A single entity, the AMP-activated protein kinase (AMPK), phosphorylates and regulates in vivo hydroxymethylglutaryl-CoA reductase and acetyl-CoA carboxylase (key regulatory enzymes of sterol synthesis and fatty acid synthesis, respectively), and probably many additional targets. The kinase is activated by high AMP and low ATP via a complex mechanism, which involves allosteric regulation, promotion of phosphorylation by an upstream protein kinase (AMPK kinase), and inhibition of dephosphorylation. This protein-kinase cascade represents a sensitive system, which is activated by cellular stresses that deplete ATP, and thus acts like a cellular fuel gauge. Our central hypothesis is that, when it detects a 'low-fuel' situation, it protects the cell by switching off ATP-consuming pathways (e.g. fatty acid synthesis and sterol synthesis) and switching on alternative pathways for ATP generation (e.g. fatty acid oxidation). Native AMP-activated protein kinase is a heterotrimer consisting of a catalytic alpha subunit, and beta and gamma subunits, which are also essential for activity. All three subunits have homologues in budding yeast, which are components of the SNF1 protein-kinase complex. SNF1 is activated by glucose starvation (which in yeast leads to ATP depletion) and genetic studies have shown that it is involved in derepression of glucose-repressed genes. This raises the intriguing possibility that AMPK may regulate gene expression in mammals. AMPK/SNF1 homologues are found in higher plants, and this protein-kinase cascade appears to be an ancient system which evolved to protect cells against the effects of nutritional or environmental stress.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1997.00259.x

The AMP‐Activated Protein Kinase

Hyperinsulinemia, loss of glucose-stimulated insulin secretion (GSIS), and peripheral insulin resistance coexist in non-insulin-dependent diabetes mellitus (NIDDM). Because free fatty acids (FFA) can induce these same abnormalities, we studied their role in the pathogenesis of the NIDDM of obese Zucker diabetic fatty (ZDF-drt) rats from 5 weeks of age (before the onset of hyperglycemia) until 14 weeks. Two weeks prior to hyperglycemia, plasma FFA began to rise progressively, averaging 1.9 +/- 0.06 mM at the onset of hyperglycemia (P < 0.001 vs. controls). At this time GSIS was absent and beta-cell GLUT-2 glucose transporter was decreased. The triacylglycerol content of prediabetic islets rose to 10 times that of controls and was correlated with plasma FFA (r = 0.825; P < 0.001), which, in turn, was correlated with the plasma glucose concentration (r = 0.873; P < 0.001). Reduction of hyperlipacidemia to 1.3 +/- 0.07 mM by pair feeding with lean littermates reduced all beta-cell abnormalities and prevented hyperglycemia. Normal rat islets that had been cultured for 7 days in medium containing 2 mM FFA exhibited increased basal insulin secretion at 3 mM glucose, and first-phase GSIS was reduced by 68%; in prediabetic islets, first-phase GSIS was reduced by 69% by FFA. The results suggest a role for hyperlipacidemia in the pathogenesis of NIDDM; resistance to insulin-mediated antilipolysis is invoked to explain the high FFA despite hyperinsulinemia, and sensitivity of beta cells to hyperlipacedemia is invoked to explain the FFA-induced loss of GSIS.

https://www.pnas.org/content/pnas/91/23/10878.full.pdf

Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships

beta-oxidation of fatty acids in mitochondria, peroxisomes, and bacteria: a century of continued progress.

Regulation of ketogenesis and the renaissance of carnitine palmitoyltransferase

Cross-sectional studies in human subjects have used 1 H magnetic 
resonance spectroscopy (HMRS) to demonstrate that insulin resistance 
correlates more tightly with the intramyocellular lipid (IMCL) concentration 
than with any other identified risk factor. To further explore the interaction 
between these two elements in the rat, we used two strategies to promote the 
storage of lipids in skeletal muscle and then evaluated subsequent changes in 
insulin-mediated glucose disposal. Normal rats received either a low-fat or a 
high-fat diet (20% lard oil) for 4 weeks. Two additional groups (low-fat + 
etoxomir and lard + etoxomir) consumed diets containing 0.01% of the carnitine 
palmitoyltransferase-1 inhibitor, R-etomoxir, which produced chronic blockade 
of enzyme activity in liver and skeletal muscle. Both the high-fat diet and 
drug treatment significantly impaired insulin sensitivity, as measured with 
the hyperinsulinemiceuglycemic clamp. Insulin-mediated glucose disposal (IMGD) 
fell from 12.57 ± 0.72 in the low-fat group to 9.79 ± 0.59, 8.96 
± 0.38, and 7.32 ± 0.28 μmol · min -1 
· 100 g -1 in the low-fat + etoxomir, lard, and lard + 
etoxomir groups, respectively. We used HMRS, which distinguishes between fat 
within the myocytes and fat associated with contaminating adipocytes located 
in the muscle bed, to assess the IMCL content of isolated soleus muscle. A 
tight inverse relationship was found between IMGD and IMCL, the correlation 
( R = 0.96) being much stronger than that seen between IMGD and either 
fat mass or weight. In conclusion, either a diet rich in saturated fat or 
prolonged inhibition of fatty acid oxidation impairs IMGD in rats via a 
mechanism related to the accumulation of IMCL.

https://diabetes.diabetesjournals.org/content/diabetes/50/1/123.full.pdf

Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats.

Characterization of the mitochondrial carnitine palmitoyltransferase enzyme system. I. Use of inhibitors.

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Characterization of the mitochondrial carnitine palmitoyltransferase enzyme system. I. Use of inhibitors.