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, the uptake of amino acids in cells, and the conversion of excess energy (protein, sugars, fat) into bodyfat.

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] Approximately 80% of people with type 2 diabetes mellitus are overweight or obese [17] 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.[18] Insulin evokes the storage of blood glucose and glucogenic amino acids as liver glycogen. Once liver glycogen is completely repleted, additional glucogenic bodies need to be stored as glycerol in triglycerides. The latter is a relatively slow process, due to the need for 3 free fatty acids for each single glycerol molecule, for which a large proportion of the excess glucogenic bodies need to be converted into fatty acids first. In the meantime (prior to complete convertion), full glycogen stores can therefore give way to repeated triggering of insulin release (and fat deposition), which may lead to insulin resistance.

Conversion of glucogenic bodies into fatty acids is a slow process because the pyruvate (from glucogenic bodies) needs to be converted into acetyl-CoA in the mitochondrion, which thereafter can only indirectly (through citrate, oxaloacetate and malate subsequently) be transported to the cytosol for conversion into malonyl CoA, which is the first step in the synthesis of fatty acids (predominantly in the liver).[19] After synthesis of fatty acids from glucogenic bodies, excess glucose / glucogenic amino acids can be stored as triglycerides in adipose tissue.

Protein Pathway

Principally, advanced glycation end products (AGEs) are the products of a reaction between an amine and a reducing sugar (see Maillard Reaction). Non-glycated biogenic amines (including amino acids) are rapidly utilized, absorbed or converted:

Half-life of histamine is only 102 seconds [20], 72 seconds for serotonin (not taken up in platelets etc) [21], 2 to 2.5 minutes for norepinephrine [22], 2 to 3 minutes for epinephrine [23], and 2 minutes for dopamine [24][25], depending on the volume of distribution [26]. Half life of amino acids may be less than 10 minutes for all amino acids [27], <1 hour [28], 11 minutes for glutamate [29], 35 minutes for leucine [30], 36 minutes for cysteine [31], +/-1 hour for phenylalanine [32]76 minutes for arginine [33], and +/-2 hours for tryptophan [34][35]; higher intakes lead to shorter half-lives [36]. Half life of peptides may be less than 1 hour [37][38][39][40])[41][42].

Aggressive, reactive AGEs may have a half-life of 3.5 hours (MeIQx) [43], or 6 hours (for acrylamide) [44]). AGEs usually have a longer half-life [45] because AGEs are irreversible chemical modifications (of protein)[46][47][48][49], strongly resistant to proteolytic processes.[50] Dietary induced AGE elevations lasted 18 to 20 hours in nondiabetic subjects, and 36 to 48 hours in diabetics. AGE clearance rates have been found to be slower than that of creatinine [51](half-life of creatinine is 3.85 hours in healthy subjects [52]) Absorbed reactive AGEs such as Pentosidine may swiftly be cleared from the blood, only to get reabsorbed and/or rapidly bind to tissue proteins to a major extend [53], preventing their turnover.[54] As part of our western diet, we ingest AGEs of which approximately 50-80% are absorbed, catabolised and excreted over a period of two days.[55]

As a result, a glycated amino acid may repeatedly trigger the release of insulin, as compared to its original non-glycated version. Similarly, AGEs increase lipid synthesis and uptake.[56] A diet that is low in AGEs may reduce the risk of type 2 diabetes by increasing insulin sensitivity.[57] This may be due to the longer half-life of AGEs versus non-glycated protein, or due to cross-linking to tissue proteins. In addition, higher blood-sugar levels resulting from insulin resistance enhance endogenous AGE formation, accelerating AGE accumulation.[58]

Similarly, half-life of beta-amyloid is prolonged in Alzheimer's Disease (AD). AD is characterized by deposits of beta-amyloid peptide, modified by AGEs.[59]

Fasting

Regular (eg daily), intermittent fasting (IF) sensitizes insulin receptors, and may decrease serum AGEs.

Fasting insulin and insulin resistance were both reduced to a greater extent in the intermittent fasting compared with the daily caloric restriction group.[60] Studies of IF and time-restricted feeding have demonstrated improvements in insulin resistance.[61] A daily 8 hour eating window (time-restricted feeding, with fat as the predominant fuel source), improved insulin resistance and reduced severity of hepatic steatosis during 7 weeks trial.[62] Two vs five days of intermittent energy restriction (in 12 weeks trial) or constant energy restriction resulted in similar improvements in glycaemic control.[63]

A one week fast (300 kcal/day), however, significantly decreased blood pressure, but resulted in non-significant improvements in glyceamic control after 4 months.[64] And one-meal-per-day intermittent fasting with low-carb and high fat or high protein diets may increase insulin resistance.[65]

For the use of fasting in people with established type 2 diabetes, this requires the cessation of medication to prevent hypoglycemia.[66]