Insulin resistance could be explained by gene

New study finds the mechanism for insulin resistance leading to type 2 diabetes.

Earlier work by  Joshua Knowles, MD, PhD, an assistant professor of cardiovascular medicine at Stanford, and his team showed the connection of a human gene, NAT2, variant with insulin resistance in humans.

The fact that type 2 diabetes was caused by insulin resistance was known to researchers for decades. However, the cause for this phenomenon was a mystery.

Insulin, a hormone secreted by the pancreas, helps fat and muscle cells take up glucose from the blood. Insulin resistance is caused when human cells don’t respond to insulin, resulting in the build up of glucose in the blood and subsequently leading to the production of even more insulin.


The cause of insulin resistance is starting to be untangled by a team led by Joshua Knowles. (Photo courtesy of: Stanford University)

“We’ve identified a mechanism for insulin resistance that involves a gene that ties insulin resistance to mitochondrial function, “ said Knowles.

Scientists at the Stanford University School of Medicine and the University of Wisconsin have begun to find the connections between a gene, mitochondria, insulin resistance, and how well the body’s metabolism functions in causing diabetes.

Suppressing a similar gene in mice called Nat1, causes metabolic dysfunction, such as lower insulin sensitivity and higher levels of blood sugar, insulin and triglycerides. In addition, mice without the Nat1 gene gained more weight and showed a decreased ability to use fat for energy.

This new study reveals that suppressing the expression of the Nat1 gene in mice hinders the function of mitochondria. These cell structures make ATP, the energy of cells, without which the cells cannot survive.

Individuals with Insulin resistance don’t necessarily develop type 2 diabetes. However, the condition will result in decreased uptake of sugar by muscle and fat cells leading to cardiovascular disease, inflammation, polycystic ovary syndrome, fatty liver diseases and other health conditions.

Severe Insulin resistance leading to damaged body tissues is common. A study in 2015 estimated that close to 35 percent of US adults are insulin-resistant to a degree to be at a higher risk for diabetes and cardiovascular disease.

Knowles said, the reasons for this skyrocketing increase in the US are poor diet and  sedentary habits.

Incretin-based drugs for diabetes and their adverse effect

A popular group of drugs used to treat type 2 diabetes was shown to have no association with acute pancreatitis but an increased risk of bile duct and gallbladder disease. This was revealed  based on the  first population-based study investigating the possibility of an association with incretin-based drugs. These drugs are proven to be excessively popular for their effectiveness without causing hypoglycaemia, a problem with other classes of diabetes medications. Furthermore, they are shown to have beneficial effects on body weight.

“Early signal detection studies suggested that an association might exist. The suspicion was credible because these drugs act directly on the pancreas and there was a concern that they could be responsible for inflammation,” said Dr. Laurent Azoulay, Senior Investigator at the Lady Davis Institute at the Jewish General Hospital and Associate Professor in the Department of Epidemiology, at McGill University. “However, ours was the largest study ever to address the question – involving a cohort of more than 1.5 million patients – and there is no evidence to support that either type of incretin-based drug causes acute pancreatitis.”


Two studies led by Dr. Azoulay at Mcgill University, demonstrated that despite an increased risk of bile duct and gallbladder disease, incretin-based drugs are not associated with increasing the risk of acute pancreatitis. (Photo courtesy of:


Although  they have been prescribed to millions of patients, the safety of the drug remains controversial. Two studies led by Dr. Azoulay, demonstrated that despite an increased risk of bile duct and gallbladder disease, these drugs are not associated with increasing the risk of acute pancreatitis. Both studies are published in the JAMA Internal Medicine.

“Notwithstanding the latter finding, the totality of the evidence accumulated to date suggests that incretin-based drugs are effective and generally safe,” Dr. Azoulay concludes. “Nonetheless, it’s important that clinicians and patients alike be well informed about possible adverse effects. As a result of the gallbladder finding, it would be prudent for doctors to warn their patients to seek treatment if they experience symptoms, such as pain in their right side.” The most prevalent adverse effect is gallstones which are treatable but can cause extreme pain. In very severe cases the surgical removal of the gallbladder may be required.

The study concluded that nearly 3 more individuals per 1000 will exhibit symptoms as compared with those not taking this medication.

“Clinical trials are the gold standard to assess whether medications are effective, but because of their relative small sample sizes and short durations of follow-up, they are not designed to assess the risk of uncommon but clinically important adverse events,” said Dr. Azoulay, “this is where well designed studies conducted in the real-world setting can provide critical information on the safety of medications.”