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Yang, W.; Jiang, W.; Guo, S. Regulation of Macronutrients during Type 2 Diabetes Mellitus. Encyclopedia. Available online: https://encyclopedia.pub/entry/52699 (accessed on 08 July 2024).
Yang W, Jiang W, Guo S. Regulation of Macronutrients during Type 2 Diabetes Mellitus. Encyclopedia. Available at: https://encyclopedia.pub/entry/52699. Accessed July 08, 2024.
Yang, Wanbao, Wen Jiang, Shaodong Guo. "Regulation of Macronutrients during Type 2 Diabetes Mellitus" Encyclopedia, https://encyclopedia.pub/entry/52699 (accessed July 08, 2024).
Yang, W., Jiang, W., & Guo, S. (2023, December 13). Regulation of Macronutrients during Type 2 Diabetes Mellitus. In Encyclopedia. https://encyclopedia.pub/entry/52699
Yang, Wanbao, et al. "Regulation of Macronutrients during Type 2 Diabetes Mellitus." Encyclopedia. Web. 13 December, 2023.
Regulation of Macronutrients during Type 2 Diabetes Mellitus
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This entry is adapted from the peer-reviewed paper 10.3390/nu15214671

Insulin resistance is an important feature of metabolic syndrome and a precursor of type 2 diabetes mellitus (T2DM). Overnutrition-induced obesity is a major risk factor for the development of insulin resistance and T2DM. The intake of macronutrients plays a key role in maintaining energy balance. The components of macronutrients distinctly regulate insulin sensitivity and glucose homeostasis. Precisely adjusting the beneficial food compound intake is important for the prevention of insulin resistance and T2DM. 

macronutrients insulin resistance glucose homeostasis type 2 diabetes mellitus

1. Introduction

Type 2 diabetes mellitus (T2DM) has become a global health issue that is tightly correlated with the prevalence of obesity and other chronic diseases. T2DM is caused by systemic insulin resistance and impaired insulin secretion in pancreatic β-cells, leading to disorders of carbohydrate, protein, and lipid metabolism [1]. Insulin resistance is a hallmark of prediabetes and gradually contributes to the development of T2DM. Insulin resistance refers to an impaired ability of insulin to lower blood glucose in target tissues at a normal plasma insulin level. Pancreatic β-cells secrete excessive insulin to compensate for the outcome of insulin resistance. Thus, fasting plasma insulin levels rise, and hyperinsulinemia eventually develops [2]. Although it is controversial about the primary defect between insulin resistance and hyperinsulinemia, they together culminate in eventual β-cell failure, resulting in hyperglycemia [3][4].
Insulin receptor (IR) is a tyrosine kinase receptor that is activated upon insulin binding, recruiting downstream substrates such as insulin receptor substrate (IRS). This initiation sets off the proximal insulin signaling pathway. Phosphorylated IRS, in turn, triggers the phosphoinositide 3-kinase (PI3K) → protein kinase B (AKT) signaling cascade, regulating the activity of critical distal downstream targets, including glucose transporter type 4 (GLUT4), mammalian target of rapamycin complex 1 (mTORC1), and forkhead box protein O1 (FoxO1), regulating glucose and energy homeostasis [5][6]. Insulin resistance can manifest at multiple cellular levels, including the desensitization of the insulin receptor at the cell surface, inhibition of IRS function via protein degradation, suppression of PI3K activity, an inability to inhibit FoxO1-induced transcriptional changes, and reduced insulin clearance from the bloodstream [6][7].
Metabolic organs cooperatively respond to nutrient intake and maintain energy balance. The interaction of nutrients, especially macronutrients, with the gastrointestinal tract stimulates the release of incretin hormones such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) [8]. GLP-1 improves insulin sensitivity in peripheral tissues through increasing insulin secretion, attenuating inflammation response and endoplasmic reticulum (ER) stress, increasing GLUT-4 expression, and enhancing insulin signal transduction [9][10][11][12]. GIP stimulates the release of both insulin and glucagon in the pancreas. Therefore, incretin hormones play a key role in regulating insulin sensitivity and glucose homeostasis. Nutrient ingestion, especially carbohydrates, increases blood glucose and stimulates insulin secretion in the pancreas, thereby suppressing glucose production in the liver, increasing lipogenesis in the adipose tissue, promoting glucose uptake in the skeletal muscle, and regulating glucose homeostasis. Overnutrition-induced obesity is highly related to insulin resistance, primarily through multiple pathological mechanisms. The nutrient-induced GLP-1 secretion is significantly reduced in obese individuals [13][14], which may contribute to systemic insulin resistance. During overnutrition, toxic metabolites including ceramides, diacylglycerol (DAG), and nonesterified fatty acids (NEFA) accumulate and stimulate the activity of protein kinase C (PKC), leading to the Ser/Thr phosphorylation of IR and IRS, thereby impairing insulin sensitivity [2]. Overnutrition elevates branched-chain amino acid levels in the bloodstream, activating mTORC1 and inhibiting IRS function [15]. Proinflammatory cytokine levels in circulation are increased during obesity, which induces Ser/Thr phosphorylation of IRS and inhibits insulin signaling by activating JNK and IKKβ [16][17][18]. Hyperinsulinemia associated with obesity leads to insulin resistance by inhibiting the activity of IRS [19].

2. Insulin and Glucagon Action and Insulin Resistance

2.1. Molecular Basis of Insulin and Glucagon Signaling

Insulin and glucagon are pivotal hormones that play essential roles in regulating glucose homeostasis. These two hormones cooperate tightly to maintain blood glucose levels within a narrow range, preventing both hyperglycemia and hypoglycemia under certain health conditions. The glucagon-to-insulin ratio is strongly linked to hyperglycemia in patients with type 2 diabetes [20].
Insulin, a peptide hormone secreted from pancreatic β-cells, plays a critical role in orchestrating the anabolic response to nutrient intake, especially the intake of glucose, fatty acids, and amino acids [21]. Insulin regulates blood glucose balance by increasing glucose uptake in skeletal muscle and fat tissues while suppressing hepatic glucose production (HGP). Insulin actions are induced by the intrinsic tyrosine kinase activity of the insulin receptor (IR). Insulin triggers conformational changes and autophosphorylation of IR, leading to the recruitment and phosphorylation of IRS and SH3-containing protein (Shc). IRS activates the PI3K → AKT pathway to govern insulin’s metabolic functions, while Shc activates the Ras → MAPK pathway, which mediates growth and differentiation at cellular and organismal levels [22]. Additionally, IR also exerts control over apoptosis, senescence, and the cell cycle, independent of ligand and tyrosine kinase activity [23]. In skeletal muscle and adipose tissues, insulin promotes the translocation of GLUT4 from the cytoplasm to the cell membrane, thereby promoting glucose uptake [24]. Insulin-stimulated GLUT4 trafficking is mediated by the PI3K → AKT → AS160 signaling cascade [25][26][27]. AS160, a Rab GTPase-activating protein, maintains Rab proteins in an inactive GDP form and results in GLUT4 retention in the cytoplasm. Phosphorylation of AS160 by AKT inactivates its Rab GTPase activity, resulting in an increase in the active GTP form of Rab, thereby promoting GLUT4 trafficking [24][25]. In addition, AKT-induced PIKfyve phosphorylation plays a role in regulating insulin-stimulated GLUT4 trafficking, potentially through PtdIns 3,5-P2 [28][29][30]. In the liver, insulin inhibits glycogenolysis and gluconeogenesis, thus suppressing glucose release. Insulin activates glycogen synthase by the PI3K → AKT → GSK-3 signaling pathway. AKT stimulates phosphorylation of GSK-3 and inhibits its kinase activity, thereby dephosphorylating glycogen synthase, stimulating its activity, and promoting glycogen accumulation [31]. The IRS → PI3K → AKT → FoxO1 signaling pathway in the liver is primarily responsible for insulin action on glucose homeostasis [32]. Insulin stimulates phosphorylation of FoxO1 at S253 via the activation of AKT, thereby decreasing FoxO1-induced expression of genes responsible for gluconeogenesis such as phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose-6-phosphatase (G6pase) and suppressing HGP [33][34][35]. The central nervous system (CNS), such as the hypothalamus, plays a pivotal role in regulating systemic insulin sensitivity and glucose homeostasis [36]. The activation of insulin signaling in agouti-related peptide (AgRP) but not pro-opiomelanocortin (POMC) neurons suppresses HGP through the hepatic vagal nerve [37]. Insulin induces the hyperpolarization of AgRP neurons and decreases their activity, thus leading to the activation of IL-6-STAT3 signaling and downregulating hepatic gluconeogenic genes, including Pck1 and G6pase [37][38].
Glucagon is secreted by the pancreatic α-cells, acting as a catabolic hormone and regulating glucose homeostasis. Glucagon promotes HGP through stimulation of glycogenolysis and gluconeogenesis, thereby maintaining euglycemia under fasting conditions. The action of glucagon is mediated by the glucagon receptor (Gcgr), a G protein-coupled receptor [39]. Upon glucagon binding, Gcgr activates Gs protein, thereby stimulating adenylate cyclase, elevating cyclic adenosine monophosphorylate (cAMP), and then activating cAMP-dependent protein kinase A (PKA) and exchange protein directly activated by cAMP 2 (EPAC2) [40]. Active PKA, in turn, stimulates the activity of phosphorylase kinase, which then converts glycogen phosphorylase b (PYG b) into the active form PYG a and promotes glycogen breakdown [41]. Glucagon promotes gluconeogenesis through the activation of two key transcriptional factors, cAMP response element-binding protein (CREB) and FoxO1 [42]. Activation of PKA by glucagon induces phosphorylation of CREB at S133, resulting in the formation of the CREB-TORC2 complex and increasing transcription of its downstream gluconeogenic genes, including Ppargc1a, Pck1, and G6pase [43][44]. Glucagon stimulates phosphorylation of FoxO1 at S273 via both PKA and EPAC2 → p38 signaling pathways, enhancing FoxO1 stability and nuclear localization [45][46].

2.2. The Molecular Basis of Insulin Resistance by Targeting FoxO1

The molecular mechanisms of insulin resistance have been extensively reviewed [2][5][6][22]. During obesity, lipotoxicity, chronic inflammation, hyperglycemia, hyperinsulinemia, mitochondrial dysfunction, and ER stress stimulate the activity of Ser/Thr kinase and impair insulin sensitivity by phosphorylating IR, IRS, and AKT proteins, resulting in insulin resistance. Insulin resistance is a critical mechanism underlying various metabolic disorders. Over the past decade, scholars have proven that FoxO1 is one of the key factors that link insulin resistance and metabolic disorders. Studies from many labs, including our own, have demonstrated that FoxO1 promotes HGP by upregulating the expression of gluconeogenic genes, including Pck1 and G6pase [47][48]. Insulin stimulates the activity of AKT and phosphorylates FoxO1 at T24, S253, and S316, thereby suppressing FoxO1 activity and inhibiting HGP [34][35][49][50]. Deletion of liver IRS1 and 2 in mice induces systemic insulin resistance, leading to diabetic symptoms that include hyperglycemia and hyperinsulinemia. Notably, these diabetic symptoms are normalized when hepatic FoxO1 is deficient [32]. The scholars recently uncovered that glucagon stimulates the phosphorylation of FoxO1-S273 through the cAMP → PKA and cAMP → EPAC2 → p38α signaling pathways; this enhances FoxO1 protein stability and promotes its nuclear localization. It also found that FoxO1-S273 phosphorylation prevents insulin-mediated FoxO1 degradation in vitro and impairs glucose tolerance in vivo [45][46]. These findings suggest that FoxO1 is a pivotal mediator connecting glucagon and insulin signaling in the regulation of glucose homeostasis. In addition, FoxO1 plays a crucial role in aging-induced glucose dysregulation and chronic inflammation. It found that the activity of FoxO1 was increased in the livers of old mice. Inhibition of FoxO1 significantly improves glucose homeostasis and attenuates chronic inflammation in Kupffer cells during aging [51]. Activation of FoxO1 impairs hepatic mitochondrial function by controlling heme homeostasis, thereby contributing to insulin resistance-mediated hepatic mitochondrial dysfunction [52][53]. Heme oxygenase-1 (HO-1) is one of the target genes regulated by FoxO1 [52]. HO-1 gain-of-function increases ferrous iron levels and promotes inflammation in livers [54]; these results indicate that the FoxO1 → HO-1 signaling pathway plays a key role in ferrous iron overload and chronic inflammation under insulin-resistant conditions. Activation of FoxO1 increases TGF-β1 levels, impairing glucose and energy metabolism as well as exacerbating CCL4-induced liver fibrosis [55][56]. 

3. Dietary Carbohydrates and Glucose Homeostasis

3.1. Dietary Sugars and Insulin Resistance

The increased consumption of refined and simple carbohydrates promotes the development of insulin resistance and T2DM. The World Health Organization and the Food and Agriculture Organization recommended a restriction on free sugar intake to prevent T2DM and obesity [57]. The clinical studies show that high fructose intake (>250 g/day) decreases insulin sensitivity and increases adiposity in both healthy and obese individuals [58][59]. However, moderate fructose intake (<100 g/day) has a limited effect on insulin sensitivity and metabolic health [60]. The overconsumption of dietary sugars promotes the development of insulin resistance, both directly and indirectly. Dietary sugar overconsumption promotes a positive energy balance, thereby increasing body weight and fat deposition and indirectly leading to insulin resistance and glucose dysregulation. Additionally, fructose reduces hypothalamic malonyl-CoA levels and increases the hunger hormone ghrelin [61][62][63], thereby stimulating appetite, increasing body weight, and impairing insulin sensitivity. On the other hand, fructose, the sweetest of all naturally occurring carbohydrates, directly causes insulin resistance via increasing hepatic lipid accumulation and promoting inflammation. Fructose is a highly lipogenic sugar and is mainly metabolized in the liver, with very little entering the systemic circulation [64]. Fructose is transported into the liver by GLUT2, phosphorylated into fructose-1-phosphate, and further metabolized to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, which stimulates de novo lipogenesis [65]. Administration of fructose to mice significantly increases the activity of carbohydrate-responsive element-binding protein (ChREBP) and sterol regulatory element-binding protein 1 (SREBP-1c), two important transcription factors stimulating lipogenesis [66][67].
On the other hand, dietary sugar or fructose impairs immune homeostasis and promotes inflammation, thereby leading to insulin resistance. Dietary fructose is transported into the enterocyte through a specific fructose transporter, GLUT5. Healthy individuals can absorb up to 25 g of fructose [68]. High-fructose diet-induced fructose overload leads to intestinal barrier deterioration and alters gut microbiota composition, thereby increasing endotoxin release, promoting systemic inflammation, and leading to insulin resistance [69][70]. The impairment of the intestinal tissue repair and the gut microbiota environment by fructose leads to intestinal barrier deterioration [71]. Fructose-stimulated endotoxin release increases TNF production in liver macrophages, mediating fructose-induced hepatic insulin resistance and lipogenesis [71][72]. Dietary sugar regulates the crosstalk between the microbiota and intestinal immunity to control insulin resistance and other metabolic disorders. Dietary sugar is a key to disrupting intestinal immune homeostasis via eliminating Th17-inducing microbiota (especially segmented filamentous bacteria).
Low-calorie sweeteners (LCS), including aspartame, saccharin, sucralose, and steviol glycoside, provide an alternative to added sugars and have been used to control body weight gain [73]. The effects of LCS on reduction of caloric intake and body weight gain make LCS a promising approach to controlling blood glucose in patients with T2DM. However, the beneficial effects of LCS are controversial in human studies. In some randomized controlled trials (RCTs), LCSs significantly decreased body weight, body mass index, fat mass, and waist circumference [74]. Contrarily, results from some RCTs fail to show a significant effect of LCSs on weight management [75]. 

3.2. Dietary Fibers and Insulin Resistance

Dietary fiber is composed of highly complicated substances that include any indigestible carbohydrate and lignin that cannot be degraded in the upper gastrointestinal tract. The viscous, gel-forming, and soluble dietary fiber derived from fruit and certain vegetables suppresses the absorption of macronutrients, reduces postprandial glucose response, and improves lipid profiles. A meta-analysis with 176,117 subjects showed that higher insoluble cereal fiber intake was significantly associated with a lower incidence of diabetes, whereas fruit and vegetable fiber intake had no significant association with the risk of T2DM [76]. Consistently, the consumption of insoluble dietary fiber significantly increases insulin sensitivity in both healthy and diabetic individuals [77][78][79]. However, other studies provide evidence that soluble dietary fibers decrease postprandial blood glucose and increase insulin sensitivity in both nondiabetic and diabetic subjects [80][81]. Compared to soluble dietary fiber, insoluble dietary fiber has a better effect on attenuation of high-fat diet-induced obesity, body fat composition, and insulin resistance in mice [82]. Short-chain fatty acids (SCFAs), including butyrate, propionate, and acetate, are generated by the gut microbiota through fermenting non-digestible dietary fibers and play an important role in the beneficial effects of dietary fibers on insulin resistance and glucose homeostasis. SCFAs stimulate the secretion of the gut hormone anorexigenic peptide YY (PYY) through free fatty acid receptor 2 (FFAR2), thereby increasing satiety, decreasing body weight, and improving insulin sensitivity [83]. Additionally, SCFAs acetate and propionate increase the secretion of GLP-1 via FFAR2 and 3, contributing to the improvement in glucose tolerance and hepatic insulin sensitivity [84][85].

4. Lipid Metabolism and Glucose Homeostasis

4.1. Dietary Fat and Insulin Resistance

Dietary fat is highly associated with the incidence of insulin resistance in both mice and humans. In mice, high-fat diet (60% calories derive from fat) feeding for 13 weeks leads to insulin resistance and glucose intolerance [86]. In humans, a higher total fat intake is significantly associated with increased fasting insulin levels, HbA1c, and 2-h post-load glucose levels [87][88][89]. It is estimated that an increase in dietary fat intake of 40 g/d is correlated with a 3.4-fold increased risk of T2DM [90]. However, several population studies failed to show a significant correlation between total fat intake and the incidence of T2DM, which may be attributed to the quantity and quality of dietary fat. There are mainly two kinds of dietary fats: saturated and unsaturated fats, which play different roles in the development of insulin resistance.

4.2. Molecular Mechanisms of FFA-Induced Insulin Resistance

Lipid overload induces insulin resistance in skeletal muscle and liver, thereby leading to defects in insulin-mediated glucose uptake and suppression of HGP, respectively. The detrimental effect of lipid overload on insulin sensitivity is mainly attributed to the increased circulating free fatty acid (FFA) levels, especially saturated free fatty acids (SFAs) [91]. In the KANWU study, high SFA diet intervention significantly impairs insulin sensitivity in both healthy men and women [92]. Aberrant SFA levels stimulate the inflammatory pathway, increase ROS production, generate insulin resistance-associated lipid production, and impair protein folding homeostasis, thereby leading to insulin resistance.
Long-chain polyunsaturated fatty acids (PUFAs), particularly the n-3 family, play a key role in regulating insulin sensitivity [93]. Several human studies have shown that omega-3 PUFAs improve insulin sensitivity in both obese non-diabetic and diabetic individuals [94][95]. Omega-3 PUFAs improve insulin sensitivity, potentially through anti-inflammation and PPAR activation. Previous studies showed that omega-3 PUFAs significantly attenuated TNF or TLR2/4 agonist-induced inflammation through GPR120 in macrophages [96][97]. Omega-3 PUFAs promote the association of GPR120 and β arrestin-2 and then induce the internalization of the GPR120/β arrestin-2 complex. The cytoplasmic β arrestin-2 interacts with TAB1 and blocks the interaction between TAB1 and TAK1, thereby inhibiting TAK1 activity, downstream IKKβ/NFκB and JNK/AP1 signaling, and improving diet-induced insulin resistance [97]. In addition, the anti-inflammatory role of omega-3 PUFAs is potentially mediated by the small lipid mediators (protectins/resolvins) that are metabolized from omega-3 PUFAs.

5. Protein Metabolism and Glucose Homeostasis

5.1. Dietary Proteins and Insulin Resistance

Dietary protein intake is important for normal growth and development. It is recommended that dietary protein accounts for 10–35% of the total diet. Numerous human studies have reported that a short-term increase in dietary protein consumption significantly decreases body weight. A high-protein diet increases satiety via the gut hormone PYY, stimulates thermogenesis [98], potentially due to the high ATP-consuming protein synthesis, and reduces subsequent energy intake, thereby leading to great weight loss [99][100]. Additionally, protein feeding induces intestinal gluconeogenesis and promotes portal glucose release, which leads to hypothalamic activation through the nerve system around the portal vein and decreases food intake [101][102]. Accordingly, short-term high dietary protein consumption stimulates insulin secretion and reduces blood glucose levels [103]. Consistently, a protein preload significantly decreases postprandial glycemia and increases plasma insulin levels in patients with type 2 diabetes, which is partially attributed to the elevation of GLP-1 and GIP levels [104][105]. A high-protein diet intervention in individuals with type 2 diabetes for 5 weeks improves glucose homeostasis [106]. However, long-term studies (over six months) in humans show that a high-protein diet is significantly associated with increased fasting glucose levels, enhanced gluconeogenesis, and impaired insulin sensitivity [107][108].

5.2. Amino Acid and Insulin Resistance

In obese individuals, most serum amino acid levels are significantly increased, suggesting that amino acids may play a role in the regulation of insulin resistance [109]. A previous study showed that a short-term increase in plasma amino acids induces insulin resistance in skeletal muscle, decreases glycogen synthesis, and reduces whole-body glucose disposal [110][111]. Amino acid infusion stimulates phosphorylation of IRS1 at serine 312 and 636/639 via activation of the mTOR/S6 kinase 1 signaling pathway, thereby decreasing the interaction of the p85 subunit of PI3K with IRS1 and leading to insulin resistance in skeletal muscle [111][112]. In vitro studies in hepatocytes and adipocytes also show that amino acid treatment negatively modulates insulin sensitivity [113][114].
Although an amino acid mixture attenuates insulin sensitivity both in vitro and in vivo, different amino acids have distinct effects on insulin sensitivity. Branched-chain amino acids (BCAAs), including valine, isoleucine, and leucine, are critical nutrient signals in regulating body weight and muscle protein synthesis. In obese patients, plasma BCAA levels are significantly elevated [109]. Previous studies have shown that BCAAs are significantly associated with the risk of insulin resistance in humans, and BCAAs exacerbate diet-induced insulin resistance in mice [115][116][117]. Elevated BCAA levels stimulate the activity of mTOR to hamper insulin signaling via inhibitory phosphorylation of IRS1 or E3 ligase Mul1-mediated AKT2 degradation [109][115]. In addition, abnormal BCAA metabolism during obesity leads to the accumulation of toxic BCAA metabolites, thereby activating stress signaling and promoting insulin resistance [118].

6. Conclusions

T2DM is marked by systemic insulin resistance and β-cell failure-induced insulin deficiency. Overnutrition promotes insulin resistance at multiple levels, including insulin receptor desensitization at the cell surface, inhibition of IRS function through degradation, suppression of PI3K activity, failure to control FoxO1-induced transcriptional changes, and reduced insulin clearance from the bloodstream. Dietary carbohydrate intake induces insulin secretion, and overconsumption of carbohydrates leads to insulin resistance. Fructose is a major driver for the development of insulin resistance through increasing hepatic lipogenesis and impairing gut immunity. Dietary fiber improves insulin sensitivity through gut microbiome-derived SCFAs. Increased dietary fat intake elevates free fatty acid levels, especially unsaturated fatty acids, thereby attenuating insulin sensitivity by inducing pro-inflammatory activity and activating DAG-PKC signaling. PUFA improves insulin resistance through suppression of TLR2/4 signaling and activation of PPAR signaling. The composition of amino acids after dietary protein intake plays a pivotal role in insulin sensitivity and glucose homeostasis. Particularly, increased BCAA levels induce insulin resistance through activation of mTOR-IRS signaling and BCAA metabolite-induced oxidative stress. Short-term protein feeding improves glucose homeostasis, which may be attributed to the increased release of gut hormones, including GLP-1 and GIP. Precision nutrition aims to design a unique nutritional recommendation for each individual according to the combination of an individual’s genetics, metabolome, microbiota, and lifestyle factors, thereby preventing metabolic diseases. Understanding the molecular mechanisms of diet-gene interactions will help us apply precision nutrition to clinical practice by integrating multi-omics approaches.

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