growth hormone on insulin sensitivity and forearm metabolism in normal man

To elucidate the short-term actions of growth hormone on insulin sensitivity and forearm metabolism, we have studied six normal male subjects receiving a 6-h hyperinsulinaemic euglycemic clamp with and without a concomitant 4-h growth hormone infusion. When infused, serum growth hormone rose to 25 +/- 4 mU/l and during administration of insulin serum insulin increased by 11 +/- 1 mU/l. During euglycemic clamp, administration of growth hormone decreased forearm glucose uptake after 180 min and onward (240 min 0.216 +/- 0.031 vs 0.530 +/- 0.090 mg/100 ml/min, p less than 0.05). Glucose infusion rate (240 min 2.83 +/- 0.24 vs 4.35 +/- 0.28 mg.kg-1.min-1, p less than 0.05) and glucose disposal rate (240 min 3.57 +/- 0.17 vs 4.00 +/- 0.15 mg.kg-1.min-1, p less than 0.05) also decreased. Growth hormone persistently increased hepatic glucose production after 120 min. After 210 min, all circulating lipid intermediates increased slightly. The decrease in forearm glucose uptake and glucose infusion rate and the increase in hepatic glucose production was observed before there was any detectable increase in circulating levels and forearm uptake of lipid intermediates. These data suggest that growth hormone induces insensitivity to insulin in liver, muscle and fat after 120, 180 and 210 min respectively. The early effects of growth hormone on glucose metabolism seems independent of changes in the rate of lipolysis.     

Effects of metformin on glucose, insulin and lipid metabolism in patients with mild hypertriglyceridaemia and non-insulin dependent diabetes by glucose tolerance test criteria.

The effect of metformin treatment was studied in nine patients with mild (fasting plasma glucose concentration less than 7.5 mmol.l-1) non-insulin-dependent diabetes mellitus (NIDDM) and fasting plasma triglyceride (TG) concentration greater than 2.0 mmol.l-1. Individuals were studied before and three months after receiving 2.5 g/day of metformin. Mean hourly plasma glucose concentration from 8 AM to 4 PM (7.5 +/- 0.5 vs 6.5 +/- 0.4 mmol.l-1, p less than 0.001), as well as glycosylated hemoglobin levels (7.0 +/- 0.5 vs 6.2 +/- 0.2%, p less than 0.02) were significantly lower following metformin treatment. The improvement in glycaemic control was not associated with an improvement in insulin stimulated glucose disposal as measured by the glucose clamp technique. Mean hourly day-long concentrations of plasma insulin (519 +/- 81 vs 364 +/- 64 pmol.l-1, p less than 0.001), FFA (502 +/- 45 vs 460 +/- 35 mu mol.l-1, p less than 0.01), and triglyceride (3.60 +/- 0.33 vs 3.02 +/- 0.31 mmol.l-1, p less than 0.001) concentrations were significantly lower following three months of metformin treatment. Finally, fasting plasma TG concentration, very low density lipoprotein (VLDL)-TG, and VLDL-cholesterol concentrations were significantly decreased, while high density lipoprotein (HDL)-cholesterol concentration was significantly increased following metformin therapy. Thus, metformin administration to individuals with NIDDM, who did not have significant fasting hyperglycaemia, led to a decrease in plasma glucose, insulin, FFA, and TG concentration, and an increase in plasma HDL-cholesterol concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Assessment of glucose turnover rates in euglycaemic clamp studies using primed-constant [3-3H]-glucose infusion and labelled or unlabelled glucose infusates.

Underestimation of glucose turnover rates has been a problem in clamp studies using primed-constant [3-3H]-glucose infusion technique. Due to slow mixing in interstitial compartments concealed specific activity gradients may arise between plasma and interstitial compartments during intravenous unlabelled glucose infusion. Such specific activity gradients, however, can be prevented if plasma specific activity is maintained constant. Two euglycaemic clamp studies (insulin infusion 40 mU m-2 min-1) were performed in six lean normal subjects. Using conventional unlabelled glucose infusates plasma specific activity declined by 74%, tracer determined glucose appearance was smaller than actual glucose infusion rates (317 +/- 11 vs 366 +/- 15 mg m-2 min-1, p < 0.001), and erroneous negative values were calculated for glucose production (- 49 +/- 7 mg m-2 min-1). Average underestimation during the first 2 h correlated with glucose infusion rates (r = 0.88, p < 0.02). In contrast, when plasma specific activity was maintained constant, using appropriately labelled glucose infusates, tracer determined glucose appearance and glucose infusion rates were similar (385 +/- 16 vs 385 +/- 17 mg m-2 min-1), and negative errors for glucose production were avoided. In conclusion, using unlabelled glucose infusates, as in previous studies, suppression of glucose production is overestimated and stimulation of glucose utilization is underestimated. As errors were greater with larger glucose infusions, the mistakes may have been greatest in insulin sensitive control subjects, and smaller in insulin resistant subjects. Therefore, re-evaluation of hepatic insulin sensitivity seems appropriate in diabetes, obesity, and other insulin resistant states.     

How insulin resistant are patients with noninsulin-dependent diabetes mellitus?

The study was carried out to quantify the ability of physiological increases in the plasma insulin concentration to stimulate glucose disposal above basal levels in 25 normal subjects and 25 patients with noninsulin-dependent diabetes mellitus (NIDDM). Patients were sex, age, and weight matched, and glucose disposal was determined under basal conditions (plasma insulin, approximately 10 microU/ml) and after plasma insulin levels had been increased to approximately 90 microU/ml. The mean (+/- SEM) glucose disposal rate was significantly greater (P less than 0.001) under basal conditions in patients with NIDDM (110 +/- 5 mg/m2 X min) than in individuals with normal glucose tolerance (77 +/- 4 mg/m2 X min). Glucose disposal rates increased in both normal subjects and NIDDM patients when plasma insulin concentrations were increased to about 90 microU/ml; however, the increment was much greater in normal subjects. Thus, glucose disposal only rose to a mean (+/- SEM) value of 145 +/- 7 mg/m2 X min in patients with NIDDM, representing an approximate 30% increase due to insulin. In contrast, a similar elevation of plasma insulin in normal subjects resulted in an increase in glucose disposal of approximately 300%, reaching a mean (+/- SEM) value of 310 +/- 24 mg/m2 X min. These results indicate that the defect in insulin-stimulated glucose uptake is significantly greater in patients with NIDDM than has previously been found.     

Reversal of steroid-induced insulin resistance by a nicotinic-acid derivative in man.

A recent report suggested that the glucose-free fatty acid (FFA) cycle may contribute to steroid-induced insulin resistance in rats, and that glucose tolerance could be restored to normal when FFA levels were lowered with nicotinic acid. To test this hypothesis in man, we measured insulin sensitivity (by euglycemic insulin clamp in combination with indirect calorimetry and infusion of tritiated glucose) before and after short-term administration of a nicotinic-acid derivative (Acipimox) in 10 steroid-treated, kidney transplant patients with insulin resistance. Thirty-five healthy subjects served as controls. Six of them received Acipimox. Total body glucose metabolism was reduced in steroid-treated patients compared with control subjects (41.7 +/- 3.3 v 50.0 +/- 2.2 mumol/kg lean body mass [LBM].min, P less than .05). The reduction in insulin-stimulated glucose uptake was mainly due to an impairment in nonoxidative glucose metabolism (primarily glucose storage as glycogen) (18.3 +/- 2.8 v 27.2 +/- 2.2 mumol/kg LBM.min, P less than .01). Acipimox lowered basal FFA concentrations (from 672 +/- 63 to 114 +/- 11 mumol/L, P less than .05) and the rate of lipid oxidation measured in the basal state (1.5 +/- 0.2 to 0.6 +/- 0.1 mumol/kg LBM.min, P less than .01) and during the clamp (0.7 +/- 0.2 to 0.03 +/- 0.2 mumol/kg LBM.min, P less than .05). In addition, Acipimox administration normalized total glucose disposal (to 54.4 +/- 4.4 mumol/kg LBM.min), mainly due to enhanced nonoxidative glucose metabolism (to 28.9 +/- 3.9 mumol/kg LBM.min) in steroid-treated patients (both P less than .05 v before Acipimox).(ABSTRACT TRUNCATED AT 250 WORDS)     

No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients

Inhibition of tumor necrosis factor (TNF)-alpha results in a marked increase in insulin sensitivity in obese rodents. We investigated the influence of a TNF antagonist [Ro 45-2081, a recombinant fusion protein that consists of the soluble TNF-receptor (p55) linked to the Fc portion of human IgG1] on insulin sensitivity of patients with android obesity. Seven patients (five women and two men; mean +/- SD age, 41 +/- 4 yr; body mass index, 36.1 +/- 4.7 kg/m2; waist to hip ratio, 0.99 +/- 0.11) were studied (three patients with normal glucose tolerance and four patients with impaired glucose tolerance or mild diabetes; all were hyperinsulinemic). Each patient underwent two consecutive euglycemic hyperinsulinemic glucose-clamp tests: 48 h after injection of placebo and 48 h after a single i.v. injection of 50 mg Ro 45-2081. In both tests, steady-state plasma glucose and insulin levels were similar. Insulin-mediated glucose disposal (2.23 +/- 0.74 vs. 2.38 +/- 0.99 mg/kg(-1) x min(-1)) and glucose metabolic clearance rate (2.28 +/- 0.85 vs. 2.48 +/- 1.03 mL/kg(-1) x min(-1)) were similar after placebo and after the drug. Indirect calorimetry showed no difference in substrate oxidation rates between the two experimental conditions. In conclusion, under the conditions of this study, no improvement in insulin sensitivity was observed in obese insulin-resistant patients following a single i.v. administration of a recombinant TNF receptor: Fc fusion protein.     

Effects of the amylin analogue pramlintide on hepatic glucagon responses and intermediary metabolism in Type 1 diabetic subjects.

AIMS: Hepatic glycogen stores have been shown to be depleted, and glucagon stimulated hepatic glucose production reduced, in Type 1 diabetic subjects. Co-administration of amylin and insulin has been shown to replete hepatic glycogen stores in diabetic animal models. The aim of the present study was to investigate the effect of amylin replacement on hepatic glucagon responsiveness in humans. METHODS: Thirteen Type 1 diabetic men were studied in a double-blind, placebo-controlled, cross-over study after 4 weeks of subcutaneous pramlintide (30 microg q.i.d.) or placebo administration. Following an overnight fast, plasma glucose was kept above 5 mmol/l (baseline 210-240 min) with an insulin infusion rate of 0.25 mU x kg(-1) x min(-1). To control portal glucagon levels, somatostatin was infused at a rate of 200 microg/h. Basal growth hormone (2 ng x kg(-1) x min(-1)) and glucagon (0.7 ng x kg(-1) x min(-1)) were replaced. Glucagon infusion was increased to 2.1 ng x kg(-1) x min(-1) at 240-360 min (step 1) and to 4.2 ng x kg(-1) x min(-1) at 360-420 min (step 2). RESULTS: Baseline plasma glucose (5.59+/-0.16 vs. 5.67+/-0.25 mmol/l) and endogenous glucose production (EGP) (1.32+/-0.22 vs. 1.20+/-0.13 mg x kg(-1). min(-1)) were similar and the response to glucagon was unaffected by pramlintide (glucose: step 1; 6.01+/-0.31 vs. 5.94+/-0.38 mmol/l, step 2; 6.00+/-0.37 vs. 5.96+/-0.50 mmol/l, EGP: step 1; 1.91+/-0.18 vs. 1.83+/-0.15 mg x kg(-1) x min(-1), step 2; 2.08+/-0.17 vs. 1.96+/-0.16 ng x kg(-1) x min(-1), pramlintide vs. placebo). Glucose disposal rates were similar at baseline (2.44+/-0.13 vs. 2.28+/-0.09 mg x kg(-1) x min(-1), pramlintide vs. placebo) as well as during the glucagon challenge (P-values all > 0.2). CONCLUSIONS: Co-administration of pramlintide and insulin to Type 1 diabetic subjects for 4 weeks does not change the plasma glucose or endogenous glucose production response to a glucagon challenge, following an overnight fast. In addition, pramlintide administration does not appear to alter insulin-mediated glucose disposal.     

Acute changes in plasma non-esterified fatty acid concentration do not change hepatic glucose production in people with type 2 diabetes

The effect of changes in plasma non-esterified fatty acid concentration (NEFA) on plasma glucose concentration, hepatic glucose production (Ra), and glucose disposal (Rd) rates was determined in 14 patients with Type 2 diabetes. Seven patients had relatively mild fasting hyperglycaemia (less than 10.0 mmol l-1), whereas the remaining seven had relatively severe fasting hyperglycaemia (greater than 14.0 mmol l-1). Each patient was infused from 2000 to 0800 h with 3-3H-glucose on two occasions, with or without neutral fat emulsion and heparin (mild hyperglycaemia group), or with or without nicotinic acid (severe hyperglycaemia group). Plasma NEFA concentration increased from 0.33 +/- 0.06 (+/- SE) to 4.78 +/- 0.42 mmol l-1 in response to the lipid and heparin infusion, but plasma glucose concentration (7.8 +/- 0.7 vs 7.4 +/- 0.8 mmol l-1), Ra (0.44 +/- 0.02 vs 0.46 +/- 0.02 mmol m-2 min-1), and Rd (0.42 +/- 0.02 vs 0.46 +/- 0.02 mmol m-2 min-1) were unchanged. Nicotinic acid decreased plasma NEFA concentration from 0.54 +/- 0.15 to 0.23 +/- 0.08 mmol l-1, but plasma glucose (15.0 +/- 1.0 vs 15.5 +/- 1.4 mmol l-1), Ra (0.74 +/- 0.07 vs 0.68 +/- 0.07 mmol m-2 min-1), and Rd (0.73 +/- 0.07 vs 0.68 +/- 0.07 mmol m-2 min-1) were unchanged. The results indicate that acute changes in plasma NEFA concentration did not lead to any change in overnight glucose production or disposal rates.