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Hyperglycemia, which occurs when glucose levels in the blood rise to dangerous levels, is a hallmark of diseases such as metabolic syndrome and type 2 diabetes. The effects of hyperglycemia are well documented and include cellular damage, inflammation, and pro-cancer effects; however, few studies have elucidated the cellular mechanisms of hyperglycemia. Findings of a new report suggest mitochondrial damage explains the connection between hyperglycemia and disease.

Glucose is consumed in the diet from simple sugars and starches. Glucose transport proteins, which move glucose from the bloodstream into cells, are expressed in the heart, skeletal muscle, adipose tissue, and brain among others. TXNIP is a protein that binds to glucose transporters, preventing the movement of glucose into cells. Mice who do not produce the TXNIP protein, called knockouts, experience uncontrolled glucose transport into cells. Glucose metabolism produces damaging compounds called reactive oxygen species, which attack the delicate lipid membranes in mitochondria, the cell structures that produce energy.

Brown adipose tissue is particularly vulnerable to the effects of hyperglycemia. This fatty tissue produces heat in response to cold temperatures, while white adipose tissue is mainly for energy storage. Brown adipose tissue appears brown because it has a higher density of mitochondria, which may make these cells more susceptible to damage from hyperglycemia, especially in cold temperatures.

The investigators compared normal mice with those that did not express the TXNIP protein in their brown adipose tissue. After exposing both groups of animals to cold temperatures (40°F, 4°C) for four hours, the researchers measured their body temperatures using a thermal camera and performed an in vitro study to examine the cellular integrity of mitochondria and their ability to produce energy from multiple common fuel sources.

These experiments revealed that TXNIP knockout mice had lower body temperatures after cold exposure than normal mice, suggesting that their brown adipose tissue was less effective at producing heat under stress conditions. Their mitochondria also showed signs of membrane damage and reduced concentration of polyunsaturated fats, which indicated that they were significantly more stressed due to reactive oxygen species produced during cold exposure compared to mitochondria in normal mice. TXNIP knockout mice had lower expression of genes related to energy metabolism and heat production.

Interestingly, the researchers found that severely restricting the TXNIP-deficient animals’ glucose intake by feeding them a ketogenic diet for five weeks mitigated the stress-induced deficit in mitochondrial function and reversed the detrimental changes to the polyunsaturated fat content of their mitochondrial membranes.

These findings indicate that excess sugar intake creates mitochondrial dysfunction, which contributes to poor health. A ketogenic diet reversed the effects of hyperglycemia on mitochondrial function.

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