Diabetes

Insulin Secretion

As a key regulator of whole body metabolism, the hormone insulin is secreted by pancreatic β-cells as a response to an elevation in nutrients. Insulin facilitates the conversion of glucose into liver- and muscle-glycogen, as well as the uptake of amino acids in cells.

Not just glucose (and fatty acids), but also amino acids (protein) directly trigger the release of insulin (eg glycine [1], arginine [2], leucine [3], isoleucine, valine [4], aspartic acid, alanine and serine [5]). Amino acids also affect glucose uptake (particularly phenylalanine [6]) and compete as oxidative fuels.[7] Lysine, tyrosine, alanine, serine and aspartic acid may play a key role in glucose-stimulated insulin secretion.[8] In pancreatic islets from both healthy young children and adults, insulin secretion is stimulated by arginine and the combination of leucine and glutamine, concentration-dependent and in an biphasic pattern, similarly to glucose-induced insulin secretion.[9] A mixture of leucine, isoleucine, valine, lysine and threonine resulted in significant glycemic and insulinemic responses.[10] Insulin responses are positively correlated with plasma leucine, phenylalanine, and tyrosine concentrations.[11]

Insulin Resistance

Insulin resistance is related to valine, glutamate, tyrosine, glutamine and glycine levels. β-cell functioning is related to leucine, tryptophan, valine, glutamate, glutamine, glycine and serine levels.[12] Dysregulated leucine metabolism progressively develops into insulin resistance [13], and high leucine exposure induced insulin resistance may be reversed by removing the high leucine exposure.[14] In a 12-year follow-up study involving adult Japanese individuals, plasma levels of isoleucine, leucine, valine, tyrosine, and phenylalanine (particularly any combination of minimally 3 of these amino acids) were reported to predict the development of diabetes in nondiabetic subjects.[15]

Overweight Pathway

Obesity is a leading pathogenic factor for developing insulin resistance.[16] Obese women show a blunted protein anabolic response to hyperinsulinemia that is consistent with resistance to the action of insulin on protein concurrent with that on glucose metabolism.[17] Insulin evokes the storage of blood glucose as liver glycogen. Once liver glycogen is completely repleted, additional blood glucose needs to be stored as glycerol in triglycerides. The latter is a relatively slow process, which can give way to repeated triggering of insulin release, which may lead to insulin resistance.

Protein Pathway

Principally, advanced glycation end products (AGEs) are the products of a reaction between an amine and a reducing sugar. Non-glycated amines, amino acids and peptides are rapidly utilized, absorbed or converted, but AGEs usually have a much longer half-life. As a result, a glycated amino acid may repeatedly trigger the release of insulin, as compared to its original non-glycatede version. A diet that is low in AGEs (see Maillard Reaction) may reduce the risk of type 2 diabetes by increasing insulin sensitivity.[18] This may be due to the longer half-life of AGEs versus non-glycated amino acids and peptides.