“If you’re insulin-resistant, your risk of developing major depressive disorder is double that of someone who’s not insulin-resistant, even if you’ve never experienced depression before,” says Natalie Rasgon, MD, PhD, a coauthor of the study and a professor of psychiatry and behavioral sciences at the Stanford University School of Medicine in California. The study was published in September 2021 in the American Journal of Psychiatry. Researchers examined data on 601 healthy adults who had tests for three proxies of insulin resistance: blood sugar levels, waist circumference, and levels of fats in the blood known as triglycerides that raise the risk of heart disease. Nearly all the participants were white, of Northern European ancestry, and were 41 years old at the start of the study. Three-fifths of them were women, and three-fourths of them were married. After nine years of follow-up, 14 percent of participants received a new diagnosis of major depressive disorder, also known as clinical depression, on the basis of psychiatric evaluations. This risk was higher for people with any of the three proxies for insulin resistance at the start of the study. People who had higher levels of triglycerides and lower levels of “good,” HDL, cholesterol that help unclog arteries had an 89 percent higher risk of developing depression during the study period. Each five-centimeter (two-inch) increase in waist circumference was linked to an 11 percent greater depression risk. And each 18 milligram per deciliter (mg/dL) increase in fasting blood sugar levels was tied to 37 percent higher risk of depression. Among people who didn’t have any of these proxies for insulin resistance at the start of the study, individuals whose blood sugar levels climbed during the first two years of follow-up had a 2.7-fold greater risk of receiving a depression diagnosis. These individuals developed what’s known as prediabetes, when blood sugar levels are slightly above normal but not high enough for a diagnosis of type 2 diabetes. Insulin resistance is associated with both conditions. RELATED: The AHA Makes the Heart-Mind Connection Official

What Does Insulin Do in the Body?

Insulin is a hormone produced in the pancreas, and cells need it to use glucose, or sugar, derived from food for energy. With insulin resistance, the body doesn’t use insulin properly, causing sugars to accumulate in the blood instead, an effect called hyperglycemia. When the pancreas cannot meet the body’s insulin demands, blood sugar stays high, causing weight gain and, potentially, type 2 diabetes. The study wasn’t designed to examine how insulin resistance might lead to depression in some people. “There could be a shared underlying factor such as poor sleep or stress, which can influence both depression and diabetes,” says Michael Jacob, MD, PhD, an assistant professor of psychiatry at the University of San Francisco and a staff psychiatrist at the San Francisco Veterans Affairs Health Care System. Dr. Jacob wasn’t involved in the current research. One limitation of the study is that researchers didn’t directly measure insulin resistance using tests that show exactly how well the body makes and uses this hormone. While proxy measures of insulin resistance are often a good indication that people have the condition, they’re not as precise as existing direct tests, researchers of the current study note. Another limitation of the study is that researchers assessed proxies for insulin resistance for just two years, making it possible that changes that occurring after this period may have influenced the development of depression. RELATED: What Are the Possible Complications of Type 2 Diabetes?

Previous studies have also linked insulin resistance to an increased depression risk, including one published in November 2017 in PLoS One and another published in August 2020 in Diabetologia. Some earlier research also examined one big question unanswered by the new study — whether reversing insulin resistance or lowering blood sugar also helps prevent or treat depression. For example, a clinical trial published in June 2020 in Neurotherapeutics tested the effectiveness of adding the diabetes drug metformin to antidepressant therapy for people with major depressive disorder who didn’t have diabetes. Depression went into remission for 81 percent of people who took both metformin and an antidepressant, compared with 46 percent of patients who took an antidepressant alone. Diabetes drugs like metformin may help reduce depression risk in individuals with or without type 2 diabetes, says Rodrigo Mansur, MD, PhD, an assistant professor of psychiatry at the University of Toronto. “If insulin resistance and hyperglycemia contribute to the development of depression, they could then be targets for treatment,” says Dr. Mansur, who wasn’t involved in the latest study. It’s far less clear that treating insulin resistance would prevent depression, says Vincent Fong, MD, PhD, an assistant professor of endocrinology, diabetes, and metabolism at the University of Cincinnati College of Medicine in Ohio. “Prevention of depression is far from a sure thing,” says Dr. Fong. “With that being said, stress is often a big factor in depression, so developing strategies to reduce or manage stress can be important, and so is having support networks for times when stress is higher.” People with diabetes can benefit from being assessed for mood disorders, and those with depression can benefit from screenings for diabetes and other metabolic disorders such as high blood pressure and obesity, says Rasgon. Screening might help people get earlier treatment for depression or for type 2 diabetes, and help some individuals get help sooner when symptoms may be less severe or easier to address. “These tests are readily available in labs around the world, and they’re not expensive,” Rasgon says. “In the end, we can mitigate the development of lifelong debilitating diseases.” RELATED: The Possible Benefits of Metformin for Type 2 Diabetes and Beyond For more information on insulin sensitivity and resistance, check out Diabetes Daily’s article “Insulin Resistance: What You Need to Know”!