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I learned the citric acid cycle in biotechnology school and how cells work; about ADP and ATP and how the Cellular respiration (C6H12O6 + 6O2 -> 6CO2+6H2O) works.

I am interested in understanding why exactly too much glucose is harmful, e.g. when having diabetes.

What happens inside the cells so that the organs get damaged over time? Why can't the cells not simply "ignore" the needless glucose or convert it into energy?

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High intracellular glucose.

Affects: all cells that do not depend on insulin to take in glucose. Examples: neurons [1], kidney cells, retina cells.

Causes: high extracellular glucose (in most cases hyperglycemia)

Effects: promoting necrotic cell death through $H_2O_2$ (peroxide) formation, which may participate in the development of diabetic vasculopathies and associated disease [2].

High extracellular glucose.

Affects: extracellular matrix, cardiac muscle

Causes: lack of / low levels of insulin, insulin resistance

Effects: enhances collagen production thus affecting kidney by thickening glomerular basal membrane [3, 4]. It promotes cardiomyocyte metabolic stress and altered glucose handling [5]. It is also a potential mechanism involved in cardiac glycogen accumulation [5].

Diabetes mellitus involves:

  • high extracellular glucose, leading to:
  • high intracellular glucose in cells that do not depend on insulin to uptake glucose;
  • low intracellular glucose in cells that depend on insulin (muscle and fat tissue).

References:

  1. David R. Tomlinson and Natalie J. Gardiner. Glucose neurotoxicity (2008). Available from http://didattica.uniroma2.it/assets/uploads/corsi/140868/Glucose_Neurotoxicity_-NATURE_Reviews-Neuro,_Jan_2008.pdf (accessed 27.07.2014)
  2. RnCeus.com. Glucose Homeostasis (2012). Available from http://www.rnceus.com/dmeds/glucose.html (accessed 27.07.2014)
  3. Takeuchi A, Throckmorton DC, Brogden AP, Yoshizawa N, Rasmussen H, Kashgarian M. Periodic high extracellular glucose enhances production of collagens III and IV by mesangial cells. Am. J. Physiol. 1995 Jan;268(1 Pt 2):F13-9. PubMed PMID: 7840239.
  4. Ayo SH, Radnik RA, Garoni JA, Glass WF, Kreisberg JI. High glucose causes an increase in extracellular matrix proteins in cultured mesangial cells. Am. J. Pathol. 1990 Jun;136(6):1339-48. PubMed PMID: 2356864.
  5. Kimberley M. Mellor , Upasna Varma , David I. Stapleton , Lea M. D. Delbridge. Cardiomyocyte glycophagy is regulated by insulin and exposure to high extracellular glucose. American Journal of Physiology - Heart and Circulatory PhysiologyPublished 15 April 2014Vol. 306no. H1240-H1245DOI: 10.1152/ajpheart.00059.2014
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    $\begingroup$ An excellent answer - it really should be accepted. $\endgroup$
    – Alan Boyd
    Jul 29, 2014 at 11:39
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The glucose can react with proteins, damaging them. This is called glycation. Note that glucose is the preferred body fuel and has a 10 fold lower ability to cause glycation than fructose.

http://en.wikipedia.org/wiki/Glycation

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    $\begingroup$ Perhaps worth adding that the level of glycated haemoglobin is used as a way of monitoring how well diabetes is being controlled over the long term. $\endgroup$
    – Alan Boyd
    Jul 27, 2014 at 12:27
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    $\begingroup$ Protein is also insulinogenic, so presumably the body tries to keep it under some level in the blood. Would the same things happen with excess amino acids as you've mentioned? $\endgroup$
    – ManRow
    May 10, 2018 at 9:53
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Too much glucose leads to the formation of advanced glycated end products, which deposit in tissues like glomerulus and cause disease like diabetic nephropathy.

Also glucose is osmotically active, so when it starts appearing in urine (because of its high levels in blood), it leads to polyuria, following which the lost water is recovered from body tissues, leading to dehydration and increased thirst.

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Glucose transports from the blood into the cells via facilitated diffusion. This means that glucose goes from higher concentrations (in the blood) to lower concentration (in the cell). Therefore, if you have super high glucose concentrations in the blood, you will have a ton of glucose in the cells. Glucose will oxidize by itself, thus it will contribute a lot to the oxidative stress experienced by the cell.

To answer your question of why they cannot "ignore" it, it is because it simply goes down its concentration gradient via facilitated diffusion.

To answer your question of why they can't convert it to energy, well they can, but too much metabolism of glucose will also generate an excess of reactive oxygen species.

In conclusion, high glucose in cells generates a lot of oxidative stress, which of course, is bad.

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  • $\begingroup$ This answer has things backwards. In diabetes the failure of the insulin response to high blood sugar means that the glucose carriers are not recruited to the cell membranes. This results in a decreased capacity for glucose uptake and so blood sugar stays high. Also, glucose does not "oxidise itself". $\endgroup$
    – Alan Boyd
    Jul 27, 2014 at 12:26

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