Metabolic Integration

What are features of metabolic integration at the physiologic level?

● The liver is the metabolic hub of the human body, functioning as a physiologic glucose regulator to maintain safe blood glucose levels of 4.5 mM. The liver removes excess glucose from the blood when carbohydrate levels are high (glucose influx) and releases glucose from stored glycogen or as a product of gluconeogenesis when blood glucose levels are low (glucose efflux).

● Glucose-6-P is converted into four major products by liver enzymes: (1) glucose for release into the blood, (2) glucose-1-P for use in glycogen synthesis, (3) 6-phosphogluconolactone to generate NADPH by the pentose phosphate pathway, and (4) fructose-6-P, which is used in the glycolytic pathway to produce pyruvate.

● The human body contains two types of muscle tissue: (1) skeletal muscle, which uses different amounts of free fatty acids, glucose, or ketone bodies for metabolic fuel, depending on the physical movements; and (2) cardiac muscle, which uses fatty acids and ketone bodies as metabolic fuel to sustain a steady heartbeat.

● Insulin and glucagon are synthesized as prohormones in regions of the pancreas called the islets of Langerhans. The β cells secrete insulin, the α cells secrete glucagon, and the δ cells secrete somatostatin.

● Insulin signaling in liver, skeletal muscle, and adipose tissue stimulates glucose uptake and glycogen and lipid storage, whereas insulin signaling in the brain stimulates the anorexigenic neurons that decrease appetite and increase energy expenditure.

● Glucagon signaling in the liver and adipose tissue stimulates glycogen and triacylglycerol degradation. Skeletal muscle and brain cells do not express glucagon receptors.

● The human body adapts to starvation conditions by altering the flux of metabolites between various tissues with the primary metabolic objective being to supply the brain with glucose to maintain ATP-dependent ion pumps and ensure normal neuronal cell functions.

What biochemical regulatory mechanisms control metabolic energy balance in humans?

● Mouse genetics led to the discovery of the leptin gene in obese (ob/ob) mice and the leptin receptor gene in diabetic (db/db) mice. Leptin is an adipokine hormone synthesized in adipose tissue at levels proportional to the amount of stored fat. Most obese humans have normal leptin signaling, unlike the obese (ob/ob) OB and diabetic (db/db) mice.

● Leptin circulates throughout the body and activates signal transduction in a variety of tissues, including the hypothalamus region of the brain. Activation of leptin receptors decreases appetite and increases energy expenditure to reduce lipid stores.

● Leptin (and insulin) bind to first-order POMC and NPY/AGRP neurons that produce neuropeptides (α-MSH, NPY, and AGRP), which bind to their cognate receptors on anorexigenic (eat less, metabolize more) and orexigenic (eat more, metabolize less) second-order neurons.

● Insulin-resistant type 2 diabetes is characterized at initial diagnosis by high levels of circulating insulin and desensitization of insulin receptor signaling in muscle, liver, and adipose tissue. In contrast, type 1 diabetes is due to insufficient insulin production by the pancreatic β cells and is treatable with insulin injections.

● Unlike individuals with normal insulin signaling, type 1 and type 2 diabetics are unable to lower blood glucose levels within 2 hours. Type 1 and type 2 diabetes can be distinguished by an insulin sensitivity test, which shows a decrease in blood glucose levels for type 1 diabetics but not for type 2 diabetics.

● Four major classes of drugs have been developed to treat type 2 diabetes: (1) α-glucosidase inhibitors (miglitol), (2) sulfonylurea drugs that inhibit the pancreatic ATP dependent K+ channel (glipizide), (3) drugs that stimulate the activity of AMPK (metformin), and (4) ligand agonists of the nuclear receptor PPARγ (thiazolidinediones).

What are the biochemical determinants of human nutrition and exercise?

● Three factors that affect metabolic homeostasis are genetic inheritance, nutrition, and exercise. Energy balance determines body weight; however, not all foods of equal Calories provide the same nutritional value.

● Four classes of compounds have been developed as weight loss drugs: (1) ephedrine is a stimulant that increases basal metabolic rates, (2) lorcaserin targets neuronal signaling in the brain to control appetite, (3) orlistat inhibits the activity of pancreatic lipase in the small intestine, and (4) olestra is a zero-Calorie food substitute containing fatty acid side chains covalently linked to sucrose.

● Consuming high amounts of saturated fatty acids and trans fatty acids on a regular basis increases LDL levels in the blood, which is associated with a higher risk of cardiovascular disease.

● The glycemic index of foods is a numerical value indicating how quickly glucose is released into the blood after eating different types of carbohydrate-containing foods. Carbohydrates with a low glycemic index cause only moderate increases in blood glucose levels over several hours.

● Exercise-induced activation of AMPK signaling alters metabolic flux through energy conversion pathways to increase ATP production in skeletal muscle cells. AMPK is a heterotrimeric serine/threonine kinase consisting of a catalytic α subunit, a regulatory γ subunit that binds AMP, and the β subunit, which functions as a molecular scaffold.

● AMPK-mediated phosphorylation of serine or threonine residues on metabolic target proteins in muscle cells leads to a net increase in ATP concentration by three mechanisms: (1) stimulation of flux through glycolysis, (2) stimulation of flux through fatty acid oxidation, and (3) increased oxidative phosphorylation.

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