Metabolics and Sugar Metabolism

Sugar Metabolism

Carbohydrates are sugar molecules and are the body's favoured fuel source, providing immediate energy. They are broken down into glucose which constitutes blood sugar.

Glucose can come from three different sources: i) intestinal absorption of dietary carbohydrates (sugar, starches and fibre), ii) glycogenolysis – breakdown of glycogen, and iii) gluconeogenesis – formation of glucose from non-carbohydrate precursors including lactate, pyruvate, glycerol and amino acids.

After glucose enters the bloodstream, insulin is released which allows it to enter the cells. Insulin is produced by the pancreas and is the body's primary anabolic hormone. It regulates the metabolism of carbohydrates, fats and proteins. Once in the cell, glucose can be used for energy production (aerobic or anaerobic) and nucleotide synthesis via the pentose phosphate pathway (PPP). Impairment of a pathway due to SNPs or environmental factors can lead to conditions such as insulin resistance, diabetes, weight gain, chronic fatigue or cancer.

Blood Glucose

The TCF7L2 (transcription factor 7-like 2) gene is involved in regulating blood sugar by influencing the production of insulin. Variants on TCF7L2 lead to over-expression, reduced insulin release and risk of hyperglycaemia. This can lead to insulin resistance, type 2 diabetes, and risk of developing gestational diabetes. Natural modulators of TCF7L2 include flavonoids, curcumin, green tea, resveratrol, retinoids and lupeol – found in olives, mangoes, strawberries, green peppers, tomatoes.

Insulin binds to its receptor and interacts with IRS1 (insulin receptor substrate 1) to facilitate glucose uptake via increased activity of GLUT4, a glucose transporter. A SNP on IRS1 results in reduced activity and impaired insulin signalling. Obesity, stress and inflammation can further promote insulin resistance. Exercise (especially aerobic) induces GLUT4 activity. GLUT2 is another transporter which controls glucose uptake in the liver. However, unlike GLUT4, it does not rely on insulin and acts as a glucose sensor. A SNP on GLUT2 can lead to a down- regulated activity and is associated with risk of gestational diabetes and noninsulin-dependent diabetes.

Glucose uptake can be influenced by several other factors. FABP2 (fatty acid-binding protein 2) has high affinity for saturated long-chain fatty acids and is involved in their uptake and metabolism. Increased FABP2 expression preferentially moves fats into cells instead of glucose, which increases the risk of insulin resistance and type 2 diabetes. PPARG (peroxisome proliferator-activated receptor gamma) is also involved in glucose uptake and fat storage. A SNP confers a less active PPARG and less efficient glucose uptake, a higher risk of insulin resistance and fatty liver.

Cellular Glucose

Once glucose has entered the cell, it is broken down by a process called glycolysis. It is firstly converted to G6P (glucose-6-phosphate) by a glucokinase, encoded by the GCK gene. Glucokinase diabetes is a type of familial diabetes often called MODY (maturity-onset diabetes of the young). Variants on GCK reduce its activity and may increase blood glucose and risk of type 2 diabetes. Carriers of this SNP may benefit from a higher intake of whey proteins, retinoic acid and biotin.

G6P can be directed to the PPP to generate NADPH to activate glutathione and ribose-5- phosphate for nucleotide synthesis or – more typically to produce pyruvate, with NAD+ and magnesium as cofactors. In the mitochondria, pyruvate is converted to acetyl-CoA, which goes into the Krebs cycle to produce ATP.

In anaerobic conditions (hypoxia/low oxygen), pyruvate is converted to lactate by fermentation. This can occur during strenuous exercise or due to infection or shock. While this produces less ATP, it can support rapid cellular division, which can be beneficial for muscle growth but detrimental in abnormal conditions (Warburg effect).

AMPD1 codes for adenosine monophosphate (AMP) deaminase 1, a component of the purine nucleotide cycle. It plays a role in energy metabolism by recycling AMP back to IMP (inosine monophosphate) — and ultimately replenishing ATP — and ammonia. A SNP results in AMPD1 deficiency, which increases the levels of AMP and leads to the activation of AMPK. This is beneficial as it has been associated with improved insulin sensitivity and glucose utilisation and less risk of type 2 diabetes. Metformin, one of the best-known drugs used to reverse insulin resistance, has a similar effect to the SNP, inhibiting AMPD1 activity and inducing AMPK. However, individuals with AMPD1 deficiency are more likely to experience muscle fatigue, cramps and pain during and after endurance exercise. This is due to the slower conversion of AMP to IMP, and less ammonia production to neutralise lactate. Well-trained, fuelled and hydrated athletes have a lower risk of experiencing muscle dysfunction symptoms.

Glucose vs Fats

Excess glucose intake promotes fat storage and inhibits fat burning. In this case, acetyl-CoA is converted into malonyl-CoA, which is a building block of triglycerides (fat droplets) in adipose tissue. Malonyl-CoA also suppresses fatty acid utilisation by inhibiting the action of CPT1A (carnitine palmitoyltransferase 1A), which transports fatty acids into the mitochondria.

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