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A precursor to diabetes might also go hand-in-hand with depression, a Dutch cohort study indicated.

Three surrogate measures for insulin resistance all showed a significant link with developing a major depressive disorder over a 9-year follow-up period, reported Kathleen T. Watson, PhD, of Stanford School of Medicine in California, and colleagues.

As shown in their study online in the , a higher ratio of triglycerides to high-density lipoproteins (HDLs) -- 0.83 or higher for females and 1.22 or higher for males -- was associated with an 89% higher risk of developing incident major depression (HR 1.89, 95% CI 1.15-3.11).

In addition, individuals with prediabetes -- defined as a fasting plasma glucose level of 5.54 mmol/L (100 mg/dL) or higher -- saw a 37% increased risk for major depression (HR 1.37, 95% CI 1.05-1.77).

And "central adiposity" -- defined as a waist circumference of 100 cm (39 in) or more -- was associated with an 11% increased risk for depression (HR 1.11, 95% CI 1.01-1.21).

The relationships were similar for both males and females, the team noted.

"We know that type 2 diabetes leads to an increased risk for depression, and here we see that insulin resistance, a highly prevalent condition that often precedes type 2 diabetes, is also associated with increased depression," Watson told 乌鸦传媒.

The findings were "a bit unexpected," she added. "The relationship between insulin resistance and depression could have gone in either direction."

In an attempt to parse out the timing of the relationship, Watson's group performed a secondary analysis looking only at participants with new-onset insulin resistance within the first 2 years after study enrollment.

"Some subjects were already insulin-resistant at the study's start -- there was no way to know when they first become insulin-resistant," Watson explained in a statement. "We wanted to more carefully determine how soon the connection kicks in."

At the 2-year follow-up screening, new-onset prediabetes was linked to a more than twofold increased risk for major depression (HR 2.66, 95% CI 1.13-6.27). But also by this timepoint, new-onset high triglyceride-HDL ratio and high central adiposity after study enrollment were not significantly tied to incident major depression, the researchers said.

"It's time for providers to consider the metabolic status of those suffering from mood disorders and vice versa, by assessing mood in patients with metabolic diseases such as obesity and hypertension," co-study author Natalie Rasgon, MD, PhD, also of Stanford, explained in a statement. "To prevent depression, physicians should be checking their patients' insulin sensitivity."

"These tests are readily available in labs around the world, and they're not expensive," she added. "In the end, we can mitigate the development of lifelong debilitating diseases."

For the analysis, the researchers drew on 9 years of data from the multisite Netherlands Study of Depression and Anxiety study. This particular analysis included 601 participants from the study, all between the ages of 18 and 65. At baseline, none of the participants had any lifetime history of depression or anxiety.

The participants then underwent a psychiatric interview at baseline and at years 2, 4, 6, and 9 of follow-up, screened for major depressive disorder, anxiety disorders, and bipolar disorder.

Triglyceride, HDL, and fasting plasma glucose levels were also each adjusted for medication use, and were measured at baseline and only at the 2-year follow-up.

During the 9-year follow-up, a total of 14% of the cohort (84 individuals) developed major depressive disorder, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria. About 5% of the cohort developed depression by year 2 (30 individuals).

Regarding possible mechanisms of action, one possible explanation, Watson and co-authors said, might be due to neuroinflammation, caused by insulin resistance, which can increase the risk for depression.

"The inflammatory hypothesis of depression suggests that the presence of proinflammatory cytokines may lead to a reduction in serotonin levels, as well as reduced neurogenesis and synaptic plasticity-physiological states, which are associated with the presence of depression," the researchers said.

Still, they added, a notable limitation of the study was that insulin resistance was only measured according to these three surrogate markers, rather than using the "gold standard" of the euglycemic clamp technique.

"We are also exploring the idea of the metabolic subtype of depression," said Watson. "It is plausible that different treatments or approaches help manage depression in people with insulin resistance. These tools may inform clinical practices in the future."

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