Showing papers by "Mark Walker published in 1993"

Acipimox increases glucose disposal in normal man independent of changes in plasma nonesterified fatty acid concentration and whole-body lipid oxidation rate

Abstract: The short-term administration of a nicotinic acid analogue (acipimox) increases insulin sensitivity and consequently glucose disposal, both in patients with non-insulin-dependent diabetes mellitus (NIDDM) and in patients with cirrhosis. This effect has been attributed to a decrease in plasma nonesterified fatty acid (NEFA) levels and fatty acid oxidation rates, and a corresponding increase in carbohydrate oxidation. The aim of the present study was to determine whether acipimox influenced glucose disposal independent of changes in lipid metabolism. Seven normal men (age, 31 ± 4 years; body mass index, 23.2 ± 1.8 kg · m−2; fat-free mass [FFM], 66.8 ± 4.2 kg) were studied on two separate occasions with hyperinsulinemic (0.06 U · kg FFM−1 · h−1) euglycemic clamps (duration, 150 minutes). A primed (150 U), continuous (0.4 U · kg−1 · min−1) infusion of heparin together with 10% intralipid (25 mL · h−1) was infused in both studies from −90 to 150 minutes to maintain comparable levels of plasma NEFA and lipid oxidation rates. Acipimox (500-mg capsules) or placebo were administered orally in a double-blind random fashion at t = −90 and t = 0 minutes. Whole-body lipid and carbohydrate oxidation were measured in the last 30 minutes of both the basal (preclamp) period (−30 to 0 minutes) and the clamp period (120 to 150 minutes). Mean plasma NEFA concentrations were similar throughout both studies (−90 to 0 minutes, 0.84 ± 0.08 v 0.85 ± 0.11 mmol · L−1; 30 to 60 minutes, 0.58 ± 0.03 v 0.58 ± 0.03 mmol · L−1; 120 to 150 minutes, 0.48 ± 0.05 v 0.51 ± 0.11 mmol · L−1; all NS), as were whole-body lipid oxidation rates (−30 to 0 minutes acipimox v placebo 0.71 ± 0.11 v 0.69 ± 0.07 mg · kg FFM−1 · min−1, NS; 120 to 150 minutes, 0.17 ± 0.08 v 0.21 ± 0.07 mg · kg FFM−1 · min−1, NS). Steady-state mean blood glucose levels were the same (120 to 150 minutes, 4.3 ± 0.2 v 4.3 ± 0.1 mmol · L−1). Despite this, there was a significant increase in glucose disposal following acipimox treatment (9.00 ± 0.8 v 7.96 ± 0.8 mg · kg FFM−1 · min−1, P < .01), which could be attributed to a significant increase in nonoxidative glucose disposal (5.36 ± 0.81 v 4.36 ± 0.64 mg · kg FFM−1 · min−1, P = .01). These data suggest that acipimox has a direct (pharmacological) effect on glucose disposal that is not mediated through changes in plasma NEFA concentrations or total-body lipid oxidation rates.

Peripheral and hepatic insulin sensitivity in non-insulin-dependent diabetes mellitus: Effect of nonesterified fatty acids☆

Abstract: Plasma nonesterified fatty acid (NEFA) levels are increased in the insulin-stimulated state in non-insulin-dependent diabetes mellitus (NIDDM) and may contribute to the decrease in peripheral and hepatic insulin sensitivity. To test this hypothesis and to avoid the confounding effect of obesity, we examined the effect of decreasing plasma NEFA levels on peripheral and total glucose metabolism in eight non-obese, NIDDM patients. Each received 250 mg Acipimox (a nicotinic acid analogue) or placebo at 0 and 120 minutes on separate occasions. [6,6-2H2]-glucose (0 to 300 minutes) and insulin (120 to 300 minutes) were infused in each study, and isoglycemia was maintained. Plasma NEFA levels (140 +/- 30 v 600 +/- 70 mumol/L [SEM]; P < .001) and forearm NEFA uptake measured with [1-14C]-palmitate (+93 +/- 21 v +313 +/- 42 nmol x 100 mL forearm-1; P < .001) were decreased with acipimox during the basal period (90 to 120 minutes), with no change in forearm glucose uptake (+334 +/- 80 and +330 +/- 60 nmol x 100 mL forearm-1 x min-1) and hepatic glucose output ([HGO] 13.6 +/- 0.9 and 13.4 +/- 0.7 mumol.kg-1 x min-1). Serum insulin (256 +/- 12 and 266 +/- 18 pmol/L) and plasma glucose (9.5 +/- 0.6 and 9.4 +/- 0.5 mmol/L) levels were comparable during the clamp period (270 to 300 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)

Erythrocyte sodium-lithium countertransport activity and total body insulin-mediated glucose disposal in normoalbuminuric normotensive Type 1 (insulin-dependent) diabetic patients

Abstract: Insulin resistance in Type 1 (insulin-dependent) diabetes mellitus may be associated with raised erythrocyte sodium-lithium countertransport activity in patients with hypertension, or nephropathy, or both. However, in these circumstances it is difficult to separate the impact of hypertension, hyperlipidaemia and nephropathy on erythrocyte sodium-lithium countertransport from that of insulin resistance. We have therefore examined the relationship between insulin-mediated glucose disposal and erythrocyte sodiumlithium countertransport in 41 normotensive (mean blood pressure 120/74 mm Hg), normoalbuminuric (mean albumin excretion 6.2 μg/min), normolipidaemic (mean serum cholesterol 4.3 mmol/l and mean serum triglycerides 1.0 mmol/l) Type 1 diabetic patients. Erythrocyte sodium-lithium countertransport was on average 0.31 mmol Li · h−1 · l erythrocytes −1 (range 0.07–0.69). Nine patients had values above 0.40 mmol Li · h−1 erythrocytes−1 (0.51±0.10 mmol Li · h−1 · l erythrocytes−1). The patients with high erythrocyte sodium-lithium countertransport were matched for age, sex, BMI, HbA1 and duration of diabetes, with nine patients with normal erythrocyte sodium-lithium countertransport. Insulin-mediated glucose disposal was evaluated during the last hour of a euglycaemic clamp (insulin 0.015 U · kg−1 · h−1; blood glucose clamped at 7.0 mmol/l). The free insulin levels were comparable between the patients with high and normal erythrocyte sodium-lithium countertransport (37.2±14.7 mU/l and 34.7±17.2 mU/l respectively). Insulin-mediated glucose disposal was on average 3.1±1.5 (range 0.8–6.8) mg · kg−1 · min−1. Erythrocyte sodium-lithium countertransport did not correlate with insulin-mediated glucose disposal in all 41 cases (rs=−0.14), but when the matched groups were compared, patients with raised erythrocyte sodium-lithium countertransport had lower insulin-mediated glucose disposal rates compared to those with normal erythrocyte sodium-lithium countertransport (2.7±1.1 vs 3.9±1.3 mg · kg−1 · min−1; p=0.044). In these 18 patients a significant inverse relationship was found between erythrocyte sodium-lithium countertransport and insulin-mediated glucose disposal (rs=−0.62; p=0.003). Raised erythrocyte sodium-lithium countertransport appears to be associated with insulin insensitivity in Type 1 diabetes, even in the absence of hyperlipidaemia, hypertension and nephropathy.

Decreased plasminogen activator inhibitor-1 activity in newly diagnosed type 2 diabetic patients following dietary modification.

Abstract: Increased plasminogen activator inhibitor-1 (PAI-1) activity has been reported in Type 2 (non-insulin-dependent) diabetes and is a recognized risk factor for coronary artery disease. Fourteen newly diagnosed Type 2 diabetic patients were studied before and 3 months after standard clinical dietary modification. To assess the effect of improved metabolic control on PAI-1 activity, nine Type 2 diabetic patients established on diet therapy and with previous stable glycaemic control served as controls. In the newly diagnosed patients diet therapy resulted in a significant decrease in HbA1c levels (8.3 ± 0.5 vs 5.2 ± 0.3 % (mean ± SEM); p < 0.001), and this was accompanied by a fall in fibrinogen (4.3 ± 0.3 vs 3.0 ± 0.2 g.1−1; p < 0.01) concentration, and PAI-1 (18.7 ± 2.3 vs 12.2 ± 0.9 arbitrary units ml−1; p < 0.02) and factor VIII (147 ± 17 vs 115 ± 13 %; p < 0.01) activities. PAI-1 activity was correlated with triglyceride levels at the first assessment in the newly diagnosed patients (r = 0.66; p < 0.01), and this was the only independent association by multiple regression analysis when all patients (n = 23) were considered (r = 0.62; p < 0.002). However, there was no association between the changes in PAI-1 activity and the changes in HbA1c BMI, and serum triglyceride levels following treatment in the newly diagnosed patients. Serum triglyceride concentrations, HBA1c, PAI-1 activity, and the coagulation factors remained unchanged in the control group over the same treatment period. In conclusion, the introduction of conventional diet therapy in newly diagnosed Type 2 diabetic patients was accompanied by a significant improvement in circulating PAI-1 activity, but this could not be related to changes in the common indices of metabolic control.

Do nonesterified fatty acids regulate skeletal muscle protein turnover in humans

Abstract: We examined whether elevated plasma nonesterified fatty acid (NEFA) levels exert a direct effect on protein metabolism by measuring [2H5]phenylalanine skeletal muscle exchange and whole body turnov...

The role of plasma non-esterified fatty acids during exercise in type 2 diabetes mellitus.

Abstract: Elevated fasting plasma non-esterified fatty acid (NEFA) levels have been reported in Type 2 diabetes. We examined whether such changes persist during low-grade exercise and influence carbohydrate metabolism. Eight Type 2 diabetic patients with moderate glycaemic control and eight healthy controls received the anti-lipolytic agent, acipimox, or placebo on separate occasions before exercising for 45 min at 35 % pre-determined Vo2max. Fasting plasma NEFA levels were similar (0.40 ± 0.06 (SEM) and 0.45 ± 0.05 mmol l−1; healthy and Type 2 diabetic subjects) following placebo, and increased to comparable levels with exercise (0.73 ± 0.07 and 0.73 ± 0.10 mmol l−1). Acipimox lowered basal NEFA levels (0.14 ± 0.03 and 0.28 ± 0.04 mmol I−1; both p < 0.05 vs placebo), and prevented the rise with exercise. Blood glucose (p < 0.001) and serum insulin (p < 0.01) levels were higher in the Type 2 diabetic patients (vs controls) for both treatments. Whole body lipid oxidation increased from baseline to a comparable degree with exercise following placebo (3.2 ± 0.3 and 2.8 ± 0.3 mg kg−1 min−1; healthy and Type 2 diabetic subjects, both p < 0.02). Although less marked, the same was also observed following acipimox (2.0 ± 0.4 and 2.1 ± 0.5 mg kg−1 min−1; both p < 0.05). Carbohydrate oxidation increased with exercise in both subject groups, but with no significant difference between the treatments. Thus, the metabolic response to low-grade exercise was normal in Type 2 diabetic patients with moderate glycaemic control, but occurred against a background of hyperinsulinaemia. Plasma NEFA do not exert a major regulatory effect on carbohydrate metabolism during low-grade exercise.