Canine diabetes is caused by the degeneration of insulin secreting pancreatic beta cells. The etiology of this condition is still unknown, but multiple factors seem to contribute to its development. Genetic factors, infections, diseases, drugs that cause insulin resistance, obesity, immune-mediated insulitis and pancreatitis have all been associated with the development of canine diabetes. Symptoms of diabetes include weight loss, excessive drinking and urination, and increased appetite. Poorly controlled diabetes can lead to the development of serious complications, such as diabetic ketoacidosis, cataracts, uveitis, nephropathy and hypertension.  

 

Hyperglycemia is the most characteristic metabolic aberration in diabetes

Insulin is a highly important hormone in glucose metabolism. It increases uptake of glucose into the liver, muscles and adipose tissue, and promotes hepatic glycogen synthesis. Lack of insulin increases blood glucose levels by reducing blood glucose transport to cells and increasing liver gluconeogenesis and glycogenolysis. Diabetes causes blood glucose levels to continually rise above the 10-12mmol/l renal threshold for glucose reabsorption, which causes glucose to leak into the urine. Blood and urine glucose measurements are the most common tests used to diagnose diabetes.

Lipid metabolism changes radically, and is associated with the development of diabetic ketoacidosis

In poorly controlled diabetes, lipid metabolism can be drastically changed. Multiple factors contribute to the development of hypertriglyceridemia; the reduced activity of lipoprotein lipase causes impaired removal of triglycerides from VLDL and chylomicrons, increased enzyme activity due to hypoinsulinemia causes long chain fatty acids to be released into the bloodstream. These long chain fatty acids accumulate into the bloodstream because fat cells require insulin for glucose uptake, and therefore are unable to form triglycerides from long chain fatty acids. These fatty acids are taken in by liver cells, which form triglycerides and release them as VLDL into the bloodstream. If the ability of the liver to form VLDL from fatty acids is exceeded or acetyl coenzyme A is excessively produced, ketones are formed. This process is associated with the development of diabetic ketoacidosis, a life-threatening complication of diabetes.
Hypercholesterolemia develops by a different mechanism than hypertriglyceridemia. It develops because hypoinsulinemia causes lack of LDL receptors and thus reduced LDL uptake. Increased intestinal cholesterol formation may also contribute to the development of hypercholesterolemia.
The blood triglyceride concentration usually normalizes with routine insulin treatment, but hypercholesterolemia may persist. If, on the other hand, diabetes is not well controlled, hypertriglyceridemia may persist. Severe hyperlipidemia, especially hypertriglyceridemia, may require treatment because it may predispose to secondary diseases such as pancreatitis, and it has also been suggested to increase insulin resistance. The primary treatment for hypertriglyceridemia is a low-fat diet. Omega-3 fatty acid supplements may also help in reducing hypertriglyceridemia.

Amino acids and muscle wasting

Leucine, isoleucine and valine are so-called branched-chain amino acids. These amino acids have an important role in maintaining muscle mass, repairing injuries, and maintaining brain function. In diabetes, the blood concentration of these amino acids increases. This increase is caused by reduced muscular branched-chain amino acid uptake due to lack of insulin, and the increased formation of branched-chain amino acids from their keto-analogues. Since muscular branched-chain amino acid uptake is disturbed, muscular protein catabolism increases greatly, which can lead to severe muscle wasting.

Diet and hyperglycemia might be connected

Glutamine is a so-called dietary non-essential amino acid, because the dog’s body is normally capable of forming glutamine sufficiently from glutamate and ammonia. However, in diabetes, blood levels of glutamine decrease. Glutamine might not be only a biomarker for diabetes diagnostics. In other animal species, glutamine supplementation has been shown to relieve hyperglycemia and lower blood pressure in diabetic patients. The role of glutamine in hyperglycemia has not yet been studied in dogs.

Hyperlactatemia can form due to increased anaerobic glycolysis

Lactate is formed when cells use anaerobic glycolysis for energy production. Blood lactate levels may rise in diabetes. The proposed cause for this change is increased intracellular anaerobic glycolysis resulting from disturbed mitochondrial aerobic glucose metabolism. In humans, this change is present already before disease onset.

 

Biomarker
Direction of change
Cause
Glucose

Reduced cellular glucose uptake
Triglycerides

Altered lipid metabolism
VLDL triglycerides

Altered lipid metabolism
VLDL

Altered lipid metabolism
Cholesterol

Altered lipid metabolism
LDL cholesterol

Altered lipid metabolism
LDL

Altered lipid metabolism
HDL cholesterol

Altered lipid metabolism
Leucine

Muscle wasting
Isoleucine

Muscle wasting
Valine

Muscle wasting
Branched-chain amino acids

Muscle wasting
Glutamine

Insufficient synthesis
Lactate

Anaerobic glucose metabolism

 

Additional information

Thrall, M. A., Weiser, G., Allison, R. W. & Campbell, T. W. Veterinary Hematology and Clinical Chemistry. (Wiley-Blackwell, 2012).
Ivy, J. H., Svec, M. & Freeman, S. Free plasma levels and urinary excretion of eighteen amino acids in normal and diabetic dogs. Am. J. Physiol. 167, 182–192 (1951).
Holecek, M. Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. Nutr. Metab. (Lond). 15, 33 (2018).
O’Kell, A. L., Garrett, T. J., Wasserfall, C. & Atkinson, M. A. Untargeted metabolomic analysis in naturally occurring canine diabetes mellitus identifies similarities to human Type 1 Diabetes. Sci. Rep. 7, 9467 (2017).
Guasch-Ferre, M. et al. Metabolomics in Prediabetes and Diabetes: A Systematic Review and Meta-analysis. Diabetes Care 39, 833–846 (2016).
Cheng, S. et al. Metabolite profiling identifies pathways associated with metabolic risk in humans. Circulation 125, 2222–2231 (2012).
Allen, S. E. & Holm, J. L. Lactate: physiology and clinical utility. J. Vet. Emerg. Crit. Care 18, 123–132 (2008).
Pang, D. S. & Boysen, S. Lactate in veterinary critical care: pathophysiology and management. J. Am. Anim. Hosp. Assoc. 43, 270–279 (2007).
Juraschek, S. P., Selvin, E., Miller, E. R., Brancati, F. L. & Young, J. H. Plasma lactate and diabetes risk in 8045 participants of the atherosclerosis risk in communities study. Ann. Epidemiol. 23, 791–796.e4 (2013).