Will We Soon Reverse Diabetes and Obesity with Gene Therapy?

New research shows that gene therapy can completely reverse markers of Type 2 diabetes and obesity in rodents.  If the theory holds, small alterations to our genes could soon repair metabolic disorders such as obesity and Type 2 diabetes in humans.

The prevalence of diabetes, or the total number of existing cases, is on the rise in the United States and globally.  According to recent estimates, over 30 million U.S. adults had diabetes in 2015.

Although the number has been relatively steady in the past few years, rates of newly diagnosed cases among children and teenagers have increased sharply.  And, worldwide, the situation is even more alarming; the number of people with diabetes almost quadrupled between 1980 and 2014, according to the World Health Organization (WHO).

Now, new research brings much-needed hope of curing this metabolic disorder.  Scientists led by Fatima Bosch, a professor at the Universitat Autònoma de Barcelona (UAB) in Catalunya, Spain, have successfully reversed the disorder in rodents.  Prof. Bosch and her colleagues achieved this using gene therapy, a technique that introduces new genetic material into cells to create beneficial proteins or to offset the effects of malfunctioning genes.  The findings were published in the journal EMBO Molecular Medicine.

Using the FGF21 gene to reverse diabetes

Prof. Bosch and team designed two mouse models of obesity and type 2 diabetes. One was diet-induced, and the other one was genetically modified.  Using an adeno-associated viral vector as “transport,” the team delivered the fibroblast growth factor 21 (FGF21) gene.

This gene is responsible for encoding the FGF21 protein, which is seen as a “major metabolic regulator” that stimulates the absorption of blood sugar in adipose tissue.  By delivering this gene, the researchers stimulated the production of the protein, which caused the rodents to lose weight and lowered their insulin resistance — a major risk factor for type 2 diabetes. Additionally, the mice lost weight and the treatment reduced the fat and inflammation in their adipose tissue.

The fat content, inflammation, and fibrosis of the rodents’ livers were completely reversed, with no side effects. In turn, these improvements increased insulin sensitivity.  These beneficial effects were noted in both murine models. Also, the team found that administering FGF21 to healthy mice prevented age-related weight gain and led to healthy aging.

Gene therapy was used to alter three tissue types: liver tissue, adipose tissue, and skeletal muscle.  “This gives a great flexibility to the therapy,” explains Prof. Bosch, “since it allows [us] to select each time the most appropriate tissue, and in case some complication prevents manipulating any of the tissues, it can be applied to any of the others.”

“When a tissue produces FGF21 protein and secretes it into the bloodstream, it will be distributed throughout the body,” adds Prof. Bosch.

First reversion of obesity, insulin resistance

Study co-author and UAB researcher Claudia Jambrina explains that their findings are particularly significant given that “the prevalence of type 2 diabetes and obesity is growing at alarming rates around the world.”

The team also says that delivering FGF21 as a conventional drug would not yield the same benefits as gene therapy; firstly, the drug would have to be administered periodically for long-term benefits, and secondly, its toxicity would be high.  Using gene therapy, however, is free of side effects, and a single administration is enough to make the mice produce the protein naturally for several years.

“This is the first time that long-term reversion of obesity and insulin resistance have been achieved upon a one-time administration of a gene therapy, in an animal model that resembles obesity and type 2 diabetes in humans.”

First study author Veronica Jimenez, a UAB researcher

“The results demonstrate that it is a safe and effective therapy,” she adds. The next steps will be to “test this therapy in larger animals before moving to clinical trials with patients,” notes Prof. Bosch.  “[The] therapy described in this study,” she concludes, “constitutes the basis for the future clinical translation of FGF21 gene transfer to treat type 2 diabetes, obesity, and related comorbidities.”

Statistics and facts about type 2 diabetes

Diabetes mellitus, or diabetes, is a disease that causes high blood sugar. It occurs when there is a problem with insulin.

Insulin is a hormone that takes sugar from foods and moves it to the body’s cells. If the body does not make enough insulin or does not use insulin well, the sugar from food stays in the blood, resulting in high blood sugar.

Diabetes is a key health concern worldwide. In the United States, the rate of new cases rose sharply from the 1990s, but it fell between 2008 and 2015, and it continues to fall, according to the Centers for Disease Control and Prevention’s (CDC) National Diabetes Report, 2017. Meanwhile, the number of adults living with diabetes continues to rise.

The most common of diabetes is type 2. According to the CDC, 90 to 95 percent of people with diabetes in the United States have type 2. Just 5 percent of people have type 1.

Key facts

Diabetes is at an all-time high in the U.S. The CDC’s Division of Diabetes Translation states that 1 percent of the population, which is about a half of a million people, had diagnosed diabetes in 1958.

In 2015, around 9.4 percent of the population in the U.S. had diabetes, including 30.2 million adults aged 18 years and over. Nearly a quarter of those with the condition do not know they have it.

Between 1990 and 2010, the number of people living with diabetes more than tripled, and the number of new cases doubled every year.

Figures suggest that the incidence is levelling off and may even be falling, but it remains unclear whether this will continue as other factors come into play, such as the aging population.

The risk of developing diabetes increases with age.

The CDC report that 4.0 percent of people aged 18 to 44 years are living with diabetes, 17 percent of those aged 45 to 64 years, and 25.2 percent of those aged over 65 years.

Causes

Type 2 diabetes is thought to result from a combination of genetic and lifestyle factors.

The exact cause is unknown, but risk factors appear to include:

  • excess body fat
  • high blood pressure or cholesterol
  • having a close family member with the condition
  • a history of gestational diabetes
  • higher age

As obesity has become more prevalent over the past few decades, so too has the rate of type 2 diabetes. In 2013, more than 1 in 3 people in the U.S. were considered to have obesity, and over 2 in 3 were either overweight or had obesity.

In 1995, obesity affected 15.3 percent of Americans, and in 2008, the figure was 25.6 percent. From 1998 to 2008, the incidence of diabetes increased by 90 percent.

Although the link between obesity and diabetes is well known, the reasons they are connected remain unclear. A report in the Journal of Clinical Endocrinology and Metabolism asks why obesity does not always lead to diabetes, given the established link between the two conditions.

The same report notes that the location of body fat appears to play a role. People with more fat in the upper body area and around the waist are more likely to get diabetes than those who carry their body fat around the hips and lower body.

Diabetes and ethnicity

Rates of diabetes vary between ethnic groups.

There may be a combination of factors, including:

  • genetics
  • health conditions
  • lifestyle
  • finances
  • environment
  • access to healthcare

The CDC’s National Diabetes Statistics Report, 2017, found that, among people aged 20 years and over, diabetes affects:

  • 7.4 percent of Non-Hispanic whites
  • 8.0 percent of Asian Americans
  • 12.1 percent of Hispanics
  • 12.7 percent of Non-Hispanic Blacks
  • 15.1 percent of American Indians and Alaska Natives

Why diabetes is serious

Diabetes can have serious health consequences.

The ADA report that more Americans die from diabetes every year than from AIDS and breast cancer combined.

According to the CDC, 79,535 deaths occur each year due to diabetes. The number of fatalities related to diabetes may be underreported.

Why and how does diabetes damage the body and cause complications?

The ADA says:

  • Adults with diabetes are significantly more likely to die from a heart attack or stroke.
  • More than a quarter of all Americans with diabetes have diabetic retinopathy, which can cause vision loss and blindness.
  • Each year, nearly 50,000 Americans begin treatment for kidney failure due to diabetes. Diabetes accounts for 44 percent of all new cases of kidney failure.
  • Each year, diabetes causes about 73,000 lower limb amputations, which accounts for 60 percent of all lower limb amputations (not including amputations due to trauma).

Costs

Because of its high prevalence and link to numerous health problems, diabetes has a significant impact on healthcare costs.

The productivity loss for reduced performance at work due to diabetes in 2012 was 113 million days, or $20.8 billion, according to the ADA.

Diabetes cost the U.S. $327 billion in 2017, including $237 billion in medical costs and $90 billion in reduced productivity.

However, this number does not include:

  • the millions of people who have diabetes but are undiagnosed
  • the cost of prevention programs for people with diabetes, which are not counted under standard medical costs
  • over-the-counter medications for eye and dental problems, which are more common in people with diabetes.
  • administrative costs for insurance claims
  • the cost of reduced quality of life, lost productivity of family members, and other factors that cannot be measured directly

Because diabetes affects various parts of the body, the medical costs span different areas of specialty. The ADA report that:

  • 30 percent of medical costs associated with diabetes are for circulation problems that reduce blood flow to the limbs
  • 29 percent of medical costs associated with diabetes are for kidney conditions
  • 28 percent of medical costs associated with diabetes are for nervous system conditions

Despite its complications, people can manage their diabetes with a comprehensive plan that includes lifestyle changes and proper medical care. If they control their blood sugar levels well, many people with diabetes can lead full, active lives.

Difference between types 1 and 2

In type 1 diabetes, the immune system attacks the cells in the pancreas that make insulin. As a result, the body does not produce insulin, and people with this condition must take insulin by injection or pump every day.

Type 1 diabetes usually develops in children or young adults, but it can occur at any age. There is no known way to prevent type 1 diabetes, and there is no cure.

In 2011-2012, around 17,900 children under the age of 18 years received a diagnosis of type 1 diabetes in the U.S., or around 49 children each day. Type 1 diabetes affects around 1.25 million American adults and children.

People with type 2 diabetes may still have insulin in their bodies, but not enough for proper blood sugar control. Or, the body may not be able to use the insulin it has properly. As a result, blood sugar levels can become too high.

Typically, adults are diagnosed with type 2 diabetes, but children can get it too. Certain factors increase a person’s risk of getting type 2 diabetes, including:

  • obesity
  • older age
  • a family history of diabetes
  • lack of exercise
  • problems with glucose metabolism

The annual relative increase for type 1 diabetes in 2002-2012 in the U.S. was 1.8 percent, but the annual increase for type 2 diabetes was 4.8 percent.

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Adapted from:

[1]  Murrell MD, Daniel.  “Statistics and facts about type 2 diabetes.” Medical News Today. 12 June 2018

[2]  Sandoiu, Ana. “Type 2 diabetes, obesity may soon be reversed with gene therapy.”  Medical News Today, 12 July 2018