“This beneficial effect remained, even after correcting for age, sex, race, obesity, and hypertension or chronic kidney disease and heart failure,” said Anath Shalev, M.D., director of UAB’s Comprehensive Diabetes Center and leader of the study.

“Since similar results have now been obtained in different populations from around the world — including China, France and a UnitedHealthcare analysis — this suggests that the observed reduction in mortality risk associated with metformin use in subjects with Type 2 diabetes and COVID-19 might be generalizable,” Shalev said.

How metformin improves prognosis in the context of COVID-19 is not known, Shalev says. The UAB findings suggest that the mechanisms may go beyond any expected improvement in glycemic control or obesity, since neither body mass index, blood glucose nor hemoglobin A1C were lower in the metformin users who survived as compared to those who died.

“The mechanisms may involve metformin’s previously described anti-inflammatory and anti-thrombotic effects,” Shalev said.

The study — first made available in MedRxiv and now published in the peer-reviewed journal Frontiers in Endocrinology — included 25,326 patients tested for COVID-19 at the tertiary care UAB Hospital between Feb. 25 and June 22 of last year. Of the 604 patients found to be COVID-19-positive, 311 were African Americans.

The primary outcome in the study was mortality in COVID-19-positive subjects, and the potential association with subject characteristics or comorbidities was analyzed.

Researchers found that Blacks, who are only 26 percent of Alabama’s population, were 52 percent of those who tested positive for COVID-19, and only 30 percent of those who tested negative. In contrast, only 36 percent of the COVID-19-positive subjects were white, while whites made up 56 percent of those who tested negative, further underlining the racial disparity. Once COVID-19-positive though, no significant racial difference in mortality was observed.

“In our cohort,” Shalev said, “being African American appeared to be primarily a risk factor for contracting COVID-19, rather than for mortality. This suggests that any racial disparity observed is likely due to exposure risk and external socioeconomic factors, including access to proper health care.”

Overall mortality for COVID-19-positive patients was 11 percent. The study found that 93 percent of deaths occurred in subjects over the age of 50, and being male or having high blood pressure was associated with a significantly elevated risk of death. Diabetes was associated with a dramatic increase in mortality, with an odds ratio of 3.62. Overall, 67 percent of deaths in the study occurred in subjects with diabetes.

The researchers looked at the effects of diabetes treatment on adverse COVID-19 outcomes, focusing on insulin and metformin as the two most common medications for Type 2 diabetes. They found that prior insulin use did not affect mortality risk.

However, prior metformin use was a different matter. Metformin use significantly reduced the odds of dying, and the 11 percent mortality for metformin users was not only comparable to that of the general COVID-19-positive population, it was dramatically lower than the 23 percent mortality for diabetes patients not on metformin.

After controlling for other covariates, age, sex and metformin use emerged as independent factors affecting COVID-19-related mortality. Interestingly, even after controlling for all these other covariates, death was significantly less likely — with an odds ratio of 0.33 — for Type 2 diabetes subjects taking metformin, compared with those who did not take metformin.

“These results suggest that, while diabetes is an independent risk factor for COVID-19-related mortality,” Shalev said, “this risk is dramatically reduced in subjects taking metformin — raising the possibility that metformin may provide a protective approach in this high-risk population.”

The researchers say future studies will need to explore how metformin is protective, as well as assess the risks and benefits of metformin treatment and the indications for its use in the face of the ongoing COVID-19 pandemic.

This study is part of a new Precision Diabetes Program, a collaboration between the UAB Comprehensive Diabetes Center and the Hugh Kaul Precision Medicine Institute at UAB.

Co-authors with Shalev for the paper, “Metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes,” are Andrew B. Crouse and Matthew Might, the Hugh Kaul Precision Medicine Institute at UAB; Tiffany Grimes and Fernando Ovalle, the Comprehensive Diabetes Center and the Department of Medicine Division of Endocrinology, Diabetes and Metabolism at UAB; and Peng Li, UAB School of Nursing.

Support came from National Institutes of Health grants DK078752, DK120379 and TR001417.

Shalev is a professor in the UAB Department of Medicine Division of Endocrinology, Diabetes and Metabolism, and she holds the Nancy R. and Eugene C. Gwaltney Family Endowed Chair in Juvenile Diabetes Research.

The researchers project that, due to the pandemic deaths last year, life expectancy at birth for Americans will shorten by 1.13 years to 77.48 years, according to their study published Thursday in the Proceedings of the National Academy of Sciences.

That is the largest single-year decline in life expectancy in at least 40 years and is the lowest life expectancy estimated since 2003.

The declines in life expectancy are likely even starker among minority populations. For Blacks, the researchers project their life expectancy would shorten by 2.10 years to 72.78 years, and for Latinos, by 3.05 years to 78.77 years.

Whites are also impacted, but their projected decline is much smaller — 0.68 years — to a life expectancy of 77.84 years.

Overall, the gap in life expectancy between Blacks and whites is projected to widen by 40%, from 3.6 to more than 5 years — further evidence of the disease’s disparate impact on disadvantaged populations.

“Our study analyzes the effect of this exceptional number of deaths on life expectancy for the entire nation, as well as the consequences for marginalized groups,” said study author Theresa Andrasfay, a postdoctoral fellow at the USC Leonard Davis School of Gerontology. “The COVID-19 pandemic’s disproportionate effect on the life expectancy of Black and Latino Americans likely has to do with their greater exposure through their workplace or extended family contacts, in addition to receiving poorer health care, leading to more infections and worse outcomes.”

COVID-19 appears to have eliminated many of the gains made in closing the Black-white life expectancy gap since 2006. Latinos, who have consistently experienced lower mortality than whites — a phenomenon known as the “Latino paradox” — would see their more than three-year survival advantage over whites reduced to less than one year.

“The huge decline in life expectancy for Latinos is especially shocking given that Latinos have lower rates than the white and Black populations of most chronic conditions that are risk factors for COVID-19,” said study co-author Noreen Goldman, the Hughes-Rogers Professor of Demography and Public Affairs at the Princeton School of Public and International Affairs. “The generally good health of Latinos prior to the pandemic, which should have protected them from COVID-19, has laid bare the risks associated with social and economic disadvantage.”

The study’s authors estimated life expectancy at birth and at age 65 for 2020 for the total U.S. population and by race and ethnicity. They used four scenarios of deaths — one in which the COVID-19 pandemic had not occurred and three others that include COVID-19 mortality projections by the Institute for Health Metrics and Evaluation, an independent global health research center at the University of Washington.

“The bigger reductions in life expectancy for the Black and Latino populations result in part from a disproportionate number of deaths at younger ages for these groups,” Goldman said. “These findings underscore the need for protective behaviors and programs to reduce potential viral exposure among younger individuals who may not perceive themselves to be at high risk.”

Life expectancy as an indicator of population health

Of the analyzed deaths for which race and ethnicity have been reported to the National Center for Health Statistics, 21% were Black and 22% Latino. Black and Latino Americans have experienced a disproportionate burden of coronavirus infections and deaths, reflecting persistent structural inequalities that heighten risk of exposure to and death from COVID-19.

The researchers say life expectancy is an important indicator of a population’s health and an informative tool for examining the impact of COVID-19 on survival.

In the decades before the COVID-19 pandemic, annual improvements in U.S. life expectancy had been small but overall life expectancy had rarely declined. An exception was the annual reduction of 0.1 year for three consecutive years — 2015, 2016, and 2017 — which were attributed in part to increases in so-called “deaths of despair” among middle-aged whites related to drug overdoses, including opioids, as well as alcohol-related liver disease and suicide.

The projected pandemic-related drop in life expectancy is about 10 times as large as the declines seen in recent years.

The last major pandemic to significantly reduce life expectancy in a short period of time was the 1918 influenza pandemic, which research indicates reduced life expectancy by an extraordinary 7-12 years.

As of Wednesday, more than 10 million Americans had received their first COVID-19 vaccination dose, according to the U.S. Centers for Disease Control and Prevention. But the vaccines may not be enough to immediately reverse the impact of the disease on U.S. life expectancy.

“While the arrival of effective vaccines is hopeful, the U.S. is currently experiencing more daily COVID-19 deaths than at any other point in the pandemic,” Andrasfay said. “Because of that, and because we expect there will be long-term health and economic effects that may result in worse mortality for many years to come, we expect there will be lingering effects on life expectancy in 2021.”

“That said,” she added, “no cohort may ever experience a reduction in life expectancy of the magnitude attributed to COVID-19 in 2020.”

The study authors say they are now studying occupational exposures to COVID-19 by race and ethnicity to further comprehend its disproportionate impact.

The research was supported by the National Institute on Aging (grant number T32AG000037).

Many plants produce chemical defenses to protect themselves against being eaten. Still little is known about what makes these substances toxic to their consumers. Researchers at the Max Planck Institute for Chemical Ecology and the University of Münster have now investigated how plants produce toxins and store them in their tissues without harming themselves. In particular, they wanted to know whether the mechanisms of autotoxicity and its prevention share similar mechanisms as the toxic characteristics that provide defense against herbivores.

Autotoxicity and defense

For their experiments, they chose diterpene glycosides from Nicotiana attenuata plants, a wild tobacco species. “These substances occur at very high concentrations in the leaves of tobacco plants. But we had no idea why they were such effective defenses or why they could be so toxic to produce. So the situation was completely different from the other very abundant toxin that this plant produces, namely, nicotine. Nicotine is a specific neurotoxin. Since plants lack nerves and muscles, they offer no target for the toxin. So producing and storing nicotine does not harm plants,” says Ian Baldwin from the Department of Molecular Ecology at the Jena Max Planck Institute, where the study was carried out.

To their surprise, the researchers found that tobacco plants which had been transformed so they could no longer produced two proteins involved in the biosynthesis of the diterpene glycosides and thus also not form the defensive substances otherwise stored in the leaves in large amounts, showed conspicuous symptoms of self-poisoning: they were sick, unable to grow normally, and could no longer reproduce. Further experiments revealed that certain components of the cell membrane, so-called sphingolipids, had been attacked.

Targeting the cell membrane

Sphingolipids are substances found in all animals and plants, including the enemies of wild tobacco, the larvae of the tobacco hawkmoth Manduca sexta. The researchers therefore asked whether the sphingolipid metabolism could be the target of the diterpene glycosides. In fact, Manduca sexta caterpillars, which had fed on plants without diterpene glycosides, grew significantly better than larvae, which had fed on controls that contained the defensive chemicals. Analyses of the frass of Manduca sexta larvae, which had ingested diterpene glycosides with their food, provided further insights, as the degradation of the plant toxins during larval digestion is more or less in reverse order to the synthesis of the substances in the plant. Plants prevent self-harm by storing the defensive substances in a non-toxic form. However, when insects feed on the plant, a part of the non-toxic molecule is cleaved off and the chemical becomes activated or “armed.” “Interestingly, in both cases, in plants with incomplete diterpene glycoside biosynthesis and in feeding caterpillars, the target of the toxins is the sphingolipid metabolism,” says first author Jiancai Li.

Sphingolipids are mediators in many physiological processes. This makes the effect of diterpene glycosides on sphingolipid metabolism so intriguing. “Diterpene glycosides and their derivatives can have broad defensive functions against many agricultural pests and pathogenic fungi. At the same time, many human diseases, such as diabetes, cancers and some neurodegenerative diseases are also associated with elevated sphingolipid metabolisms,” says Shuqing Xu from the Institute for Evolution and Biodiversity at the University of Münster, who is one of the senior authors of the study. Physicians have been searching for effective substances to treat these diseases by inhibiting the sphingolipid metabolism. The diterpene glycosides studied here could be potential candidates for further investigations.

“Frassomics” — a new powerful tool to study interactions between organisms

The analysis of larval frass proved to be the key to success in this study. The scientists call this new approach “frassomics”: a combination of frass (larval droppings) and metabolomics — the analysis of all metabolites in an organism. “From this work, we realized that frassomics can be a very powerful research tool. The analysis of larval frass can provide metabolic clues about how what one organism produces is metabolized by consumer organisms,” says Ian Baldwin.

The scientists plan to gain more insights into the “digestive duets” that occur between plants and insects, in order to better understand ecological interactions between plants, insects and microorganisms.

“The opioid crisis and resulting overdose deaths in the United States are now well known, but what is less recognized is that there is a growing crisis of overdose deaths involving methamphetamine and other stimulants. However, unlike for opioids, there are currently no approved medications for treating methamphetamine use disorder,” said NIDA Director Nora D. Volkow, M.D. “This advance demonstrates that medical treatment for methamphetamine use disorder can help improve patient outcomes.”

The study known as the Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder study, or ADAPT-2, was conducted from 2017 to 2019 at clinics in multiple community treatment programs nationwide and enrolled 403 adult volunteers ages 18 to 65 years with moderate to severe methamphetamine use disorder. All participants wished to reduce or cease use of the drug and were randomly assigned to the treatment or control group.

In each of two six-week stages, volunteers in the treatment group were given an injection of extended-release naltrexone, a drug used to treat opioid and alcohol use disorders, every three weeks and took daily extended-release tablets of bupropion, an antidepressant also used as a treatment to aid nicotine cessation. Those in the control group were given matched injectable and oral placebos over the same time periods. Investigators performed four urine drug screens at the end of each stage of the trial. Participants were considered to have responded to treatment if at least three of four urine screens were negative.

Overall, participants responded at a significantly higher rate in the treatment group. When screened during weeks five and six, 16.5% of those given the altrexone/bupropion combination responded, compared to only 3.4% of those in the control group. Similarly, when screened in weeks 11 and 12, 11.4% of the treatment group responded, compared to 1.8% of the control group. Researchers calculated that the number needed to treat (NNT) was 9. NNT is a way to describe the utility of a medical intervention that indicates the number of people who would need to receive a treatment for it to benefit one person. The investigators reported that, with an NNT of 9, naltrexone/bupropion’s benefit as a treatment for methamphetamine use disorder is similar to most medical treatments for mental health disorders, including antidepressants prescribed for depression or naltrexone prescribed for alcohol use disorder.

Participants in the treatment group were assessed to have fewer cravings than those in the placebo group and reported greater improvements in their lives as measured by a questionnaire called the Treatment Effectiveness Assessment. Importantly, there were no significant adverse effects associated with the dual medication treatment. Adherence to treatment was encouraged by adherence counseling and mobile app reminders and remained high at 77.4% and 82.0% in the treatment and placebo groups, respectively, in the final six weeks of the study.

“Long-term methamphetamine misuse has been shown to cause diffuse changes to the brain, which can contribute to severe health consequences beyond addiction itself,” said Madhukar H. Trivedi, M.D., of the University of Texas Southwestern Medical Center, Dallas, who led the trial. “The good news is that some of the structural and neurochemical brain changes are reversed in people who recover, underscoring the importance of identifying new and more effective treatment strategies.”

Methamphetamine use disorder is a serious illness often associated with severe medical and mental health complications and a risk of fatal overdose. Methamphetamine is a potent stimulant, and, like other addictive drugs, it hijacks the reward pathways in the brain by raising levels of dopamine, a brain chemical associated with repeating actions that cause pleasurable feelings.

Finding treatments that disrupt these processes has been challenging for scientists. Research suggests bupropion may alleviate dysphoria associated with methamphetamine withdrawal by acting on the dopamine and norepinephrine systems. Alleviating dysphoria may in turn reduce cravings and help prevent return to methamphetamine use. Naltrexone may reduce the euphoric effects and cravings associated with taking methamphetamine. In previous clinical studies, however, both bupropion and naltrexone administered alone showed limited, inconsistent efficacy in treating methamphetamine use disorder. Now, in combination, these compounds seem to have an additive or synergistic effect.

While there are U.S. Food and Drug Administration-approved medications for other substance use disorders, no medications have yet received FDA approval for methamphetamine use disorder. The effectiveness of this medication combination is progress toward improving treatment of this addiction.

The investigators recommend that future research build on this work by testing if longer naltrexone/bupropion treatment or concurrent behavioral therapy, such as contingency management, brings still better responses. Contingency management , which uses motivational incentives and tangible rewards to help a person attain their treatment goals, has demonstrated to be the most effective therapy for stimulant use disorders but is not widely used, stemming in part from a policy limiting the monetary value of incentives allowable as part of treatment.