The study, conducted in mice and corroborated in human liver samples, unveils a metabolic process that could upend previous ideas about how the body becomes resistant to insulin and eventually develops diabetes.
"There is still significant controversy as to whether sugar consumption is a major contributor to the development of diabetes," said senior author.
"Some investigators contend that commonly consumed amounts of sugar do not contribute to this epidemic," senior author said. "While others are convinced that excessive sugar ingestion is a major cause. This paper reveals a specific mechanism by which consuming fructose in large amounts, such as in soda, can cause problems."
Insulin is a key hormone that regulates blood glucose after eating. Insulin resistance, when the body's metabolic tissues stop responding normally to insulin, is one of the earliest detectable changes in the progression to diabetes.
However, according to this study, the cause of insulin resistance may have little to do with defects in insulin signaling and might actually be caused by a separate process triggered by excess sugar in the liver that activates a molecular factor known as carbohydrate-responsive element-binding protein, or ChREBP.
The ChREBP protein is found in several metabolic organs in mice, humans and other mammals. In the liver, it is activated after eating fructose, a form of sugar naturally found in fruits and vegetables, but also added to many processed foods including soft drinks. The study found that fructose initiates a process that causes the liver to keep making glucose and raising blood glucose levels, even as insulin tries to keep glucose production in check.
"For the past several decades, investigators have suggested that there must be a problem in the way the liver senses insulin, and that is why insulin-resistant people make too much glucose," senior author said. "We found that no matter how much insulin the pancreas made, it couldn't override the processes started by this protein, ChREBP, to stimulate glucose production. This would ultimately cause blood sugar and insulin levels to increase, which over time can lead to insulin resistance elsewhere in the body."
To test their hypothesis, researchers studied mice that were genetically altered so their liver insulin signaling pathways were maximally activated—in other words, their livers should not have been able to produce any glucose.
The researchers found that even in these mice, eating fructose triggered ChREBP-related processes in the liver, causing it to make more and more glucose, despite insulin signals telling it to stop.
Previous studies have reported that high fructose diets can cause multiple metabolic problems in humans and animals, including insulin resistance and fatty liver disease. Because most people found to be insulin-resistant also have fatty liver, many investigators have proposed that the fructose-induced fatty liver leads to liver dysfunction, which causes insulin resistance, diabetes and high risk for heart disease.
The new findings suggest fatty liver disease may be a red herring, senior author said. The likely cause of insulin resistance may not be the buildup of fat in the liver, as commonly believed, but rather the processes activated by ChREBP, which may then contribute to the development of both fatty liver and increased glucose production.
Although much more research is required, the scientists believe they better understand a key mechanism leading to pre-diabetes and can now explore how to possibly interrupt that chain of events. ChREBP may not be the only pathway by which this happens, and the protein may also be activated in other ways, senior author said. But the study provides an important lead, he said.
As a medical doctor, senior author said the advice to patients remains the same: make sure you're not eating too much sugar, which often shows up on labels as sucrose (the main ingredient in beet and cane sugar) and high fructose corn syrup. Both sweeteners contain both glucose and fructose and are rapidly absorbed, he said.
In its naturally occurring form and quantity, fructose is not particularly harmful, senior author explained, because if you're eating an apple, for example, you're eating a relatively small amount of sugar and it's combined with other nutrients such as fiber that may slow its absorption.
"You could eat three apples and not get the same amount of fructose you might get from a 20-ounce sugar-sweetened beverage," senior author said. "The major sources of excessive fructose are in foods like sodas and many processed foods, which are foods most doctors would say to limit in your diet."
Latest News
Complete vascularization of…
By newseditor
Posted 28 Mar
Immune cells identified as…
By newseditor
Posted 28 Mar
TB blood test which could d…
By newseditor
Posted 27 Mar
Propionate supplementation…
By newseditor
Posted 27 Mar
Role of human Kallistatin i…
By newseditor
Posted 26 Mar
Other Top Stories
How mechanical forces nudge tumors toward malignancy
Read more
How cancer evades the immune system
Read more
Genes that drive ovarian cancer identified!
Read more
Neural Differentiation Defect from Loss of a Single Gene Fuels Dead…
Read more
How a protein mutation leads to colorectal cancer
Read more
Protocols
Spatial proteomics in neuro…
By newseditor
Posted 28 Mar
All-optical presynaptic pla…
By newseditor
Posted 23 Mar
Epigenomic tomography for p…
By newseditor
Posted 20 Mar
A mouse DRG genetic toolkit…
By newseditor
Posted 17 Mar
An optogenetic method for t…
By newseditor
Posted 13 Mar
Publications
A microfluidic platform int…
By newseditor
Posted 28 Mar
Salmonella manipulates macr…
By newseditor
Posted 28 Mar
BHLHE40/41 regulate microgl…
By newseditor
Posted 28 Mar
Balancing neuronal activity…
By newseditor
Posted 28 Mar
OSBP-mediated PI(4)P-choles…
By newseditor
Posted 28 Mar
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar