The "Smell" of Insulin Contributes to Diabetes

Diabetes is any disorder characterized by excessive urine excretion. The most common form of diabetes is diabetes mellitus, a metabolic disorder in which there is an inability to maintain carbohydrate and lipid homeostasis due to disturbances in insulin function, resulting in hyperglycemia and excess urinary excretion of glucose as well as hyperlipidemia. Diabetes mellitus is characterized by chronic hyperglycemia and the potential for episodic ketoacidosis. Additional symptoms of diabetes mellitus include excessive thirst, (polydipsia) glucosuria (elevated glucose in the urine), polyuria (excessive urination), lipemia (excess fat in the blood), and polyphagia (excessive hunger).

There are two primary forms of diabetes mellitus, type 1 and type 2. Type 1 is defined by the loss of insulin production by the beta(β)-cells of the pancreas and type 2 is defined by resistance to the peripheral responses to insulin. If left untreated type 1 diabetes can lead to fatal ketoacidosis. Of the two major forms of diabetes mellitus, type 2 represents the prevalent form of the disease. Indeed, in the US type 2 diabetes could easily be considered at epidemic proportions.

A characteristic feature of type 2 diabetes, particularly in the poorly controlled situation, is a progressive loss of insulin production and secretion. When insulin protein is synthesized in β-cells it is packaged into secretory vesicles where it awaits secretion in response to the appropriate signal. The regulation of insulin secretion is discussed in the Insulin Function, Insulin Resistance, and Food Intake Control of Secretion page of my website. In addition to functional insulin, the secretory vesicles contain diabetes-associated insulin peptides as

well as denatured insulin. These insulin peptides trigger islet autoimmunity, which is functionally associated with the incidence of type 2 diabetes.

As described in a recent paper in the prestigious journal, Cell Metabolism, insulin peptides function in an autonomous manner to suppress secretion of insulin as a result of their binding to and activation of a receptor that is a member of the large family of olfactory (smell) receptors:

Autonomous sensing of the insulin peptide by an olfactory G protein-coupled receptor modulates glucose metabolism

When the investigators examined pancreatic islets for expression of members of the olfactory receptor family [all of which are members of the G protein-coupled receptor (GPCR) superfamily], they discovered that six were expressed in both human and mouse islets and that the levels of all six receptors increased in response to high glucose stimulation. However, only one receptor, encoded by the OLFR109 gene in mice and the OR12D3 gene in humans, was increased in all models of obesity and diabetes. Also, of the six olfactory receptors identified, only two, Olfr109 (human OR12D3) and Olfr110 (human OR5V1) were detected in the plasma membranes of cultured islet cells.

In mouse models of obesity and diabetes, the elimination of the Olfr109 receptor resulted in increased glucose homeostasis. In the obesity mouse model, where feeding a high-fat diet results in rapid weight gain, the loss of Olfr109 resulted in less weight gain and increased energy expenditure, and increased glucose utilization.

Equally significant for potential therapeutic intervention in humans is the fact that pharmacological blockade of Olfr109 function results in improved glucose homeostasis. These investigators used a pepducin as the inhibitor of the Olfr109 receptor. The pepducin class of molecules are lipopeptides (lipidated peptides) that consist of a fatty acid (most often the 16 carbon saturated fatty acid palmitic acid which is the most abundant fatty acid in the human circulation) attached to a short peptide of, usually, 16 amino acids or less.

TAKE HOME: New therapeutic potential in the treatment and prevention of type 2 diabetes and possible obesity, is now possible with this recent discovery of the role of GPCR of the olfactory receptor family contributing to the regulation of insulin synthesis and section by pancreatic β-cells.