obesity

Restless legs syndrome associated with use of stevia nonnutritive sweetener

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Abstract

Restless legs syndrome is a common sensorimotor movement disorder affecting an estimated 15–20% of the general adult population in the United Sates. Several drugs and drug classes have been shown to either cause and/or exacerbate symptoms of restless legs syndrome. With the epidemic of obesity and the heightened awareness of the harmful effects of added sugars, the consumption of low and no-calorie sweeteners has substantially increased. We report a case where the patient developed restless legs syndrome symptoms with the use of a stevia extract–based no calorie sweetener. To our knowledge, this is the first case report of restless legs syndrome possibly associated with low or no-calorie sweetener use.

Citation:

Goswami U, Pusalavidyasagar S. Restless legs syndrome associated with use of stevia nonnutritive sweetener. J Clin Sleep Med. 2020;16(10):1819–1821.

INTRODUCTION

Restless legs syndrome (RLS) is a common1 sensorimotor disorder characterized by an unpleasant sensation in the legs during periods of rest or inactivity, with an urge to move them to obtain relief, resulting in difficulty initiating or maintaining sleep. Lower limbs, particularly the upper calves and legs, are most commonly affected, but the sensations can either spread to or be confined to other parts of body including buttocks, groin, back, abdomen, trunk, chest, neck, and face.2

RLS can be either primary (idiopathic) or secondary to iron deficiency associated with renal failure or pregnancy, rheumatoid arthritis, diabetes mellitus, and use of certain medications. Several drug classes including tricylic antidepressants, selective serotonin or norepinephrine reuptake inhibitors, antipsychotics, antihistamines, antiemetics, and antiepileptics have been shown to either cause and/or exacerbate RLS symptoms. With the epidemic of obesity and the heightened awareness of the adverse metabolic effects of added sugars, the consumption of nonnutritive (low-calorie or no-calorie) sweeteners has substantially increased.3 We report a case where the patient developed RLS symptoms with the use of a stevia extract.

REPORT OF CASE

A 54-year-old man with obstructive sleep apnea (apnea-hypopnea index, 40.9 events/hr; nadir SpO2, 86%), treated with autotitrating continuous positive airway pressure at 15–20 cmH2O pressure, was seen in the sleep clinic for follow-up of his obstructive sleep apnea. His other comorbidities included revascularized coronary artery disease; end-stage kidney disease secondary to diabetes mellitus type 2 and possible IgA nephropathy, treated with a living donor kidney transplant 15 years before; polyneuropathy; mild major depression; and generalized anxiety disorder.

He reported excellent control of obstructive sleep apnea symptoms, and continuous positive airway pressure adherence was confirmed with objective compliance measures showing 10 hours of average nightly use. During the visit, patient reported new concern for restlessness in both arms and neck, feeling of jitteriness in both legs before bedtime at night, improved only with movement of the affected body parts but returning with cessation of the movement and interfering with his ability to fall asleep. These symptoms were suggestive of a likely RLS diagnosis, estimated to be of moderate severity with a score of 20 on the International RLS Rating Scale. A thorough review of medications did not yield any potential causes. He had a history of anemia from chronic renal disease, with hemoglobin levels stable at 11.5–12 g/dL over the last 2 years. His iron function tests obtained approximately 1 year before the visit showed serum ferritin level of 22 μg/dL (reference range, 8–250 μg/dL), serum iron level of 66 μg/dL (reference range, 35–180 μg/dL), iron-binding capacity level of 344 μg/dL (reference range, 240–430 μg/dL), and iron saturation index of 19% (reference range, 15–46%). He had been maintained on an iron supplementation dose of ferrous sulfate 325 mg with vitamin C 500 mg twice daily without any changes for the last 1 year. A repeat measurement of the level of serum ferritin was 60 μg/dL. His diabetes mellitus was inadequately controlled, with a hemoglobin A1C value of 7.4%. He had a previous history of severe length-dependent sensorimotor polyneuropathy involving the bilateral sural nerve, right ulnar digit V, and right median and superficial radial sensory nerves. A traumatic accident several years before had resulted in a left leg injury that caused permanent left footdrop. The chronic symptoms of his polyneuropathy included numbness, tingling, and sharp pain in both feet and minimal numbness in both hands on awakening in the morning. The pattern of the current symptoms did not match with his neuropathic symptoms. On examination, he had normal muscle strength in the upper extremities and proximal lower extremities with left footdrop and atrophy of the left anterior compartment. Distal lower extremities sensation was reduced, particularly on the dorsum of the left foot, and ankle jerks were absent. The remainder of the detailed neurologic examination was unremarkable.

While reviewing for lifestyle changes, the patient reported switching to using a stevia sugar substitute for use with his morning coffee in the previous few weeks. The timing of onset of RLS symptoms correlated with the initiation of stevia use. He was instructed to discontinue the use of this supplement and monitor his symptoms. On 3-week follow-up, the patient reported complete resolution of symptoms with discontinuation of stevia. A brief trial of reintroduction of stevia a few months later resulted in recurrence of original RLS symptoms within 2 days. These again resolved with discontinuation of use.

DISCUSSION

The prevalence of diabetes mellitus and cardiovascular disease has increased with the global epidemic of obesity. The American Association of Clinical Endocrinologists recommends reduction in total caloric intake as one of the main components of any weight-loss intervention.4 Various studies have pointed to added sugars as a determinant of body weight.5 The consumption of nonnutritive sweeteners, both artificial (eg, aspartame, sucralose) and natural (eg, stevia), has substantially increased. The prevalence of low-calorie/no-calorie sweetener consumption, assessed using the National Health and Nutrition Examination Survey data from 2009 to 2012, showed 25% children and 41% adults consuming these agents, with higher consumption reported in those who were overweight or obese.3 Use of low-calorie sweeteners is associated with an approximate 10% reduction in daily energy intake and modest weight loss (0.80 kg).6

Stevia is a bio-sweetener, extracted from the leaves of the plant species Stevia rebaudiana Bertoni, native to Brazil and Paraguay. It produces a taste up to 400 times sweeter than sucrose with no nutritional value.7 Stevioside and rebaudioside A are the most common steviol glycosides and are used in beverages as a sugar substitute. Stevia has also been shown to have antioxidant, antihyperglycemic, antihypertensive, anti-inflammatory, hypolipidemic, antitumor, and immunomodulatory effects.7,8 The high-purity extracts of stevia glycoside have received generally recognized as safe designation in the United States since 2008 and are allowed as ingredients in food products.

This case demonstrates the possible association of stevia use to RLS symptoms. To the best of our knowledge, such an association has never been reported. Given that RLS is a diagnosis based primarily on clinical criteria, a thorough evaluation of differential diagnoses focused on patients’ comorbidities and their pharmaceutical treatment is essential. This patient had several potential causes of confusing symptoms, such as sensorimotor polyneuropathy that may resemble RLS. Demonstration of improvement in symptoms with movement of the affected body regions and pattern of symptoms different from the preexisting polyneuropathy suggested RLS as the likely diagnosis in this case. Also, known iron deficiency may independently result in emergence of RLS; however, because the patient showed significant improvement in serum ferritin level with previously prescribed oral iron supplementation, new-onset RLS is less likely to be precipitated by iron deficiency. Moreover, reemergence of RLS with a second trial of stevia strongly supports this possible correlation.9

The effects of stevia on the dopaminergic system and iron metabolism, the 2 primary pathways implicated in pathophysiology of RLS, need further evaluation. Although there are no studies to date on the effects of nonnutritive sweeteners on dopamine levels in humans, Garcia et al10 recently demonstrated a reduction in the dopamine levels in corpus striatum and a concurrent increase in antioxidants such as glutathione and lipoperoxidation levels after oral administration of stevia for 5 days in young male rats. Similar effects were not seen with a sucralose-based artificial sweetener. This suggests that the effects on brain dopamine levels resulting in RLS may be unique to stevia and not seen with other nonnutritive sweeteners. No evidence of effects of stevia on iron absorption or utilization in the brain is available.

CONCLUSIONS

As demonstrated by this case, use of the nonnutritive supplement stevia possibly results in emergence of RLS, putatively because of its effects on reduction of dopamine levels in selective brain regions. It is important to consider changes in dietary habits and use of supplements or medications when evaluating patients with new-onset RLS symptoms. This is of particular importance in patients with comorbid conditions, such as obesity and diabetes, who are attempting to lose weight by substituting their sugar source with low-calorie/no-calorie sweeteners. As in the case of medication-induced RLS, discontinuation of the offending agent is the main stay of treatment.

Is obesity raising your risk of dementia?

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Obesity damages the tiny vessels supplying blood to the brain, and is a major cause of high blood pressure, diabetes and chronic inflammation, all of which have been repeatedly linked to dementia risk

Is obesity raising your risk of dementia?

Although there was a clear association between higher levels of obesity and lower cognitive skills in midlife, this probably wasn’t because one was causing the other. Image used for representational purpose/Pixabay

Many dementia charities advise people to maintain a healthy weight to reduce their risk of dementia. But some studies have suggested that obesity might actually protect against dementia. What does the science say?

The evidence linking obesity to dementia does at first appear to be convincing. For example, we know that being obese in middle age is associated with an increased risk of developing dementia in later life.

We also know that obesity damages the tiny vessels supplying blood to the brain, and is a major cause of high blood pressure, diabetes and chronic inflammation, all of which have been repeatedly linked to dementia risk.

However, the picture is not that clear. For example, if obesity really does cause dementia, why have dementia rates been falling in the west in recent decades at the same time as the number of obese people has been increasing? And why have several studies reported evidence of something termed an “obesity paradox” , where being obese appears to be associated with a reduced risk of dementia?

Putting aside the longstanding problem of defining what we mean when we refer to obesity and dementia (both of which are relatively broad terms for conditions that can be defined in different ways), much of the difficulty in establishing whether one causes the other arises from limitations in the type of data available to scientists trying to answer this question.

In an ideal world, we would look to test the question by designing a randomised trial . In this trial, thousands of people would be randomly assigned to an intervention that would result in half of them being obese for an extended period, while the other half are not.

Maintaining a healthy weight will reduce your risk for a wide range of other major health problems, and it may even reduce your risk of dementia.

If the obese people were then found to be more likely to have dementia in later life, we could be fairly confident that this must be the cause. These types of trials are rarely possible to conduct, however, as not only are they extremely time-consuming and expensive, they are unethical, too. (Imagine the outcry if you randomly assigned a group of people to purposefully be obese for an extended period of time.)

Most studies therefore rely on data from observational studies . This involves following a large group of people for a long time so that the long-term associations between obesity and dementia can be studied.

Although observational studies are a valuable resource for scientists, these studies can be plagued with biases that can often make it difficult to interpret the results.

One such bias relevant to dementia research is “reverse causation”, particularly if the people being studied are old and the follow-up time is short. In this situation, it is possible that people already in the early stages of developing dementia when the study begins may lose weight over time as a result of the disease, rather than the other way around. This is what is suspected to underlie the obesity paradox .

Another common issue is “confounding bias”. This is where the apparent link between obesity and dementia is caused by a different measure that is related to both. One such example is childhood intelligence, a factor that is rarely measured in observational studies, but, when available, has been shown to potentially explain associations that could otherwise be blamed on obesity in later life .

For example, recent work from my lab using data from three separate groups, each followed for 50 years from birth, has shown that lower childhood intelligence probably explains why middle-aged people with obesity are often found to already have slightly worse cognitive skills than those with normal weight.

although there was a clear association between higher levels of obesity and lower cognitive skills in midlife, this probably wasn’t because one was causing the other.

We found that although there was a clear association between higher levels of obesity and lower cognitive skills in midlife, this probably wasn’t because one was causing the other.

Instead, it was likely because a third factor (childhood intelligence) was associated with both. That is, individuals with low intelligence in childhood not only had a higher risk of becoming obese as they grew up, but were also more likely to continue to be of lower intelligence (and therefore consistently have slightly worse cognitive skills).

Without knowing the intelligence levels of children in childhood, we may have interpreted this association between midlife obesity and cognitive skills as being one of cause and effect. In reality though, both are probably just a result of this third factor from earlier in the lifespan.

Nature’s randomised trial

So how can we try to tackle these bias issues? One recent clever technique is to conduct something called a Mendelian randomisation study – sometimes referred to as “nature’s randomised trial”.

In this type of study, scientists separate a large population into two groups based solely on whether or not they have a gene (or genes) that cause obesity. As these genes are randomly inherited from both parents, this results in a “natural randomisation” of the population into two groups who are collectively balanced for every factor except for their obesity status.

Although not without its own potential biases , any differences in dementia risk are therefore interpreted to be directly caused by this obesity.

At least 10 studies have used this technique to test if obesity might cause Alzheimer’s disease – the most common form of dementia. Only one has suggested a link between the two.

So, returning to the question: does obesity really increase your risk of dementia? As scientists like to say, an absence of evidence is not the same as evidence of absence. Or put another way, just because we don’t yet have enough data yet to say that it does, it doesn’t mean that it doesn’t.

Science is an incremental process. In time, a clearer answer to this question will emerge as more data is collected and better techniques are developed.

Until then, my advice would be to follow the suggestion of dementia charities and try to maintain a healthy weight, anyway. At the very least, it will reduce your risk for a wide range of other major health problems, and it may even reduce your risk of dementia.

Tirzepatide improves sleep apnea symptoms for adults with OSA plus obesity

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Key takeaways:

  • Adults with obstructive sleep apnea had a greater reduction in events per hour at 1 year with tirzepatide vs. placebo.
  • Tirzepatide reduced OSA symptoms for adults using and not using positive airway pressure.

Adults with moderate to severe obstructive sleep apnea and obesity had reductions in sleep apnea severity at 1 year with 10 mg or 15 mg of tirzepatide, according to topline results from two phase 3 trials.

As Healio previously reported, tirzepatide (Zepbound, Eli Lilly) was approved by the FDA for chronic weight management among adults with obesity in November 2023. Topline results from the SURMOUNT-OSA trials showed tirzepatide may have benefit beyond body weight reductions, as participants receiving the agent had greater reductions in apnea-hypopnea index (AHI) than placebo. AHI is a measure of the number of times a person with OSA has a restricted or complete block of airflow per hour of sleep.

Sleep apnea
Tirzepatide reduced sleep apnea severity and lowered body weight among adults with moderate-to-severe OSA and obesity. Image: Adobe Stock

The first SURMOUNT-OSA study enrolled adults with moderate to severe OSA and obesity who were not using positive airway pressure therapy. Participants were randomly assigned to once-weekly 10 mg or 15 mg tirzepatide or placebo for 1 year.

At 1 year, adults receiving tirzepatide had a mean AHI reduction of 27.4 events per hour from baseline compared with a mean AHI reduction of 4.8 events per hour for the placebo group according to the efficacy estimand. The tirzepatide group reduced their AHI from baseline by 55% compared with 5% for the placebo group. Adults receiving tirzepatide lost a mean 18.1% of their body weight from baseline to 1 year vs. a 1.3% reduction with placebo.

The second SURMOUNT-OSA study included adults with moderate to severe OSA plus obesity who continued positive airway pressure therapy during the study. In the efficacy estimand, adults receiving tirzepatide had a mean AHI reduction of 30.4 events per hour from baseline to 1 year compared with a mean reduction of 6 events per hour for the placebo group. The mean AHI reduction was 62.8% for the tirzepatide group vs. 6.4% for the placebo group. Those receiving tirzepatide lost a mean 20.1% of body weight from baseline to 1 year compared with a mean 2.3% weight loss with placebo.

The safety profile of tirzepatide in SURMOUNT-OSA was similar to what was previously reported in the SURMOUNT and SURPASS trials. The most common adverse events were gastrointestinal-related and were generally mild to moderate in severity. The most common adverse events in the first SURMOUNT-OSA study were diarrhea, nausea and vomiting, and the most common adverse events in the second study were diarrhea, nausea and constipation.

“Obstructive sleep apnea impacts 80 million adults in the U.S., with more than 20 million living with moderate to severe obstructive sleep apnea,” Jeff Emmick, MD, PhD, senior vice president of product development for Lilly, said in a press release. “However, 85% of obstructive sleep apnea cases go undiagnosed and therefore untreated. Addressing this unmet need head-on is critical, and while there are pharmaceutical treatments for the excessive sleepiness associated with OSA, tirzepatide has the potential to be the first pharmaceutical treatment for the underlying disease.”

Results from the SURMOUNT-OSA trial will be presented at the American Diabetes Association Scientific Sessions on June 21 at 3:45 p.m. EDT. Based on the results, Lilly said it plans to submit an application for approval with the FDA and other global regulatory agencies beginning mid-2024.

Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes

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Abstract

BACKGROUND

Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes.

METHODS

We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level.

Download a PDF of the Research Summary.

RESULTS

A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was −9.8% with semaglutide and −3.4% with placebo (estimated difference, −6.4 percentage points; 95% CI, −7.6 to −5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P=0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group.

CONCLUSIONS

Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure–related symptoms and physical limitations and greater weight loss than placebo at 1 year.

Body Composition Changes After Very-Low-Calorie Ketogenic Diet in Obesity Evaluated by 3 Standardized Methods

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Abstract

Context: Common concerns when using low-calorie diets as a treatment for obesity are the reduction in fat-free mass, mostly muscular mass, that occurs together with the fat mass (FM) loss, and determining the best methodologies to evaluate body composition changes.

Objective: This study aimed to evaluate the very-low-calorie ketogenic (VLCK) diet-induced changes in body composition of obese patients and to compare 3 different methodologies used to evaluate those changes.

Design: Twenty obese patients followed a VLCK diet for 4 months. Body composition assessment was performed by dual-energy X-ray absorptiometry (DXA), multifrequency bioelectrical impedance (MF-BIA), and air displacement plethysmography (ADP) techniques. Muscular strength was also assessed. Measurements were performed at 4 points matched with the ketotic phases (basal, maximum ketosis, ketosis declining, and out of ketosis).

Results: After 4 months the VLCK diet induced a -20.2 ± 4.5 kg weight loss, at expenses of reductions in fat mass (FM) of -16.5 ± 5.1 kg (DXA), -18.2 ± 5.8 kg (MF-BIA), and -17.7 ± 9.9 kg (ADP). A substantial decrease was also observed in the visceral FM. The mild but marked reduction in fat-free mass occurred at maximum ketosis, primarily as a result of changes in total body water, and was recovered thereafter. No changes in muscle strength were observed. A strong correlation was evidenced between the 3 methods of assessing body composition.

Conclusion: The VLCK diet-induced weight loss was mainly at the expense of FM and visceral mass; muscle mass and strength were preserved. Of the 3 body composition techniques used, the MF-BIA method seems more convenient in the clinical setting

Unlocking the Genetic Puzzle of Obesity Across Sexes and Ages

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A study has identified genes that influence obesity risk differently across sexes and age groups, offering new insights into the biological pathways of obesity. These discoveries underscore the importance of considering sex and age in obesity research and could lead to new treatments.

Researchers have discovered genes that impact obesity risk differently in men and women and across various ages, revealing potential new pathways for understanding and treating obesity.

From influencing how our body stores fat to how our brain regulates appetite, hundreds of genes, along with environmental factors, collectively determine our weight and body size. Now, researchers add several genes, that appear to affect obesity risk in certain sexes and ages, to that list. The study, published in the journal Cell Genomics, may shed light on new biological pathways that underlie obesity and highlight how sex and age contribute to health and disease.

The Impact of Sex and Age on Obesity Risk

“There are a million and one reasons why we should be thinking about sex, age, and other specific mechanisms rather than just lumping everyone together and assuming that disease mechanism works the same way for everyone,” says senior author John Perry, a geneticist and professor at the Wellcome-MRC Institute of Metabolic Science, University of Cambridge, U.K. “We’re not expecting people to have completely different biology, but you can imagine things like hormones and physiology can contribute to specific risks.”

To untangle sex’s role in obesity risk, the research team sequenced the exome—the protein-coding part of the genome—of 414,032 adults from the UK Biobank study. They looked at variants, or mutations, within genes associated with body mass index (BMI) in men and women, respectively. Based on height and weight, BMI is an estimated measurement of obesity. The search turned up five genes influencing BMI in women and two in men.

Researchers identified age-specific and sex-specific obesity genes by looking into the genome of 414,032 people from the UK.

Among them, faulty variants of three genes—DIDO1, PTPRG, and SLC12A5—are linked to higher BMI in women, up to nearly 8 kg/m² more, while having no effect on men. Over 80% of the women with DIDO1 and SLC12A5 variants had obesity, as approximated by their BMI. Individuals carrying DIDO1 variants had stronger associations with higher testosterone levels and increased waist-to-hip ratio, both risk indicators for obesity-related complications like diabetes and heart disease. Others with SLC12A5 variants had higher odds of having type 2 diabetes compared with non-carriers. These findings highlight previously unexplored genes that are implicated in the development of obesity in women but not men.

Gene Variants and Their Specific Effects

Perry and his colleague then repeated their method to look for age-specific factors by searching for gene variants associated with childhood body size based on participants’ recollections. They identified two genes, OBSCN and MADD, that were not previously linked to childhood body size and fat. While carriers of OBSCN variants had higher odds of having higher weight as a child, MADD variant carriers were associated with smaller body sizes. In addition, the genetic variants acting on MADD had no association with adult obesity risk, highlighting age-specific effects on body size.

“What’s quite surprising is that if you look at the function of some of these genes that we identified, several are clearly involved in DNA damage response and cell death,” says Perry. Obesity is a brain-related disorder, whereas biological and environmental factors act to influence appetite. “There’s currently no well-understood biological paradigm for how DNA damage response would influence body size. These findings have given us a signpost to suggest variation in this important biological process may play a role in the etiology of obesity.”

Implications for Future Research

Next, the research team hopes to replicate the study in a larger and more diverse population. They also plan to study the genes in animals to peer into their function and relationship with obesity.

“We’re at the very earliest stages of identifying interesting biology,” says Perry. “We hope the study can reveal new biological pathways that may one day pave the way to new drug discovery for obesity.”

Diabesity: How Obesity Is Related to Diabetes

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And the one thing you can do to turn diabetes around

Dibesity diabetes and weight

You’ve probably heard of diabetes. And obesity. But what the heck is diabesity? It’s a new medical term for a condition that’s becoming a worldwide epidemic. And if you have it, losing weight could cure the condition. Endocrinologist Jay Waddadar, MD, explains.

What is diabesity?

Diabesity isn’t an official diagnosis. It means you have both obesity and Type 2 diabetes. Together, these closely related conditions greatly increase your risk of heart disease — the leading cause of death in the country.

“Diabesity is a disease with enormous potential to cause ill effects on the body in the long run,” says Dr. Waddadar. “Some people don’t understand the importance of taking the steps to manage it because they’re feeling well at the time of diagnosis. But that’s a big mistake. Diabesity is a silent disease that damages your body if it’s not controlled, even while you feel fine.”

The good news: You can prevent, control and even reverse it. Dr. Waddadar shares more about how obesity causes and worsens diabetes. And why losing weight holds the key to possibly making it all go away.

How diabetes is related to obesity

Having obesity makes you more likely to develop diabetes, the condition of having too much glucose (sugar) circulating in your bloodstream. Obesity also causes diabetes to worsen faster.

Here’s what happens: Managing the level of glucose in your blood is the job of the pancreas. The pancreas creates insulin, which is a hormone that moves glucose out of your blood. Normally, insulin transports glucose to your muscles to use right away for energy or to the liver, where it’s stored for later.

But when you have diabesity, your cells resist letting insulin move glucose into them. To make matters worse, the area of your liver where excess glucose is usually stored is filled with fat. It’s like trying to put furniture in a room that’s already packed. “There’s no space for anything else,” Dr. Waddadar explains.

With nowhere to be stored, the glucose remains in the bloodstream. “So your pancreas creates even more insulin trying to accomplish the job of moving glucose out of the blood,” says Dr. Waddadar. “It’s trying to push against the resistance created by the fat. Your pancreas becomes overworked, and as a result, it wears out. It starts producing less insulin. Diabetes develops and then quickly worsens if the fat resistance remains.”

Does everyone with obesity develop diabesity?

If you have obesity, you’re about six times more likely to develop Type 2 diabetes than those at a healthy weight. But not everyone with obesity automatically gets diabetes. Other factors are likely at play, too, including:

It may be that some people with obesity can produce more insulin without overtaxing the pancreas, says Dr. Waddadar. Others might be limited in insulin production, making it more likely that obesity will lead to diabesity.

Effects of weight loss on diabesity

Since excess fat worsens diabetes, losing weight can greatly improve the condition. “When you have diabesity, you may start with one medication to get the pancreas to produce enough insulin. But very soon and much earlier, you need two or more medicines for diabetes. But if you lose weight, you may do fine with just one medication or even go off medication entirely,” explains Dr. Waddadar.

Losing as little as 5% to 10% of your overall body weight can greatly improve Type 2 diabetes. For example, if you weigh 200 pounds, 5% of that is 10 pounds. So bringing your weight down to 190 pounds can significantly help your health. “The first treatment goal for diabesity is to get to and maintain a healthy weight along with eating a low-carb diet,” Dr. Waddadar says.

Changing your diet and increasing exercise to lose weight can be challenging. But the hard work is worth it to avoid serious complications of uncontrolled diabetes like heart disease, kidney failure and nerve damage.

Ready to take the first step toward better health? Ask your doctor for resources and guidance to help you beat diabetes.

Fasting May Reduce Inflammation

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Summary: Researchers uncovered a new mechanism by which fasting reduces inflammation, a key factor in chronic diseases.

Their study reveals that fasting increases blood levels of arachidonic acid, which inhibits the NLRP3 inflammasome, thereby reducing inflammation. This discovery sheds light on the anti-inflammatory effects of fasting and offers insights into the benefits of calorie restriction for conditions like obesity, diabetes, heart disease, and neurodegenerative disorders.

The research also provides clues to how drugs like aspirin might function, further highlighting the intricate relationship between diet, inflammation, and disease prevention.

Key Facts:

  1. Fasting elevates arachidonic acid levels in the blood, leading to reduced activity of the NLRP3 inflammasome and inflammation.
  2. The findings offer a potential explanation for how fasting and calorie restriction can protect against chronic inflammation-related diseases.
  3. This research may also explain the anti-inflammatory effects of non-steroidal anti-inflammatory drugs like aspirin, which increase arachidonic acid levels.

Source: University of Cambridge

Cambridge scientists may have discovered a new way that fasting helps reduce inflammation, a potentially damaging side-effect of the body’s immune system that underlies a number of chronic diseases.

In a paper titled “Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting,” published in Cell Reports, the team describes how fasting raises levels of a chemical in the blood known as arachidonic acid, which inhibits inflammation.

The researchers say it may also help explain some of the beneficial effects of drugs such as aspirin.

Scientists have known for some time that our diet—particularly a high-calorie Western diet—can increase our risk of diseases including obesity, type 2 diabetes and heart disease, which are linked to chronic inflammation in the body.

This shows an empty plate.
Studies have shown that some patients who have a high-fat diet have increased levels of inflammasome activity.

Inflammation is our body’s natural response to injury or infection, but this process can be triggered by other mechanisms, including by the so-called “inflammasome,” which acts like an alarm within our body’s cells, triggering inflammation to help protect our body when it senses damage.

But the inflammasome can trigger inflammation in unintentional ways—one of its functions is to destroy unwanted cells, which can result in the release of the cell’s contents into the body, where they trigger inflammation.

Professor Clare Bryant from the Department of Medicine at the University of Cambridge said, “We’re very interested in trying to understand the causes of chronic inflammation in the context of many human diseases, and in particular the role of the inflammasome.

“What’s become apparent over recent years is that one inflammasome in particular—the NLRP3 inflammasome—is very important in a number of major diseases such as obesity and atherosclerosis, but also in diseases like Alzheimer’s and Parkinson’s disease, many of the diseases of older age people, particularly in the Western world.”

Fasting can help reduce inflammation, but the reason why has not been clear. To help answer this question, a team led by Professor Bryant and colleagues at the University of Cambridge and National Institute for Health in the U.S. studied blood samples from a group of 21 volunteers, who ate a 500-kcal meal and then fasted for 24 hours before consuming a second 500-kcal meal.

The team found that restricting calorie intake increased levels of a lipid known as arachidonic acid. Lipids are molecules that play important roles in our bodies, such as storing energy and transmitting information between cells. As soon as individuals ate a meal again, levels of arachidonic acid dropped.

When the researchers studied arachidonic acid’s effect in immune cells cultured in the lab, they found that it turns down the activity of the NLRP3 inflammasome. This surprised the team, as arachidonic acid was previously thought to be linked with increased levels of inflammation, not decreased levels.

Professor Bryant, a Fellow of Queens’ College, Cambridge, added, “This provides a potential explanation for how changing our diet—in particular by fasting—protects us from inflammation, especially the damaging form that underpins many diseases related to a Western high-calorie diet.

“It’s too early to say whether fasting protects against diseases like Alzheimer’s and Parkinson’s disease, as the effects of arachidonic acid are only short-lived, but our work adds to a growing amount of scientific literature that points to the health benefits of calorie restriction. It suggests that regular fasting over a long period could help reduce the chronic inflammation we associate with these conditions. It’s certainly an attractive idea.”

The findings also hint at one mechanism whereby a high-calorie diet might increase the risk of these diseases. Studies have shown that some patients who have a high-fat diet have increased levels of inflammasome activity.

“There could be a yin and yang effect going on here, whereby too much of the wrong thing is increasing your inflammasome activity and too little is decreasing it,” said Professor Bryant. “Arachidonic acid could be one way in which this is happening.”

The researchers say the discovery may also offer clues to an unexpected way in which so-called non-steroidal anti-inflammatory drugs such as aspirin work. Normally, arachidonic acid is rapidly broken down in the body, but aspirin stops this process, which can lead to an increase in levels of arachidonic acid, which in turn reduce inflammasome activity and hence inflammation.

Professor Bryant said, “It’s important to stress that aspirin should not be taken to reduce risk of long terms diseases without medical guidance, as it can have side effects such as stomach bleeds if taken over a long period.”

Abstract

Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting

Highlights

  • In fasting compared to fed subjects, plasma IL-1β is lower and arachidonic acid (AA) is higher
  • Exogenous AA impairs NLRP3 inflammasome activity in human and mouse macrophages
  • AA inhibits phospholipase C and reduces JNK stimulation and hence NLRP3 activity

Summary

Elevated interleukin (IL)-1β levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the mechanistic basis for this is unclear.

Here, we show that levels of plasma IL-1β are lower in fasting compared to fed subjects, while the lipid arachidonic acid (AA) is elevated.

Lipid profiling of NLRP3-stimulated mouse macrophages shows enhanced AA production and an NLRP3-dependent eicosanoid signature.

Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production. It also reduces both IL-1β and IL-18 production in response to NLRP3 activation.

AA inhibits NLRP3 inflammasome activity in human and mouse macrophages. Mechanistically, AA inhibits phospholipase C activity to reduce JNK1 stimulation and hence NLRP3 activity.

These data show that AA is an important physiological regulator of the NLRP3 inflammasome and explains why fasting reduces systemic inflammation and also suggests a mechanism to explain how nonsteroidal anti-inflammatory drugs work.

Baseline HbA1c over 6% greatly increases type 2 diabetes risk for adolescents with obesity

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  • The risk for developing type 2 diabetes increases with higher baseline HbA1c for adolescents with overweight or obesity.
  • A large increase in type 2 diabetes risk was observed with a baseline HbA1c more than 6%.

The risk for developing type 2 diabetes is substantially higher for adolescents with overweight or obesity and an HbA1c of at least 6.1% compared with those with an HbA1c of 5.5% or less, according to study data.

“Our study is one of the first large population studies to report the incidence and risk of type 2 diabetes by incremental level of HbA1c in a racially and ethnically diverse group of adolescents with overweight and obesity,” Francis M. Hoe, MD, a pediatric endocrinologist with Kaiser Permanente in Northern California, told Healio. “In our study, HbA1c was a very strong predictor for developing type 2 diabetes. Absolute risk for developing type 2 diabetes was low, especially for those with an HbA1c of less than 5.9%.”

Incidence of type 2 diabetes increase with baseline HbA1c for adolescents with overweight or obesity.
Data were derived from Hoe FM, et al. JAMA Netw Open. 2024;doi:10.1001/jamanetworkopen.2023.51322.

Hoe and colleagues conducted a retrospective cohort study using electronic health record data from Kaiser Permanente Northern California from 2010 to 2019. The study included adolescents aged 10 to 17 years without diabetes at baseline who had at least one HbA1c recorded from 2010 to 2018 and a BMI in the 85th percentile or higher for age and sex according to CDC growth chart reference data. Participants were defined as having developed type 2 diabetes during follow-up if they were diagnosed by a health care provider or had an HbA1c, fasting glucose, random glucose or 2-hour glucose level in the diabetes range as defined by American Diabetes Association glycemic thresholds. Adolescents were classified as having type 2 diabetes unless they had at least one positive diabetes autoantibody indicating type 1 diabetes, were diagnosed with maturity-onset diabetes of the young or were diagnosed with a secondary form of diabetes.

Diabetes risk rises with baseline HbA1c

There were 74,552 adolescents with overweight or obesity and a baseline HbA1c of less than 6.5% included in the study (mean age, 13.4 years; 50.6% female; 43.6% Hispanic; 21.6% white; 17.6% Asian/Pacific Islander; 11.1% Black). Participants were followed for a median of 3.5 years. Of the study group, 0.9% developed incident diabetes during follow-up. Of those diagnosed with diabetes, 89.7% were classified as having type 2 diabetes.

The 5-year cumulative incidence of type 2 diabetes was 1%. Incidence rates climbed with baseline HbA1c, reaching 11% for those with a baseline HbA1c of 6.1% to 6.2% and 28.5% for adolescents with a baseline HbA1c of 6.3% to 6.4%. Cumulative incidence of type 2 diabetes was 0.3% with a baseline HbA1c of less than 5.5%, 0.5% with a baseline HbA1c of 5.5% to 5.6%, 1.1% with a baseline HbA1c of 5.7% to 5.8%, and 3.8% with a baseline HbA1c of 5.9% to 6%.

Risk higher for girls, older adolescents

In multivariable analysis, adolescents with a baseline HbA1c of 6.3% to 6.4% had a nearly 72-fold increased risk for developing type 2 diabetes than those with a baseline HbA1c of less than 5.5% (adjusted HR = 71.9; 95% CI, 51.1-101.1). Those with moderate obesity (aHR = 2; 95% CI, 1.4-2.7) or severe obesity (aHR = 5.2; 95% CI, 3.9-7.1) had a higher risk for type 2 diabetes than those with overweight. Girls were more likely to develop type 2 diabetes than boys (aHR = 1.5; 95% CI, 1.3-1.8). Participants aged 15 to 17 years had a higher risk for type 2 diabetes than those aged 10 to 11 years (aHR = 1.7; 95% CI, 1.4-2.1). Asian and Pacific Islander adolescents had a higher risk for developing type 2 diabetes than white adolescents (aHR = 1.7; 95% CI, 1.3-2.2).

Hoe said the findings reveal which adolescents would benefit most from closer monitoring based on their initial HbA1c levels.

“Those with a HbA1c in the higher end of the prediabetes range (6.1% to 6.2% and 6.3% to 6.4%) had a 23-fold and 72-fold greater risk for developing type 2 diabetes, compared to those with HbA1c of less 5.5%,” Hoe said. “These adolescents are at greatest risk and will benefit most from intervention and follow-up diabetes monitoring. Adolescents with prediabetes but at an HbA1c in the low end of the prediabetes range (5.7% to 5.8%) have a low risk of developing diabetes. Although this group will still likely benefit from lifestyle intervention, they could perhaps be considered for follow-up diabetes monitoring less frequently than once per year, as currently recommended by the ADA.”

In future studies, Hoe said the researchers plan to examine the effects of weight and BMI change over time and look at how that may change type 2 diabetes risk.

Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity

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Effect of Tirzepatide on Maintenance of Weight Reduction

Key Points

Question  Does once-weekly subcutaneous tirzepatide with diet and physical activity affect maintenance of body weight reduction in individuals with obesity or overweight?

Findings  After 36 weeks of open-label maximum tolerated dose of tirzepatide (10 or 15 mg), adults (n = 670) with obesity or overweight (without diabetes) experienced a mean weight reduction of 20.9%. From randomization (at week 36), those switched to placebo experienced a 14% weight regain and those continuing tirzepatide experienced an additional 5.5% weight reduction during the 52-week double-blind period.

Meaning  In participants with obesity/overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction.

Abstract

Importance  The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown.

Objective  To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction.

Design, Setting, and Participants  This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes.

Interventions  Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks.

Main Outcomes and Measures  The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period.

Results  Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was −5.5% with tirzepatide vs 14.0% with placebo (difference, −19.4% [95% CI, −21.2% to −17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo.

Conclusions and Relevance  In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction.

Discussion

The SURMOUNT-4 trial results emphasize the need to continue pharmacotherapy to prevent weight regain and ensure the maintenance of weight reduction and its associated cardiometabolic benefits.22 At least 5 trials (including the present study) across various classes of medications, including potent antiobesity medications such as semaglutide, have demonstrated that weight is substantially regained after cessation of pharmacotherapy.5,6,23,24

The consistency of these data across therapeutic classes spanning more than 2 decades suggests that obesity is a chronic metabolic condition similar to type 2 diabetes and hypertension requiring long-term therapy in most patients.

A notable finding in the SURMOUNT-4 trial is that after switching to placebo for 1 year, participants ended the study with substantial body weight reduction (9.9%). However, much of their initial improvement in cardiometabolic risk factors had been reversed. Further studies are needed to understand the potential long-term benefits and risks (ie, legacy effects) of such short-term therapy.

The health benefits seen with continued treatment with the maximum tolerated dose of tirzepatide during this study were achieved with a safety profile consistent with that previously reported in SURMOUNT and SURPASS trials and in studies of incretin-based therapies approved for the treatment of obesity and overweight.18,25–32

The strengths of this study include its large sample size and the randomized withdrawal design. The duration of the open-label lead-in period allowed the study to assess the maintenance of body weight reduction. Dose escalation protocols during the open-label lead-in period helped to maximize tolerability and reflect dose adjustment strategies that may be helpful to future prescribers.

Conclusions

After achieving clinically meaningful weight reduction during a 36-week tirzepatide lead-in treatment period, adults with obesity or overweight who continued treatment with maximum tolerated dose tirzepatide for an additional 52 weeks demonstrated superior weight maintenance and continued weight reduction compared to those who switched to placebo.