IRS
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IR IRS GLUT I II III IV V FFA TG TCA β oxidation fATP Hyperinsulinemia Fasting IR IRS GLUT Glucose Pyruvate I II III IV V TCA β oxidation fATP Metabolic flexibility IR IRS GLUT Glucose Pyruvate I II III IV V TCA β oxidation fATP Insulin-sensitive Insulin-resistant a. c. b. d. IR IRS Pyruvate I II III IV V TCA β oxidation fATP X X GLUT Glucose X Hyperinsulinemia Fasting Metabolic inflexibility Acyl-CoA FFA TG Acyl-CoA DAG Ceramides FFA TG Acyl-CoA DAG Ceramides
description
Metabolic flexibility. V. V. V. II. II. II. III. III. III. IV. IV. IV. I. I. I. V. II. III. IV. I. Metabolic inflexibility. Hyperinsulinemia. Fasting. X. Hyperinsulinemia. Fasting. a. c. Glucose. IR. IR. GLUT. GLUT. IRS. IRS. DAG Ceramides. DAG Ceramides. - PowerPoint PPT Presentation
Transcript of IRS
IR
IRS
GLUT
I II III IV V
FFA
TGTCAβ oxidation
fATP
HyperinsulinemiaFasting
IR
IRS
GLUT
Glucose
Pyruvate
I II III IV V
TCAβ oxidation
fATP
Metabolic flexibility
IR
IRS
GLUT
Glucose
Pyruvate
I II III IV V
TCAβ oxidation
fATP
Insulin-sensitive
Insulin-resistant
a.c.
b. d.IR
IRS
Pyruvate
I II III IV V
TCAβ oxidation
fATP
X X
GLUT
Glucose
X HyperinsulinemiaFastingMetabolic inflexibility
Acyl-CoA
FFA
TG
Acyl-CoA
DAGCeramides
FFA
TG
Acyl-CoA
DAGCeramides
Figure S1. Cellular processes in insulin-responsive tissues. a. In the fasting state, glucose uptake into insulin-responsive tissues decreases and fuel selection switches from glucose to lipid oxidation (metabolic flexibility). Substrate availability and energy demand are low. b. Theinsulin-resistant state is characterized by the inability to adapt ATP synthetic rates (fATP) to substrate availability; lipid oxidation rates are, therefore, not increased adequately. Lipid metabolites (Acyl-CoA, DAG, ceramides) increase and TG accumulate. Mitochondrial plasticity, for example metabolic flexibility, is the limiting factor for in vivo ATP synthetic rates in insulin-resistant humans. c. During hyperinsulinemia, glucose uptake increases in insulin-responsive tissues, fuel selection switches from lipid to glucose oxidation (metabolic flexibility). In the insulin-stimulated state, energy demand is high and ATP synthetic flux rate is increased. d. In the insulin-resistant state, glucose transport and phosphorylation is reduced and lipid oxidation rates are not decreased adequately. DAG and ceramides induce insulin resistance. Abbreviations: DAG, diacylglycerol; FFA, free fatty acids; GLUT, glucose transporter; IR, insulin receptor IRS, insulin receptor substrate; TCA, tricarboxylic acid cycle; TG, triglycerides.
