Many people focus on counting carbs when managing blood sugar levels. However, recent research from the University of British Columbia suggests that for some individuals, it’s equally important to consider the proteins and fats in their diet.

The study is the first large-scale comparison of how different people produce insulin in response to each of the three macronutrients: carbohydrates (glucose), proteins (amino acids), and fats (fatty acids).

The findings show that insulin production is more individualized and dynamic than previously thought. Additionally, it reveals a subset of the population with a hyper-responsive to fatty foods.

“Glucose is well known as a driver of insulin, but we were surprised to see such high variability. Some individuals show a strong response to proteins, while others respond more to fats, a characteristic that had never been characterized before,” said senior author Dr. James Johnson, a professor of cellular and physiological sciences at UBC. “Insulin plays a major role in human health, from diabetes, where it is too low, to obesity, weight gain, and even some forms of cancer, where it is too high. These findings lay the groundwork for personalized nutrition that could transform how we treat and manage a range of conditions.”

For their study, the researchers conducted tests on pancreatic islets from 140 deceased male and female donors spanning a wide age range. The islets were exposed to each of the three macronutrients, while the researchers measured the insulin response alongside 8,000 other proteins.

Although most donors’ islet cells had the strongest insulin response to carbohydrates, about 9% responded strongly to proteins, while another 8% were more responsive to fats than any other nutrient, including glucose.

“The research challenges the long-held belief that fats have negligible effects on insulin release in everyone,” said Dr. Jelena Kolic, a research associate in the Johnson lab at UBC and the first author of the study. “With a better understanding of an individual’s drivers of insulin production, we could potentially provide tailored dietary guidance to help people better manage their blood sugar and insulin levels.”

The research team examined a subset of islet cells from donors with Type 2 diabetes. As expected, these donor cells showed a low insulin response to glucose. However, the researchers were surprised to find that their insulin response to proteins remained largely intact.

The research team examined a subset of islet cells from donors with Type 2 diabetes. As expected, these donor cells showed a low insulin response to glucose. However, the researchers were surprised to find that their insulin response to proteins remained largely intact.

The research team carried out a thorough analysis of protein and gene expression in pancreatic islet cells, offering valuable insights into the molecular and cellular factors that influence insulin production. In the future, the researchers believe it may be possible to utilize genetic testing to identify which macronutrients are likely to stimulate an individual’s insulin response.

The research team carried out a thorough analysis of protein and gene expression in pancreatic islet cells, offering valuable insights into the molecular and cellular factors that influence insulin production. In the future, the researchers believe it may be possible to utilize genetic testing to identify which macronutrients are likely to stimulate an individual’s insulin response.

What if current treatment of insulin resistance was only perpetuating the disease and causing disease to get worse?  According to Boston University School of Medicine (BUSM) researchers type 2 diabetes patients are often prescribed drugs that increase insulin release into the blood, which lowers blood glucose but may in fact increase the insulin resistance with long-term use. Many of these patients have elevated insulin even when glucose is normal.

Insulin is the hormone that allows tissues like muscle and fat to take up glucose from the blood to be used as fuel for energy needs. It is released from the pancreas into the blood stream when blood glucose levels increase, such as after a meal. Thus, insulin is secreted to lower blood glucose and keep it at a normal healthy level.

When nutrients such as fatty acid circulate through the blood at a constant high level it can damage tissue function. Insulin resistance is an impairment that occurs in muscle and fat making it harder for insulin to allow these tissues to take up glucose and lower blood glucose to a normal level. As a result, insulin increases to a level that is above normal and remains elevated even between meals and overnight. This causes the pancreas to maintain greater than normal blood insulin levels, a condition known as hyperinsulinemia and that precedes and can result in type 2 diabetes (T2D).

The medical field has long believed that insulin resistance is the root cause of this elevated blood insulin. However, a new review article highlights an opposing view that hyperinsulinemia is initially driven by insulin hypersecretion from beta cells impaired by the excess nutrients and environmental toxins. “Thus increased insulin release from the pancreas drives blood insulin levels higher causing/contributing to insulin resistance,” explains corresponding author Barbara E. Corkey, PhD, professor emeritus of medicine at BUSM.

According to the researchers, T2D patients often are prescribed drugs that increase insulin release into the blood, which lowers blood glucose but may in fact increase the insulin resistance with long-term use. “Our article describes a testable model in which chronic excess nutrient exposure results in insulin hypersecretion from the beta cell contributing to hyperinsulinemia. Hyperinsulinemia normally precedes measurable insulin resistance and T2D. It is viewed by many as a normal response to insulin resistance rather than its potential cause,” says Corkey.  

The researchers hope this review will highlight the potential damaging effects of increasing insulin release into the blood when levels are already elevated above normal levels due to insulin resistance. “Rather new therapeutic solutions that include lowering insulin levels before T2D develops may be warranted to prevent insulin resistance further developing into T2D,” said Corkey. 

Mitochondria inside liver cells (hepatocytes). CREDIT Mayuko Segawa, Liesa lab at UCLA Health

A new multi-institution study led by a team of researchers at the David Geffen School of Medicine demonstrated that blocking a protein called ABCB10 in liver cells protects against high blood sugar and fatty liver disease in obese mice. Furthermore, ABCB10 activity prompted insulin resistance in human liver cells.

The findings are the first to show that ABCB10 transports biliverdin out of the mitochondria – the cell’s “energy generating powerhouses.” Biliverdin is the precursor of bilirubin, a substance with antioxidant properties. Consequently, ABCB10 transport activity causes an increase in bilirubin synthesis inside liver cells undergoing fatty liver disease.

BACKGROUND

Non-alcoholic fatty liver disease is closely linked to obesity and other disorders related to insulin resistance and is becoming increasingly common throughout the world, affecting an estimated 100 million people in the United States.

The liver filters everything that people consume and sorts it for the nutrients that will stay in the body or for the toxins that it will expel. The liver is also one of the organs richest in mitochondria – the small organelles in cells that convert food into usable energy through a process called metabolism. Consequently, the mitochondria produce high levels of free radicals, as well as antioxidants to keep these free radicals at healthy levels. Both free radicals and antioxidants play a key role in regulating metabolism and are elevated in insulin resistance and fatty liver disease.

One of these antioxidants is bilirubin, a yellow-bile substance that is released from the breakdown of biliverdin – its green-bile precursor. Bilirubin is produced at high levels in livers from people with fatty liver disease. Both biliverdin and bilirubin are found naturally in the body and released during the breakdown of heme – the deep red iron-containing molecule in red blood cells, which can be seen in the changing color of bruises – from green (biliverdin) to yellow (bilirubin).

Previous research established that mild increases in blood bilirubin content could be associated with protection from metabolic diseases. However, the effects of bilirubin content inside mitochondria and their relationship to fatty liver disease and insulin resistance, remained unknown. This current study shows that increased bilirubin content inside the mitochondria driven by ABCB10 activity is contributing to fatty liver disease.

METHODS

In the study, the researchers removed the ABCB10 protein selectively from the livers of mice to test whether ABCB10 removal impacted the ability of obese mice to tolerate glucose, if they developed fat in the liver and how well the mitochondria in their livers were working to convert nutrients into usable energy.

In lean mice, the researchers found no difference in metabolism and health when ABCB10 was removed from their livers, while in obese mice they found that removing ABCB10 protected against insulin resistance and fatty liver disease.

Secondly, the researchers measured bilirubin in the mitochondria of liver cells using fluorescent sensors, as well as testing purified ABCB10 to determine what ABCB10 transports. They found that ABCB10 transports biliverdin out of the mitochondria and increases bilirubin production in liver cells, with ABCB10 removal decreasing mitochondrial bilirubin content to levels observed in lean mice.

Thirdly, the researchers found that when they restored bilirubin content in the mitochondria, the benefits on the function of mitochondria resulting from the removal of ABCB10 were reversed.

IMPACT

These findings shed light on the relevance of the association of some genetic ABCB10 variants with insulin resistance in Type 2 diabetes. While still very early to draw any conclusions, these findings could inspire the development of therapies that target ABCB10 or mitochondrial bilirubin in the liver to reverse fatty liver disease in obese individuals.