Key Nutrients for Mental Health in Diabetes: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Raedeh Basiri.

Diabetes is associated with an increased risk of mental disorders, including depression, anxiety, and cognitive decline. Mental disorders can also contribute to the development of diabetes through various mechanisms including increased stress, poor self-care behaviors, and adverse effects on glucose metabolism. Consequently, individuals suffering from either of these conditions frequently experience comorbidity with the other. Nutrition plays an important role in both diabetes and mental health disorders including depression and anxiety. Deficiencies in specific nutrients such as omega-3 fatty acids, vitamin D, B vitamins, zinc, chromium, magnesium, and selenium have been implicated in the pathogenesis of both diabetes and mental disorders.

  • diabetes
  • mental health
  • anxiety
  • depression
  • supplementation
  • nutrients
  • nutrition
  • vitamin D
  • vitamin B12
  • iron

1. Introduction

The prevalence of diabetes has more than doubled in recent years, making it one of the most devastating diseases of the 21st century [1]. In 2021, the estimated global diabetes prevalence stood at 537 million, with projections indicating a rise to 643 million by 2030, and a further increase to 783 million by 2045 [2]. The mortality rate of diabetes is alarmingly high. It has been reported that 1.5 to 5.1 million people per year lost their lives due to diabetes and related complications, placing it as the 8th leading cause of death worldwide [3]. According to the United Kingdom Prospective Diabetes Study (UKPDS) clinical trial, strict glycemic regulation decreases the risk of developing diabetes complications [4] and can significantly improve comorbid conditions, such as mental health disorders [5].
Major depression and anxiety have often been linked to diabetes [6,7][6][7]. While some researchers have shown that diabetes is a risk factor for developing depression and anxiety [8], other studies have found that depression and stress are risk factors for type 2 diabetes [9,10][9][10]. Depression and anxiety can negatively affect the quality of life of individuals due to the impact of symptoms and adverse effects [11]. Chronic stress can augment the production of inflammatory cytokines directly or through the hypothalamic–pituitary–adrenocortical (HPA) axis, which negatively affects the functioning of pancreatic β-cells, creates insulin resistance, and ultimately can lead to diabetes [12]. Anxiety and depression have also been noted to negatively influence eating patterns and food choices [13]. This behavior may contribute to adiposity and the risk of developing diabetes [11]. Changes in appetite and a lack of interest in physical activity (behavior) can further trigger the development of diabetes [12].
In addition, diabetes self-management, which typically entails the perpetual management of blood glucose levels and sometimes taking insulin injections, may increase emotional burden and mental disturbances [14,15][14][15], which can result in depressive and anxiety symptoms. Although the best quality of care among individuals with diabetes typically helps improve diabetes symptoms, other factors heighten the risk of developing depression and anxiety, such as worry about the increase in morbidity and mortality of the condition, developing related complications, and the risk of hypoglycemia [16,17][16][17]. The incidence of depression has been noted to be high among people with diabetes compared to people with normal glycemic levels [18].

2. Key Nutrients for Mental Health in Diabetes

Optimizing nutritional status is a key component of diabetes management, mental health, and general well-being [19]. Over the past decade, dietary intake has been considered a modifiable risk factor for mitigating the symptoms of diabetes, depression, and anxiety [20]. However, it’s important to note that more clinical trials need to be conducted to confirm the effects of specific nutrients on diabetes and mental health outcomes when they coexist. It has been shown that individuals with diabetes who follow a specialized diet can maintain the best glycemic control and decrease the chance of diabetes-related complications [21,22,23,24,25,26,27,28][21][22][23][24][25][26][27][28]. In addition, the poor nutritional intake of essential nutrients can impact the body’s ability to produce hormones and neurotransmitters and further influence blood glucose levels and mental health [29]. Polyunsaturated fatty acids, notably omega-3, vitamin D, vitamin E, B vitamins, zinc, magnesium, chromium, selenium, and iron are the most important nutrients for improving mental health, blood glucose, and diabetes-related complications [30,31][30][31].

2.1. Carbohydrates, Fibers, and Fats

Over the years, studies have pointed to reducing or restricting carbohydrate intake, particularly simple carbohydrates, in preventing diabetes and reducing anxiety [34][32]. Carbohydrates are important macronutrients for the body and brain [35][33]; however, a high intake of refined carbohydrates is associated with cognitive impairment, emotional stress, and negatively affects brain function and overall health [36][34]. A limited number of studies have been conducted to evaluate the impact of either low or high carbohydrate consumption, as well as the effects of glycemic index (GI) and glycemic load (GL), on depressive symptoms in individuals with diabetes. In a cross-sectional study by Umegaki et al., a high intake of carbohydrates was associated with depression in women but not men [37][35].
Studies suggest that frequent intake of dietary fiber mitigates anxiety [42][36], slows the absorption of carbohydrates, and enhances insulin sensitivity, thus better controlling blood glucose [43][37]. Dietary fiber also has the potential to change the gut microbiota [44][38]. It interacts with the gut microbiota to produce short-chain fatty acids (SCFA), which help improve glucagon-like peptide 1 (GLP-1) and blood glucose levels [45][39]. The positive outcome of SCFA on blood sugar regulation, body mass index (BMI), resting energy expenditure, and lipolysis has been shown in both animal [46][40] and human [47][41] studies. The gut microbiota has also been shown to play a critical role in mental health [48][42].

2.2. Polyunsaturated Fatty Acids

Omega-3 fatty acids have shown positive effects on mental health [30]. Additionally, long-chain omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA; 20:5n − 3) and docosahexaenoic acid (DHA; 22:6n − 3) have favorable relationships with risk factors for diabetes, mental health disorders, inflammation, and adiposity [31]. Moreover, PUFA-derived specialized proresolving lipid mediators play a significant role in both diabetes and depression. In diabetes, these mediators contribute to the resolution of inflammation associated with chronic hyperglycemia and insulin resistance, potentially helping to mitigate the progression of diabetic complications [32][43]. In depression, these lipid mediators are thought to influence neuroinflammatory processes and synaptic plasticity, suggesting a link between their dysregulation and the development of depressive symptoms.

2.3. Vitamin B

The vitamin B complex, including B6, B12, and folate, has numerous benefits to brain health and psychological well-being [58,69][44][45]. These water-soluble vitamins are vital for optimum brain functioning and the creation of neurotransmitters like dopamine, serotonin and GABA [59,60][46][47] while neurological disorders, including anxiety and depression, have been reported in cases of deficiency of these micronutrients [70][48]. It has recently been discovered that taking high doses of vitamin B6 supplements significantly reduces anxiety, stress, and depression: supplementing adults with 25 mg of vitamin B6 twice daily for six months improved symptoms of anxiety and depression [71][49].

2.4. Vitamin D

Vitamin D is as crucial to diabetes control and mental well-being as it is for bone health [79,80][50][51]. Studies have shown that vitamin D deficiency negatively impacts insulin sensitivity [81,82][52][53]. There is evidence that vitamin D can directly increase insulin secretions from pancreatic β-cells [83][54]. Additionally, supplementing with vitamin D significantly improved fasting blood glucose, insulin, and HOMA-IR in patients with diabetes [84][55]. Diabetes development is characterized by the ineffectiveness of insulin, modifications in pancreatic β-cells, and higher levels of inflammation [81][52]. Studies have identified inflammation and oxidative stress as part of the pathophysiology of type 2 diabetes and mood dysfunction [85,86,87][56][57][58]. When systemic inflammation occurs due to diabetes, modified functions of β-cells, including the putative stress signal to periphery, can occur due to elevated cytokines, which further stimulate insulin resistance [88][59]. Emerging evidence highlights the significant role of inflammation and oxidative stress as primary contributors to the observed neuroprogression in major depressive disorder (MDD) [91][60]. Patients with MDD exhibit elevated inflammatory and oxidative stress biomarkers [92][61]. This neuroprogressive process involves stage-related neurodegeneration, cell death, reduced neurogenesis, diminished neuronal plasticity, and heightened autoimmune responses [91][60]. Oxidative stress results from an imbalance between reactive oxygen species (ROS) and antioxidants, disrupting intracellular redox-related signaling pathways and biomolecules. Excessive ROS lead to damage, generating pro-inflammatory molecules and triggering an immune response, ultimately causing cell death [93][62]. Failure to adapt to redox changes and damage from inflammatory mediators are major factors in neuroprogression and MDD [94][63]. Transcription factors, particularly nuclear factor (erythroid-derived 2)-like 2 and nuclear factor-κB, orchestrate the cascade of antioxidative and inflammatory events, holding relevance for MDD [95][64]. It has been shown that optimal levels of vitamin D cause most intracellular oxidative stress-related events to be downregulated [96][65]. An individual’s intracellular Nuclear factor erythroid 2-related factor 2 (Nrf2) status is associated with the buildup of mitochondrial reactive oxygen species (ROS) and an increase in oxidative stress [97,98][66][67].

2.5. Vitamin E

The significance of vitamin E in the prevention and maintenance of diabetes and co-existing complications cannot be overemphasized. Elevated blood glucose levels contribute to heightened oxidative stress, thereby initiating and advancing the development of diabetes along with its concomitant symptoms [103][68]. Vitamin E is a lipid-soluble antioxidant found in cell tissues that acts as a shield against lipid peroxide, and, hence, is required for the regular functioning of immune cells [104][69]. Vitamin E plays a pivotal role in glucose homeostasis [105][70]. The vitamin improves the body’s response to insulin, which improves blood glucose levels, and acts as a potent antioxidant that safeguards cells from damage caused by oxidative stress, thereby reducing the likelihood of diabetes and its related complications [106][71]. The human brain is vulnerable to antioxidant deficiency, which can result in oxidative damage [111][72]. Deficiency of vitamin E is linked to both depression and anxiety [112][73], while an association between the increased intake of vitamin E (up to 15 mg/day) and a reduction in depressive symptoms has been observed [113][74]. The available data suggests that the optimal levels of vitamin E are contingent upon the intake of polyunsaturated fatty acids (PUFAs), including dietary linoleic acid. As a result, the precise vitamin E needs cannot be definitively determined, given that these requirements are intricately linked to the varying concentrations of PUFAs within an individual’s dietary regimen [114][75].

2.6. Zinc

Zinc is a critical micronutrient involved in several cell functions and necessary for glycemic regulation [116][76]. While some studies have reported lower levels of zinc among people with diabetes [117][77], other reports have also emphasized that zinc deficiency is often associated with a reduced responsiveness to insulin [116][76]. In a recent meta-analysis (n = 3978 subjects), supplementation with zinc improved fasting glucose concentrations [118][78]. Zinc is an important cofactor in glucose homeostasis, supports the function of the immune system, and reduces oxidative stress [119][79]. Several complications of diabetes are linked to free radicals and raised intracellular oxidants, which are caused by decreased intracellular zinc and other antioxidants [120][80]. Depression and anxiety are also associated with a low intake of dietary zinc [123][81]. Zinc-containing neurons form a trail through the cerebral cortex, hippocampus, and amygdala, impacting mood and cognitive ability [124][82]. Zinc deficiency was found to be common among patients with depression and anxiety [125][83].

2.7. Magnesium

Magnesium is a cofactor for more than 300 enzymes involved in cholesterol synthesis and glucose metabolism [126][84]. The association between diabetes and hypomagnesemia in extracellular and intracellular compartments is well-established [127][85]. Over the past decades, hypomagnesemia (serum magnesium < 0.7 mmol/L) has been strongly associated with type 2 diabetes mellitus [128][86]. Patients with hypomagnesemia show a more rapid disease progression and have an increased risk for diabetes complications [129][87]. Intracellular magnesium regulates glucokinase, KATP channels, and L-type Ca2+ channels in pancreatic β-cells, preceding insulin secretion [128][86]. Psychological disorders such as depression and anxiety also occur in individuals who have magnesium deficiency. In a randomly selected, population-based study, the relationship between magnesium and mental disorders was observed using a validated food frequency questionnaire and the General Health Questionnaire-12 to assess psychological symptoms [135][88]. Although there was no association between anxiety and magnesium levels, a link between a deficit of magnesium and depression was detected.

2.8. Chromium

Chromium, an essential mineral, is important in lipid and carbohydrate metabolism and aids in improving glycemic control, and can prevent the onset of diabetes and related complications [139][89]. Recent studies have revealed that low levels of chromium have been associated with an increased risk of diabetes, while optimum levels of chromium enhance glucose homeostasis in patients with hyperglycemia [141][90]. Further, a deficiency in chromium has been linked to elevated inflammation and increased cardiometabolic risk [142][91]. Several RCTs have also found significant improvements in diabetes complications after serum levels of chromium were improved in the treatment groups [143,144,145][92][93][94].

2.9. Selenium

The benefits of dietary selenium in reducing the risk of diabetes are currently inconclusive [151][95]. While some studies have shown a positive effect in preventing the onset of diabetes [152][96], others have shown the opposite effect [153][97]. The RDA for selenium is 55 μg/d for both men and women [154][98]. Although some researchers claim that optimum blood concentrations of selenium are required to reduce the risk of type 2 diabetes, large cross-sectional and intervention trials confirm, rather, that supplementation among people who already have an adequate intake of selenium might increase their risk of type-2 diabetes [151,152,155][95][96][99]. Collectively, selenium appears to possess both beneficial and toxic effects. The preventive effect of selenium is attributed to the antioxidant role of selenoproteins and selenocysteine [156][100]. There is also evidence that selenium deficiency not only impacts glucose control negatively [163][101] but is also linked to a heightened risk of cognitive decline, depression, and anxiety [155,164,165][99][102][103]. In a recent study examining the relationship between reduced selenium levels and anxiety, the findings revealed a heightened risk of generalized anxiety disorder linked to lower serum concentrations of selenium [166][104]. Corresponding research has identified a connection between deficient selenium levels and minor and major depressive disorder [167,168][105][106]. 

2.10. Iron

A low serum iron concentration is the most common nutrient deficiency globally and increases the risk of various health conditions, including mental health disorders [170][107] such as anxiety, depression, and challenges with more intricate cognitive tasks [171][108]. The incidence of anemia among individuals with a mental disorder is significantly greater than in the general population [172][109]. Iron is a crucial component in the synthesis of dopamine, which is an important neurotransmitter involved in various functions such as mood regulation, motivation, and movement control [173][110]. Additionally, iron is essential for DNA synthesis, which is a fundamental process in the growth, repair, and maintenance of cells [174,175,176][111][112][113]. In contrast, increased iron intake enhances the risk of diabetes and its complications [181][114]. Iron overload affects vital tissues by quickening mitochondrial decay and causing systemic free radical destruction of healthy tissues [182,183][115][116]. Excessive iron accumulation can impact critical tissues involved in glucose and lipid metabolism, such as pancreatic β cells, liver, muscle, and adipose tissue, as well as organs affected by the chronic complications of diabetes [184][117]. The Dietary Reference Intake (DRI) sets the Recommended Dietary Allowances (RDA) for iron to prevent anemia, ranging from 7 mg/day to 18 mg/day based on age and gender, with pregnant women needing 27 mg/day [185][118].

3. Conclusions

Available evidence indicates that certain nutrients may have beneficial effects on enhancing both mental health and diabetes symptoms in individuals with type 2 diabetes; however, further clinical trials are necessary to determine the optimal dosages of these nutrients for effectively addressing diabetes, as well as comorbid depression and anxiety in patients with diabetes. Additionally, it is essential to consider recommended nutrient amounts tailored to individual needs. For example, for nutrients such as vitamins B6 and B12, when administered in higher doses to research subjects with insufficient levels of the vitamins, there were significant improvements in their serum concentration levels while their symptoms also improved. On the other hand, higher doses of chromium, vitamin E, and folate, if dispensed to individuals in doses higher than the RDA, might be toxic, increasing the risk of diabetes complications and mental health disorders. Overall, the adequate intake of the reported essential nutrients from food sources is a priority, as it has the potential to aid in glucose homeostasis, prevention or treatment of diabetes and related complications as well as mental disorders such as depression and anxiety. When dietary intake falls short, targeted supplementation with identified nutrients may offer a strategy for mitigating diabetes and mental health-related issues.

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