AMP-activated protein kinase, a metabolic master switch: possible roles in Type 2 diabetes

1999 ◽  
Vol 277 (1) ◽  
pp. E1-E10 ◽  
Author(s):  
W. W. Winder ◽  
D. G. Hardie
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Ampk Activation ◽  
Signaling System ◽  
Ampk Signaling ◽  
Stimulation Of

Adenosine 5′-monophosphate-activated protein kinase (AMPK) now appears to be a metabolic master switch, phosphorylating key target proteins that control flux through metabolic pathways of hepatic ketogenesis, cholesterol synthesis, lipogenesis, and triglyceride synthesis, adipocyte lipolysis, and skeletal muscle fatty acid oxidation. Recent evidence also implicates AMPK as being responsible for mediating the stimulation of glucose uptake induced by muscle contraction. In addition, the secretion of insulin by insulin secreting (INS-1) cells in culture is modulated by AMPK activation. The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by pancreatic β-cells. In skeletal muscle, AMPK is activated by contraction. Type 2 diabetes mellitus is likely to be a disease of numerous etiologies. However, defects or disuse (due to a sedentary lifestyle) of the AMPK signaling system would be predicted to result in many of the metabolic perturbations observed in Type 2 diabetes mellitus. Increased recruitment of the AMPK signaling system, either by exercise or pharmaceutical activators, may be effective in correcting insulin resistance in patients with forms of impaired glucose tolerance and Type 2 diabetes resulting from defects in the insulin signaling cascade.

scholarly journals Susceptibility of podocytes to palmitic acid is regulated by fatty acid oxidation and inversely depends on acetyl-CoA carboxylases 1 and 2

2014 ◽  
Vol 306 (4) ◽  
pp. F401-F409 ◽  
Author(s):  
Kapil Kampe ◽  
Jonas Sieber ◽  
Jana Marina Orellana ◽  
Peter Mundel ◽  
Andreas Werner Jehle
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Palmitic Acid ◽  
Er Stress ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Genome Wide Association Studies ◽  
Acetyl Coa ◽  
Stimulation Of

Type 2 diabetes is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are susceptible to saturated FFAs, which induce endoplasmic reticulum (ER) stress and podocyte death. Genome-wide association studies indicate that expression of acetyl-CoA carboxylase (ACC) 2, a key enzyme of fatty acid oxidation (FAO), is associated with proteinuria in type 2 diabetes. Here, we show that stimulation of FAO by aminoimidazole-4-carboxamide-1β-d-ribofuranoside (AICAR) or by adiponectin, activators of the low-energy sensor AMP-activated protein kinase (AMPK), protects from palmitic acid-induced podocyte death. Conversely, inhibition of carnitine palmitoyltransferase (CPT-1), the rate-limiting enzyme of FAO and downstream target of AMPK, augments palmitic acid toxicity and impedes the protective AICAR effect. Etomoxir blocked the AICAR-induced FAO measured with tritium-labeled palmitic acid. The beneficial effect of AICAR was associated with a reduction of ER stress, and it was markedly reduced in ACC-1/-2 double-silenced podocytes. In conclusion, the stimulation of FAO by modulating the AMPK-ACC-CPT-1 pathway may be part of a protective mechanism against saturated FFAs that drive podocyte death. Further studies are needed to investigate the potentially novel therapeutic implications of these findings.

scholarly journals Muscle-Specific Overexpression of CD36 Reverses the Insulin Resistance and Diabetes of MKR Mice

Endocrinology ◽  
2004 ◽  
Vol 145 (10) ◽  
pp. 4667-4676 ◽  
Author(s):  
Lisa Héron-Milhavet ◽  
Martin Haluzik ◽  
Shoshana Yakar ◽  
Oksana Gavrilova ◽  
Stephanie Pack ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Cell Function ◽  
Dominant Negative ◽  
Whole Body ◽  
Acid Oxidation

Abstract Insulin resistance is one of the primary characteristics of type 2 diabetes. Mice overexpressing a dominant-negative IGF-I receptor specifically in muscle (MKR mice) demonstrate severe insulin resistance with high levels of serum and tissue lipids and eventually develop type 2 diabetes at 5–6 wk of age. To determine whether lipotoxicity plays a role in the progression of the disease, we crossed MKR mice with mice overexpressing a fatty acid translocase, CD36, in skeletal muscle. The double-transgenic MKR/CD36 mice showed normalization of the hyperglycemia and the hyperinsulinemia as well as a marked improvement in liver insulin sensitivity. The MKR/CD36 mice also exhibited normal rates of fatty acid oxidation in skeletal muscle when compared with the decreased rate of fatty acid oxidation in MKR. With the reduction in insulin resistance, β-cell function returned to normal. These and other results suggest that the insulin resistance in the MKR mice is associated with increased muscle triglycerides levels and that whole-body insulin resistance can be, at least partially, reversed in association with a reduction in muscle triglycerides levels, although the mechanisms are yet to be determined.

scholarly journals Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer

2016 ◽  
Vol 310 (6) ◽  
pp. E452-E460 ◽  
Author(s):  
K. J. Mather ◽  
G. D. Hutchins ◽  
K. Perry ◽  
W. Territo ◽  
R. Chisholm ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Oxygen Consumption ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Metabolic Flexibility ◽  
Work Efficiency ◽  
Myocardial Fatty Acid ◽  
Fuel Selection

Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[18F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([11C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU·m−2·min−1) to 3-h saline infusion. Lean controls ( n = 10) were compared with glycemically controlled volunteers with T2DM ( n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption ( P = 0.04) and perfusion ( P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids ( P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions ( P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups ( P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM ( P = 0.003). Myocardial work efficiency was lower in T2DM ( P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization ( P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM.

scholarly journals Blunted Reduction of Postprandial Acylcarnitine in Type 2 Diabetes and Identification of C16:0 as a New Marker of Excessive Fatty Acid Oxidation

2013 ◽  
Vol 37 ◽  
pp. S62
Author(s):  
Fatima-Zahra Bouchouirab ◽  
Mélanie Fortin ◽  
Frédérique Frish ◽  
Jean Dubé ◽  
André Carpentier
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation

Fatty Acid Oxidation by Skeletal Muscle During Rest and Activity

1958 ◽  
Vol 194 (2) ◽  
pp. 379-386 ◽  
Author(s):  
Irving B. Fritz ◽  
Don G. Davis ◽  
Robert H. Holtrop ◽  
Harold Dundee
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Palmitic Acid ◽  
Fatty Acid Oxidation ◽  
Latissimus Dorsi ◽  
Acid Metabolism ◽  
Fat Metabolism ◽  
Acid Oxidation ◽  
Stimulation Of

The metabolism of C14-labeled acetate, octanoate and palmitate by isolated skeletal muscle (latissimus dorsi and diaphragm) from normal, fed rats has been examined. The rates at which these substrates were converted to C14O2 have been shown to vary with concentration, temperature, functional state of the muscle, and the presence of albumin. Increased concentration of fatty acids led to enhanced conversion of substrate to C14O2. Electrical stimulation of muscles under tension resulted in approximately a 60% increase in oxygen consumption and about a 100% rise in fatty acid oxidation. The addition of glucose did not alter the rate of fatty acid metabolism by muscle. The addition of bovine albumin at concentrations up to approximately 1 µm albumin/7 µm palmitate resulted in augmented palmitic acid oxidation. However, at concentrations of albumin greater than 1 µm albumin/7 µm palmitate, palmitic acid degradation by resting diaphragm was inhibited, suggesting a firmer binding of fatty acid to albumin. The Q10 for palmitic acid oxidation by resting diaphragm was 2.23 in the absence of added albumin between 25° and 37°C. The data are discussed in relation to the present concepts of fat metabolism and transport in vivo. It is suggested that fat degradation in isolated muscle may provide an energy source during activity.

Lipid metabolism, exercise and insulin action

2006 ◽  
Vol 42 ◽  
pp. 47-59 ◽  
Author(s):  
Arend Bonen ◽  
G. Lynis Dohm ◽  
Luc J.C. van Loon
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Insulin Signalling ◽  
Acid Oxidation ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Severely Obese

Skeletal muscle constitutes 40% of body mass and takes up 80% of a glucose load. Therefore, impaired glucose removal from the circulation, such as that which occurs in obesity and type 2 diabetes, is attributable in large part to the insulin resistance in muscle. Recent research has shown that fatty acids, derived from adipose tissue, can interfere with insulin signalling in muscle. Hence, insulin-stimulated GLUT4 translocation to the cell surface is impaired, and therefore, the rate of glucose removal from the circulation into muscle is delayed. The mechanisms provoking lipid-mediated insulin resistance are not completely understood. In sedentary individuals, excess intramyocellular accumulation of triacylglycerols is only modestly associated with insulin resistance. In contrast, endurance athletes, despite accumulating large amounts of intramyocellular triacylglycerols, are highly insulin sensitive. Thus it appears that lipid metabolites, other than triacylglycerols, interfere with insulin signalling. These metabolites, however, are not expected to accumulate in athletic muscles, as endurance training increases the capacity for fatty acid oxidation by muscle. These observations, and others in severely obese individuals and type 2 diabetes patients, suggest that impaired rates of fatty acid oxidation are associated with insulin resistance. In addition, in obesity and type 2 diabetes, the rates of fatty acid transport into muscle are also increased. Thus, excess intracellular lipid metabolite accumulation, which interferes with insulin signalling, can occur as a result of impaired rates of fatty acid oxidation and/or increased rates of fatty acid transport into muscle. Accumulation of excess intramyocellular lipid can be avoided by exercise, which improves the capacity for fatty acid oxidation.

scholarly journals Fatty acid metabolism in obesity and type 2 diabetes mellitus

2003 ◽  
Vol 62 (3) ◽  
pp. 753-760 ◽  
Author(s):  
E. E. Blaak
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Type 2 Diabetes Mellitus ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Acid Oxidation ◽  
Acid Uptake

Disturbances in pathways of lipolysis and fatty acid handling are of importance in the aetiology of obesity and type 2 diabetes mellitus. There is evidence that a lowered catecholamine-mediated lipolytic response may play a role in the development and maintenance of increased adipose tissue stores. Increased adipose tissue stores, a disturbed insulin-mediated regulation of lipolysis and subnormal skeletal muscle non-esterified fatty acid (NEFA) uptake under conditions of high lipolytic rate may increase circulating NEFA concentrations, which may promote insulin resistance and cardiovascular complications. In addition, a disturbance of NEFA uptake by adipose tissue postprandially is also a critical determinant of plasma NEFA concentration. Furthermore, evidence is increasing that insulin-resistant muscle is characterised by a lowered ability to oxidise fatty acids. A dysbalance between fatty acid uptake and fatty acid oxidation may in turn be a factor promoting accumulation of lipid intermediates and triacylglycerols within skeletal muscle, which is strongly associated with skeletal muscle insulin resistance. The present review describes the reported disturbances in pathways of lipolysis and skeletal muscle fatty acid handling, and discusses underlying mechanisms and metabolic consequences of these disturbances.

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