Effect of Fatty Acids on Glucose Metabolism and Type 2 Diabetes

Abstract

Type 2 diabetes is an inflammatory, non-infectious disease characterized by dysfunctional pancreatic β-cells and insulin resistance. Although lifestyle, genetic, and environmental factors are associated with a high risk of type 2 diabetes, nutrition remains one of the most significant factors. Specific types and increased amounts of dietary fatty acids are associated with type 2 diabetes and its complications. Dietary recommendations for the prevention of type 2 diabetes advocate for a diet that is characterized by reduced saturated fatty acids and trans fatty acids alongside an increased consumption of monounsaturated fatty acids, polyunsaturated fatty acids, and omega-3 fatty acids. Although following the recommendations for dietary fatty acid intake is important for reducing type 2 diabetes and its related complications, the underlying mechanisms remain unclear. This review will provide an update on the mechanisms of action of fatty acids on glucose metabolism and type 2 diabetes, as well as dietary recommendations for the prevention of type 2 diabetes.

INTRODUCTION

In addition to being a source of energy in metabolism, fatty acids are found in the structural component of the cell membrane, regulate gene expression, and act as eicosanoid precursors. They play a role in the etiopathogenesis of diseases such as cardiovascular diseases, type 2 diabetes, inflammatory diseases, and cancer.¹ Fatty acids can be classified as short-chain fatty acids (SCFAs) if they have less than 6 carbon (C) atoms, medium-chain fatty acids if they have 6–10 C atoms, long-chain fatty acids if they have 10–22 C atoms, and very long–chain fatty acids if they have more than 22 C atoms. Fatty acids are also classified as saturated fatty acids (SFAs) and unsaturated fatty acids according to the number of double bonds in their structures. Unsaturated fatty acids consist of monounsaturated (MUFAs) and polyunsaturated fatty acids (PUFAs).²

Type 2 diabetes is a chronic disease characterized by abnormalities in glucose metabolism, dyslipidemia, and insulin resistance, and it affects more than 400 million adults worldwide. The increasing number of people diagnosed with diabetes results in increasing morbidity and mortality, and a greater burden on national economies.³ Apart from nonmodifiable risk factors, such as age and family history of diabetes, various lifestyle-related factors such as smoking, obesity, abdominal adiposity, and physical inactivity are associated with an increased risk of type 2 diabetes. In addition, diet is a key modifiable factor in preventing type 2 diabetes.⁴ Epidemiological and clinical studies have shown that lifestyle, especially nutrition, is vital in the development and treatment of type 2 diabetes.⁵

It is recommended that dietary fat contributes up to 20–35% of energy intake. It is not just the total dietary fat intake, but also the intakes of certain subtypes of dietary fat intake (such as SFAs, MUFAs, PUFAs, and trans fatty acids), that are associated with insulin resistance and type 2 diabetes. Although managing dietary fatty acid composition is important for reducing type 2 diabetes and its related complications, the underlying mechanisms remain unclear. The general view is that fatty acids in the diet can alter cell membrane function. The fatty acid composition of the cell membrane regulates its fluidity, membrane protein incorporation, cellular activities, enzyme activities, ion permeability, receptor functions, interaction with the insulin receptor, and interaction with glucose transporters and second messengers. All these changes can alter the insulin sensitivity of tissues and organs.^6,7 Recent studies have found that fatty acids play a role in regulating rate-limiting enzymes involved in glucose metabolism such as glucose transporters through a number of post-translational modifications of proteins, including phosphorylation,^2,6 acetylation,⁸ glycosylation (eg, CD36),⁹ and palmitoylation.¹⁰ Elevated ratios of SFAs to PUFAs in the skeletal muscle cell membrane have been associated with decreased glucose effectiveness and insulin sensitivity, potentially increasing the risk of developing type 2 diabetes.¹¹ Moreover, both the proportion and absolute quantity of fatty acids can influence plasma concentrations, underscoring their importance in determining skeletal muscle phospholipid composition.⁷

Multiple studies have demonstrated that elevated plasma fatty acid concentrations are a risk factor for type 2 diabetes, particularly in individuals with poorly controlled diabetes.^12–16 High fatty acid levels may initiate peripheral insulin resistance by impeding insulin accessibility to skeletal muscles or disrupting insulin signaling, thereby reducing glucose transport into skeletal muscle. Moreover, chronic elevation of fatty acids could exert toxicity on pancreatic β-cells, leading to impaired insulin secretion.¹² A prospective pilot study found significantly higher levels of free fatty acids in both newly diagnosed and long-term controlled type 2 diabetes participants, compared with matched controls. This difference provided a high diagnostic accuracy of 87% and 91%, respectively.¹³

The fatty acid composition of dietary fat can affect various metabolic processes, including energy balance, chronic inflammation, glucose tolerance, and insulin action. In this review, the mechanisms of action of fatty acids on glucose metabolism and type 2 diabetes will be discussed.

METHODS

This narrative review involved a literature search of the PubMed, Google Scholar, Web of Science, Scopus, Oxford University Press, Wiley, and Taylor & Francis databases, accessed through the libraries of both Anadolu and Gazi Universities, up until January 2024. Only studies published in English were included. The review focused on literature from 2005 onwards, with over 90% of the citations in this article being published within the last 5 years. The following keywords were used for the literature search: “Glucose Metabolism” OR “Insulin Resistance” OR “Type 2 Diabetes” OR “T2DM” AND “Fatty Acids” OR “Saturated Fatty Acids” OR “Short Chain Fatty Acids” OR “Medium Chain Fatty Acids” OR “Monounsaturated Fatty Acids” OR “Polyunsaturated Fatty Acids” OR “Trans Fatty Acids” AND “Dietary Recommendations” OR “Nutrition”.

EFFECTS OF FATTY ACIDS ON GLUCOSE METABOLISM AND TYPE 2 DIABETES

The effects of fatty acids with different numbers of double bonds on type 2 diabetes are shown in Table 1.

Table 1.

Effects of Fatty Acids on Type 2 Diabetes According to the Double Bond in Their Structures

Fatty Acids		Type 2 Diabetes Risk
SFAs	Lauric acid (C12:0)	Negatively associated with the risk of type 2 diabetes17
	Myristic acid (C14:0)	Negatively associated with the risk of type 2 diabetes17
	Palmitic acid (C16:0)	Positively2,13,18–21 and not17 associated with the risk of type 2 diabetes
	Stearic acid (C18:0)	Not associated with the risk of type 2 diabetes17
SCFAs	Acetic acid (C2:0)	Positively22 and negatively23 associated with the risk of type 2 diabetes
	Propionic acid (C3:0)	Positively24 and negatively23 associated with the risk of type 2 diabetes
MCFAs		Negatively associated with the risk of type 2 diabetes25,26
MUFAs	Oleic acid (C18:1)	Negatively associated with the risk of type 2 diabetes2,27,28
	Palmitoleic acid (C16:1n7)	Positively associated with the risk of type 2 diabetes29–31
W-6 PUFAs	Linoleic acid (C18:2)	Negatively32–34 and not7,35 associated with the risk of type 2 diabetes
	Arachidonic acid (C20:4)	Negatively or not associated with the risk of type 2 diabetes32,36
W-3 PUFAs	α-linolenic acid (C18:3)	Negatively7 and positively4,6,37–42 associated with the risk of type 2 diabetes
	EPA (C20:5) DHA (C22:6)	Negatively6,43–45 and not44,46–48 associated with the risk of type 2 diabetes
TFAs	Industrial	Positively associated with the risk of type 2 diabetes16
	Natural	Negatively associated with the risk of type 2 diabetes17

DHA, Docosahexaenoic Acid; EPA, Eicosapentaenoic Acid; MCFA, medium-chain fatty acid; MUFA, Monounsaturated Fatty Acid; PUFA, Polyunsaturated Fatty Acid; SCFA, Short-Chain Fatty Acid; SFA, Saturated Fatty Acid; TFA, trans fatty acid; W-3, omega-3; W-6, omega-6

Saturated Fatty Acids

Dietary sources of SFAs are animal sources such as meat, milk, and dairy products, and plant sources such as cocoa, coconut, palm, and palm kernel oils. The primary dietary types of SFAs are lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0), and stearic acid (C18:0).¹⁷

Fatty acids play a direct role in influencing both gene expression and the functionality of enzymes. SFAs, for instance, influence glucose metabolism by modulating the expression of inflammatory genes, transcription factors, and enzyme activity.^6,17,18 Furthermore, they impact glucose transporter molecules through alterations in membrane lipid composition, leading to reduced insulin sensitivity.¹⁹ High-saturated-fat diets have been associated with a decrease in the number of pancreatic islets, prompting an increased release of insulin in response to glucose intake. These changes in islet structure and function contribute to glucose intolerance and an elevated susceptibility to diabetes.^6,20

Palmitic acid, which accounts for 27% of the total fatty acids and is commonly found in animal-derived foods, has been demonstrated to stimulate nitric oxide production, inflammation, and oxidative stress.^21,22 These effects can disrupt insulin signaling and lead to lasting damage to cardiometabolic health.^13,21 Palmitic acid contributes to insulin resistance and type 2 diabetes through several mechanisms (Figure 1). One primary mechanism by which palmitic acid contributes to insulin resistance and type 2 diabetes involves inducing lipotoxicity through elevated levels of diacylglycerol (DAG) and ceramide. DAG activates protein kinase C (PKC), which phosphorylates insulin receptor substrate-1 (IRS-1) at serine residues, thereby impairing the insulin signaling pathway. Additionally, DAG activates the inhibitor of nuclear factor kappa beta (NF-Κβ) kinase (IKK), leading to activation of the NF-κB pathway, further disrupting insulin signaling and promoting inflammation. Ceramide accumulation further exacerbates insulin resistance by inducing interleukin (IL)-1β release and activating protein phosphatase 2A (PP2A) and PKC, which inhibit the insulin signaling pathway and trigger inflammation.² The second mechanism involves the disruption of endoplasmic reticulum and mitochondrial function by palmitic acid. Endoplasmic reticulum homeostasis disruption leads to inflammation, activating pathways such as NF-κB, c-Jun N-terminal kinase (JNK), and the NOD-like receptor pyrin domain 3 (NLRP3) inflammasome, and promoting apoptosis, particularly in β cells. In addition, increased palmitic acid transport into the mitochondria, due to elevated non-esterified fatty acid (NEFA) levels, leads to incomplete fatty acid oxidation and increased generation of reactive oxygen species (ROS). This results in mitochondrial stress and the formation of lipid hydroperoxides and reactive aldehydes, which can modify and activate uncoupling proteins. Ultimately, this process leads to cellular damage and insulin resistance.^2,23 Third, palmitic acid can activate toll-like receptor 4 (TLR4) with the assistance of fetuin A. High-fat diets lead to elevated lipopolysaccharide levels and alter the gut microbiota, both of which serve as activators of TLR4. Lipopolysaccharides trigger inflammation via the TLR4 pathway and induce the secretion of pro-inflammatory cytokines (such as IL-6) into the plasma. This cascade further amplifies the activity of the IKKβ–NF-κB pathway.^2,17 Furthermore, palmitic acid induces pro-inflammatory responses and leptin resistance by affecting hypothalamic leptin signaling.²⁴ However, this mechanism is not fully characterized.

Figure 1.

Mechanism of Action of Palmitic Acid on Insulin Resistance and Type 2 Diabetes. Abbreviations: DAG, diacylglycerol; GPR, G-protein coupled receptor; IKKβ, inhibitor of nuclear factor kappa-B kinase; IL-1β, interleukin 1 beta; IL-6, interleukin 6; IRS-1, insulin receptor substrate I; JNK, C-jun N-terminal kinase; KLF7, Krüppel-like factor 7; (NF)-κB, nuclear factor kappa-B; NLRP3, NOD-like receptor containing a pyrin domain 3; PKC, protein kinase C; PP2A, protein phosphatase 2A; ROS, reactive oxygen species; TLR-4, toll-like receptor 4

G protein-coupled receptors (GPRs), which are locate on the cell membrane, are specifically activated by various fatty acids. Palmitic acid can promote autophagy by activating GPR40 and GPR120, reducing insulin sensitivity and leading to the occurrence of type 2 diabetes. Palmitic acid has been shown to induce inflammatory responses and glucose metabolic disorders by upregulating the expression of Krüppel-like factor 7 (KLF7). KLF7 plays a vital role in the regulation of inflammation, glucose, and lipid metabolism through the activation of GPR40 and GPR120.¹⁸

In HepG2 hepatocytes, exposure to palmitate severely inhibited insulin-stimulated activation of the insulin receptor (IR), IRS-1, and protein kinase B/Akt phosphorylation. This resulted in significantly increased lipid accumulation and enhanced gluconeogenesis in the cells, characteristic symptoms of insulin resistance.²⁵ Markedly excessive consumption of SFAs, including palmitic acid, promotes both liver and visceral fat accumulation in individuals with type 2 diabetes, compared with PUFAs.²⁶

The relationship between dietary saturated fat intake and type 2 diabetes is multifaceted, with studies reporting positive,¹⁴ negative,²⁷ and neutral associations.²⁸ In a case–control study, dietary SFA intake was shown to be associated with the development of type 2 diabetes.¹⁹ In a prospective cohort study involving 37 421 participants followed for approximately 10 years, the relationship between dietary intake of SFAs and type 2 diabetes risk was investigated. It was found that the amount of dietary SFAs, as well as the type and food source of the saturated fat, were associated with type 2 diabetes risk. Notably, saturated fat from cheese was associated with a lower risk of type 2 diabetes.²⁷ Conversely, another prospective cohort study reported different findings regarding specific sources of saturated fat. In that study, saturated fat from butter and cheese was associated with an increased risk of diabetes, while a lower risk was observed with the intake of whole-fat yogurt. Additionally, while baseline intake of saturated and animal fats did not show an association with the incidence of type 2 diabetes, the yearly updated intake of these fats was found to be linked to a higher risk of developing type 2 diabetes.²⁸

A systematic review and meta-analysis revealed that total dietary SFA intake, as well as intake of dietary palmitic acid and stearic acid were not associated with the risk of type 2 diabetes, when comparing the highest and the lowest intake categories. However, there was an 11% decrease in the risk of type 2 diabetes for the highest compared to with the lowest intake categories of dietary lauric acid and a 17% decrease for dietary myristic acid. Notably, a negative association was observed between dietary myristic acid intake and the risk of type 2 diabetes.²⁹ Another systematic review and dose–response meta-analysis of prospective observational studies concluded that a detrimental association of SFAs with the incidence of type 2 diabetes has not been confirmed.⁴

Short- and Medium-Chain Fatty Acids

SCFAs are 2–4 C atoms by-products of the fermentation of carbohydrates, proteins, and glycoproteins that are not digested by intestinal bacteria. Acetate, propionate, and butyrate constitute 95% of SCFAs. SCFAs improve intestinal health by maintaining the integrity of the intestinal barrier, producing mucus, and preventing inflammation.³⁰ Medium-chain fatty acids are fatty acids with 6–10 C atoms, consisting of caproic, capric, and caprylic acids. Unlike long-chain fatty acids, short- and medium-chain fatty acids are absorbed from the portal vein without binding to chylomicrons, and enter the mitochondria independently of carnitine and undergo β-oxidation. Short and medium-chain fatty acids are hydrolyzed and absorbed faster than long-chain fatty acids, because they are not bound to chylomicrons. Coconut and palm kernel oil from natural sources contain some medium-chain fatty acids.^30,31

SCFAs can increase the expression of glucose transporter type 4 (GLUT4), a rate-limiting protein that allows glucose to enter the cell, thus allowing glucose to be taken up into the cell. In addition, they increase glucose uptake in skeletal muscle and adipose tissue by increasing GLUT4 expression through adenosine monophosphate-activated protein kinase (AMPK) activity.³² SCFAs have functions that provide blood glucose regulation through hormones. These fatty acids activate free fatty acid receptor 2 (FFAR2), which, in turn, indirectly influences blood glucose levels. This occurs through the promotion of insulin secretion and the reduction of pancreatic glucagon secretion, ultimately stimulating the release of glucagon-like peptide-1 (GLP-1).³⁰

SCFAs increase the activation of GPR43, a cell receptor that prevents fat storage in adipose tissue, regulates fat and glucose metabolism in various tissues, increases insulin sensitivity, and reduces inflammation.³³ Further indications of the beneficial effect of SCFAs on insulin sensitivity and glucose homeostasis have been obtained from clinical studies using fermentable polysaccharides. SCFAs can directly reduce the release of adipose tissue–derived proinflammatory cytokines and chemokines.^33,34

SCFAs are crucial for maintaining intestinal permeability, reducing nitrate production, and supporting metabolic homeostasis in conjunction with peroxisome proliferator-activated receptor gamma (PPARγ).³⁵ They also enhance insulin secretion and sensitivity by increasing the release of GLP-1 and peptide YY. These mechanisms are significantly impaired during the onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD) and gut dysbiosis.³⁵ Gut microbiota dysbiosis can adversely affect these processes, leading to disrupted insulin biosynthesis. Furthermore, the severity of MASLD may be exacerbated by a reduction in SCFAs.³⁶ Disruption of the gut microbiota also impairs the ability of intestinal epithelial cells to release the fasting-induced adipose factor, a lipoprotein lipase inhibitor, resulting in elevated levels of free fatty acids in the liver.³⁷

SCFAs increase insulin sensitivity by enhancing insulin signaling and have beneficial effects against systemic inflammation and endotoxemia by reducing intestinal permeability.³⁸ Acetate and propionate demonstrate anti-inflammatory properties when they activate FFAR2. This activation of the receptor signaling pathway hinders NF-κB nuclear translocation, resulting in reduced expression of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), IL-1, and IL-6.³⁹ However, some studies have found that propionate (0.5–2.0 g/kg body weight) causes insulin resistance and hyperinsulinemia,⁴⁰ while acetate (20 μmol/kg) causes activation of the parasympathetic nervous system and increases insulin secretion, ghrelin secretion, hyperphagia, and obesity.⁴¹

There are limited studies on the effect of medium-chain fatty acids on glucose metabolism and type 2 diabetes. In animal studies, it has been reported that a diet consisting of coconut oil or medium-chain fatty acids protects insulin and glucose tolerance in contrast to diets containing saturated or unsaturated fats.^42,43 Substitution of approximately 30 g (5% of energy) of long-chain SFAs with medium-chain fatty acids in the diet has been shown to prevent insulin resistance.⁴⁴

Monounsaturated Fatty Acids

The primary dietary sources of MUFAs are olive oil, canola oil, and certain vegetable oils. Additionally, red meat, milk, and dairy products also contribute to MUFA intake. Notably, olive oil and rapeseed oil, both containing significant amounts of oleic acid (C18:1n-9) and erucic acid (C22:1n-9), stand out as prominent dietary providers of MUFAs. Oleic acid plays a crucial role in preventing insulin resistance and the onset of type 2 diabetes by mitigating glucolipotoxicity and oxidative stress. Moreover, it enhances the function of β-cells, endothelial cells, and the hypothalamus.²⁰ Oleic acid increases insulin sensitivity by increasing adiponectin levels and gene upregulation. It has the potential to stimulate fatty acid oxidation (by increasing levels of carnitine palmitoyltransferase 1⁴⁵) elevate inflammatory mediators, and influence the transfer of glucose to muscles.^2,46 Oleic acid reduces the increase in mitochondrial ROS production and concomitant inhibition of insulin signaling induced by exposure of skeletal muscle cells to palmitic acid.^2,47

Diets rich in MUFAs improve insulin sensitivity by reducing glycemic load and insulin requirement. MUFAs protect β cells from apoptosis by improving insulin sensitivity and glucose control, while improving blood lipid profiles.⁴⁸ However, some of their effects are not fully understood. Despite the favorable effects of MUFAs, their intake was not found to be associated with a reduction in the incidence of type 2 diabetes.^7,15 Additionally, increased plasma MUFA levels may adversely affect the incidence of type 2 diabetes.⁴⁹ Evidence suggests that metabolic effects may differ between different MUFAs.

In the Nurses’ Health Study (NHS) and NHS II, the food consumption frequency of female individuals without chronic disease at baseline was measured every 4 years, while the food consumption of those individuals diagnosed with type 2 diabetes was evaluated. Twenty-two years of follow-up showed that those who consumed >1 tablespoon (>8 g) of olive oil per day had a lower risk of type 2 diabetes than those who consumed no olive oil.⁵⁰ Similarly, studies have indicated that the ratio of palmitic acid to oleic acid can increase the risk of diabetes in women.²

Palmitoleic Acid (C16:1n-7) (POA) is the most abundant omega-7 MUFA. Primarily, POA is endogenously synthesized by the enzyme stearoyl-coenzyme A desaturase 1. Both animal and human research has demonstrated a correlation between circulating POA levels and factors such as insulin sensitivity, glucose regulation, lipid metabolism, and the production of inflammatory cytokines.⁵¹ However, alternate research findings suggest a potential link between elevated POA levels and an increased susceptibility to type 2 diabetes, along with the onset of insulin resistance.⁵² Additionally, there is a suggestion that POA functions not solely as a lipokine but also as a regulatory molecule, exerting influence over insulin signaling, inflammatory processes, and various metabolic pathways across diverse tissues.⁵³

In a study examining the effect of POA and oleic acid on lipid metabolism, inflammation, and insulin sensitivity in a non-obese prediabetic male rat model (with hereditary hypertriglyceridemia), it was revealed that both POA and oleic acid modulate insulin sensitivity, but by different mechanisms, by increasing circulating adiponectin and omentin levels and decreasing inflammation markers. While adiponectin and omentin levels were higher in the POA group, leptin was significantly higher in the oleic acid group. In addition, NEFAs were found to be higher in the POA group. It has been explained that when lipolysis increases, NEFAs increase, which is associated with more metabolic activity in adipose tissue and contributes to the decrease in visceral adiposity.⁴⁸ However, in other studies, it has been reported that plasma NEFAs released by adipose tissue reflect the amount of dietary fat intake, and that increased NEFA release in obese individuals causes insulin resistance by increasing the amount of inflammatory cytokines.²

Replacing a portion of palmitic acid intake with oleic acid intake has been shown to markedly reduce the adverse effects of saturated fat intake on adipose tissue, skeletal muscle, liver, and β cells.² Likewise, substituting a diet high in oleic acid with one rich in SFAs enhances insulin sensitivity. Oleic acid plays a role in preventing the decline in AMPK activity induced by palmitic acid. Notably, AMPK serves as a recognized therapeutic target for type 2 diabetes and is activated by metformin. Several studies have indicated that oleic acid shares similar protective properties with metformin, both effectively countering the adverse impacts of palmitic acid. This suggests that oleic acid may possess metformin-like qualities.² Further studies are needed to uncover the specific mechanisms through which oleic acid safeguards against the onset of type 2 diabetes in humans. However, it is essential to investigate whether this potential beneficial effect is attributed to the composition of fatty acids derived from vegetable oils or whether other dietary components, such as dietary fiber, polyphenols, and vitamins, play a significant role.

Polyunsaturated Fatty Acids

PUFAs are categorized into omega-6 (w-6) and omega-3 (w-3) acids, based on the distance from the first double bond to the methyl end. Essential fatty acids refer to fats that cannot be synthesized within the human body and must be obtained from dietary sources. Both w-3 and w-6 fatty acids fall into this category. w-3 fatty acid consists of alpha-linolenic acid (ALA, 18:3) and has 18 carbons and 3 double bonds; w-3 fatty acid consists of linoleic acid (LA, 18:2) and has 18 carbons and 2 double bonds. LA is found in many plant seeds and vegetable oils, such as sunflower oil, canola, soya bean, and corn, while ALA is found in the seeds of some oil plants, such as flax, chia, canola, and seafood. As a result of elongation and desaturation reactions from LA, arachidonic fatty acid (20:4 w-6), an w-6 fatty series, is formed. Eicosapentaenoic acid (EPA, 20:5, w-3) and docosahexaenoic Acid (DHA, 22:6, w-3) are formed from ALA.^54,55

A meta-analysis of randomized controlled trials showed that replacing just 5% of energy from saturated fats with PUFAs resulted in significant changes in fasting blood glucose.⁵⁶ The potential mechanisms linking between LA and type 2 diabetes have not been fully elucidated. However, several possible mechanisms have been suggested, for example, unsaturated fats in the diet may improve cell membrane fluidity and functions such as GLUT4 translocation, insulin receptor binding and affinity, cell signaling, and ion permeability, which increase insulin sensitivity.^57,58 LA may also affect the balance between fat oxidation and synthesis by regulating gene expression.⁵⁸

The findings on the relationship between dietary LA intake and the incidence of type 2 diabetes remain unclear. While there are studies are showing an inverse association between dietary LA intake and type 2 diabetes risk,⁵⁸ there are also studies finding no association.^7,59 In a meta-analysis of prospective cohorts, higher LA biomarker levels were associated with a 35% lower risk of type 2 diabetes.⁶⁰ That study quantitatively summarized the findings from published prospective cohort studies on the association between dietary intake, LA biomarkers and the risk of type 2 diabetes in the general population. However, since LA biomarkers reflect diet as well as other factors like metabolism, differences in type 2 diabetes risk should not be considered solely attributable to dietary LA.

An extensive analysis of prospective cohort studies, conducted through a systematic review and dose–response meta-analysis, explored the impact of dietary LA consumption and its concentration in the body on the risk of developing type 2 diabetes. The findings revealed a significant relationship between high LA intake and high LA levels in the body with a reduced risk of type 2 diabetes. The dose–response analysis further demonstrated that, for each 5% increase in energy derived from LA consumption, the risk of type 2 diabetes decreased by 10%. Likewise, a 15% reduction in diabetes risk was observed for each standard deviation increase in the LA biomarker. Notably, a substantial decrease in the risk of diabetes was associated with LA when it constituted 5.5–7.0% of the total energy intake.⁶¹ It is worth mentioning that in the dietary guidelines of the United States, the recommended amount of LA in the diet is 5–10% of total energy, while other guidelines suggest a lower intake of LA, typically no more than 4%.^61,62

In a large prospective cohort study examining the association between dietary LA intake and the risk of type 2 diabetes, it was shown that LA as a dietary PUFA may be a healthy source of energy for the prevention of type 2 diabetes compared with SFA, trans fats, and carbohydrates. Substituting 5% of total energy from SFAs, trans fatty acids, and carbohydrates with energy from LA was associated with 14%, 17%, and 9% lower risk of type 2 diabetes, respectively.⁵⁸

A study conducted by Miao and colleagues⁶³ revealed that dietary w-6 fatty acids and the presence of circulating w-6 fatty acids, particularly gamma-linolenic acid, might elevate the likelihood of developing type 2 diabetes. This increased risk is thought to arise from a mechanism that disturbs the diversity and composition of the gut microbiota.

Arachidonic acid is known to be a precursor of proinflammatory eicosanoids that may support the pathogenesis of type 2 diabetes. Studies focusing on circulating fatty acids as biomarkers have shown that arachidonic acid has an inverse or no association with the risk of type 2 diabetes.^60,64

w-3 fatty acids enhance insulin sensitivity by alleviating endoplasmic reticulum stress in mitochondria and promoting the β-oxidation of fatty acids.⁶⁵ This process reduces the accumulation of lipids and ROS. EPA and DHA influence insulin sensitivity through their effects on Akt phosphorylation, AMPK, and the PPARγ pathway. Additionally, w-3 fatty acids play a role in regulating insulin secretion in pancreatic β-cells by impacting the function and structure of adipose tissue. This, in turn, indirectly restricts the generation of proinflammatory mediators in adipose tissue and increases the synthesis of adipokines.⁶

w-3 fatty acids offer protection against obesity by reducing fat accumulation in adipose tissue, inhibiting the activity of lipogenic enzymes, and promoting the β-oxidation of fatty acids. Additionally, they exhibit notable anti-inflammatory properties, effectively shielding against the onset of insulin resistance and disruptions in glucose regulation. These fatty acids contribute to averting insulin resistance and the onset of type 2 diabetes through various mechanisms. They enhance the diversity of intestinal microbiota, reduce the levels of lipopolysaccharides and proinflammatory cytokines, which are products of harmful microorganisms, and elevate the production of SCFAs.^6,19

w-3 fatty acids additionally inhibit inflammatory cytokines, induce adipose tissue to produce adipokines, and directly impact β-cell activity by binding to receptors such as PPARγ, GPR40, and GPR120. In adipose tissue, the binding to GPR120 increases GLUT4 translocation and enhances glucose uptake.⁶

Systematic reviews of observational studies have revealed mixed associations between w-3 fatty acids and glucose metabolism, with both positive and negative relationships being reported.^5,66–69 However, in randomized controlled trials investigating the impact of w-3 fatty acids on glycemic control, improvements were observed in parameters such as fasting plasma glucose, glycated hemoglobin A1c (HbA1c), and homeostatic model assessment insulin resistance (HOMA-IR), indicating a reduction in insulin resistance.^70,71 Notably, the consumption of lean seafood and fish has been shown to enhance insulin sensitivity and reduce insulin resistance in individuals with existing insulin resistance.^72–75 In a prospective cohort study of middle-aged women, it was found that high intake of total w-3 was associated with an increased risk of type 2 diabetes, independent of other fatty acids and body mass index (BMI).⁷

The results of meta-analyses suggest a protective association between vegetable oil intake and the incidence of type 2 diabetes. Higher quantities of vegetable fat in the diet were associated with a decreased incidence of type 2 diabetes. Additionally, lower doses of PUFAs, including the plant-based fatty acid ALA, were also associated with a decreased risk of type 2 diabetes.⁴

Research has shown that EPA and DHA are pivotal in diminishing the risk of lipotoxicity and preserving insulin sensitivity.^76–78 However, certain studies have not identified a significant association between w-3 fatty acids and glycemic indicators, including fasting plasma glucose, insulin, and HbA1c.^77,79 A randomized controlled trial of 15 480 participants investigating whether w-3 fatty acid supplementation benefits cardiovascular disease in participants with diabetes showed that 0.84 g/day of w-3 supplementation did not make a significant difference in the incidence of serious vascular events.⁸⁰ A systematic review of randomized controlled trials showed that w-3, w-6, and total PUFAs had little or no effect on preventing or treating type 2 diabetes.⁸¹ These discrepancies may be attributed to differences in study methods, such as study design and duration, ethnicity of participants, and dosage administered.

The Tehran Lipid and Glucose Study found a positive correlation between the ratios of w-6 to w-3 fatty acids and of total fat to w-3 fatty acids and the risk of developing type 2 diabetes.⁵⁹ An adverse alteration in the ratio of w-6 to w-3 fatty acids initiates prothrombotic and proinflammatory processes in the body, ultimately playing a role in the development of atherosclerosis, obesity, and diabetes. Long-chain PUFAs enhance insulin receptor numbers through the improvement of adipocyte membrane fluidity and the promotion of GLUT4 expression. This leads to increased insulin receptor density on cell membranes and enhanced insulin receptor affinity, consequently amplifying insulin’s effects on the body. Nevertheless, an excess of w-6 fatty acids and a deficiency of w-3 fatty acids can release arachidonic acid from cell membranes, leading to the production of proinflammatory mediators. It has been suggested that maintaining a dietary w-6 to w-3 fatty acid ratio of 1:1 or 2:1 is optimal for promoting good health.⁸²

Trans Fatty Acids

Industrially, trans fatty acids are produced through the partial hydrogenation of vegetable oils, utilizing a metal catalyst, a vacuum, and a high temperature.⁸³ Naturally, they form during biohydrogenation of unsaturated fatty acids in ruminants, facilitated by bacterial enzymes.²⁹ Since the relationship between dietary trans fatty acids and type 2 diabetes is based on food consumption records, measurement errors may occur. Therefore, studies using trans fatty acid biomarkers (as a more objective and reliable assessment tool) are needed to evaluate the effect of trans fatty acids on glucose metabolism and type 2 diabetes. So far, few studies have examined the relationship between isomers of circulating trans fatty acids and diabetes, and there have been inconsistent findings.^84–86

Certain meta-analyses have indicated no significant impact on glucose metabolism parameters when comparing diets high and low in trans fatty acids.^4,87 Nonetheless, biomarker studies have demonstrated an association between natural trans fatty acids and a reduced incidence of type 2 diabetes,²⁹ whereas industrial trans fatty acids have been shown to elevate the incidence of type 2 diabetes.¹⁶

Elevated dietary consumption of trans fatty acids has been linked to reduced insulin sensitivity, systemic inflammation, and an increased risk of type 2 diabetes. Both in vivo and in vitro studies have demonstrated that trans fatty acids can impede the expression of PPARγ, a key player in glucose metabolism.¹⁶

In the National Health and Nutrition Examination Survey (NHANES) study, examining the relationship between plasma total trans fatty acid levels and type 2 diabetes in adults in 1999–2000 and 2009–2010, it was found that high concentrations of total trans fatty acids, especially elaidic acid, had a significant positive relationship with the risk of type 2 diabetes in adults after adjustment for risk factors. The study reported that increasing plasma trans fatty acids increased the risk of type 2 diabetes by 2.19 and 1.59 times, according to the data between 1999–2000 and 2009–2010, respectively.¹⁶ This difference may be related to the country’s policies on trans fatty acids in these years.

Other factors, including study design, population characteristics, and confounding factors may have led to inconsistent findings regarding the association between trans fatty acids and diabetes. More importantly, the years in which these studies were conducted are likely to have been an important factor. The nutrition policies and guidelines in force play an active role in this regard.

In addition, it should not be forgotten that the main source of trans fatty acids affects the results of the study. Milk and dairy products, the natural source of trans fatty acids, contain various amounts of other bioactive nutrients (calcium, magnesium, and casein). Since these nutrients are associated with a lower risk of type 2 diabetes, they may mask the potential adverse effects of trans fatty acids on type 2 diabetes.⁸⁸ Further research is needed to clarify the relationship between specific trans-fatty acid isomers and diabetes. Dietary guidelines advise limiting trans fats to less than 1% or as low as practically achievable in terms of energy consumption.²⁹ In 2010, the Food and Agriculture Organization (FAO) concluded that a high intake of trans fatty acids is a “possible” risk factor for type 2 diabetes.⁶ The FDA has taken significant measures to reduce artificial trans fat in the food supply. Since trans fat increases low-density lipoprotein, the FDA mandates that trans fats be listed on the Nutrition Facts label. In 2015, the FDA made a significant determination that partially hydrogenated oils, which were the primary source of artificial trans fat in the food supply, are no longer generally recognized as safe.⁸⁹

CONCLUSION

The evidence indicates that lifestyle changes can prevent or delay the onset of type 2 diabetes, with nutrition being a crucial factor in reducing its incidence. The quantity of fat in the diet and the specific fatty acid types significantly contribute to the prevention and treatment of type 2 diabetes.

Dietary fats encompass various fatty acids with distinct chemical structures and biological functions, playing a pivotal role in metabolic pathways that influence the risk of type 2 diabetes. The impact of dietary fatty acids extends to tissue and organ insulin sensitivity, affecting cell membrane function, hormone release, gut microbiota diversity and composition, glucose metabolism, and markers of inflammation.

Contemporary dietary recommendations for the prevention of type 2 diabetes advocate for a diet that is characterized by reduced total fat and animal fat consumption, while emphasizing a higher intake of vegetable fats. Furthermore, these guidelines suggest an increased consumption of MUFAs, PUFAs, and w-3 fatty acids, alongside a decrease in the consumption of SFAs and trans fatty acids.

The effectiveness of dietary fatty acids varies according to the source, dose, frequency of consumption, and individual differences. Therefore, further studies are needed to elucidate the mechanisms responsible for the effects of fatty acids on the development of type 2 diabetes in humans.

Author Contributions

All authors (D.S., Y.A.) wrote the original draft, contributed to discussions about the content, and reviewed and edited the manuscript. All authors (D.S., Y.A.) have read and approved the final manuscript.

Funding

Open access funding provided by the Turkish institutions affiliated with ANKOS (Anadolu University). The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Conflict of Interest

None declared.