Diabetes: A comprehensive review of the Indian landscape in contrast with global trends

Table 5 The pathophysiological processes and genetic network that underlie type 1 diabetes mellitus, type 2 diabetes mellitus, and gestational diabetes mellitus

Pathophysiology of T1D with genetic network
Ref.	Landin-Olsson[77], 2002; Liu et al[82], 2023; Noble and Valdes[92], 2011; Bacchetta and Roncarolo[93], 2024; James et al[94], 2023; Yang et al[95], 2024; Herold and Krischer JP[96], 2024; Mancuso et al[97], 2023; Wang et al[98], 2024; De Franco[99], 2020; Abdul-Ghani and DeFronzo[100], 2008
Pathophysiological process	Description	Key genes
Autoimmune beta-cell destruction	Insulin insufficiency results from CD4+ and CD8+ T-cell-mediated immune destruction of pancreatic β-cells	HLA-DR, HLA-DQ, INS, PTPN22
Antigen presentation and immune activation	β-cell antigens are presented by MHC class II molecules to autoreactive T-cells, initiating an immune response	HLA-DR3, HLA-DR4, HLA-DQ8
T-cell receptor signaling and immune regulation	Defective regulatory T-cell function and abnormal activation of T-cells contribute to loss of immune tolerance	PTPN22, CTLA4, IL2RA, FOXP3
β-cell stress and apoptosis	Endoplasmic reticulum stress and exposure to proinflammatory cytokines lead to apoptosis of β-cells	INS, EIF2AK3, TXNIP
Cytokine-mediated inflammation	Inflammatory cytokines like IFN-γ, TNF-α, and IL-1β induce β-cell dysfunction and promote cell death	IFIH1, IL2RA, STAT4, IL-10
Genetic susceptibility and environmental triggers interaction	Viral infections and other environmental factors interact with genetic predispositions to initiate autoimmunity	HLA, IFIH1, PTPN22
Defective central and peripheral tolerance	Autoreactive T-cells escape elimination in the thymus or are not suppressed in peripheral tissues	AIRE, FOXP3, CTLA4
Innate immune response dysregulation	Abnormal innate immune activity enhances proinflammatory responses and autoimmunity	IFIH1, TLR7, NOD2
Pancreatic islet inflammation (Insulitis)	Persistent infiltration of immune cells into pancreatic islets leads to chronic inflammation and β-cell damage	CXCL10, CCR5
Beta-cell regeneration failure	Impaired β-cell regenerative capacity limits the replacement of destroyed insulin-producing cells	PDX1, MAFA
Autoantibody production	Production of autoantibodies against β-cell proteins marks autoimmune activity and precedes clinical diagnosis	INS, GAD65, IA-2, PTPRN
Pathophysiology of T2D with a genetic network
Ref.	Liu et al[101], 2021; Febbraio and Karin[102], 2021;Donath[103], 2014; Zhu et al[104], 2025; Dhatariya[105], 2022; Zhang et al[106], 2016; Wu et al[107], 2023
Pathophysiological process	Description	Key genes
Insulin resistance	Decreased insulin sensitivity of peripheral tissues (liver, muscle, and fat)	IRS1, PPARG, TCF7 L2, INSR, AKT2
Impaired insulin secretion	Pancreatic β-cells’ inability to detect glucose and release insulin	KCNJ11, ABCC8, HNF1A, TCF7 L2, GLIS3
Lipotoxicity and ectopic fat accumulation	Fatty acid buildup in the liver and muscles disrupts insulin transmission.	PNPLA3, SREBF1, FABP4
Mitochondrial dysfunction	The metabolism of glucose is impacted by decreased oxidative phosphorylation and ATP generation	NDUFS4, UCP2, SIRT1
Inflammation and immune activation	Insulin resistance is facilitated by persistent low-grade inflammation	TNF, IL-6, NLRP3, TLR4
Adipokine dysregulation	Metabolic homeostasis is disturbed by an imbalance in adipokines, such as leptin and adiponectin	LEP, ADIPOQ, RETN
Glucose transport dysfunction	Lower glucose uptake is caused by decreased GLUT4 translocation in muscle and fat	SLC2A4, AS160
Hepatic gluconeogenesis overactivity	Overproduction of glucose in the liver in spite of hyperglycemia	G6PC, PCK1, FOXO1, CREB
Β-cell dedifferentiation and apoptosis	β-cell failure is a result of both increased apoptosis and loss of β-cell identity	PDX1, MAFA, NKX6-1, FOXO1
Gut microbiota and metabolic endotoxemia	Changes in the microbiota impact insulin sensitivity and inflammation	NOD2, TLR5, FFAR2
Pathophysiology of GDM with genetic network
Ref.	Damm et al[108], 2016; Kwak et al[109], 2012; Godfrey[110], 2002; Wicklow and Retnakaran[111], 2023; Dias et al[112], 2023; Franzago et al[113], 2019; Ruchat et al[114], 2013; Neven et al[115], 2022; Ibrahim et al[116], 2022; Zhang et al[117], 2022; Niu et al[118], 2023
Pathophysiological process	Description		Key genes
Progressive insulin resistance in pregnancy	Later in pregnancy, maternal insulin resistance is increased by placental hormones (such as hPL, estrogen, and progesterone)		IRS1, PPARG, INSR, SOCS3
Inadequate β-cell adaptation	Hyperglycemia results from the inability of pancreatic β-cells to compensate for the increased demand for insulin		TCF7 L2, HNF1A, GCK, CDKAL1
Placental hormonal dysregulation	Systemic insulin resistance and disturbed glucose metabolism are caused by altered placental hormone production		LEP, TNF, PAPP-A, PSGs
Adipokine imbalance and metabolic stress	Insulin signaling and energy homeostasis are hampered by decreased adiponectin and elevated leptin/resistin		ADIPOQ, LEP, RETN, NAMPT
Inflammation and oxidative stress	Insulin resistance is brought on by cytokine-mediated inflammation (IL-6, TNF-α) through interference with signaling		IL-6, TNF, CRP, NLRP3
Epigenetic modifications and fetal programming	Changes in miRNA and DNA methylation impact long-term results and maternal-fetal metabolism		DNMT3B, miR-29a, miR-103, MEG3
Obesity-associated insulin resistance	Insulin resistance and the risk of GDM are increased by maternal obesity via inflammatory and hormonal mechanisms		FTO, MC4R, SLC30A8, IL-1β
Gut microbiota alterations and endotoxemia	Endotoxemia and chronic inflammation brought on by microbial imbalance exacerbate insulin resistance		TLR4, NOD2, FFAR2, LBP
Mitochondrial dysfunction	β-cell dysfunction and reduced ATP generation are caused by impaired mitochondrial oxidative capability		UCP2, SIRT3, MFN2
Impaired insulin signaling pathway	The absorption and use of glucose are impacted by disruptions in the insulin receptor and downstream signaling.		INSR, IRS2, AKT2
Endocrine disruptor exposure and GDM risk	Through epigenetic modifications, EDCs like BPA and phthalates may affect β-cell activity and insulin sensitivity		ESR1, NR3C1, PPARG

T1D: Type 1 diabetes; HLA: Human leukocyte antigen; INS: Insulin; PTPN22: Protein tyrosine phosphatase non-receptor type 22; CTLA4: Cytotoxic T-lymphocyte associated protein 4; IL2RA: Interleukin-2 receptor alpha; FOXP3: Forkhead box P3; EIF2AK3: Eukaryotic translation initiation factor 2 alpha kinase 3; TXNIP: Thioredoxin interacting protein; IFIH1: Interferon induced with helicase C domain 1; STAT4: Signal transducer and activator of transcription 4; IL-10: Interleukin 10; AIRE: Autoimmune regulator; TLR7: Toll-like receptor 7; NOD2: Nucleotide-binding oligomerization domain containing 2; CXCL10: C-X-C motif chemokine ligand 10; CCR5: C-C motif chemokine receptor 5; PDX1: Pancreatic and duodenal homeobox 1; MAFA: MAF BZIP transcription factor A; GAD65: Glutamic acid decarboxylase 65; IA-2: Protein phosphatase-like islet antigen 2; PTPRN: Protein tyrosine phosphatase receptor type N; IRS1: Insulin receptor substrate 1; PPARG: Peroxisome proliferator-activated receptor gamma; TCF7 L2: Transcription factor 7 Like 2; INSR: Insulin receptor; AKT2: AKT serine/threonine kinase 2; KCNJ11: Potassium inwardly rectifying channel subfamily J member 11; ABCC8: Adenosine triphosphate binding cassette subfamily C member 8; HNF1A: Hepatocyte nuclear factor 1 alpha; GLIS3: GLIS family zinc finger 3; PNPLA3: Patatin-like phospholipase domain containing 3; SREBF1: Sterol regulatory element binding transcription factor 1; FABP4: Fatty acid binding protein 4; NDUFS4: NADH ubiquinone oxidoreductase subunit S4; UCP2: Uncoupling protein 2; SIRT: Sirtuin; TNF: Tumor necrosis factor; IL-6: Interleukin 6; NLRP3: NLR family pyrin domain containing 3; TLR4: Toll like receptor 4; LEP: Leptin; ADIPOQ: Adiponectin; RETN: Resistin; SLC2A4: Solute carrier family 2 member 4; GLUT4: Glucose transporter type 4; AS160: Akt Substrate of 160; G6PC: Glucose-6-phosphatase catalytic subunit; PCK1: Phosphoenolpyruvate carboxykinase 1; FOXO1: Forkhead box O1; CREB: CAMP response element-binding protein; NKX6-1: NK6 homeobox 1; TLR5: Toll-like receptor 5; FFAR2: Free fatty acid receptor 2; SOCS3: Suppressor of cytokine signaling 3; GCK: Glucokinase; CDKAL1: CDK5 regulatory subunit associated protein 1 like 1; PAPP-A: Pregnancy-associated plasma protein A; PSGs: Pregnancy-specific beta-1-glycoproteins; NAMPT: Nicotinamide phosphoribosyltransferase; CRP: C-reactive protein; DNMT3B: DNA methyltransferase 3 beta; miR-29a: MicroRNA-29a; miR-103: MicroRNA-103; MEG3: Maternally expressed 3; FTO: Fat mass and obesity-associated gene; MC4R: Melanocortin 4 receptor; SLC30A8: Solute carrier family 30 member 8; IL1β: Interleukin 1 beta; LBP: Lipopolysaccharide binding protein; MFN2: Mitofusin 2; IRS2: Insulin receptor substrate 2; ESR1: Estrogen receptor 1; NR3C1: Nuclear receptor subfamily 3 group C member 1; GDM: Gestational diabetes mellitus; EDC: Epidermal differentiation complex; BPA: Bisphenol A.