metabolic disorders

Spinal Injuries Trigger Metabolic Disorders

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Summary: A new study demonstrates how spinal cord injuries can lead to significant metabolic disruptions, including the onset of conditions such as diabetes and heart disease. The study found that abnormal neuronal activities post-injury lead to excessive breakdown of triglycerides in fat tissue, releasing harmful compounds into organs like the liver.

By administering gabapentin, a nerve pain medication, researchers successfully prevented these metabolic effects in animal models. This discovery could pave the way for new treatments that mitigate the secondary health issues caused by spinal injuries.

Key Facts:

  1. The study identifies a link between spinal cord injuries and metabolic dysfunctions due to abnormal neuronal activity affecting fat tissue.
  2. Gabapentin was effective in normalizing metabolic functions in mice by inhibiting problematic neural proteins and preventing the excessive breakdown of fats.
  3. Despite its benefits, gabapentin induced insulin resistance, prompting researchers to adjust dosing strategies to retain therapeutic effects while minimizing side effects.

Source: Ohio State University

Conditions such as diabetes, heart attack and vascular diseases commonly diagnosed in people with spinal cord injuries can be traced to abnormal post-injury neuronal activity that causes abdominal fat tissue compounds to leak and pool in the liver and other organs, a new animal study has found.

After discovering the connection between dysregulated neuron function and the breakdown of triglycerides in fat tissue in mice, researchers found that a short course of the drug gabapentin, commonly prescribed for nerve pain, prevented the damaging metabolic effects of the spinal cord injury.

This shows a spine.
Results also showed an increase in blood flow in fat tissue and recruitment of immune cells to the environment.

Gabapentin inhibits a neural protein that, after the nervous system is damaged, becomes overactive and causes communication problems – in this case, affecting sensory neurons and the abdominal fat tissue to which they’re sending signals.

“We believe there is maladaptive reorganization of the sensory system that causes the fat to undergo changes, initiating a chain of reactions – triglycerides start breaking down into glycerol and free fatty acids that are released in circulation and taken up by the liver, the heart, the muscles, and accumulating, setting up conditions for insulin resistance,” said senior author Andrea Tedeschi, assistant professor of neuroscience in The Ohio State University College of Medicine.

“Through administration of gabapentin, we were able to normalize metabolic function.”

The study is published today (April 24, 2024) in Cell Reports Medicine.

Previous research has found that cardiometabolic diseases are among the leading causes of death in people who have experienced a spinal cord injury.

These often chronic disorders can be related to dysfunction in visceral white fat (or adipose tissue), which has a complex metabolic role of storing energy and releasing fatty acids as needed for fuel, but also helping keep blood sugar levels at an even keel. 

Earlier investigations of these diseases in people with neuronal damage have focused on adipose tissue function and the role of the sympathetic nervous system – nerve activity known for its “fight or flight” response, but also a regulator of adipose tissue that surrounds the abdominal organs.

Instead, Debasish Roy – a postdoctoral researcher in the Tedeschi lab and first author on the paper – decided to focus on sensory neurons in this context. Tedeschi and colleagues have previously shown that a neuronal receptor protein called alpha2delta1 is overexpressed after spinal cord injury, and its increased activation interferes with post-injury function of axons, the long, slender extensions of nerve cell bodies that transmit messages.

In this new work, researchers first observed how sensory neurons connect to adipose tissue under healthy conditions, and created a spinal cord injury mouse model that affected only those neurons – without interrupting the sympathetic nervous system.

Experiments revealed a cascade of abnormal activity within seven days after the injury in neurons – though only in their communication function, not their regrowth or structure – and in visceral fat tissue.

Expression of the alpha2delta1 receptor in sensory neurons increased as they over-secreted a neuropeptide called CGRP, all while communicating through synaptic transmission to the fat tissue – which, in a state of dysregulation, drove up levels of a receptor protein that engaged with the CGRP.

“These are quite rapid changes. As soon as we disrupt sensory processing as a result of spinal cord injury, we see changes in the fat,” Tedeschi said. “A vicious cycle is established – it’s almost like you’re pressing the gas pedal so your car can run out of gas but someone else continues to refill the tank, so it never runs out.”

The result is the spillover of free fatty acids and glycerol from fat tissue, a process called lipolysis, that has gone out of control. Results also showed an increase in blood flow in fat tissue and recruitment of immune cells to the environment.

“The fat is responding to the presence of CGRP, and it’s activating lipolysis,” Tedeschi said. “CGRP is also a potent vasodilator, and we saw increased vascularization of the fat – new blood vessels forming as a result of the spinal cord injury. And the recruitment of monocytes can help set up a chronic pro-inflammatory state.”

Silencing the genes that encode the alpha2delta1 receptor restored the fat tissue to normal function, indicating that gabapentin – which targets alpha2delta1 and its partner, alpha2delta2 – was a good treatment candidate.

Tedeschi’s lab has previously shown in animal studies that gabapentin helped restore limb function after spinal cord injury and boosted functional recovery after stroke.

But in these experiments, Roy discovered something tricky about gabapentin: The drug prevented changes in abdominal fat tissue and lowered CGRP in the blood – and in turn prevented spillover of fatty acids into the liver a month later, establishing normal metabolic conditions. But paradoxically, the mice developed insulin resistance – a known side effect of gabapentin.

The team changed drug delivery tactics, starting with a high dose and tapering off – and stopping after four weeks.

“This way, we were able to normalize metabolism to a condition much more similar to control mice,” Roy said. “This suggests that as we discontinue administration of the drug, we retain beneficial action and prevent spillover of lipids in the liver. That was really exciting.”

Finally, researchers examined how genes known to regulate white fat tissue were affected by targeting alpha2delta1 genetically or with gabapentin, and found both of these interventions after spinal cord injury suppress genes responsible for disrupting metabolic functions.

Tedeschi said the combined findings suggest starting gabapentin treatment early after a spinal cord injury may protect against detrimental conditions involving fat tissue that lead to cardiometabolic disease – and could enable discontinuing the drug while retaining its benefits and lowering the risk for side effects.

Artificial sweeteners linked to obesity and metabolic disorders

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A joint team headed by Eran Segal and Eran Elinav of the Weizmann Institute of Science in Rehovot led a study that found links between the use of sugar substitutes such as saccharine and obesity. It is also the first study to suggest that sweeteners cause metabolic disorders when they are exposed to the gut microbiome—the diverse community of bacteria in the human intestines.

The researchers studied the effects of sweetener consumption on mice and found that the mice became glucose intolerant. To check whether the sweeteners were affecting the murine microbiome, the researchers used antibiotics to kill the gut bacteria, which reversed the metabolic changes, suggesting that artificial sweeteners were making microbiome unhealthy. The researchers then studied the effect of sweeteners on healthy human volunteers. While some became glucose intolerant and showed susceptibility to metabolic diseases, others did not. This indicates that generic use of sweeteners should be avoided. However, more research is required to draw any firm conclusions.

 

Soft drinks are just some of the many products that use artificial sweeteners.

The artificial sweeteners that are widely seen as a way to combat obesity and diabetes could, in part, be contributing to the global epidemic of these conditions.

Sugar substitutes such as saccharin might aggravate these metabolic disorders by acting on bacteria in the human gut, according to a study published by Nature this week (J. Suez et al. Nature http://dx.doi.org/10.1038/nature13793; 2014). Smaller studies have previously purported to show an association between the use of artificial sweeteners and the occurrence of metabolic disorders. This is the first work to suggest that sweeteners might be exacerbating metabolic disease, and that this might happen through the gut microbiome, the diverse community of bacteria in the human intestines. “It’s counter-intuitive — no one expected it because it never occurred to them to look,” says Martin Blaser, a microbiologist at New York University.

The findings could cause a headache for the food industry. According to BCC Research, a market-research company in Wellesley, Massachusetts, the market for artificial sweeteners is booming. And regulatory agencies, which track the safety of food additives, including artificial sweeteners, have not flagged such a link to metabolic disorders. In response to the latest findings, Stephen Pagani, a spokesman for the European Food Safety Authority (EFSA) in Parma, Italy, says that, as with all new data, the agency “will decide in due course whether they should be brought to the attention of panel experts for review”.

A team led by Eran Elinav of the Weizmann Institute of Science in Rehovot, Israel, fed mice various sweeteners — saccharin, sucralose and aspartame — and found that after 11 weeks, the animals displayed glucose intolerance, a marker of propensity for metabolic disorders.

To simulate the real-world situation of people with varying risks of these diseases, the team fed some mice a normal diet, and some a high-fat diet, and spiked their water either with glucose alone, or with glucose and one of the sweeteners, saccharin. The mice fed saccharin developed a marked glucose intolerance compared to those fed only glucose. But when the animals were given antibiotics to kill their gut bacteria, glucose intolerance was prevented. And when the researchers transplanted faeces from the glucose-intolerant saccharin-fed mice into the guts of mice bred to have sterile intestines, those mice also became glucose intolerant, indicating that saccharin was causing the microbiome to become unhealthy.

Elinav’s team also used data from an on­going clinical nutrition study that has recruited nearly 400 people in Israel. The researchers noted a correlation between clinical signs of metabolic disorder — such as increasing weight or decreasing efficiency of glucose metabolism — and consumption of artificial sweeteners.

But “this is a bit chicken-and-egg”, says Elinav. “If you are putting on weight, you are more likely to turn to diet food. It doesn’t necessarily mean the diet food caused you to put on weight.”

So his team recruited seven lean and healthy volunteers, who did not normally use artificial sweeteners, for a small prospective study. The recruits consumed the maximum acceptable daily dose of artificial sweeteners for a week. Four became glucose intolerant, and their gut microbiomes shifted towards a balance already known to be associated with susceptibility to metabolic diseases, but the other three seemed to be resistant to saccharin’s effects. “This underlines the importance of personalized nutrition — not everyone is the same,” says Elinav.

He does not yet propose a mechanism for the effect of artificial sweeteners on the micro­biome. But, says Blaser, understanding how these compounds work on some species in the gut might “inspire us in developing new therapeutic approaches to metabolic disease”.

Yolanda Sanz, a nutritionist and vice-chair of the EFSA’s panel on dietetic products, nutrition and allergies, says that it is too soon to draw firm conclusions. Metabolic disorders have many causes, she points out, and the study is very small.

Night Owls at Risk for Metabolic Disorders

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Men who are “night owls” have an increased risk of type 2 diabetes and general wasting of muscle mass than their “early-bird” counterparts, while women are more likely to have the metabolic syndrome if they are nocturnal than women who are not, new research shows.

The study was published in the April issue of the Journal of Clinical Endocrinology and Metabolism byJi Hee Yu, PhD, from Korea University College of Medicine, Ansan, and colleagues.

“To the best of our knowledge, this is the first study to reveal an association between chronotype and sarcopenia or metabolic disorders at the population level,” they write.

Asked to comment, Endocrine Society spokesperson Orfeu Buxton, PhD, from Harvard Medical School, Boston, Massachusetts, told Medscape Medical News that it is well documented that shortened sleep duration reduces insulin sensitivity and promotes diabetes and obesity risk.

Sleep quality also influences diabetes and obesity risk, although probably through a different mechanism, he added.

“That’s what’s so fascinating about this paper — they showed that it’s the later timing and poor-quality sleep that’s related to diabetes and the metabolic syndrome,” Dr Buxton said.

Gender Differences Apparent

In the study of 1620 middle-aged adults between the ages of 47 and 59, Dr Yu and colleagues found 29.6% of the cohort qualified as morning chronotype, or early birds, while 5.8% of the cohort qualified as evening chronotype, or night owls.

The majority of the cohort, 64.5%, was neither a morning nor evening chronotype.

In all participants, the risk for diabetes for evening types was 73% higher than it was for morning types at an odds ratio (OR) of 1.73 after researchers controlled for confounders including lifestyle factors.

The risk of the metabolic syndrome was 74% higher for evening types compared with morning types at an OR of 1.74, again after adjustment for confounding factors.

The risk of sarcopenia or general muscle-mass wasting in turn was over threefold higher for evening types compared with morning types (OR, 3.16).

In contrast, visceral obesity was not significantly associated with being either an evening or a morning person.
The investigators also saw gender differences in the associations between chronotype and metabolic disorders. In men, the risk for diabetes was almost threefold higher among the night owls compared with the early birds (OR, 2.98). And the risk of sarcopenia was almost fourfold higher among night-owl men compared with the early-bird men (OR, 3.89).

In contrast, the metabolic syndrome was not related to chronotype in men.

Women who were night owls, on the other hand, were over twice as likely to have the metabolic syndrome as women who were early birds (OR, 2.22).
In contrast to men, neither diabetes nor sarcopenia was associated with the evening chronotype in women.

Shortened Sleep Duration, Disruption, and Timing All Influence Risk

As the authors discuss, the evening chronotype is likely associated with a worse metabolic profile than others for multiple reasons, one of which may “sleep debt.”

“Individuals with evening chronotype are more likely to suffer from sleep curtailment because of the discrepancy between intrinsic sleep-wake rhythm and actual bedtime, the former determined by biological clock and the latter influenced by social requirement,” they observe.

Although average sleep duration was not different between night owls and early birds in their study, “evening persons are known to accumulate sleep debt on weekdays and then have extended catch-up sleep on the weekend,” the authors point out.

The findings support the potential negative consequences of circadian disruptions in individuals with evening chronotype, they say.

At the recent ENDO 2015 annual meeting of the Endocrine Society in San Diego, Shahrad Taheri, PhD, from Weill Cornell Medical College in Doha, Qatar, and colleagues found that as little as 30 minutes a day of sleep debt can have significant effects on obesity and insulin resistance, increasing obesity by 17% and insulin resistance by 39% for every 30 minutes of weekday sleep debt at study end point 12 months later.

Dr Buxton has also reported that sleep deprivation and sleep disruption experienced by shift workers both increase obesity and diabetes risk, but they do so through different pathways.

“You can’t take health behaviors, or for that matter poverty and socioeconomic status, out from these studies, as they are important factors as well,” he observed.

“My point is that with respect to sleep duration, sleep quality, and sleep timing, all three components contribute to diabetes and obesity risk.”

Diabetes, metabolic disorders linked to urban stressors

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Diabetes and metabolic disorders may be more common among people in developing nations who live in cities vs. those who remain in rural areas because of increased stress affecting hormone levels, according to recent study findings.

“Our findings indicate that people who leave a rural lifestyle for an urban environment are exposed to high levels of stress and tend to have higher levels of the hormone cortisol,” Peter Herbert Kann, MD, PhD, MA, of the Philipp University of Marburg, Germany, said in a press release. “This stress is likely contributing to the rising rates of diabetes we see in developing nations.”

Kann and colleagues evaluated men and women aged 30 to 80 years of the Ovahimba people from Namibia in southwestern Africa to determine the prevalence of disorders and glucose metabolism. Participants were divided into two groups: urban, living in the regional capital of Opuwo (n=60); and rural, living at least 50 km away from the nearest village or town (n=63).

The urban group had a higher prevalence of glucose metabolism disorders (28.3%) vs. the rural group (12.7%; P=.04). Significantly higher cortisol levels also were found among the urban group compared with the rural group.

Compared with the rural group, the urban group had greater changes in hip circumference (P<.001), waist circumference (P<.001), BMI (P=.014), systolic blood pressure at rest (P<.001), diastolic BP at rest (P=.002), systolic BP after exercise (P<.001), heart rate after exercise (P=.007), fasting glucose (P<.001), 2-hour glucose by oral glucose tolerance test (P=.002), triglycerides (P=.04), HDL cholesterol (P=.014) and prevalence of metabolic syndrome (P<.001). The rural group exhibited higher LDL cholesterol levels compared with the urban group.

The rural group participated in more intense physical activity, whereas the urban group ate more fast food.

“The results suggest sociocultural instability caused by urbanization contributes to an increased risk of developing diabetes or another metabolic disorder,” Kann said in the release. “This is the first prospective study to systematically show the body’s regulation of the hormone cortisol plays a part in the metabolic changes brought on by the shift to an urban lifestyle.”