Diabetes Mellitus specifically type 2 diabetes is a serious consequences resulting from resistance to insulin action, inadequate insulin secretion and excessive or inappropriate glucagon secretion. It is associated with multiple array of macrovascular, microvascular and neuropathic complications. It is estimated in 2015 alone, in United States, 30.3 million people of all ages, or 9.4% from the general population, had diabetes and 84.1 million adults or 33.9% of adult population had prediabetes.

Source: https://nurseslabs.com

According to the American Diabetes Association, prediabetes is defined as the state in which blood glucose levels are higher than normal level but not high enough to be diagnosed as diabetes. However, they have a higher tendency to get diabetes later in life.

There are 4 principle theories that can explain the microvascular complications in diabetic patient:

• Polyol pathway influx
• Advanced Glycation End (AGE) Product
• Activation of Protein Kinase C (PKC) Isoform
• Hexokinase pathway influx

Polyol Pathway Influx

Polyol pathway is a two-step metabolic pathway which reduced glucose to Sorbitol and then converts the Sorbitol into Fructose. This pathway is activated when the intracellular glucose levels are elevated (hyperglycaemic state). Aldose Reductase (AR) acts as the first and rate limiting enzyme of the pathway which helps reducing glucose to Sorbitol by using a co-factor Nicotinamide Adenine Dinucleotide Phosphate (NADPH). Sorbitol then would be oxidized into Fructose by an enzyme Sorbitol Dehydrogenase by using a co-factor; Nicotinamide Adenine Dinucleotide.

Source: http://pubs.rsc.org

How do this pathway causes microvascular complication in a diabetic patient? There is several explanations for that but the most important events that we should turn our attention to are:

• Production of Sorbitol
• Production of Fructose
• The usage of NADPH as a co-factor for reduction of glucose
• The usage of NAD as a co-factor for oxidation of Sorbitol

Production of Sorbitol and utilization of NADPH as a co-factor for the reaction

Sorbitol is an alcohol, polyhydroxylated and strongly hydrophilic compound. That means, it can’t diffuse readily through cell membranes and cause it to accumulate intracellularly. This can cause osmotic complication which can lead to cellular damage.

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NADPH which is used by the AR to reduce glucose into Sorbitol was an important co-factor which is being used in the production of reduced Glutathione (GSH) by the enzyme Glutathione Reductase (GR). It is an important antioxidant in plants, animals, fungi and some of the bacteria and Archaea. Glutathione is capable of preventing oxidative damage to important cellular components cause by reactive oxygen species such as free radicals, lipid peroxides and heavy metals.

Source: https://healthimpactnews.com

When there is an increase utilization of NADPH by the enzyme, Aldose Reductase, the amount of NADPH available for the production of Glutathione decreases. During hyperglycaemic state, up to 30% of glucose can enter Polyol pathway which uses an abundant amount of NADPH co-factor which ultimately, reduced the production of Glutathione. This makes diabetic patients prone to the complications of increase oxidative stress which can be impacted on the microvascular system.

Production of Fructose and utilization of NAD as a co-factor for the reaction

Fructose is a product formed from the oxidization of Sorbitol by Sorbitol Dehydrogenase by using a co-factor NAD. This compound can be phosphorylated to Fructose-3-Phosphate which is broken down to 3-Deoxyglucosone. Both of the compound produced from the phosphorylation of Fructose was a powerful glycosylating agents that contribute in the formation of Advanced Glycation End (AGE) Product.

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As the reaction goes, NADH was produced from the reduction of NAD. This NADH can be used by the enzyme NADH oxidase to produce superoxide – a reactive free radical through an electron transfer from NADH to oxygen as the electron acceptor. We have been discussing the effect of utilization of NADPH in the production of Sorbitol previously which caused reduced production of Glutathione. It turns out, not only our body defense mechanism against the free radical reduces, but the provoking compound (free radicals) increases which cause further damage to the cell.

Source: https://www.biotek.com

Summary

Activation of the Polyol pathway, by altering intracellular tonicity, generating AGE's precursors, and exposing cells to oxidative stress perhaps through decreased antioxidant defenses and generation of oxidant species, can initiate and multiply several mechanisms of cellular damage.

References

• Gabbay KH. The sorbitol pathway and the complications of diabetes. The New England Journal of Medicine. 1973;288(16):831–836.
• https://emedicine.medscape.com/article/117853-overview#a5 accessed on 25th December 2017