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Can We Fix the Body’s Dysmetabolic State?

  • An epidemic of obesity is leading to multiple diseases that share as their basis a problem called the dysmetabolic state.
  • This condition increases the risk of diabetes, cardiovascular disease and a serious, progressive form of nonalcoholic fatty liver disease known as nonalcoholic steatohepatitis, or NASH.
  • Now scientists believe they may have found a way to fight back.

It’s no secret that obesity, diabetes and heart disease are among the most devastating illnesses of the developed world. But while many health care professionals used to view them as separate, stand-alone conditions, there’s now a growing awareness that the three are tightly connected, caused by a shared problem called the dysmetabolic state, which can take hold when people become overweight. The bodies of those with extra weight, like cars in need of tuning, have an increased risk of wearing out and malfunctioning, gumming up their gears — the internal metabolic pathways.

Now scientists are studying new therapeutic approaches to tackle this challenge — aimed at fixing those metabolic “gears” of the body.

As patients become overweight, their bodies start losing the ability to regulate the insulin hormone properly, which in turn affects how the body absorbs and uses glucose. In particular, obesity contributes to a state of insulin resistance, in which the tissues of the body such as muscle, adipose and the liver become less responsive to the signal of insulin to take up and utilize glucose.

Female African American doctor and her patient

Source Getty

As blood glucose levels go up, the body tries to compensate by secreting more insulin to overcome this insulin resistance, creating a condition of excess insulin, or hyperinsulinemia. “That’s the beginning of the dysmetabolic state, and that’s not a favorable metabolic state for the body to be in,” says Jeffrey Pfefferkorn, vice president of discovery & development for Pfizer’s Internal Medicine Research Unit.

It’s also the start of a cascade reaction throughout the body. The overabundance of insulin, and eventually glucose, begins to interfere with the health and function of multiple organ systems, leading to metabolic and cardiovascular disease. For example, the liver begins to accumulate excess fat, leading to nonalcoholic fatty liver disease (NAFLD). That then creates a pro-inflammatory state, an environment in which inflammatory processes develop easily, damaging healthy liver tissues. Liver cells — known as hepatocytes — start to rupture and die, Pfefferkorn explains. Ruptured hepatocytes result in scarring and fibrosis, which lead to so-called nonalcoholic steatohepatitis (NASH).

Type 2 diabetes, cardiovascular disease, NASH … these are life-threatening diseases that impact patients on a massive scale and share one root cause: the dysmetabolic state.

Jeffrey Pfefferkorn, Vice President of Discovery & Development, Internal Medicine Research Unit, Pfizer

The Dysmetabolic State in Action: NASH as an Example

A healthy liver contains no more than 5 percent fat by weight, but in NAFLD patients, the proportion of fat can be more than 25 percent. And while nonalcoholic fatty liver itself isn’t typically life-threatening, it can, over years, develop into NASH, a more dangerous form that can increase the risk of liver failure and liver cancer. NAFLD affects about 100 million Americans and nearly 2 billion people worldwide, according to the American Liver Foundation. And the prevalence of NASH is expected to balloon from 17 million Americans today to about 24 million by 2035.

Doctors have machines that act as artificial kidneys, hearts and lungs, but there’s no technology that can replace the liver, explains Dr. Tom Hemming Karlsen, a gastroenterologist at the University of Oslo and former secretary-general for the European Association for the Study of the Liver. If the liver fails, the only option is a transplant, which requires a donor and a complex surgery that may or may not be successful.

At present, there are no U.S. Food and Drug Administration or European Medicines Agency approved treatments for NASH. But scientists believe that by targeting specific metabolic pathways, they can clear the fat out of the liver. That could potentially prevent NASH in people who might be susceptible and could reverse fibrosis and inflammation in patients who already have the disease.

“At Pfizer, we are intervening in the metabolic pathway that drives the fat accumulation, because we believe that’s the engine that ultimately drives the inflammation that leads to fibrosis,” says Pfefferkorn.

The impact on the liver makes NASH particularly dangerous. Liver cells perform a gamut of vital functions, without which humans wouldn’t last a day, says Karlsen. Our liver produces bile, which we need to digest fat. It stores energy, releasing it as glucose. It regulates the immune system and acts as a “cleaning machine,” filtering bacteria and toxins from the body. “That’s why when the liver gets sick, you get sick in a very complex way, because there are so many things that don’t work anymore,” Karlsen says.

Unrecognizable overweight woman at home preparing a delicious healthy vegetable salad in her kitchen.

Some patients can reverse NAFLD/NASH through a healthy diet and exercise.

Source Getty

Currently, screening for NAFLD isn’t part of your annual physical exam, so it’s often overlooked. However, there are telltale signs that doctors can look for, such as elevated liver enzymes. Liver imaging scans can also detect NAFLD, alerting patients and their health care providers.

Some patients can reverse their NAFLD/NASH through a healthy diet, exercise and weight loss, but in many cases, these changes are not sustained and the disease continues to progress, so therapeutics are desperately needed. That’s what Pfefferkorn and his colleagues are working on, hoping to attack the disease by intervening in the metabolic pathways they’ve identified as critical for driving the disease.

Therapeutics targeting other pathways to stop inflammation or block fibrosis and make the disease regress are also worth exploring, he says, and the ultimate way of treating a NASH patient may be combining all these mechanisms into one potent therapeutic punch. “You can imagine hitting the disease in all of the ways it is negatively impacting the liver,” Pfefferkorn says.

The Big Picture

These research advances in trying to tackle NASH offer a glimpse of the broader progress scientists believe they’re making in addressing the multiple dangerous conditions that stem from the dysmetabolic state.

“Obesity-driven diseases such as type 2 diabetes, cardiovascular disease, NASH … these are life-threatening diseases that impact patients on a massive scale and share one root cause: the dysmetabolic state,” says Pfefferkorn. “Our strategy is to address the underlying drivers of these diseases by helping to correct this abnormal metabolic state.”

If that approach is successful, these metabolic interventions could roll back multiple diseases — for example, heart failure — prolonging lives and improving the quality of life too. It’s like tuning the gears in your car to their original, well-oiled shape. With the right intervention, your body could run for many more miles once again.

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