Controlling carbs and fat: learning from the fruit fly

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Incretins are hormones secreted by intestinal cells that regulate pancreatic insulin and glucagon to control sugar metabolism in mammals. Although counterparts of insulin and glucagon have been identified in invertebrates, no hormone equivalent to incretin has been described. Now, researchers at the University of Tsukuba demonstrate that Neuropeptide F (NPF), a hormone produced by the midgut, performs this complex role in the fruit fly.

Life processes are orchestrated by diverse neuroendocrine feedback systems that retain fundamental similarities across the animal kingdom. In response to dietary sugars, incretins from the mammalian gut stimulate pancreatic cells to produce insulin and to suppress its counter-regulatory hormone glucagon. Together they antagonistically fine-tune sugar levels: insulin clears circulating carbohydrate and promotes fat storage while glucagon plays a modulatory role.

Having earlier discovered the reproductive function of NPF in the fruit fly, Drosophila melanogaster, the research team wondered about its role in other biological processes, particularly in energy homeostasis. Their research strategy included advanced genetic engineering to generate mutant flies of specific gene knockout strains (in which genetic expression has been inactivated or deleted) and knock-in strains (in which a one-for-one substitution of a genetic sequence has been created at a particular location). Cutting-edge laboratory techniques were used to reveal the genetic and molecular signaling pathways and underlying cellular mechanisms.

The researchers were able to demonstrate that NPF is secreted by intestinal endocrine cells in response to dietary sugar. It signals NPF receptor in the corpora cardiaca, a gland-like organ in insects, and stimulates insulin producing cells in the insect brain to suppress glucagon-like hormone while enhancing insulin-like peptide production. This increases the glucose level in the hemolymph (the circulatory fluid in the insect’s body cavity) and promotes lipid accumulation in body fat.

“Our investigations showed that loss of midgut NPF or disordered NPF/NPFR signaling in the fruit fly produced metabolic disorders similar to incretin loss in mammals, such as lipodystrophy (loss of healthy fat), hypoglycemia and hyperphagia (overfeeding),” Professor Ryusuke Niwa, main author of the study, explains. “Significantly, although NPF is also produced by the brain, we proved that brain-derived NPF lacks this function, and that Drosophila NPF is structurally distinct from mammalian incretins. However, further research to investigate the role of NPF in other potential target tissues is necessary.”

This study highlights the underlying similarities of sugar-dependent metabolic processes between insects and mammals. Better understanding of the functional role of incretins may inform therapeutic strategies for medical disorders associated with their dysfunction such as obesity and type 2 diabetes.

Skipping simple urine test leaves diabetics with untreated kidney disease

Skipping simple urine test leaves high-risk groups with untreated kidney disease
Skipping simple urine test leaves high-risk groups with untreated kidney disease

Despite their higher risk of chronic kidney disease, people with hypertension or diabetes usually are not given a simple test for protein in the urine to screen for this potentially deadly disorder, according to a study led by researchers at Johns Hopkins Bloomberg School of Public Health.

The researchers analyzed data on nearly four million hypertension and diabetes patients around the world, and found that only about 4 percent of the former and 35 percent of the latter had been screened for chronic kidney disease with a test for albuminuria, a standard measure of protein in the urine. This was despite the relatively high rates of chronic kidney disease that are generally found among hypertension and diabetes patients.

The study was published online August 9 in the journal Hypertension.

“These results highlight the need to widen albuminuria testing for early detection of chronic kidney diseases—especially now that we have new and more effective treatments that could benefit these patients,” says study first author Jung-Im Shin, MD, an assistant professor in the Department of Epidemiology at the Bloomberg School.

“We’re really missing a huge number of chronic kidney disease cases that should be detected and treated, and apart from all the other downsides of letting it go untreated, there is the fact that COVID-19 outcomes are often much worse for people with kidney disease,” says study senior author Josef Coresh, MD, the George W. Comstock Professor in the Department of Epidemiology at the Bloomberg School.

According to the Centers for Disease Control and Prevention, about 37 million U.S. adults have chronic kidney disease, although the vast majority do not know it. Chronic kidney disease is easy to miss, especially in its early stages, because it typically features mild and nonspecific symptoms such as unexplained itching and swollen feet and ankles. It often progresses undiagnosed until late stages when kidney failure is unavoidable.

Testing for an abnormally high level of protein in the urine, a marker of kidney damage, is an accepted method for detecting possible chronic kidney disease. The clinically preferred test is called the ACR test, which measures the level in a urine sample of albumin, a common protein, corrected for the urine concentration as determined by the level of a molecule called creatinine.

Medical associations now recommend frequent ACR testing for people with diabetes, which often co-occurs with chronic kidney disease, and that patients with ACR levels of at least 30 mg/g—the threshold of albuminuria and a potential sign of early chronic kidney disease—be given medications to protect the kidneys. Many researchers believe that ACR testing in people with hypertension, another condition strongly linked to chronic kidney disease, would have significant benefits for similar reasons.

“There are new treatments for patients with albuminuria, including a class of drugs called SGLT2 inhibitors, which appear to be quite effective in protecting the kidneys as well as the cardiovascular system,” Shin says. “Our findings suggest that albuminuria screening should be used much more often for detecting chronic kidney disease early, so that patients can benefit from earlier treatment.”

To find out how often patients with diabetes or hypertension are given ACR urine tests to detect albuminuria, Shin, Coresh and their colleagues analyzed datasets including medical records for a total of 1,344,594 adults with diabetes and 2,334,461 adults who had hypertension but not diabetes. The datasets were assembled as part of the Chronic Kidney Disease Prognosis Consortium, a global research collaboration on chronic kidney disease that includes over 80 cohorts of patients across 40 countries. Coresh is a co-principal investigator for the consortium’s Data Coordinating Center.

A key finding was that only 4.1 percent of the hypertension patients and 35.1 percent of the diabetes patients had had an ACR test during a two-year time window starting with their inclusion in a dataset. This was despite the fact that in these groups, those who were given ACR tests had relatively high rates of albuminuria defined as ACR ≥ 30 mg/g: 32.1 percent for the diabetes patients, and 21.8 percent for the hypertension patients. Additionally, in both groups more than 20 percent of those with ACR < 30 mg/g in the initial time window converted to ACR ≥ 30 mg/g in the ensuing five years.

The analysis further showed that whether a patient received an ACR test or not essentially had nothing to do with his or her predicted risk of ACR ≥ 30 mg/g.

“People who were tested were not those at highest risk—they were just a random subset,” Coresh says. “So we estimate that the number of patients with undetected ACR ≥30 mg/g was far greater than the number of detected cases—almost 20 times greater among the hypertension patients.”

The study also included the development of a risk model—one of many now available for physicians who are considering the possibility of chronic kidney disease in a patient—that predicts the development of ACR ≥ 30 mg/g within a few years. Prominent risk factors in the model included older age, male sex, history of heart failure, and a lower measure of kidney filtration rate.

Small protein protects pancreatic cells in model of type 1 diabetes

Histology of pancreatic islets without and with MOTS-c treatment

In mice that had been genetically engineered to develop autoimmune diabetes, “killer” T-cells (darker spots) infiltrate and destroy insulin-producing cells in the pancreas (left). Treatment with injections of MOTS-c reduced T-cell infiltration and prevented the onset of the disease (right). CREDIT Seoul National University College of Medicine and USC Leonard Davis School of Gerontology

new study has shown that treating type 1 diabetes-prone mice with the small protein MOTS-c prevented the immune system from destroying insulin-producing pancreatic cells, effectively preventing the onset of the autoimmune disease.

The small protein that first made headlines as an “exercise mimetic” increasingly appears to also have a big role in regulating the immune system, said Assistant Professor of Gerontology Changhan David Lee, co-corresponding author of the study.

Regulating the immune system

Type 1 diabetes, previously known as juvenile diabetes, is an autoimmune disease that accounts for 5 to 10% of diabetes cases. In patients with type 1 diabetes, the immune system attacks the islet regions of the pancreas, which are made up of hormone-producing cells. When immune cells mistakenly destroy healthy beta cells—the pancreatic cells that produce the sugar-regulating hormone insulin—the body loses the ability to make insulin, control blood sugar levels and properly use sugar for energy.

In mice that had been genetically engineered to develop autoimmune diabetes, treatment with injections of MOTS-c prevented the onset of the disease. The new study illustrates how treating mice with MOTS-c supports regulatory T-cells—the immune cells that recognize which cells are the body’s own—and thereby reduces the activation of “killer” T-cells that improperly attack healthy cells in the pancreatic islets.

“We are able to prevent the onset of type 1 diabetes in mouse models,” Lee said. “MOTS-c injections seem to tame the immune system and to tell them not to tackle their own cells.”

Conversely, in a subsequent analysis in humans, type 1 diabetes patients had significantly lower levels of MOTS-c circulating in their blood compared to non-diabetic patients, and a study of human cells from both diabetic and non-diabetic patients revealed that MOTS-c treatment reduced the activation of “killer” T-cells.

New targets for treatments

This potential immune-regulating role of MOTS-c highlights possible new targets for treatment of autoimmune diseases beyond type 1 diabetes, Lee explained.

“It’s been thought for the longest time that the immune system is exclusively encoded in the nuclear genome,” Lee said. “Now we’re bringing into play an immune regulator that’s encoded in the mitochondrial genome.”

MOTS-c is one of several more recently identified hormones that are encoded in the DNA of mitochondria, the “powerhouses” of cells that convert food into energy; most other hormones are encoded in DNA in the nucleus.

Lee and Professor Pinchas Cohen, dean of the USC Leonard Davis School, first described MOTS-c in 2015, along with its role in restoring insulin sensitivity and counteracting diet-induced and age-dependent insulin resistance – effects commonly associated with exercising. The team has also studied MOTS-c’s role in intracellular communication as well as how the hormone is expressed in the brain to help regulate metabolism.

“The mitochondrial genome encodes for previously unknown genes that yield small proteins with multiple physiological roles, including aging, exercise, metabolism, and immunity,” Lee said. “Further studies on the molecular mechanism of these mitochondrial-encoded peptides are ongoing and may provide novel therapeutic targets for autoimmune conditions, which increases as we age.”

Arthritis diagnosed before or during peak reproductive years may curb men’s fertility

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Rheumatoid arthritis or one of the other types of inflammatory arthritis, diagnosed before or during peak reproductive years, may curb men’s fertility, finds research published online in the Annals of the Rheumatic Diseases.

Inflammatory arthritis is associated with fathering fewer children, higher rates of infertility, involuntary childlessness, and fertility issues, such as poor sperm quality, the findings show.

Inflammatory arthritis, which includes rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis and ankylosing spondylitis (inflammation of the spine, joints, and tendon-bone joins)–has been linked to male infertility, erectile dysfunction, and insufficient testosterone and/or sperm production (hypogonadism).

But the impact of inflammatory arthritis on men’s ability to father children remains largely unknown.

To explore this further, the researchers compared the fertility rate, or number of children per man, among men diagnosed with inflammatory arthritis based on their age at diagnosis; 30 or younger; between 31 and 40 (considered peak reproductive years); and 41 and older.

Participants were drawn from 8 different hospitals across The Netherlands between September 2019 and January 2021. 

Some 628, who were older than 40 and who indicated that their family size was complete, filled in a questionnaire on the medical and fertility issues they had had before and after being diagnosed with inflammatory arthritis.

The researchers also compared the total number of pregnancies for each man, desired family size,  the proportion of childless men and the results of medical assessments for fertility issues.

After adjusting for potentially influential factors, including current age, educational attainment, history of cardiovascular disease, a partner’s infertility,  men diagnosed with any type of inflammatory arthritis before the age of 30 had significantly fewer children than men in the two other age groups.

These men had an average of 1.32 children compared with 1.56 for those diagnosed between 31 and 40, and 1.88 for those diagnosed when they were 41 or older.  

Men diagnosed before or when they were 30 also had fewer pregnancies (1.45) than those diagnosed between 31 and 40 (1.73) or the older men (1.98).

In the Netherlands, between 1 in 5 and 1 in 4 men are childless. Among the participants, 143 (just over 22%) were childless, around two thirds of whom (99; 69%) were voluntarily childless. 

Once again, the percentage of childless men was significantly higher among those diagnosed before or at the age of 30 (45;34%) than it was among those diagnosed between 31 and 40 (39;27%) and those diagnosed in their 40s (59;17%). 

What’s more, the proportion of men who were involuntarily childless was significantly different among the 3 groups: respectively, 16 (12%); 15 (10%); and 13 (4%). Voluntary childlessness also differed 29 (25%); 24 (18%); and 46 (15%). 

But among the voluntarily childless, the statement: ‘My disease reduced my desire to have children’ was graded higher by men diagnosed at the youngest age than by those in either of the two other age groups.

And significantly more men diagnosed before or at the age of 30 (17%) and between 31 and 40 (10%) said they were dissatisfied with their final number of children than men diagnosed when they were older (5.5%). 

Around a third of these men gave as their primary reason(s) for having fewer children their diagnosis and/or the medical treatment associated with it.

Compared with the older age group, significantly more of those diagnosed before or during peak fertility years reported having been medically assessed for fertility problems, the outcome of which was poor sperm quality.

While the number of desired children was lower in men diagnosed before and during their peak reproductive years, this didn’t differ significantly among the 3 groups, overall, and it was similar to the figure reported per man for the general population of the Netherlands.

But, emphasise the researchers: “The difference between the desired and final number of children was significantly larger in men diagnosed before and during the reproductive [years], indicating that the lower fertility rates are primarily affected by reduced fertility potential and not by a reduced desire for parenthood.”

This is an observational study, and as such, can’t establish cause. And the researchers point out several caveats, including a low response rate to the questionnaire (628 out of 1841 men), while men with fertility problems might be more willing to take part in this kind of research, so representing a self-selected group. 

Infertility rates were also higher among the partners of men diagnosed before or at the age of 30.

Nevertheless, there are some plausible biological explanations for the associations found, explain the researchers. 

Several inflammatory proteins that feature in the immune response associated with inflammatory arthritis, such as tumour necrosis factor (TNF), have key roles in regulating testicular stability and sperm production.

The drugs used to treat arthritis may also have a role, they suggest. Side effects such as hypogonadism and poor sperm quality have been associated with frequently used immunosuppressive agents.

And it’s been estimated that among involuntarily childless men who go to infertility clinics, 1 in 4  take drugs that could affect sexual function while 1 in 10 take drugs associated with impaired fertility.

Several psychosocial factors, associated with their diagnosis, may also have contributed to the lower fertility rate, suggest the researchers. 

“Due to problems or concerns associated with [the diagnosis] and its treatment and based on medical advice (or the lack of it), men with [inflammatory arthritis] and their partners decided to become voluntarily childless or to delay their plans to become parents. These psychosocial factors were of special importance for men diagnosed before the peak of reproductive age.” 

Smoking exposure during childhood may increase risk of rheumatoid arthritis

Give up smoking!
Give up smoking!


A new study by investigators from Brigham and Women’s Hospital found a potential direct link between exposure to parental smoking during childhood and increased risk of seropositive rheumatoid arthritis (RA) later in life. Researchers utilized established longitudinal data from 90,923 women in the Nurses’ Health Study II (NHSII) to elucidate the relationship between passive smoking exposure and incident RA. Passive exposure was broken down into three categories, including maternal smoking during pregnancy, parental smoking during childhood, and years lived with smokers since age 18. Even with personal smoking accounted for, passive exposure to parental smoking during childhood was found to increase risk of incident seropositive RA by 75-percent. Findings are published in Arthritis & Rheumatology.

“There has been intense interest in mucosal lung inflammation from personal smoking as a site of RA pathogenesis,” said senior author Jeffrey A. Sparks, MD, MMSc, of the Department of Medicine at the Brigham. “But the majority of RA patients aren’t smokers, so we wanted to look at another inhalant that might precede RA.”

RA is an inflammatory disease characterized by arthritis at multiple joints and is associated with morbidity and mortality outcomes. Many people with RA have signs of lung inflammation, and while genetic and environmental factors contribute to risk of developing RA, smoking has long been implicated as a key RA risk factor. Personal (active) smoking is the most well-established environmental risk factor associated with RA, with passive smoking left relatively unexplored.

To link passive smoking and incident RA more conclusively, Sparks and colleagues used data from NHSII questionnaires collected biennially between 1989 and 2017 from 90,923 women aged 35-52 years. Researchers used participant medical records to confirm incident RA and serostatus. Statistical modeling was then used to estimate the direct effect of each passive smoking exposure on RA risk, as well as to control for other factors such as personal smoking.

A 75-percent higher risk of RA was found in individuals who experienced passive childhood exposure to parental smoking. This risk increased in participants who themselves became active smokers. Over the median follow-up of 27.7 years, 532 women in the cohort developed confirmed incident RA cases — the majority (352) of which were seropositive (positive for RA autoantibodies). Maternal smoking during pregnancy and years lived with smokers beyond age 18 showed no significant association with incident RA risk.

Although the all-female nurse participant pool led to high response rates and retention, the study is limited by the absence of men. The team intends to continue with longitudinal studies that encompass both men and women, as to provide critical insight into other rheumatoid conditions and even other autoimmune diseases.

“Our findings give more depth and gravity to the negative health consequences of smoking in relation to RA, one of the most common autoimmune diseases,” said lead and co-corresponding author Kazuki Yoshida, MD, ScD, of the Brigham’s Division of Rheumatology, Inflammation and Immunity. “This relationship between childhood parental smoking and adult-onset RA may go beyond rheumatology — future studies should investigate whether childhood exposure to inhalants may predispose individuals to general autoimmunity later in life.”