Glucose Metabolism and Diabetes

And now we're up to what seems like the obligatory diabetes lecture for the semester...

Big Picture – energy metabolism
Control of energy substrates
Carbohydrate (main external source of energy)
ATP (Adenosine triphosphate – ‘holds’ the energy for internal use)
Glycolysis / Krebs Cycle / Electron Transport Chain

*sighs internally*

• Glycolysis and the Pentose Phosphate Pathway
• The TCA Cycle
• Electron Transport Chain and Oxidative Phosphorylation
• Extracting Energy from Food

Control of blood glucose / Insulin / Diabetes

We use glucose at a more or less constant rate, but since we're not eating at a more or less constant rate (okay, I guess some people do, but let's just ignore them for now), our supply of glucose is pulsatile. Therefore, in order to stop glucose levels from spiking and dipping, we need some hormones to regulate our glucose levels. Insulin is the main hormone that stops glucose levels from getting too high, and glucagon stops glucose levels from getting too low.

Insulin is produced in the beta-cells of the Islets of Langerhans in the pancreas. (Beta-cells make up roughly 75% of cells in the Islets of Langerhans, which in turn make up around 1% of the pancreas.) As described here, insulin is originally transcribed as preproinsulin. When it enters the rough ER, it is cleaved to form proinsulin. Finally, in the Golgi apparatus, it is cleaved to form the A and B chains (which are connected via disulfide linkages) and C-peptide.

Insulin secretion is stimulated by glucose, amino acids, and glucagon, and inhibited by somatostatin and the sympathetic nervous system. Glucose is the main regulator, however, so let's look at glucose. Glucose enters beta-cells via GLUT2 transporters and undergoes glycolysis to form ATP. ATP closes ATP-sensitive K⁺ channels, causing depolarisation. Depolarisation opens voltage-sensitive Ca²⁺ channels, causing an influx of calcium, which in turn causes release of insulin-containing vesicles. 60% of secreted insulin is removed from the blood on first pass through the liver, which is why C-peptide, not insulin, is used as an indicator of beta-cell function.

Insulin receptors are heterotetramers with two extracellular alpha-chains and two intracellular beta-chains. The beta-chains have tyrosine kinase activity. I've discussed the insulin receptor in more detail here.

Insulin has slightly different effects on different organs:

• Liver- Stimulates glycolysis, glycogenesis, lipogenesis, and protein deposition. Inhibits gluconeogenesis and glycogenolysis. End result is lowering of blood glucose and storage of energy.
• Skeletal muscle- Upregulates GLUT4 (an insulin-dependent glucose transporter). Stimulates glycogenesis, glycolysis, and protein deposition. Inhibits glycogenolysis and protein degradation. End result is lowering of blood glucose, storage of energy, and maintenance of muscle mass.
• Adipose tissue- Upregulates GLUT4. Stimulates glycolysis, shuttling of phosphoenolpyruvate to glycerol, shuttling of acetyl-CoA to free fatty acids, and lipoprotein lipase expression (and, by extension, free fatty acid uptake from VLDL). Inhibits hormone sensitive lipase. End result is lowering of blood glucose and storage of energy as triglyceride.

What happens if we have insufficient insulin? Insufficient insulin results in diabetes, as discussed here and here. Without insulin, lots of gluconeogenesis occurs (due to lack of inhibition), keeping blood glucose levels high. Ketone body metabolism also occurs, placing diabetic patients at risk of ketoacidosis.