Nocturnal and Postprandial Free Fatty Acid Kinetics in Normal and Type 2 Diabetic Subjects

Miles, John M.; Wooldridge, David; Grellner, Wayne J.; Windsor, Sheryl L.; Isley, William L.; Klein, Samuel; Harris, William S.

doi:10.2337/diabetes.52.3.675

Cited by 101 publications

(97 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accordingly, in the present study a tendency was observed for a less significant suppression of arterial palmitate concentration and systemic palmitate turnover rate in diabetic patients during the hyperinsulinaemic-euglycaemic clamp. This observation is also in agreement with the impaired postprandial suppression of systemic fatty acid turnover demonstrated in type 2 diabetic patients [26]. From the present study it is clear that the skeletal muscles of the leg more than those of the arm may play an important role in the reduced insulin sensitivity with regard to the systemic fatty acid turnover in type 2 diabetes, since no suppression was observed in palmitate uptake or release by the leg.…”

Section: Discussionsupporting

confidence: 92%

Heterogeneity in limb fatty acid kinetics in type 2 diabetes

et al. 2005

View full text Add to dashboard Cite

Aims/hypothesis: In order to test the hypothesis that disturbances in skeletal muscle fatty acid metabolism with type 2 diabetes are not equally present in the upper and lower limbs, we studied fatty acid kinetics simultaneously across the arm and leg of type 2 diabetic patients (n=6) and matched control subjects (n=7) for 5 h under baseline conditions and during a 4-h hyperinsulinaemiceuglycaemic clamp. Methods: Limb fatty acid kinetics was determined by means of continuous [U-13 C]palmitate infusion and measurement of arteriovenous differences. Results: The systemic palmitate rate of appearance was 3.6±0.4 and 2.7±0.3 μmol·kg lean body mass −1 ·min −1 and decreased during the clamp by 26% (p=0.04) and 43% (p<0.01) in the diabetic patients and in the control subjects respectively. At baseline, palmitate uptake across the arm was similar in the two groups, whereas leg palmitate uptake was lower than in the arm in the diabetic patients. During the clamp, palmitate uptake decreased in the arm (−48%, p=0.02) and the leg (−38%, p=0.04) of the control subjects, whereas it decreased in the arm (−30%, p=0.04) but not in the leg of the diabetic patients. Similarly, during the clamp palmitate release was substantially suppressed in the arm (−47%, p<0.01) and the leg of the control subjects (−45%, p<0.01), but only in the arm of the diabetic patients (−45%, p<0.01). Conclusions/interpretation: The present data indicate that type 2 diabetes is characterised by heterogeneity in the dysregulation of skeletal muscle fatty acid metabolism, with only the leg, but not the arm, showing an impairment of fatty acid kinetics at baseline and during a hyperinsulinaemic-euglycaemic clamp causing a physiological increase in insulin concentration.

show abstract

Section: Discussionsupporting

confidence: 92%

Heterogeneity in limb fatty acid kinetics in type 2 diabetes

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Previous studies suggested that thiazolidinediones lower NEFA concentrations in type 2 diabetes via improved insulin suppression of lipolysis [17][18][19][20]. In the current study of non-diabetic adults with upper body obesity we did not find greater insulin suppression of lipolysis.…”

Section: Discussioncontrasting

confidence: 36%

“…Examples include diet/exercise and thiazolidinediones [16]. Thiazolidinediones, peroxisome proliferator-activated receptor-γ agonists, have been reported to enhance the insulin suppression of lipolysis in type 2 diabetes [17][18][19][20]; this could account for the improved insulin regulation of glucose disposal seen in response to thiazolidinediones.…”

Section: Introductionmentioning

confidence: 99%

Pioglitazone increases non-esterified fatty acid clearance in upper body obesity

Shadid

Jensen

2005

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis: Plasma NEFA concentrations are largely determined by adipose tissue lipolysis. Insulin suppression of lipolysis is commonly impaired with insulin resistance and improves with thiazolidinedione treatment of type 2 diabetes. The present studies were designed to assess the effects of thiazolidinedione on NEFA (oleate) metabolism that are independent of improved glycaemic control. Materials and methods: We measured plasma oleate concentration and flux ([ H 2 ] glucose) and substrate oxidation (indirect calorimetry) before and after pioglitazone (30 mg/day for ∼20 weeks) in 20 non-diabetic adults with upper body obesity. To assess the effects of improved insulin sensitivity per se we performed the same measurements in a matched group of volunteers treated with diet/exercise. Half of the two groups underwent these measurements during a hyperinsulinaemic-euglycaemic clamp, and the other half had their measurements taken during a (control) saline infusion before and after the intervention. Results: Both interventions increased insulinstimulated glucose disposal and reduced plasma oleate concentrations during the insulin clamp. After diet/exercise, oleate flux decreased (p=0.03) during the insulin clamp and oleate clearance remained unchanged (p=0.55), whereas in the pioglitazone group, oleate flux during the clamp was unchanged (p=0.97) and oleate clearance increased (p=0.003). Oleate clearance in the saline control condition was increased in the pioglitazone group compared with the diet/exercise group (p=0.02).Conclusions/ interpretation: In insulin-resistant, non-diabetic adults, pioglitazone increases NEFA clearance during physiological hyperinsulinaemia, whereas improved insulin sensitivity achieved by diet/exercise does not alter NEFA clearance but enhances insulin suppression of NEFA release. This action of pioglitazone may contribute to improved glucose metabolism in type 2 diabetes.

show abstract

“…The biguanide metformin decreases the high hepatic glucose output observed in type 2 diabetes, whereas thiazolidinediones such as pioglitazone or rosiglitazone increase muscle glucose uptake in response to insulin and are called insulin sensitisers. Metformin and thiazolidinediones have been reported to decrease the plasma concentrations of non-esterified fatty acids in type 2 diabetic patients [17][18][19][20][21] and the lipolytic rate in obese humans [22][23][24]. In rodent adipocytes, biguanides and thiazolidinediones are able to activate AMPK, and biguanides are able to reduce lipolysis [8,25,26].…”

Section: Introductionmentioning

confidence: 99%

Biguanides and thiazolidinediones inhibit stimulated lipolysis in human adipocytes through activation of AMP-activated protein kinase

et al. 2009

View full text Add to dashboard Cite

Aims/hypothesis In rodent adipocytes, activated AMPactivated protein kinase reduces the lipolytic rate. As the hypoglycaemic drugs metformin and thiazolidinediones activate this enzyme in rodents, we tested the hypothesis that in addition to their known actions they could have an anti-lipolytic effect in human adipocytes. Methods Adipose tissue was obtained from individuals undergoing plastic surgery. Adipocytes were isolated and incubated with lipolytic agents (isoprenaline, atrial natriuretic peptide) and biguanides or thiazolidinediones. Lipolysis was quantified by the glycerol released in the medium. AMPactivated protein kinase activity and phosphorylation state were determined using standard procedures. Results In human adipocytes, isoprenaline and atrial natriuretic peptide stimulated the lipolytic rate three-to fourfold. Biguanides and thiazolidinediones activated AMPactivated protein kinase and inhibited lipolysis by 30-40%, at least in part by inhibiting hormone-sensitive lipase translocation to the lipid droplet. Inhibition of AMPactivated protein kinase by compound C precluded this inhibitory effect on lipolysis. Stimulation of lipolysis also induced an activation of AMP-activated protein kinase concomitant with a drop in ATP concentration. Conclusions/interpretation We show for the first time in human adipocytes that biguanides and thiazolidinediones activate AMP-activated protein kinase, thus counteracting lipolysis induced by lipolytic agents. In addition, β-agonistor ANP-stimulated lipolysis increases AMP-activated protein kinase activity. This is because of an increase in the AMP/ATP ratio, linked to activation of some of the released fatty acids into acyl-CoA. AMP-activated protein kinase activation could represent a physiological means of avoiding a deleterious drain of energy during lipolysis but could be used to restrain pharmacological release of fatty acids.

show abstract

Nocturnal and Postprandial Free Fatty Acid Kinetics in Normal and Type 2 Diabetic Subjects

Cited by 101 publications

References 49 publications

Heterogeneity in limb fatty acid kinetics in type 2 diabetes

Heterogeneity in limb fatty acid kinetics in type 2 diabetes

Pioglitazone increases non-esterified fatty acid clearance in upper body obesity

Biguanides and thiazolidinediones inhibit stimulated lipolysis in human adipocytes through activation of AMP-activated protein kinase

Contact Info

Product

Resources

About