Diabetic Ketoacidosis
Introduction
Section titled “Introduction”Diabetic ketoacidosis (DKA) is a serious and potentially life-threatening complication of diabetes, primarily affecting individuals with type 1 diabetes, but also occurring in type 2 diabetes under certain circumstances. It arises when the body, lacking sufficient insulin, cannot use glucose for energy and instead begins to break down fat. This process produces an excessive amount of acidic substances called ketones, which accumulate in the blood and urine, leading to a metabolic imbalance.
Biological Basis
Section titled “Biological Basis”The fundamental biological basis of DKA lies in severe insulin deficiency. Insulin is a hormone crucial for transporting glucose from the bloodstream into cells, where it is used for energy. When insulin levels are critically low, cells are starved of glucose. In response, the body initiates alternative metabolic pathways to generate energy, primarily by breaking down fats. This fat breakdown yields fatty acids, which are then converted into ketones (beta-hydroxybutyrate, acetoacetate, and acetone) in the liver. As ketones accumulate, the blood’s pH decreases, leading to acidosis. Simultaneously, the lack of insulin causes blood glucose levels to rise significantly (hyperglycemia), and the kidneys attempt to excrete excess glucose and ketones through urine, leading to dehydration and electrolyte imbalances.
Clinical Relevance
Section titled “Clinical Relevance”DKA is a medical emergency requiring immediate treatment. Its onset can be triggered by various factors, including infection, inadequate insulin dosage, missed insulin doses, certain medications, or other acute illnesses. Common symptoms include excessive thirst, frequent urination, nausea, vomiting, abdominal pain, fatigue, rapid deep breathing (Kussmaul respirations), and a fruity odor on the breath. If left untreated, DKA can progress rapidly, leading to severe dehydration, electrolyte disturbances, cerebral edema, kidney failure, coma, and ultimately death. Early diagnosis and prompt treatment with intravenous fluids, insulin, and electrolyte replacement are critical for recovery.
Social Importance
Section titled “Social Importance”The social importance of DKA stems from its high morbidity and mortality rates if not managed effectively. It places a significant burden on healthcare systems due to hospitalizations and intensive care requirements. For individuals with diabetes, particularly type 1, understanding DKA prevention, early recognition of symptoms, and appropriate self-management strategies (e.g., blood glucose and ketone monitoring during illness) are vital for improving health outcomes and quality of life. Education for patients, caregivers, and healthcare providers is crucial in reducing the incidence and severity of DKA, highlighting its importance in public health initiatives related to diabetes management.
Limitations of Genetic Studies in Diabetic Complications
Section titled “Limitations of Genetic Studies in Diabetic Complications”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Genetic studies investigating diabetic complications frequently face challenges related to statistical power and replication. Despite efforts to assemble large sample sizes, many studies acknowledge insufficient power to detect variants with modest effect sizes, particularly for complex traits where genetic risk may be a small proportion of overall risk. [1] For instance, power calculations in one study showed a significant drop from 100% power for a variant with a genotypic relative risk of 1.5 to only 5% power for a relative risk of 1.2, highlighting the difficulty in identifying subtle genetic contributions. [1] This limitation is further compounded by the inherent design of genome-wide association studies (GWAS), which are primarily designed to identify associations rather than causal variants, making definitive causal inference challenging for identified loci. [2]
Replication of genetic findings also presents a considerable hurdle, often failing even for top-associated variants. This can stem from various forms of heterogeneity between discovery and replication cohorts, including differences in study design, population characteristics, and analytical approaches. [1] Such inconsistencies, along with the potential for inflated effect sizes in initial discovery phases, contribute to a landscape where many identified associations do not achieve genome-wide significance upon meta-analysis across combined discovery and replication efforts. [1]
Phenotypic Definition and Ascertainment Challenges
Section titled “Phenotypic Definition and Ascertainment Challenges”Precise and consistent phenotyping is critical for robust genetic discovery but is often difficult to achieve in studies of complex diabetic complications like diabetic retinopathy and diabetic kidney disease. Researchers often encounter limits to complete harmonization of phenotypes, especially when relying on diverse cohorts with varying data collection methods, such as limited-field or no photography for diabetic retinopathy ascertainment.[1] This lack of complete harmonization can lead to misclassification of participants, which may bias results towards the null hypothesis and obscure true genetic associations. [1]
Furthermore, the definitions used for diabetic complications themselves may not be optimal for genetic discovery. Some studies acknowledge that their phenotype definitions, while standardized, are not without limitations, and that the most productive configurations for identifying genetic signals are still largely unknown. [3] Inconsistent application of advanced analytical models, such as liability threshold modeling for duration of diabetes and glycemic control, between discovery and replication cohorts can also introduce bias and hinder the ability to confirm genetic associations. [1]
Ancestry, Generalizability, and Environmental Confounders
Section titled “Ancestry, Generalizability, and Environmental Confounders”The generalizability of genetic findings for diabetic complications is often restricted by the specific ancestral populations included in the studies. Many large-scale GWAS primarily focus on individuals of European descent, limiting the direct applicability of findings to other ethnic groups. [4] When multiethnic cohorts are included, differences in minor allele frequencies and genetic architectures across populations can lead to a lack of trans-ethnic replication, indicating that genetic effects may not be universally shared. [5]
Beyond genetic factors, the influence of environmental or non-genetic confounders poses a significant challenge. The genetic risk for developing diabetic complications, such as diabetic retinopathy, may be relatively small when compared to the substantial impact of non-genetic risk factors.[1] Clinical heterogeneity among study cohorts, including differences in age, sex, duration of diabetes, and especially glycemic control (e.g., HbA1c levels), can act as confounders if not adequately accounted for, potentially masking or distorting true genetic signals. [6]
Variants
Section titled “Variants”Genetic variations play a crucial role in an individual’s susceptibility to diabetic ketoacidosis (DKA), particularly those affecting immune response and metabolic regulation. Key variants within the human leukocyte antigen (HLA) complex, such asrs9273363 and rs539981616 in the HLA-DQA1 and HLA-DQB1 genes, are strongly associated with autoimmune conditions like Type 1 Diabetes (T1D), the primary cause of DKA. These genes encode components of the MHC class II proteins, which are critical for presenting antigens to T-cells, thereby shaping the immune system’s recognition of self versus non-self. [7]Specific alleles at these loci are known to increase the risk of autoimmune destruction of pancreatic beta cells, leading to insulin deficiency and the subsequent development of DKA if left untreated. Similarly, thers9273508 variant, located near HLA-DQB1-AS1 and HLA-DQB1, may influence the expression or function of these immune-related genes, further contributing to the genetic predisposition for T1D and its acute complications, including DKA. [7]
Other variants contribute to DKA risk through their roles in metabolic pathways and cellular functions. The rs186568031 variant in SLC16A11 and rs77552976 near CLEC10A are of interest; SLC16A11encodes a monocarboxylate transporter that affects glucose and lipid metabolism, whileCLEC10A is involved in immune regulation, particularly in antigen presentation and inflammatory responses, which can be critical in the context of metabolic stress and DKA. [7]Alterations in these genes could impact how the body handles glucose and lipids during insulin deficiency or how it responds to the inflammatory state characteristic of DKA. Furthermore, theZFPM2 gene, associated with rs557788509 , is a transcription factor involved in organ development and cell differentiation, including pancreatic development, and its variations might subtly influence pancreatic function or resilience to metabolic insults. The PBX1 gene, with variant rs561726636 , also functions as a transcription factor essential for embryonic development and cell fate, potentially impacting endocrine cell development within the pancreas and thus contributing to diabetes susceptibility. [7]
Beyond direct metabolic or immune genes, other genetic loci may influence DKA risk through less direct mechanisms. The rs181291048 variant, located between SHISA9 and TMF1P1, could affect neuronal development and cellular stress responses, which are relevant in severe metabolic states. Variants like rs185905894 in the intergenic region of MIR646HG and LINC01718involve non-coding RNAs that regulate gene expression, potentially impacting a wide range of cellular processes, including those involved in glucose homeostasis or stress adaptation.[7] Similarly, rs139686691 involving RNU6-533P and RPL23P10 points to variations in small nuclear RNA and ribosomal protein genes, which are fundamental to protein synthesis and gene regulation, suggesting broad cellular impacts. The RFLNA gene, associated with rs183910463 , plays a role in actin cytoskeleton organization, important for cell structure and signaling, while ANKRD42, with variant rs141499620 , is an ankyrin repeat domain-containing protein that can be involved in protein-protein interactions and various cellular pathways, including those related to inflammation or cellular stress, all of which can be exacerbated during DKA. [7] These diverse genetic influences highlight the complex polygenic nature of DKA susceptibility.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs9273363 rs539981616 | HLA-DQA1 - HLA-DQB1 | inflammatory bowel disease ulcerative colitis chronic lymphocytic leukemia CD74/DLL1 protein level ratio in blood CD74/IL18BP protein level ratio in blood |
| rs9273508 | HLA-DQB1-AS1, HLA-DQB1 | streptococcus seropositivity peak expiratory flow diabetic ketoacidosis |
| rs186568031 rs77552976 | SLC16A11 - CLEC10A | type 2 diabetes mellitus type 1 diabetes mellitus diabetic ketoacidosis insulin measurement |
| rs181291048 | SHISA9 - TMF1P1 | diabetic ketoacidosis |
| rs185905894 | MIR646HG - LINC01718 | diabetic ketoacidosis |
| rs557788509 | ZFPM2 | diabetic ketoacidosis |
| rs139686691 | RNU6-533P - RPL23P10 | diabetic ketoacidosis |
| rs183910463 | RFLNA | diabetic ketoacidosis |
| rs561726636 | PBX1 | diabetic ketoacidosis |
| rs141499620 | ANKRD42 | diabetic ketoacidosis |
Biological Background
Section titled “Biological Background”Genetic Predisposition and Heritability of Diabetic Kidney Disease
Section titled “Genetic Predisposition and Heritability of Diabetic Kidney Disease”Diabetic kidney disease (DKD) exhibits a significant genetic component, with early studies indicating that it often clusters within families, suggesting underlying genetic susceptibility.[4] The heritability of DKD is estimated to be approximately 35% in individuals with type 1 diabetes (T1D) but only around 8% in those with type 2 diabetes (T2D), a difference potentially attributed to the greater phenotypic heterogeneity observed in T2D. [4] Genome-wide association studies (GWAS) have identified several genetic variants and loci associated with DKD, including novel variations such as rs3128852 near OR5V1 and rs117744700 near HIATL1, which show association with DKD independently of T1D-associated HLA variants. [2] Additionally, a variant within the FTO gene has been found to confer susceptibility to diabetic nephropathy in certain populations. [8] Genetic risk scores, which integrate multiple genetic variants, are also utilized to assess an individual’s predisposition to DKD and other related diabetic complications. [3]
Molecular Pathways and Cellular Dysregulation in DKD
Section titled “Molecular Pathways and Cellular Dysregulation in DKD”The development of DKD involves complex molecular and cellular pathways disrupted by chronic hyperglycemia. Key biomolecules and signaling pathways play a crucial role, such as the JAK/STAT pathway, which has been implicated in diabetic nephropathy. [9]High glucose conditions can lead toVEGF upregulation, a process that can be inhibited by PEDF through its interaction with the JAK2/STAT3 pathway, highlighting the intricate regulatory networks involved in cellular responses to metabolic stress. [9] Furthermore, genes like Nidogen-1 (NID1) are being investigated for their potential role in DKD development, suggesting extracellular matrix components may contribute to disease progression.[4] Other relevant genes include ERAP2, whose locus has been associated with oral glucose tolerance, implying a mediating role of diabetes in its impact on DKD, andAPOL1, which is linked to forms of end-stage kidney disease.[10]
Progression of Renal Damage and Systemic Consequences
Section titled “Progression of Renal Damage and Systemic Consequences”Diabetic kidney disease is characterized by a progressive decline in kidney function, often beginning with increased urinary albumin excretion and eventually leading to reduced estimated glomerular filtration rate (eGFR). DKD is typically defined by a history of diabetes, along with significant albuminuria (e.g., 24-hour urinary albumin excretion ≥30 mg/day) and/or reduced eGFR (e.g., <60 mL/min/1.73m²), which collectively reflect compromised renal function.[10]The disease can advance to severe stages, including end-stage kidney disease (ESKD), marked by conditions such as renal replacement therapy, very low eGFR (≤30 ml/min/1.73 m²), or macroalbuminuria (urine albumin to creatinine ratio ≥300 mg/g), underscoring the severe systemic consequences of uncontrolled diabetes on kidney health.[11]The chronic high glucose environment drives these pathophysiological changes, leading to cellular damage and homeostatic disruptions within the kidney tissues.
Immunological and Inflammatory Contributions to DKD
Section titled “Immunological and Inflammatory Contributions to DKD”The immune system plays a significant role in the pathogenesis of DKD, particularly in type 1 diabetes where autoimmune processes are central. Genetic variants in the human leukocyte antigen (HLA) region, such as rs28366355 near HLA-DRB1 and HLA-DQA1, have been associated with DKD, and these HLA genes are known to be involved in antigen processing and presentation. [2]Pathway analyses have revealed enrichment for immune-related pathways like “Antigen processing and presentation” and “Type I diabetes mellitus,” alongside “Autoimmune thyroid disease,” “Allograft rejection,” and “Graft-versus-host disease,” indicating a complex interplay of immune responses in the development and progression of DKD.[2] Inflammatory mediators, including elevated levels of certain cytokines, are also observed in diabetic microvascular complications, further highlighting the contribution of chronic inflammation to tissue damage in diabetes. [1]
Dysregulation of Insulin Signaling and Glucose Metabolism
Section titled “Dysregulation of Insulin Signaling and Glucose Metabolism”Diabetic ketoacidosis (DKA) is profoundly influenced by the dysregulation of pathways central to insulin action and glucose metabolism. Under diabetic conditions, impaired insulin signaling is observed, for instance, in subcutaneous microvascular endothelial cells in type 2 diabetes, which is often accompanied by increased activation of theMAPK pathway. [12]Insulin normally activates cascades like theAKT and ERKpathways, which are crucial for glucose uptake and utilization, and their enhancement can even accelerate wound healing in diabetes.[13]However, in the context of diabetes, glucose itself can activatep38 mitogen-activated protein kinasevia different pathways, indicating a complex interplay where high glucose directly impacts cellular signaling independent of normal insulin-mediated responses.[14]This dysregulation profoundly affects energy metabolism, shifting cells from efficient glucose utilization towards alternative catabolic pathways and contributing to the metabolic derangements seen in diabetes.
The altered metabolic regulation and flux control stemming from impaired insulin signaling contribute to systemic metabolic imbalances that can precipitate DKA. TheJAK/STATsignaling pathway, for example, plays a role in diabetic nephropathy, where high glucose conditions can lead toVEGF upregulation. [15]Such signaling cascades are critical in mediating cellular responses to metabolic stress, and their chronic activation or dysregulation under conditions of insulin deficiency and hyperglycemia contributes to the overall pathology of diabetes. The continuous activation of stress-response pathways by elevated glucose levels signifies a breakdown in normal metabolic homeostasis, setting the stage for acute metabolic decompensation.
Cellular Stress and Inflammatory Cascades
Section titled “Cellular Stress and Inflammatory Cascades”Chronic hyperglycemia in diabetes triggers various cellular stress and inflammatory responses, which are integral to the progression of diabetic complications and can exacerbate the conditions leading to DKA. Key inflammatory cytokines, such as vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-beta), and interferon gamma (IFN-gamma), are implicated in conditions like proliferative diabetic retinopathy, with polymorphisms in their genes influencing disease susceptibility.[16]Elevated levels of cytokines associated with Th2 and Th17 cells are also observed in the vitreous fluid of patients with proliferative diabetic retinopathy, highlighting a systemic inflammatory component.[17] Furthermore, conditions like diabetes activate p38 MAPKthrough various pathways, including those involving reactive oxygen species, which are known to be elevated under high glucose conditions, leading to oxidative stress.[14]
Oxidative stress, often mediated by enzymes like _NADPH oxidase 4 (NOX4), is a significant contributor to cellular damage and pathway dysregulation in diabetes, with NOX4specifically associated with severe diabetic retinopathy.[18] Oxidative stress can also influence other critical pathways, such as the Wntpathway, whose activation is involved in diabetic retinopathy.[19]These inflammatory and stress-related signaling pathways represent a compensatory mechanism initially, but their chronic activation leads to tissue damage and further metabolic dysfunction, contributing to the systemic environment conducive to DKA. The complex interplay of these cascades underscores the multifaceted nature of diabetic pathophysiology beyond simple glucose dysregulation.
Genetic Predisposition and Immune System Interactions
Section titled “Genetic Predisposition and Immune System Interactions”Genetic factors play a significant role in an individual’s susceptibility to diabetes and its complications, influencing various pathways and mechanisms. For instance, specific genetic variants within the human leukocyte antigen (HLA) region, such as HLA-DQA1 and HLA-A, are strongly associated with Type I diabetes mellitus, as well as autoimmune thyroid disease and antigen processing and presentation pathways.[2] These HLA genes are critical in immune system regulation, and their specific alleles can predispose individuals to autoimmune destruction of pancreatic beta cells, a primary cause of Type I diabetes and a major risk factor for DKA. This highlights a direct link between immune system genetics and the etiology of diabetes.
Beyond Type I diabetes, genetic susceptibility also impacts the development of diabetic complications, reflecting broader pathway dysregulation. For example, heritability studies indicate a genetic component to diabetic kidney disease (DKD), although with varying estimates between Type 1 and Type 2 diabetes.[4] Specific genetic variants, such as those in the FTO gene, have been found to confer susceptibility to diabetic nephropathy in patients with type 2 diabetes. [8] Similarly, the MAPK14gene is associated with diabetic foot ulcers[18] and variants like those in APOL1are linked to Type 2 diabetes-attributed end-stage kidney disease.[11] Even the ERAP2locus has been associated with oral glucose tolerance and DKD, suggesting that genetic predisposition influences both glucose metabolism and disease-relevant outcomes.[10]These genetic predispositions underscore a hierarchical regulation where inherited factors modulate receptor activation, intracellular signaling, and transcription factor regulation, influencing the overall disease trajectory.
Interconnected Regulatory Networks
Section titled “Interconnected Regulatory Networks”The various pathways and mechanisms involved in diabetes and its complications do not operate in isolation but are intricately interconnected, forming complex regulatory networks. This systems-level integration is characterized by extensive pathway crosstalk, where signals from one pathway can modulate the activity of another. An example of such crosstalk is observed between the TGF-beta and MAPK signaling pathways, which interact during processes like corneal wound healing. [20] These interactions demonstrate how different signaling cascades converge or diverge to regulate cellular functions, and dysregulation in one pathway can have cascading effects across the network.
The hierarchical regulation within these networks ensures a coordinated cellular response to metabolic changes, but in diabetes, this coordination is often disrupted, leading to emergent properties characteristic of the disease state. For instance, the chronic high glucose environment and impaired insulin signaling lead to a persistent activation of stress-response pathways and inflammatory cascades, creating a vicious cycle that perpetuates cellular damage and metabolic dysfunction. Understanding these network interactions and their emergent properties is crucial for identifying novel therapeutic targets, as interventions aimed at single pathways might be less effective than those addressing the broader network dysregulation in diabetes.
Frequently Asked Questions About Diabetic Ketoacidosis
Section titled “Frequently Asked Questions About Diabetic Ketoacidosis”These questions address the most important and specific aspects of diabetic ketoacidosis based on current genetic research.
1. My mom had DKA, does that mean I’ll definitely get it?
Section titled “1. My mom had DKA, does that mean I’ll definitely get it?”Not necessarily, but your family history does suggest a higher genetic predisposition to diabetes, which is the underlying cause of DKA. While specific genes for DKA itself are hard to pinpoint due to their often modest effects and complex interactions, inherited factors for Type 1 or Type 2 diabetes can increase your risk. However, DKA is frequently triggered by non-genetic factors like infections or missed insulin doses, so managing your diabetes and being vigilant is key.
2. If I keep my blood sugar perfect, can I avoid DKA even with family history?
Section titled “2. If I keep my blood sugar perfect, can I avoid DKA even with family history?”Yes, maintaining excellent glycemic control is one of the strongest ways to reduce your DKA risk, even with a family history. While genetics influence your susceptibility to diabetes, non-genetic factors like consistent insulin management and avoiding triggers like infections are often more impactful. The genetic contribution to diabetic complications can be relatively small compared to these strong environmental and lifestyle influences.
3. Does being from a certain ethnic group make me more prone to DKA?
Section titled “3. Does being from a certain ethnic group make me more prone to DKA?”Your ethnic background can play a role, as genetic risk factors for diabetes and its complications can vary across populations. Many large genetic studies primarily focus on people of European descent, meaning findings might not directly apply or fully explain risk in other ethnic groups. Differences in genetic architectures and environmental factors across ancestries can lead to varying DKA susceptibility.
4. Why do some people with diabetes get DKA and others never do?
Section titled “4. Why do some people with diabetes get DKA and others never do?”This often comes down to a complex interplay of genetic susceptibility and significant environmental factors. While some genetic variations might slightly increase DKA risk by influencing glucose metabolism or insulin sensitivity, these effects are often modest and hard to pinpoint. Instead, factors like insulin management adherence, presence of infections, or other acute illnesses frequently determine who develops DKA.
5. Can extreme stress or lack of sleep trigger DKA for me?
Section titled “5. Can extreme stress or lack of sleep trigger DKA for me?”Yes, extreme stress or illness can definitely act as non-genetic triggers for DKA, especially if you have diabetes. These factors can disrupt your body’s insulin needs and blood sugar control. While genetics might predispose you to diabetes itself, environmental confounders and acute illnesses are often the immediate catalysts for DKA, highlighting their significant impact over solely genetic risk.
6. Is there a special genetic test to see my personal DKA risk?
Section titled “6. Is there a special genetic test to see my personal DKA risk?”Currently, there isn’t a specific genetic test that can precisely predict your individual risk for DKA. While genetic tests exist for underlying diabetes types, identifying specific genetic variants for complications like DKA is challenging. This is because many variants have only small effects, and studies face hurdles in replication and defining phenotypes for genetic discovery, making definitive causal inference difficult.
7. Do doctors find DKA harder to diagnose in some people?
Section titled “7. Do doctors find DKA harder to diagnose in some people?”Diagnosing DKA primarily relies on clinical symptoms and lab tests, not genetic factors influencing diagnosis difficulty. However, challenges in defining and consistently ascertaining phenotypes for diabetic complications can affect how genetic studies identify risk, not necessarily how doctors diagnose. In real-life, DKA symptoms are generally clear, but individual presentation and promptness in seeking care can influence early diagnosis.
8. Will eating a specific diet help lower my DKA risk if it’s in my family?
Section titled “8. Will eating a specific diet help lower my DKA risk if it’s in my family?”Eating a healthy, consistent diet is crucial for managing your diabetes and significantly lowers your DKA risk, regardless of family history. While genetics can influence your predisposition to diabetes, the impact of non-genetic factors like diet and glycemic control is often far more substantial. A well-managed diet helps maintain stable blood sugar, reducing the chances of DKA triggers.
9. My sibling has diabetes but never DKA – why am I different?
Section titled “9. My sibling has diabetes but never DKA – why am I different?”Even with shared genetic background, individual differences in DKA susceptibility are common. While you share many genes, specific genetic variants influencing diabetes complications often have small effects, and they combine uniquely. Crucially, environmental factors like how well each of you manages blood sugar, exposure to infections, or even medication use play a very large role in who experiences DKA.
10. Does my DKA risk change a lot as I get older?
Section titled “10. Does my DKA risk change a lot as I get older?”DKA risk is primarily tied to the management of your underlying diabetes, which can change with age due to varying insulin needs or other health conditions. While specific genetic factors for DKA aren’t known to change over time, the clinical heterogeneity among individuals, including age, can influence how genetic signals for complications are studied. Focusing on consistent diabetes management remains paramount throughout your life.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Pollack S et al. Multiethnic Genome-wide Association Study of Diabetic Retinopathy using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. Diabetes, 2018.
[2] Jin H et al. Identification of genetic variants associated with diabetic kidney disease in multiple Korean cohorts via a genome-wide association study mega-analysis. BMC Med, 2023.
[3] van Zuydam NR et al. A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes. Diabetes, 2018.
[4] Khattab A et al. Nidogen-1 could play a role in diabetic kidney disease development in type 2 diabetes: a genome-wide association meta-analysis. Hum Genomics, 2022.
[5] Sheu, WH., et al. “Genome-wide association study in a Chinese population with diabetic retinopathy.”Hum Mol Genet, vol. 22, no. 14, 2013, pp. 2977-2985.
[6] Awata, T., et al. “A genome-wide association study for diabetic retinopathy in a Japanese population: potential association with a long intergenic non-coding RNA.”PLoS One, vol. 9, no. 11, 2014.
[7] Reiner, A. P. et al. “Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein.”Am J Hum Genet, vol. 82, no. 5, 2008, pp. 1188-92.
[8] Taira M, et al. A variant within the FTO confers susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes. PLoS One 2013;8:e83214.
[9] Hsieh AR et al. Lack of association of genetic variants for diabetic retinopathy in Taiwanese patients with diabetic nephropathy. BMJ Open Diabetes Res Care, 2020.
[10] Pan Y et al. Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease. Hum Mol Genet, 2022.
[11] Guan M et al. Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans. Hum Genomics, 2019.
[12] Gogg S, Smith U, Jansson PA. Increased MAPK activation and impaired insulin signaling in subcutaneous microvascular endothelial cells in type 2 diabetes: the role of endothelin-1. Diabetes 2009;58:2238–45.
[13] Lima MH, Caricilli AM, de Abreu LL et al. Topical insulin accelerates wound healing in diabetes by enhancing the AKT and ERK pathways: a double-blind placebo-controlled clinical trial. PLoS ONE 2012; 7:e36974.
[14] Igarashi M, Wakasaki H, Takahara N et al. Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways. J Clin Invest 1999; 103:185–95.
[15] Marrero MB, Banes-Berceli AK, Stern DM, et al. Role of the JAK/STAT signaling pathway in diabetic nephropathy. Am J Physiol Renal Physiol 2006;290:F762–8.
[16] Paine SK, Basu A, Mondal LK, et al. Association of vascular endothelial growth factor, transforming growth factor beta, and interferon gamma gene polymorphisms with proliferative diabetic retinopathy in patients with type 2 diabetes. Mol Vis 2012;18:2749–2757.
[17] Takeuchi M, Sato T, Tanaka A, et al. Elevated levels of cytokines associated with Th2 and Th17 cells in vitreous fluid of proliferative diabetic retinopathy patients. PLoS One 2015;10:e0137353.
[18] Meng W, et al. A genome-wide association study suggests that MAPK14 is associated with diabetic foot ulcers. Br J Dermatol 2017;177:1523–30.
[19] Liu Q, Li J, Liu Z & Ma J. Salutary effect of fenofibrate on diabetic retinopathy via inhibiting oxidative stress-mediated Wnt pathway activation. Invest Ophthalmol Vis Sci 2014;55:E-Abstract 1027.
[20] Terai K, Call MK, Liu H et al. Crosstalk between TGF-beta and MAPK signaling during corneal wound healing. Invest Ophthalmol Vis Sci 2011; 52:8208–15.