Molecular Aspects in the Development of Type 2 Diabetes and Possible Preventive and Complementary Therapies
Abstract
:1. Introduction
1.1. History of Diabetes
1.2. Type 2 Diabetes Mellitus
2. Metabolic Syndrome (MetS)
2.1. Hypertension
2.2. Dyslipidemia
2.3. Abdominal Obesity
2.4. Insulin Action and Insulin Resistance
2.4.1. Normal Function of Insulin
2.4.2. Insulin Pathway
Mitogenic Pathway
Metabolic Pathway
- The glycogen synthase kinase 3 (GSK3) is one of the Akt substrates in the cytosol. This is responsible for the regulation of glycogen synthase (GS), and the eukaryotic initiation factor 2B (eIF2B), among others. Inactivation of GSK3 by Akt activates GS, which then induces glycogenesis [62], as well as the eIF2B, which then enhances the cell growth (Figure 1B) [63].
- Forkhead transcription factors (FOXOs) are another targets of Akt. FOXOs acting in glucose metabolism increase the gene expression of key enzymes of gluconeogenesis, such as glucose-6-phosphatase and phospho-enol-pyruvate carboxykinase (PEPCK) [64]. When FOXOs are inactivated through phosphorylation by Akt, they exit the nucleus and are degraded by proteasomes; thereby Akt inhibit gluconeogenesis (Figure 1B) [65]. FOXOs also control gene expression that regulates the cell cycle, apoptosis, oxidative stress resistance, differentiation, and muscle atrophy as well as energy homeostasis. Thus, this can induce apoptosis through activation of FasL and Bim, and can promote cell-cycle arrest and stress resistance by induction of catalase and manganese superoxide dismutase (MnSOD) for inactivation of reactive oxygen species (ROS) as well as by facilitating DNA repair [66].
- The GTPase-activating protein Akt substrate of 160 kDa (AS160), also known as TBC1D4, is also an Akt substrate [67]. It is attached to vesicles of glucose transporter 4 (GLUT4)—an insulin-dependent transporter in muscle and adipose tissues [68]—and inhibits the efflux, and translocation of these vesicles from the Golgi to the plasma membrane through inactivation of Rab protein, thus restraining GLUT4 exocytosis (Figure 1B) [69]. When AS160 activity is blocked by Akt via phosphorylation, AS160 detaches from the GLUT4 vesicles and increases their efflux and exocytosis (Figure 1B) [70]. However, insulin-stimulated phosphorylation of AS160 impaired the skeletal muscle in T2DM [23]. Similarly to AS160, the AS160 paralog TBC1D1, which is highly expressed in skeletal muscle, is also phosphorylated by insulin, as well as by exercise and AMP kinase (AMPK); moreover, AMPK is suggested as the most robust regulator of this signaling molecule [23,71,72]. GLUT4 exocytosis can be also stimulated by PDK1 through PKCλ phosphorylation. PKCλ then stimulates Rab4 activity, which initiates GLUT4 exocytosis [73]. Additionally, TC10 lipid raft microdomain is also associated with and promotes GLUT4 fusion to the plasma membrane lipid rafts [74].
- Akt activates mammalian target of rapamycin complex 1 (mTORC1) by inhibiting tuberous sclerosis complex 2 (TSC2), which forms heterodimer with tuberous sclerosis complex 1 (TSC1) (Figure 1B) [77]. TSC2 is a GTPase-activating protein (GAP) for Ras homologue enriched in brain (Rheb) protein. When inhibition of Rheb is blocked by inactivated TSC complex, mTORC1 become activated, and then throughout the activation of p70 ribosomal protein S6 kinase (S6K1) and inhibition of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), the protein synthesis is enhanced (Figure 1B) [78].
- Akt, mTOR, and PKC λ/ζ can activate sterol regulatory binding proteins (SREBPs) to enhance lipid synthesis and regulate cholesterol homeostasis (Figure 1B). SREBPs are localized in the ER membrane and bind to the sterol cleavage protein (SCA) and sterol regulatory element (SRE). At low sterol levels, this complex is transported to the Golgi, where the transcription factor is deliberated by proteases. After translocation to the nucleus, genes of lipid synthesis will be induced (Figure 1B) [81,82].
2.4.3. Insulin Resistance
Endoplasmic Reticulum (ER) Stress
- On the IRE-1 pathway, activating phosphorylation of IRE-1α leads to the recruitment of tumor necrosis factor receptor-associated factor 2 (TRAF2), which then activates apoptosis signal-regulating kinase 1 (ASK1) and the stress-activated c-Jun N-terminal kinase (JNK) [111]. JNK then inactivates the insulin signaling by serine phosphorylation of IRS-1 (Figure 3), as well as inducing apoptosis, while inhibiting autophagy [103]. IRE-1α has endonuclease activity as well, which cleaves 26 base–pair sequences from the mRNA of X-box binding protein-1 (XBP1). This spliced variant sXBP-1 is facilitating the transcription of chaperons to enhance the folding capacity of ER. The misfolded proteins are removed from the ER, ubiquitinated, and transferred to proteasomal degradation; this process is called endoplasmic reticulum-associated degradation (ERAD). sXBP-1 also induces factors involved in ERAD to facilitate damaged protein clearance from ER lumen [109,112].
- The PERK pathway: after PERK activation by autophosphorylation, it subsequently phosphorylates the eukaryotic translation initiation factor 2α (eIF2α), generally inhibiting the translation of the proteins. However, some proteins will be translated properly in this unusual translational condition, such as the activating transcription factor 4 (ATF4), a member of cAMP-responsive element-binding protein (CREB) family [113], which induces the transcription of ER chaperons and the C/EBP homologous protein (CHOP), or, by another name, growth-arrest and DNA-damage-inducible protein (GADD153) (Figure 3) [23].
- In normal conditions, ATF6 occurs in its monomer, dimer, and oligomer forms in the ER membrane. Upon ER stress, it is reduced and forms monomers, which translocate to the Golgi apparatus, where it is activated by the cleavage of serine protease site-1 protease (S1P) and metalloprotease site 2 protease (S2P) [114]. Only the reduced monomer form can reach the Golgi and be released as an activated cytosolic fragment (ATF6f), which then enters the nucleus and enhances transcription of ER chaperons and CHOP (Figure 3) [110].
Inducing IR by Ser/Thr Phosphorylation of the IRS-1
IR by Protein Tyrosine Phosphatase 1B (PTP1B)
IR by Lipid Phosphatases—SHIP and PTEN
Role of Phosphoprotein Phosphatases in IR
Role of Adapter Proteins in IR
3. Molecular Targets in Insulin Signaling/Resistance in Preventive, Complementary, or Drug Treatment Strategies
3.1. Preventive or Complementary Treatment Options
3.1.1. Diet and Supplementation
Diet/Supplementation | Physiological and Cellular Effect(s) on T2DM/IR | Cellular and Molecular Target(s) | Reference Number |
---|---|---|---|
phytochemicals | |||
polyphenols | •decreased inflammation and mitogenic processes | •inactivated NFκB, MAPK and arachidonic acids pathways | [155] |
resveratrol | •diminish IR, decreased FFA, lipotoxycity and inflammation | •activates SIRT1 and AMPK; these activate PPARα and inhibit PPARγ, SREBP1c and NFκB, decrease TNFα and IL-6, management of AGEs | [19,20,104] [156] |
support gluconeogenesis/glucose uptake, ER stress- resistance, apoptosis | by activating FOXOs, increasing GLUT4, inhibiting mTORC1 | ||
carotenoid | |||
astaxanthin | •attenuates IR, glucose intolerance, enhance exercise tolerance/FFA metabolism, stimulates anti-inflammatory effects | •oxidative phosphorylation and biogenesis through AMPK, through its antioxidant properties | [157] |
lycopene | •promote angiogenesis for utilization of glucose and energy metabolism improves IR and vascular aging | •reactivation of SIRT1 | [158] |
phytosterols | •decrease the absorption of cholesterol, LDL cholesterol, promote insulin action through its receptors | •normalizing lipid metabolism increased GLUT4 translocation to plasma membrane | [159] |
inhibit mitochondrial dysfunction and ROS production | inhibit TNFα induced IKKβ/NFκB and JNK signaling | ||
phytosterols & saponins | •hypolipidemic and angioprotective effects | [159] | |
micronutrients | |||
vitamin D3 | •increases glucose uptake inhibit oxidative stress | •inducing insulin-independent SIRT1/AMPK/IRS1/GLUT4 signaling pathway | [160] [161] |
optimal glucose and lipid homeostasis | adiponectin, AMPK | [20] | |
selenium | •necessary for normal inulin action, prevent IR | •support glucagon-like peptid receptor expression in beta cells necessary in the phosphorylation of insulin receptor | [162] |
Zn&Mg | •necessary for normal inulin action, prevent IR | •necessary for autophosphorylation of insulin receptor, activation of PI3K and Akt and appropriate GLUT4 translocation to plasma membrane | [163,164] |
lipids | |||
n-3 PUFAs | •increase β-oxidation of TGs and protein synthesis in skeletal muscle | •activates mTORC1 in skeletal muscle | [165] |
decrease lipogenesis in liver | inhibit diacylglycerol and SREBP1c | ||
decrease lipogenesis in adipose tissue | activate AMPK, β-oxidation, increase adiponectin level | ||
other natural compounds | improve IR and support glucose utilization | [166] |
3.1.2. Physical Activity and Exercise
Systemic Effects of Physical Activity: Inflammation
Systemic Effects of Physical Activity: Hormone Secretion
Tissue-Specific Effects of Physical Activity and Exercise
3.2. Targets of Currently Used Drugs in Treatments of T2DM and IR
4. In Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
4E-BP1 | eukaryotic translation initiation factor 4E-binding protein 1. |
AGEs | glycation end-products. |
AMPK | AMP-kinase. |
AS160 (TBC1D4) | Akt substrate of 160 kDa. |
ASK1 | apoptosis signal-regulating kinase 1. |
ATF4 | activating transcription factor 4. |
ATF6 | activating transcription factor-6. |
ATF6f | activating transcription factor-6 cytosolic fragment. |
Bad | BCL2-antagonist of cell death. |
BiP | immunoglobulin heavy-chain-binding protein. |
BMI | body mass index. |
CCs and CXCs | chemokines. |
CHOP | C/EBP homologous protein. |
CREB | cAMP-responsive element-binding protein. |
CSFs | colony-stimulating factors. |
CVD | cardiovascular disease. |
DHA | docosahexaenoic acid. |
DPP-4 | dipeptidyl-peptidase 4. |
eIF2B | eukaryotic initiation factor 2B. |
eIF2α | eukaryotic translation initiation factor 2α. |
EPA | eicosapentaenoic acid. |
ER stress | endoplasmic reticulum stress. |
ERAD | endoplasmic reticulum-associated degradation. |
FFA | fatty acid. |
FOXOs | forkhead transcription factors. |
GADD153 | growth-arrest and DNA-damage-inducible protein. |
GAP | GTPase-activating protein. |
GCs | glucocorticoids. |
GEF | guanine exchange factor. |
GFs | growth factors. |
GH | growth hormone. |
GK | glucokinase. |
GLP | glucagon-like peptide. |
GLUT4 | glucose transporter 4. |
GRB2 | growth factor receptor-bound protein 2. |
GRP78 | 78 kDa glucose-regulated protein. |
GS | glycogen synthase. |
GSK3 | glycogen synthase kinase 3. |
HDL-C | high-density lipoprotein cholesterol. |
HOMA-IR | homeostasis model assessment of IR. |
IFNs | interferons. |
IGF-1 | insulin-like growth factor 1. |
IGF-2 | insulin-like growth factor 2. |
IKKβ | inhibitor of nuclear factor kappa-B kinase subunit beta. |
IL-6 | interleukin-6. |
IR | insulin resistance. |
IRE1 | inositol requiring enzyme 1. |
IRS | insulin receptor substrate. |
JNK | c-Jun N-terminal kinase. |
LDL-C | low-density lipoprotein cholesterol. |
MAPK | mitogen activated protein kinase. |
MCP-1 | monocyte chemoattractant protein-1. |
MetS | metabolic syndrome. |
MIP-1 | macrophage inflammatory protein 1. |
MnSOD | manganese superoxide dismutase |
mTORC1 | mammalian target of rapamycin complex 1. |
MyD88 | myeloid differentiation primary response gene 88. |
NFκB | nuclear factor κB. |
NO | nitrogen–monoxide. |
OGTT | oral glucose tolerance test. |
PDK-1 | phosphatidyl-inositol dependent kinase 1. |
PEPCK | phospho-enol-pyruvate carboxykinase |
PERK | PKR-like eukaryotic initiation factor 2α kinase |
PGC-1α | proliferator-activated receptor gamma coactivator 1α |
PHLPPs | PH domain and leucine rich repeat protein phosphatases |
PI3K | phosphatidylinositol-3-kinase |
PIP2 | phosphatidylinositol 4,5-bisphosphate |
PIP3 | phosphatidylinositol 3,4,5-trisphosphate |
PKB | protein kinase B. |
PKC | protein kinase C. |
PKCλ and PKCζ | PKC isomers. |
PP2A | protein phosphatase 2A |
PP2B | protein phosphatase 2B |
PPARα and γ | peroxisome proliferator-activated receptor α and γ. |
PTEN | phosphatase and tensin homolog deleted on chromosome ten |
PTP1B | protein tyrosine phosphatase 1B |
PUFA | polyunsaturated fatty acids |
RAC1 | Ras-related C3 botulinum toxin substrate 1. |
ROS | reactive oxygen species |
S1P/S2P | site-1 protease/ site-2 protease |
S6K1 | S6 kinase. |
SCA | sterol cleavage protein |
SELENOP/SELENOS | selenoprotein P/selenoprotein S. |
Ser/Thr | serine/threonine |
SGLT2 | sodium–glucose co-transporter-2 |
SHIP1/SHIP2 | SH2 domain containing inositol 5’phosphatase 1 and 2. |
SIRT1 | sirtuin 1 |
SNP | single nucleotide polymorphism |
SOCS1/3 | suppressor of cytokine signaling 1/3 |
SOS | son of sevenless |
SRE | sterol regulatory element |
SREBP | sterol regulatory binding proteins |
T1DM | Type 1 Diabetes Mellitus |
T2DM | Type 2 Diabetes Mellitus |
TBC1D1 | AS160 paralog. |
TGs | triglycerides |
TSC1/TSC2 | tuberous sclerosis complex 1 and 2 |
UPR | unfolded protein response |
VLDL | very-low-density lipoprotein |
XBP1 | X-box binding protein-1 |
Y | tyrosine |
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Drugs | Physiological and Cellular Effect(s) on T2DM/IR | Cellular and Molecular Target(s) | Reference Number |
---|---|---|---|
Biguanides Metformin | Improved IR, decreased inflammation | AMPK and AMPK-independent mechanisms | [104,207,208,209] |
DPP-4 inhibitors | Increased insulin secretion | β-cells in pancreas | [208,210] |
GLP-1 receptor agonists Liraglutid Semaglutid | Improved insulin production and weight loss | β-cells in pancreas | [191,208] |
Glucocorticoids | Peripheral IR, insulin secretion | PGC-1α | [92] |
Glucokinase activators | Glucose-6-phosphate production, subsequent insulin release | Glucose | [211] |
α-glucosidases inhibitors | Inhibit breakdown of carbohydrates in small intestine | Alpha-glucosidase enzymes in small intestine | [208] |
Glimins Imeglimin | Increased mitochondrial function, increased insulin secretion, reduced hepatic gluconeogenesis, increased glucose uptake in muscle | Mitochondria, ROS β-cells in pancreas AMPK | [212] |
SGLT2 inhibitor Dapagliflozin | Decreased oxidative stress and inflammation, increased insulin sensitivity | SIRT1/AMPK/PGC1α/FOXO1 axis | [208,213] |
Sulfonylureas Glimepiride Glycosylated sul fonylurea | Improved insulin production Improved insulin sensitivity | β-cells in pancreas IRS–PI3K–PKC–AKT–GLUT4 | [207] [214] |
Thiazolidinediones | Improved insulin resistance, decreased inflammation | AMPK | [104] |
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Simon-Szabó, L.; Lizák, B.; Sturm, G.; Somogyi, A.; Takács, I.; Németh, Z. Molecular Aspects in the Development of Type 2 Diabetes and Possible Preventive and Complementary Therapies. Int. J. Mol. Sci. 2024, 25, 9113. https://doi.org/10.3390/ijms25169113
Simon-Szabó L, Lizák B, Sturm G, Somogyi A, Takács I, Németh Z. Molecular Aspects in the Development of Type 2 Diabetes and Possible Preventive and Complementary Therapies. International Journal of Molecular Sciences. 2024; 25(16):9113. https://doi.org/10.3390/ijms25169113
Chicago/Turabian StyleSimon-Szabó, Laura, Beáta Lizák, Gábor Sturm, Anikó Somogyi, István Takács, and Zsuzsanna Németh. 2024. "Molecular Aspects in the Development of Type 2 Diabetes and Possible Preventive and Complementary Therapies" International Journal of Molecular Sciences 25, no. 16: 9113. https://doi.org/10.3390/ijms25169113