What happens in untreated type 1 diabetes?

Type 1 diabetes is characterized by autoimmune destruction of beta cells in the islets of Langerhans, which results in lack of insulin secretion (1). Glucose, then cannot be taken up by cells leading to hyperglycemia and osmotic diuresis (1). The low insulin will also stimulate hepatic glycogenolysis and gluconeogenesis to produce glucose released into blood leading into accentuated hyperglycemia (1).

What’s more is that gluconeogenesis becomes chronic depleting body proteins to break down into amino acids (1). Muscle,in effect, atrophes converting to glucose and lost through the diuresis (1). Weakness, fatigue and weight loss all occur (1).

Insulin inhibits degradation of protein and increases protein synthesis (2). Opposite to this, lack of insulin creates an environment favoring glucagon leaving degradation of protein unchecked and protein synthesis diminished (2). The degradation occurs by action of proteases—lysosomal or proteosomal—or via the calcium-activated proteolytic degradation pathway (2p234). The increased protein degradation increases nitrogen output resulting in a negative nitrogen balance (2p232).

One example of proteosomal degradation relies on activation of ubiquitin, steps of which are inhibited by insulin (2p208). Insulin also antagonizes activation of a few enzymes—such as the phosphorylation of phenylalanine hydroxylase—responsible for amino acid oxidation (2). The catabolism of amino acids involve transamination or damination (2p209). The amino groups are form alpha-ketobutyrate and ammonia, which must be removed in the urea cycle (2p209).

A mixture of amino acids that is high in alanine and glutamine would be released into the blood (2p246). Alanine, in particular, is a preferred substrate for gluconeogenesis and also stimulates secretion of glucagon, which stimulates gluconeogenesis (2p246).

Deamination/transamination of glycine, serine, cysteine, tryptophan and threonine leaves skeletons oxaloacetate and pyruvate ready for glucose production (2p212). Apart from those, phenylalanine and tyrosine could also be used for glucose when degraded to fumarate (2p212). Valine and methionine are gluconeogenic and isoleucine and threonine are partially glucogenic and partially ketogenic (2p212). Leucine and lycine would not contribute to gluconeogenesis since theyare ketogenic and catabolized to acetyl CoA (2p212).

Because muscle protein provides most of amino acids, particularly in stress situations, muscle cachexia occurs (2p242). The degradation of fast-twitch muscle would be more pronounced than that of the red slow-twitch (2p242). The protein degradation would not be unlike that of starvation with each gram of nitrogen equivalent to 30g of hydrated lean tissue (2p246).

Ketoacidosis is also a logical result. Just as in fasting and starvation, lack of insulin in type 1 diabetes disabling uptake of glucose in cells would lead tissues to use fatty acid oxidation for energy (apart from amino acids) (2p247). Fatty acid oxidation provides energy through production of acetyl CoA, a TCA cycle substrate (2p160). The acetyl CoA use can end up in the “overflow” pathway of ketone body formation (2p160). The ketones would be used as a source of fuel, but in excess can disturb acid-base balance causing acidosis (2p160;2p247).

Reference List
1. Nowak TJ, Handford AG. Pathophysiology: Concepts and Applications for Health Professionals. New York: McGraw-Hill, 2004.
2. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.

Published by David Despain, MS, CFS

David is a science and health writer living on Long Island, New York. He's written for a variety of publications including Scientific American, Outside Online, the American Society for Nutrition's (ASN) Nutrition Notes Daily, and Institute of Food Technologists' (IFT) Food Technology magazine and Live! blog. He's also covered new findings reported at scientific meetings including Experimental Biology, AAAS, AOCS, CASW, Sigma Xi, IFT, and others on his personal blog "Evolving Health." David is also an active member of organizations including the National Association of Science Writers (NASW), the American Association for the Advancement of Science (AAAS), the American Society for Nutrition, the Institute of Food Technologists, and the National Audubon Society. David has a master's degree in human nutrition from the University of Bridgeport, and a bachelor's degree in English from University of Illinois at Springfield. He also earned his Certified Food Scientist credential from the Institute of Food Technologists.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: