Chapter 34: Integration of Carbohydrate and Lipid Metabolism

During the fed state following a meal, elevated insulin levels promote anabolic pathways by activating glucokinase, glycogen synthase, phosphofructokinase-1, and acetyl-CoA carboxylase, channeling glucose toward glycogen storage in liver and muscle while simultaneously stimulating fatty acid synthesis. Excess acetyl-CoA derived from glucose oxidation is exported from mitochondria as citrate for cytosolic lipogenesis and cholesterol production. Simultaneously, adipose tissue captures circulating triglycerides from dietary chylomicrons and hepatic VLDL through lipoprotein lipase activity, which is enhanced by insulin and apolipoprotein CII. The chapter then contrasts this with fasting metabolism, where a declining insulin-to-glucagon ratio shifts cells toward catabolic processes. Glucagon activates the cAMP-protein kinase A cascade, causing phosphorylation of glycogen phosphorylase to mobilize hepatic glucose and simultaneous inhibition of glycogen synthase to prevent futile cycling. In adipose tissue, hormone-sensitive lipase and triglyceride lipase release fatty acids that undergo beta-oxidation in the liver to generate ketone bodies, which serve as alternative fuels for brain and muscle while sparing glucose and muscle protein. During exercise, AMP-activated protein kinase activation in response to rising AMP-to-ATP ratios shifts muscle metabolism toward fatty acid oxidation while promoting glucose uptake independent of insulin signaling. The chapter emphasizes regulatory nodes such as fructose 2,6-bisphosphate, which reciprocally controls glycolysis versus gluconeogenesis, and highlights the central role of AMPK in suppressing energy-consuming anabolic pathways including fatty acid synthesis, cholesterol synthesis, and protein synthesis through mTOR inhibition. Clinical cases illustrate insulinoma causing hypoglycemia and weight gain, diabetic ketoacidosis with severe lipid abnormalities in type 1 diabetes, and metabolic syndrome in type 2 diabetes with insulin resistance and dyslipidemia, demonstrating how metabolic derangements increase coronary artery disease risk.