Bioc 460 Spring 1999
Lecture 41 - Chapter 30

- Metabolic profiles of major organs
- Hormonal regulators of fuel metabolism
- Adaptation to prolonged starvation
- Metabolic defects leading to diabetes

The following sections in Stryer chapter 30 are useful reviews:

- Strategy of metabolism: a recapitulation - recommended reading
- Recurring motifs in metabolic regulation - recommended reading
- Major metabolic pathways and control sites - recommended reading
- Key junctions: glucose-6-P, pyruvate, and acetyl CoA - recommended reading

The metabolic patterns of the brain, muscle, adipose tissue, and the liver are very different due to their distinct physiological functions.

Table 30.1

Figure 30.13

Figure 30.14

Brain - glucose is the sole source of energy fuel except during times of prolonged starvation at which times ketone bodies contribute to the total energy requirement. There are no stored energy sources in the brain. The brain lacks glucose-6-P phosphatase and therefore retains glucose.

Muscle - glucose, fatty acids and ketone bodies are all used by the muscle tissues for energy. The muscle has readily stored energy in the form of glycogen and lacks the enzyme glucose-6-P phosphatase. In actively contracting muscle, energy is obtained anaerobically from glycolysis and lactate production is recycled to the liver to form glucose.

Adipose tissue - the main function of adipose tissue is to store the body's primary source of energy fuel in the form of triglycerides. Triglycerides are hydrolyzed by hormone-sensitive lipase in adipose tissue and the fatty acids are carried through the blood complexed to albumin.

Liver - The metabolic activities of the liver are essential to providing fuel to the brain, muscle and peripheral tissues. When fuel is abundant, the level of malonyl CoA is high and fatty acids are synthesized in the liver (the fat-free bagel is fattening syndrome), however, when fuel is scarce (diabetes or starvation), fatty acids are transported into the mitochondrial matrix and ketone bodies are made to make up for the lack of glucose.

The hormones, insulin, glucagon, and epinephrine play key roles in integrating fuel metabolism.

Figure 30.17

Figure 30.18

Insulin - signals the fed state. Insulin is secreted by the beta cells of the pancreas and stimulates the storage of fuels and the synthesis of proteins. Binding of insulin to the insulin receptor initiates a kinase cascade culminating in altered rates of gene expression, phosphorylation of target enzymes (inactivating some while activating others) and has an overall effect on stimulating glucose uptake in the liver.

Glucagon - signals low blood sugar and is secreted by the alpha cells of the pancreas. Glucagon signaling stimulates cAMP production and activation of protein kinase A which leads to glycogen breakdown and release of glucose from the liver.

Epinephrine - acts similar to glucagon in that this hormone signal stimulates glucose release from the liver. However, epinephrine also stimulates glycogen breakdown in the muscle and increases muscle consumption of fatty acids to spare glucose for use by the brain.

An average human of 70 kg has sufficient energy stores in the form protein, glycogen and triglycerides to survive for 1 - 3 months without food (although water is required!). The first priority of metabolism is to provide glucose, via glycogen degradation, to the brain and to red blood cells.

After a few days most all metabolism shifts to fatty acid oxidation and the muscle, liver and heart using ketone bodies as their major energy source. Eventually, the brain derives much of its energy from ketone bodies, although glucose is still required. There are only two sources of carbon intermediates for gluconeogenesis during starvation; amino acid skeletons and glycerol from triglycerides. Muscle breakdown is spared as much as possible to permit mobility and food scavenging.

Figure 30.20

Table 30.2

Diabetes is a complex disease that is characterized by abnormal glucose utilization. The liver overproduces glucose and other tissues under-utilize glucose. High glucose levels in the serum are a clinical sign of diabetes. In an untreated diabetic, insulin levels are below normal and glucagon levels are above normal - the body is under a state of perceived starvation. Ketone body production and acetone breath is also found in severe diabetics.

Type I diabetes - also known as juvenile diabetes or insulin-dependent diabetes. It appears in children under the age of 20 and is caused by a lack of insulin production (usually the result of an immunological reaction that destroys pancreatic beta cells). Type I diabetics require daily insulin injections.

Type II diabetes - also known as adult onset diabetes or insulin-independent diabetes. This disease is less well understood and found in obese elderly individuals. It is thought to be the result of insulin resistance, perhaps at the level of the insulin receptor or intracellular kinase signaling. Type II diabetics can have measurable levels of insulin in their serum.

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Department of Biochemistry The University of Arizona Spring 1999  RLM@u.arizona.edu cusanovi@u.arizona.edu http://www.biochem.arizona.edu/classes/bioc460/spring/springindex.html All contents copyright © 1999. All rights reserved.