Reduced mRNA and protein expression of perilipin A and G0/G1 switch gene 2 (G0S2) in human adipose tissue in poorly controlled type 2 diabetes

TY - JOUR

T1 - Reduced mRNA and protein expression of perilipin A and G0/G1 switch gene 2 (G0S2) in human adipose tissue in poorly controlled type 2 diabetes

AU - Nielsen, Thomas Svava

AU - Kampmann, Ulla

AU - Nielsen, Roni R

AU - Jessen, Niels

AU - Orskov, Lotte

AU - Pedersen, Steen B

AU - Jørgensen, Jens Otto Lunde

AU - Lund, Sten

AU - Møller, Niels

PY - 2012/7

Y1 - 2012/7

N2 - Context: Increased lipolysis and free fatty acid (FFA) levels contribute significantly to the pathogenesis of chronic and acute insulin resistance in type 2 diabetes, but the underlying mechanisms are uncertain. Objective: Our objective was to test whether increased lipolysis and FFA levels induced by insulin withdrawal are accompanied by increased adipose tissue (AT) contents of adipose triglyceride lipase (ATGL) and/or altered intracellular ATGL regulation. Design and Participants: Nine patients with type 2 diabetes were examined twice in a randomized crossover design after 16 h of 1) hyperglycemia/insulin withdrawal and 2) euglycemia/insulin infusion. Blood samples were drawn and a sc abdominal AT biopsy was obtained. Setting: The study was conducted at a university hospital research unit. Results: Circulating glucose (7.2 ± 0.3 vs. 11.2 ± 0.8 mmol/liter) and FFA (0.51 ± 0.05 vs. 0.65 ± 0.04 mmol/liter) were increased and insulin levels decreased after insulin withdrawal. AT ATGL protein tended to be increased (P = 0.075) after insulin withdrawal; by contrast, AT protein and mRNA content of perilipin A (Plin) and G0/G1 switch gene 2 (G0S2), known negative regulators of ATGL activity, were decreased by 20-30% (all P values <0.03). All measured parameters related to hormone-sensitive lipase remained unaffected. Conclusions: We found reduced mRNA and protein content of Plin and G0S2 and borderline increased ATGL protein in sc AT from poorly controlled type 2 diabetic subjects. This suggests that increased ATGL activity may contribute to the elevated lipolysis and circulating FFA levels in acute insulin withdrawal and metabolic dysregulation in type 2 diabetic patients and that this mechanism may be modifiable.

AB - Context: Increased lipolysis and free fatty acid (FFA) levels contribute significantly to the pathogenesis of chronic and acute insulin resistance in type 2 diabetes, but the underlying mechanisms are uncertain. Objective: Our objective was to test whether increased lipolysis and FFA levels induced by insulin withdrawal are accompanied by increased adipose tissue (AT) contents of adipose triglyceride lipase (ATGL) and/or altered intracellular ATGL regulation. Design and Participants: Nine patients with type 2 diabetes were examined twice in a randomized crossover design after 16 h of 1) hyperglycemia/insulin withdrawal and 2) euglycemia/insulin infusion. Blood samples were drawn and a sc abdominal AT biopsy was obtained. Setting: The study was conducted at a university hospital research unit. Results: Circulating glucose (7.2 ± 0.3 vs. 11.2 ± 0.8 mmol/liter) and FFA (0.51 ± 0.05 vs. 0.65 ± 0.04 mmol/liter) were increased and insulin levels decreased after insulin withdrawal. AT ATGL protein tended to be increased (P = 0.075) after insulin withdrawal; by contrast, AT protein and mRNA content of perilipin A (Plin) and G0/G1 switch gene 2 (G0S2), known negative regulators of ATGL activity, were decreased by 20-30% (all P values <0.03). All measured parameters related to hormone-sensitive lipase remained unaffected. Conclusions: We found reduced mRNA and protein content of Plin and G0S2 and borderline increased ATGL protein in sc AT from poorly controlled type 2 diabetic subjects. This suggests that increased ATGL activity may contribute to the elevated lipolysis and circulating FFA levels in acute insulin withdrawal and metabolic dysregulation in type 2 diabetic patients and that this mechanism may be modifiable.

KW - Adipose Tissue

KW - Blood Glucose

KW - Carrier Proteins

KW - Cell Cycle Proteins

KW - Cross-Over Studies

KW - Diabetes Mellitus, Type 2

KW - Down-Regulation

KW - Humans

KW - Hypoglycemic Agents

KW - Insulin

KW - Insulin Infusion Systems

KW - Lipase

KW - Middle Aged

KW - Phosphoproteins

KW - RNA, Messenger

KW - Subcutaneous Fat, Abdominal

U2 - 10.1210/jc.2012-1159

DO - 10.1210/jc.2012-1159

M3 - Journal article

C2 - 22535977

SN - 0021-972X

VL - 97

SP - E1348-52

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 7

ER -