Type I Diabetes Pathoetiology and Pathophysiology

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		George Anderson	--	3288	2023-02-14 13:27:58	\|
2	format change	Peter Tang	-19 word(s)	3269	2023-02-15 02:43:42	\| \|
3	format change	Peter Tang	Meta information modification	3269	2023-02-15 02:44:16	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms24043300

Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate insulin, usually as a consequence of extensive pancreatic β-cell destruction. T1DM is classed as an immune-mediated condition. However, the processes that drive pancreatic β-cell apoptosis remain to be determined, resulting in a failure to prevent ongoing cellular destruction. Alteration in mitochondrial function is clearly the major pathophysiological process underpinning pancreatic β-cell loss in T1DM. This entry highlights the role of intercellular interactions among different cell types in pancreatic islets. It is proposed that the pathoetiology of T1DM arises from mitochondrial interactions among different pancreatic cells, leaving pancreatic B-cells with suppressed capacity to induce the mitochondrial melatonergic pathway, with the associated decrease in pancreatic B-cell melatonin leading to suboptimal mitochondrial function and increased oxidative stress that suppresses PINK1/parkin/mitophagy, leading increased major histocompatibility complex (MHC)-1. This results in the chemoattraction of CD8⁺ T cells and immune-mediated cell destruction. Variations in different gut bacteria and fungi contribute to pancreatic B-cell loss via their impacts on mitochondrial function within the interacting cells of the pancreatic islets. T1DM may therefore be more of a ‘mitochondria/metabolic’ disorder than an ‘autoimmune’ or ‘immune-mediated’ disorder.

type 1 diabetes mitochondria melatonin

1. Introduction

Type 1 diabetes mellitus (T1DM) is a chronic condition arising from a failure of pancreatic β-cells to produce adequate insulin, often as a consequence of pancreatic β-cell destruction, thereby dysregulating circulating glucose level homeostasis. T1DM is classified as an immune-mediated disorder, with raised levels of autoantibodies. The risk of progressing to T1DM is negatively correlated with age ^[1]. A number of risk factors are evident, including genetic and viral, with pathoetiology predominantly driven by environmental and epigenetic factors. T1DM most commonly emerges in childhood and adolescence, although it can also arise in adulthood. Whilst screening can lead to an earlier diagnosis, the majority of T1DM diagnoses are made when most pancreatic β-cells and their function are significantly disturbed. There is no known treatment that tackles the primary site of T1DM pathoetiology, namely pancreatic β-cell loss and dysfunction. Rather, treatment is primarily targeted to monitoring and regulating blood glucose levels. As T1DM is associated with functional disturbances in many organs, it is linked to an elevated risk of numerous other medical conditions, including dementia ^[2]^[3], cardiovascular disorders, kidney disorders, retinopathy, neuropathy, hypertension, lung disorders, obesity, and amyotrophic lateral sclerosis (ALS) ^[4], as well as bacterial and fungal infections ^[5]^[6]. As all these comorbidities show alterations in the gut microbiome and gut permeability ^[7]^[8], the gut dysbiosis evident in T1DM is an important mediator of its pathophysiological associations of these comorbidities ^[9].

2. Classical Type 1 Diabetes Mellitus Pathoetiology

T1DM arises from the dysregulation of pancreatic β-cell insulin production and insulin effects. Pancreatic β-cell function and insulin release are intimately linked to variations in blood glucose. At low/basal levels of blood glucose, the ATP-sensitive potassium (K_ATP) channels in pancreatic β-cells remain open, leading to maintained membrane hyperpolarization coupled to Ca²⁺ channel closure, thereby inhibiting insulin secretion by pancreatic β-cells ^[10]. When blood glucose concentration levels rise, glucose is taken up by the glucose transporter (GLUT)1 into pancreatic β-cells where it is quickly phosphorylated by glucokinase and then converted to pyruvate. The conversion of pyruvate to acetyl-CoA by the pyruvate dehydrogenase complex (PDC) increases ATP production by the tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS), resulting in K_ATP channel closure, plasma membrane depolarization, and the opening of voltage-dependent Ca²⁺ channels in association with insulin vesicle exocytosis. Mitochondrial function is therefore a crucial aspect of pancreatic β-cell function and plasticity of response to variations in circulating glucose ^[10].

Islet amyloid polypeptide (amylin) is simultaneously secreted by pancreatic β-cells along with insulin. Amylin accumulates in diabetes, forming amyloid deposits in the pancreas that are a relevant aspect of T1DM and T2DM pathophysiology, driving pancreatic β-cell dysfunction and apoptosis, as well as contributing to islet transplantation failure ^[11]^[12]. Amylin fibrillation follows amylin over-production in association with insulin resistance and hyperinsulinemia, which triggers a nucleation-dependent self-assembly of amylin into intracellular or extracellular amyloid deposits ^[13]. Amylin fibrillation is proposed to parallel other amyloidosis, such as amyloid-β in dementia, in driving pancreatic β-cell apoptosis and may therefore be an important treatment target in T1DM ^[13], including in relation to the ‘autoimmune’ aspects of T1DM. Amylin, Ca²⁺ dysregulation, reactive oxygen species (ROS), endoplasmic reticulum alterations, and metabolic dysregulation have all been proposed to drive post-translational protein modifications that underpin the autoimmune-like response in T1DM ^[11].

T1DM pathophysiology is classically described as a T cell-mediated autoimmune disorder, whereby predominantly CD8⁺ T cells become autoreactive, leading to the destruction of pancreatic β-cells. A failure in the capacity of regulatory T cells (Treg) to suppress such processes is also implicated. Elevated levels of major histocompatibility complex (MHC) class 1 molecules on pancreatic β-cells drive the autoreactivity responses of CD8⁺ T cells. Such autoreactive CD8⁺ T cells usually undergo negative selection in the thymus, which seems to be altered/impaired in T1DM due, at least partly, to an allelic variant of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) modulator, NF-κB-inhibitor Delta (Nfkbid), which is an atypical NF-κB inhibitor and an important regulator of B cell immunity across a host of medical conditions ^[14]. Modulation of Nfkbid thymic expression levels indicates that it may act to regulate levels of both autoreactive CD8⁺ T cells and Treg ^[15]^[16].

T1DM susceptibility is linked to several genetic and environmental factors. Familial transmission is apparent in about 10% of T1DM patients, with the human leukocyte antigen complex (HLA) located on chromosome 6 showing the strongest familial association ^[17]. Numerous single nucleotide polymorphisms (SNPs) have been linked to T1DM risk, including P53 ^[18], the NF-κB modifying gene, small ubiquitin-related modifier 4 (SUMO4) ^[19], and many other genes ^[20] as well as HLA haplotypes ^[21]. Many T1DM susceptibility genes act to regulate mitochondrial function and mitophagy in pancreatic β-cells, including Clec16a ^[22], highlighting the importance of optimal mitochondrial function and OXPHOS ^[23] in the regulation of pancreatic β-cell function and insulin regulation.

T1DM environmental risk factors include the consumption of a Western-type diet, with a number of ligands for the receptor for advanced glycation end-products (RAGE) contained within many such foods ^[24]. These authors propose that RAGE activation leads to the activation and proliferation of islet infiltrating CD8⁺ and CD4⁺ T cells, coupled to Treg suppression, thereby impacting on the patterned immune response that contributes to pancreatic β-cell injury, with effects mediated via NF-κB upregulation, coupled to increased ROS and oxidative stress ^[24]. RAGE has numerous other ligands, including high-mobility group box (HMGB)1 and S100/calgranulin family members, such as S100A9, as well as amyloid-β and pre-fibrillar amylin aggregates ^[25]^[26]. Preclinical data show that the administration of soluble RAGE dramatically suppresses T1DM via Treg upregulation, and associated inhibition of conventional T cell division ^[27]. Such data would implicate a significant clinical impact of RAGE ligands that can be suppressed by soluble RAGE, as well as melatonin ^[28]. The antioxidant, anti-inflammatory, circadian, and mitochondrial optimizing effects of melatonin are important aspects of T1DM, whilst the immediate precursor of melatonin, N-acetylserotonin (NAS) may also be a crucial regulator of pancreatic β-cell survival, via its capacity to activate the brain-derived neurotrophic factor (BDNF) receptor TrkB, as shown in Figure 1.

Figure 1. The tryptophan–melatonin pathway. Tryptophan is converted to serotonin by tryptophan hydroxylase (TPH)1 or TPH2, which requires stabilization by 14-3-3e. AANAT converts serotonin to N-acetylserotonin (NAS), with AANAT requiring stabilization by another 14-3-3 isoform and the presence of acetyl-CoA as a co-substrate. ASMT converts NAS to melatonin. NAS is a BDNF mimic, via its activation of the BDNF receptor, TrkB. NAS may also induce BDNF. Melatonin is a powerful antioxidant and anti-inflammatory that optimizes mitochondrial function. Abbreviations: AANAT: aralkylamine N-acetyltransferase; Acetyl-CoA: acetyl coenzyme A; ASMT: N-acetylserotonin O-methyltransferase; BDNF: brain-derived neurotrophic factor; NAS: N-acetylserotonin; TPH: tryptophan hydroxylase.

However, many of the genetic and epigenetic susceptibility factors for T1DM may ultimately act on mitochondrial function in pancreatic β-cells ^[23], immune cells, and other cells across the body.

3. Wider T1DM Pathophysiology

A wide array of diverse signaling pathways, processes, and factors are associated with T1DM pathoetiology and pathophysiology.

The inability to prevent pancreatic β-cell loss and to induce regeneration, coupled with the complexity of immune-mediated processes underpinning autoimmune-like changes, has generated the investigation of a wide range of possible pathophysiological processes and factors in T1DM, including the aryl hydrocarbon receptor (AhR) ^[29], toll-like receptor (TLR)4 activation ^[30], NF-κB ^[31], yin yang (YY)1 ^[32], the melatonergic pathway ^[33], P53 ^[18], circadian dysregulation ^[34], and gut dysbiosis/permeability ^[35].

The AhR is predominantly expressed in a complex with other proteins in the cytoplasm, with its activation by endogenous and exogenous ligands leading to its translocation to the nucleus, where it forms a dimer that upregulates genes containing the xenobiotic response element. The AhR has complex effects that are partly dependent upon the specific AhR-activating ligand, cell type, and concurrent wider cellular processes ^[36]. The AhR is also expressed on the mitochondrial membrane where it can regulate Ca²⁺ influx via the voltage-dependent anion channel (VDAC)1 ^[37]. The AhR has diverse effects in different cells and tissues relevant to T1DM pathophysiology, with AhR activation leading to suppressed function and cytotoxic capacity in CD8⁺ T cells and natural killer (NK) cells ^[38], the maintenance of the gut barrier ^[39], and pancreatic β-cell regulation ^[40]. The diverse, and sometimes contrasting, effects of AhR activation in different cells and tissues by various ligands complicate its incorporation into T1DM pathophysiology.

Western diet-driven increases in palmitate and lipopolysaccharide (LPS) can synergistically damage pancreatic β-cells via TLR4 activation, including via enhanced pancreatic β-cell ceramide and suppressed sphingosine-1-phosphate (S1P) levels ^[30]. The role of TLR4 signaling in pancreatic β-cell dysfunction has been widely replicated ^[41], with factors acting to regulate TLR signaling, including miR-383 and TLR4 knockout, ameliorating high fat/sugar diet-induced β-cell dysfunction, as mostly assessed in T2DM ^[42]^[43]. The protection afforded by melatonin in pancreatic β-cells is at least partly mediated via TLR2/4 level suppression ^[44]. Such data also indicate the relevance of increased gut permeability to pancreatic β-cell dysfunction via raised circulating LPS levels ^[45], with the association of palmitate with pancreatic β-cell dysfunction partly mediated via increased gut permeability ^[46].

LPS activation of TLR4 induces the transcription factors, NF-κB and YY1, in many cell types, including leukocytes, macrophages, microglia, and astrocytes ^[36]^[47]. The induction of pro-inflammatory processes in pancreatic β-cells is intimately linked to NF-κB upregulation ^[31]^[48]^[49]. The downstream consequences of NF-κB upregulation are associated with a diverse array of factors, including non-steroidal anti-inflammatory drug activated gene-1, growth differentiation factor-15 (NAG-1/GDF15) ^[48], or intercellular adhesion molecule (ICAM)-1 ^[31]. YY1 knockout in pancreatic β-cells leads to rapid hyperglycemia onset, impaired glucose tolerance, and suppressed pancreatic β-cell mass, both in neonates and adult murine models ^[32]. These authors showed YY1 to bind the enhancer regions in exon 2 of Ins1 and Ins2, activating pro-insulin and insulin transcription and thereby insulin production from pancreatic β-cells ^[32].

Such data on NF-κB and YY1 indicate contrasting effects in T1DM pathophysiology. However, it is important to note that both transcription factors can induce the melatonergic pathway, as shown in different cell types ^[50]^[51]. Variation in the capacity of these transcription factors to upregulate the melatonergic pathway is of some importance to T1DM pathophysiology, given that melatonin protects and optimizes pancreatic β-cell function and insulin regulation at nM levels ^[33]^[52], including via the optimization of mitochondrial function. This may be of relevance to data showing that the induction and activation of NF-κB may afford protection against pancreatic β-cell loss in T1DM models, which the authors attribute to NF-κB induction of miR-150, thereby preventing T1DM-associated inflammation and pancreatic β-cell apoptosis ^[53]. As NF-κB is associated with the induction of the melatonergic pathway in several cells so far investigated ^[51]^[54], it is of note that the most commonly used preclinical T1DM model, the streptozotocin-induced T1DM model, suppresses local melatonin production and melatonergic pathway activity, as shown in the retina ^[55]. This could indicate that the suppression of the mitochondrial melatonergic pathway may be a significant factor in pancreatic β-cell apoptosis in clinical T1DM.

Other intracellular signaling processes and transcription factors are associated with T1DM, including SNPs in, and upregulation of, the classical tumor suppressor and transcription factor, P53 ^[18]. However, although P53 is upregulated during apoptosis in pancreatic β-cell in the course of T1DM and T2DM, recent data indicate that P53 is not essential to pancreatic β-cell loss ^[56]. Using pancreatic β-cell specific P53 knockout, these authors showed pancreatic β-cell specific P53 knockout failed to ameliorate insulin secretion and glucose tolerance, as well as failing to raise pancreatic β-cell numbers in an array of genetic, dietary, and pharmacological models of T1DM and T2DM ^[56]. These authors suggest that the induction of poly [ADP-ribose] polymerase 1 (PARP-1) may be a more relevant mediator of pancreatic β-cell loss in T1DM models ^[56], by decreasing NAD⁺ availability, thereby suppressing the sirtuin-induced PDC and mitochondrial OXPHOS.

Circadian dysregulation, both genetic and environmental, is closely associated with metabolic syndrome and T2DM, involving the uncoupling of OXPHOS, ATP production, and glucose-stimulated insulin secretion ^[34], mediated—in part—via the suppression of the circadian gene, Bmal1, and the endogenous antioxidant inducing transcription factor, Nrf2 ^[34]. These changes can be reversed by melatonin ^[57]^[58], highlighting the importance of pineal melatonin in the circadian optimization of pancreatic β-cell function. Circadian dysregulation is also intimately linked to a diverse array of T1DM symptomatology ^[59], including nocturnal non-dipping blood pressure increasing kidney disease ^[60], cardiac autonomic neuropathy ^[61], platelet morphology ^[62], microvascular complications ^[63], and patterned immune activity ^[64], whilst circadian variation in basal insulin requirement can be an early marker of autoimmune polyendocrine syndromes in T1DM ^[65]. Such data highlight the role of alterations in the circadian rhythm in T1DM pathophysiology.

The growing appreciation of the role of the gut microbiome and gut permeability across a host of diverse medical conditions is also highly relevant in T1DM ^[66]^[67]. The role of microbiota in T1DM and T2DM is highlighted by data showing the impact of the maternal endometrial and/or vaginal microbiomes of diabetic mothers, including in gestational diabetes mellitus, which can act through epigenetic mechanisms to increase T2DM—and possibly T1DM—risk in the offspring ^[67]. Such data highlight the importance of microbiota in the regulation of metabolism and the likelihood of prenatal priming of later T1DM related processes in pancreatic β-cells. This requires future investigation.

Recent data causal models the beneficial effects of human umbilical cord mesenchymal stem cell vesicles containing exenatide as being mediated not only directly in pancreatic β-cells but also via alterations in the gut microbiome/permeability ^[68]. The beneficial effects of Lactobacillus johnsonii strain N.6 nanovesicles in T1DM are proposed to be mediated via the upregulation of AhR ligands and AhR activation, with effects in both pancreatic β-cells as well as in macrophages, which are induced into a M2b-like phenotype ^[69]. A number of preclinical studies over the past decade have shown the beneficial effects of Lactobacillus johnsonii in delaying T1DM onset, which is proposed to be mediated by a number of processes, including suppression of Th17 cells, increasing intestinal crypt Paneth cell numbers, and suppressing gastro-intestinal caspase-1 induction ^[70]^[71]^[72], whilst also decreasing the kynurenine/tryptophan ratio, increasing cytotoxic CD8⁺ T cells, and changing the patterned immune response, as shown in healthy human volunteers ^[73]. Whether Lactobacillus johnsonii, and other bacteria, in the gut drive the induction of AhR ligands (such as indole-3-propionate) will be important to determine. Lactobacillus johnsonii also increases the short-chain fatty acids, butyrate, propionate, and acetate, indicating wider effects of gut microbiome-derived products, including butyrate’s epigenetic effects as a histone deacetylase (HDAC) inhibitor ^[74]. HDACi, via PKA upregulation and tryptophan hydroxylase (TPH)1 induction, derepresses serotonin production, thereby potentiating pancreatic β-cell function ^[75]. As butyrate optimizes mitochondrial function with effects that involve the upregulation of the melatonergic pathway, as shown in intestinal epithelial cells ^[76], alterations in the capacity to upregulate the melatonergic pathway in pancreatic β-cells will be important to determine. It clearly requires investigation as to the relevance of gut microbiome-derived butyrate, including as regulated by Lactobacillus johnsonii, in the pathoetiology of T1DM and the importance of a functional tryptophan–melatonin pathway in pancreatic β-cells. The full effects of butyrate require the capacity of a cell to upregulate the mitochondrial melatonergic pathway ^[76].

Importantly, the gut microbiome is comprised of not only bacteria, but also fungi and viruses, including enteroviruses and bacteriophages, with all these groupings showing changes at the initiation of pediatric T1DM ^[77]^[78]. Investigations on the gut microbiome in T1DM, versus controls, have focused on changes in gut bacteria, showing elevations in Prevotella copri and Eubacterium siraeum, with relative attenuation of Firmicutes bacterium and Faecalibacterium prausnitzii ^[79] in T1DM patients. Other studies have investigated a wider range of changes in the gut microbiome, indicating no significant differences in α-diversity between T1DM and controls ^[80]. However, these authors found T1DM patients to have 43 bacterial taxa significantly depleted and 37 bacterial taxa significantly enriched ^[80]. This study also found disease duration and glycated hemoglobin (HbA1c) to explain a significant part of the gut microbiome variation in T1DM, whilst neuropathy and macrovascular complications were significantly linked to variations in several microbial species ^[80]. However, as noted by the authors of these studies ^[79]^[80], and other studies ^[81], the mechanistic links to pancreatic β-cell loss and wider T1DM pathophysiology remain to be determined.

Limited data on bacteriophages in the pathoetiology of T1DM indicate that amyloid-producing Escherichia coli (E. coli), E. coli phages, and bacteria-derived amyloid may be involved in the early stages of T1DM pathoetiology, as indicated in data derived from children at high risk of T1DM ^[82]. This study and other data indicate that changes in the gut virome may precede the initial signs of T1DM, and therefore be of relevance to T1DM pathoetiology ^[83]. The causative relationship has still to be determined. However, such data may indicate that the gut virome may be more relevant to T1DM pathoetiology than gut bacteria, which tend to show diversity only after the emergence of T1DM. Enteroviruses are one of the major environmental triggers of childhood-onset T1DM, with recent data indicating that enteroviruses may also be an important trigger in adult-onset T1DM ^[84]. Overall, data indicate an interrelatedness of the gut microbiota, metaproteome, and virome that is relevant to T1DM onset, as investigated in young children, with a functional remodeling of the gut microbiota accompanying islet autoimmunity ^[77]. An initial bacteriophage or enterovirus impact on gut microbiome diversity seems followed by a decrease in butyrate-producing bacteria, with consequences for mitochondrial function systemically. As to whether the suppressed butyrate and/or other gut bacteria products are drivers of changes in pancreatic β-cells, either directly or indirectly suppressing the mitochondrial melatonergic pathway in pancreatic β-cells requires investigation.

Interestingly, Candida albicans fungi is elevated in T1DM, including at the time of initial presentation ^[85]. As Lactobacillus johnsonii can eliminate Candida albicans fungi from the gut ^[86], the clinical benefits of Lactobacillus johnsonii are likely to include alterations in the wider gut microbiome. However, it still requires clarification as to whether the gut is a primary site of change or whether the emergence of fungal infections is driven by a suppressed anti-fungal immune response ^[87], which may also involve alterations in the gut microbiome ^[67]. Two fatty acids produced by Lactobacillus johnsonii (and Bacteroides thetaiotaomicron), namely oleic acid and palmeic acid, mediate many of Lactobacillus johnsonii benefits, including within the gut and immune cells, indicating that gut microbiome-associated regulation of the immune response is a relevant aspect of T1DM pathoetiology ^[88]. Future research will have to clarify the relevance of Lactobacillus johnsonii specific effects in T1DM, including in interaction with Candida albicans fungal infection.

References

Ferrannini, E.; Mari, A.; Monaco, G.S.F.; Skyler, J.S.; Evans-Molina, C. The effect of age on longitudinal measures of beta cell function and insulin sensitivity during the progression of early stage type 1 diabetes. Diabetologia. 2023, 66, 508–519.
Zhang, Y.R.; Yang, L.; Wang, H.F.; Wu, B.S.; Huang, S.Y.; Cheng, W.; Feng, J.F.; Yu, J.T. Immune-mediated diseases are associated with a higher incidence of dementia: A prospective cohort study of 375,894 individuals. Alzheimers Res Ther. 2022, 14, 130.
Smolina, K.; Wotton, C.J.; Goldacre, M.J. Risk of dementia in patients hospitalised with type 1 and type 2 diabetes in England, 1998-2011: A retrospective national record linkage cohort study. Diabetologia 2015, 58, 942–950.
Cui, C.; Longinetti, E.; Larsson, H.; Andersson, J.; Pawitan, Y.; Piehl, F.; Fang, F. Associations between autoimmune diseases and amyotrophic lateral sclerosis: A register-based study. Amyotroph Lateral Scler Front. Degener. 2021, 22, 211–219.
Smidtslund, P.; Jansson Sigfrids, F.; Ylinen, A.; Elonen, N.; Harjutsalo, V.; Groop, P.H.; Thorn, L.M.; FinnDiane Study Group. Prognosis After First-Ever Myocardial Infarction in Type 1 Diabetes Is Strongly Affected by Chronic Kidney Disease. Diabetes Care 2023, 46, 197–205.
Sacchetta, L.; Chiriacò, M.; Nesti, L.; Leonetti, S.; Forotti, G.; Natali, A.; Solini, A.; Tricò, D. Synergistic effect of chronic kidney disease, neuropathy, and retinopathy on all-cause mortality in type 1 and type 2 diabetes: A 21-year longitudinal study. Cardiovasc Diabetol. 2022, 21, 233.
Anderson, G. Amyotrophic Lateral Sclerosis Pathoetiology and Pathophysiology: Roles of Astrocytes, Gut microbiome and muscle interactions via the Mitochondrial melatonergic pathway, with disruption by Glyphosate-based herbicides. Int. J. Mol. Sci. 2023, 24, 587.
Qian, B.; Zhang, K.; Li, Y.; Sun, K. Update on gut microbiota in cardiovascular diseases. Front. Cell. Infect. Microbiol. 2022, 12, 1059349.
Ismail, H.M.; Evans-Molina, C. Does the Gut Microbiome Play a Role in Obesity in Type 1 Diabetes? Unanswered Questions and Review of the Literature. Front. Cell. Infect. Microbiol. 2022, 12, 892291.
Haythorne, E.; Rohm, M.; van de Bunt, M.; Brereton, M.F.; Tarasov, A.I.; Blacker, T.S.; Sachse, G.; Silva Dos Santos, M.; Terron Exposito, R.; Davis, S.; et al. Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells. Nat Commun. 2019, 10, 2474.
Makam, A.A.; Biswas, A.; Kothegala, L.; Gandasi, N.R. Setting the Stage for Insulin Granule Dysfunction during Type-1-Diabetes: Is ER Stress the Culprit? Biomedicines 2022, 10, 2695.
Potter, K.J.; Scrocchi, L.A.; Warnock, G.L.; Ao, Z.; Younker, M.A.; Rosenberg, L.; Lipsett, M.; Verchere, C.B.; Fraser, P.E. Amyloid inhibitors enhance survival of cultured human islets. Biochim. Biophys. Acta 2009, 1790, 566–574.
Guillemain, G.; Lacapere, J.J.; Khemtemourian, L. Targeting hIAPP fibrillation: A new paradigm to prevent β-cell death? Biochim. Biophys. Acta Biomembr. 2022, 1864, 184002.
Khan, I.A.; Moretto, M. Nfkbid-mediated humoral immunity during secondary toxoplasmosis. Trends Parasitol. 2022, 38, 272–273.
Dwyer, J.R.; Racine, J.J.; Chapman, H.D.; Quinlan, A.; Presa, M.; Stafford, G.A.; Schmitz, I.; Serreze, D.V. Nfkbid Overexpression in Nonobese Diabetic Mice Elicits Complete Type 1 Diabetes Resistance in Part Associated with Enhanced Thymic Deletion of Pathogenic CD8 T Cells and Increased Numbers and Activity of Regulatory T Cells. J. Immunol. 2022, 209, 227–237.
Presa, M.; Racine, J.J.; Dwyer, J.R.; Lamont, D.J.; Ratiu, J.J.; Sarsani, V.K.; Chen, Y.G.; Geurts, A.; Schmitz, I.; Stearns, T.; et al. Hypermorphic Nfkbid Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8+ T Cells in NOD Mice. J. Immunol. 2018, 201, 1907–1917.
Kieleväinen, V.; Turtinen, M.; Luopajärvi, K.; Härkönen, T.; Ilonen, J.; Knip, M.; Finnish Pediatric Diabetes Register. Increased HLA class II risk is associated with a more aggressive presentation of clinical type 1 diabetes. Acta Paediatr. 2022.
Haghnazari, L.; Sabzi, R. Relationship between TP53 and interleukin-6 gene variants and the risk of types 1 and 2 diabetes mellitus development in the Kermanshah province. J. Med. Life 2021, 14, 37–44.
Guo, D.; Li, M.; Zhang, Y.; Yang, P.; Eckenrode, S.; Hopkins, D.; Zheng, W.; Purohit, S.; Podolsky, R.H.; Muir, A.; et al. A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nat. Genet. 2004, 36, 837–841.
Gui, Y.; Lei, X.; Huang, S. Collective effects of common single nucleotide polymorphisms and genetic risk prediction in type 1 diabetes. Clin. Genet. 2018, 93, 1069–1074.
Gootjes, C.; Zwaginga, J.J.; Roep, B.O.; Nikolic, T. Functional Impact of Risk Gene Variants on the Autoimmune Responses in Type 1 Diabetes. Front. Immunol. 2022, 13, 886736.
Pearson, G.; Chai, B.; Vozheiko, T.; Liu, X.; Kandarpa, M.; Piper, R.C.; Soleimanpour, S.A. Clec16a, Nrdp1, and USP8 Form a Ubiquitin-Dependent Tripartite Complex That Regulates β-Cell Mitophagy. Diabetes 2018, 67, 265–277.
Rutter, G.A.; Georgiadou, E.; Martinez-Sanchez, A.; Pullen, T.J. Metabolic and functional specialisations of the pancreatic beta cell: Gene disallowance, mitochondrial metabolism and intercellular connectivity. Diabetologia 2020, 63, 1990–1998.
Du, C.; Whiddett, R.O.; Buckle, I.; Chen, C.; Forbes, J.M.; Fotheringham, A.K. Advanced Glycation End Products and Inflammation in Type 1 Diabetes Development. Cells 2022, 11, 3503.
Dong, H.; Zhang, Y.; Huang, Y.; Deng, H. Pathophysiology of RAGE in inflammatory diseases. Front. Immunol. 2022, 13, 931473.
Abedini, A.; Derk, J.; Schmidt, A.M. The receptor for advanced glycation endproducts is a mediator of toxicity by IAPP and other proteotoxic aggregates: Establishing and exploiting common ground for novel amyloidosis therapies. Protein Sci. 2018, 27, 1166–1180.
Leung, S.S.; Borg, D.J.; McCarthy, D.A.; Boursalian, T.E.; Cracraft, J.; Zhuang, A.; Fotheringham, A.K.; Flemming, N.; Watkins, T.; Miles, J.J.; et al. Soluble RAGE Prevents Type 1 Diabetes Expanding Functional Regulatory T Cells. Diabetes 2022, 71, 1994–2008.
Ergenc, M.; Ozacmak, H.S.; Turan, I.; Ozacmak, V.H. Melatonin reverses depressive and anxiety like-behaviours induced by diabetes: Involvement of oxidative stress, age, rage and S100B levels in the hippocampus and prefrontal cortex of rats. Arch. Physiol. Biochem. 2022, 128, 402–410.
Yue, T.; Sun, F.; Yang, C.; Wang, F.; Luo, J.; Yang, P.; Xiong, F.; Zhang, S.; Yu, Q.; Wang, C.Y. The AHR Signaling Attenuates Autoimmune Responses During the Development of Type 1 Diabetes. Front. Immunol. 2020, 11, 1510.
Xu, Y.N.; Wang, Z.; Zhang, S.K.; Xu, J.R.; Pan, Z.X.; Wei, X.; Wen, H.H.; Luo, Y.S.; Guo, M.J.; Zhu, Q. Low-grade elevation of palmitate and lipopolysaccharide synergistically induced β-cell damage via inhibition of neutral ceramidase. Mol. Cell. Endocrinol. 2022, 539, 111473.
Martin, T.M.; Burke, S.J.; Batdorf, H.M.; Burk, D.H.; Ghosh, S.; Dupuy, S.D.; Karlstad, M.D.; Collier, J.J. ICAM-1 Abundance Is Increased in Pancreatic Islets of Hyperglycemic Female NOD Mice and Is Rapidly Upregulated by NF-κB in Pancreatic β-Cells. J. Immunol. 2022, ji2200065.
Liu, D.; Yang, K.Y.; Chan, V.W.; Ye, W.; Chong, C.C.N.; Wang, C.C.; Wang, H.; Zhou, B.; Cheng, K.K.Y.; Lui, K.O. YY1 Regulates Glucose Homeostasis Through Controlling Insulin Transcription in Pancreatic Beta Cells. Diabetes 2022, 71, db210695.
Jung, E.M.; Joo, S.S.; Yoo, Y.M. Nanomolar melatonin influences insulin synthesis and secretion in rat insulinoma INS-1E cells. J. Physiol. Pharmacol. 2020, 71, 705–716.
Lee, J.; Liu, R.; de Jesus, D.; Kim, B.S.; Ma, K.; Moulik, M.; Yechoor, V. Circadian control of β-cell function and stress responses. Diabetes Obes. Metab. 2015, 17 (Suppl. 1), 123–133.
Mousa, W.K.; Chehadeh, F.; Husband, S. Microbial dysbiosis in the gut drives systemic autoimmune diseases. Front. Immunol. 2022, 13, 906258.
Anderson, G. Depression Pathophysiology: Astrocyte Mitochondrial Melatonergic Pathway as Crucial Hub. Int. J. Mol. Sci. 2023, 24, 350.
Anderson, G.; Maes, M. Interactions of Tryptophan and Its Catabolites With Melatonin and the Alpha 7 Nicotinic Receptor in Central Nervous System and Psychiatric Disorders: Role of the Aryl Hydrocarbon Receptor and Direct Mitochondria Regulation. Int. J. Tryptophan. Res. 2017, 10, 1178646917691738.
Anderson, G. Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types-Tumour Microenvironment and Metabolism. Int. J. Mol. Sci. 2020, 22, 141.
Scott, S.A.; Fu, J.; Chang, P.V. Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. USA 2020, 117, 19376–19387.
Kim, Y.H.; Shim, Y.J.; Shin, Y.J.; Sul, D.; Lee, E.; Min, B.H. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces calcium influx through T-type calcium channel and enhances lysosomal exocytosis and insulin secretion in INS-1 cells. Int. J. Toxicol. 2009, 28, 151–161.
Mukhuty, A.; Fouzder, C.; Kundu, R. Blocking TLR4-NF-κB pathway protects mouse islets from the combinatorial impact of high fat and fetuin-A mediated dysfunction and restores ability for insulin secretion. Mol. Cell. Endocrinol. 2021, 532, 111314.
Cheng, X.; Huang, Y.; Yang, P.; Bu, L. miR-383 ameliorates high glucose-induced β-cells apoptosis and hyperglycemia in high-fat induced diabetic mice. Life Sci. 2020, 263, 118571.
Yan, S.; Jiang, Z.; Cheng, L.; Lin, Y.; Fan, B.; Luo, L.; Yan, Y.; Yang, L.; Shen, X. TLR4 knockout can improve dysfunction of β-cell by rebalancing proteomics disorders in pancreas of obese rats. Endocrine 2020, 67, 67–79.
Taskin, E.; Guven, C.; Kaya, S.T.; Sahin, L.; Kocahan, S.; Degirmencioglu, A.Z.; Gur, F.M.; Sevgiler, Y. The role of toll-like receptors in the protective effect of melatonin against doxorubicin-induced pancreatic beta cell toxicity. Life Sci. 2019, 233, 116704.
Zhou, L.; Song, X.D.; Xu, H.; Liang, G.Q.; Wang, F.; Zhang, L.R.; Huang, F.; Cai, J.; Jiang, G.R. Exogenous 3-Deoxyglucosone-Induced Carbonyl and Oxidative Stress Causes β-Cells Dysfunction by Impairing Gut Permeability in Rats. Biochemistry 2018, 83, 1358–1368.
Ghezzal, S.; Postal, B.G.; Quevrain, E.; Brot, L.; Seksik, P.; Leturque, A.; Thenet, S.; Carrière, V. Palmitic acid damages gut epithelium integrity and initiates inflammatory cytokine production. Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2020, 1865, 158530.
Khan, H.N.; Perlee, D.; Schoenmaker, L.; van der Meer, A.J.; Franitza, M.; Toliat, M.R.; Nürnberg, P.; Zwinderman, A.H.; van der Poll, T.; Scicluna, B.P. Leukocyte transcriptional signatures dependent on LPS dosage in human endotoxemia. J. Leukoc. Biol. 2019, 106, 1153–1160.
Wang, Y.; Chen, J.; Sang, T.; Chen, C.; Peng, H.; Lin, X.; Zhao, Q.; Chen, S.; Eling, T.; Wang, X. NAG-1/GDF15 protects against streptozotocin-induced type 1 diabetes by inhibiting apoptosis, preserving beta-cell function, and suppressing inflammation in pancreatic islets. Mol. Cell. Endocrinol. 2022, 549, 111643.
Darville, M.I.; Eizirik, D.L. Cytokine induction of Fas gene expression in insulin-producing cells requires the transcription factors NF-kappaB and C/EBP. Diabetes 2001, 50, 1741–1748.
Bernard, M.; Voisin, P. Photoreceptor-specific expression, light-dependent localization, and transcriptional targets of the zinc-finger protein Yin Yang 1 in the chicken retina. J. Neurochem. 2008, 105, 595–604.
Markus, R.P.; Fernandes, P.A.; Kinker, G.S.; da Silveira Cruz-Machado, S.; Marçola, M. Immune-pineal axis—Acute inflammatory responses coordinate melatonin synthesis by pinealocytes and phagocytes. Br. J. Pharmacol. 2018, 175, 3239–3250.
Lee, Y.H.; Jung, H.S.; Kwon, M.J.; Jang, J.E.; Kim, T.N.; Lee, S.H.; Kim, M.K.; Park, J.H. Melatonin protects INS-1 pancreatic β-cells from apoptosis and senescence induced by glucotoxicity and glucolipotoxicity. Islets 2020, 12, 87–98.
Tian, J.; Pan, W.; Xu, X.; Tian, X.; Zhang, M.; Hu, Q. NF-κB inhibits the occurrence of type 1 diabetes through microRNA-150-dependent PUMA degradation. Life Sci. 2020, 255, 117724.
Muxel, S.M.; Pires-Lapa, M.A.; Monteiro, A.W.; Cecon, E.; Tamura, E.K.; Floeter-Winter, L.M.; Markus, R.P. NF-κB drives the synthesis of melatonin in RAW 264.7 macrophages by inducing the transcription of the arylalkylamine-N-acetyltransferase (AA-NAT) gene. PLoS ONE 2012, 7, e52010.
do Carmo Buonfiglio, D.; Peliciari-Garcia, R.A.; do Amaral, F.G.; Peres, R.; Nogueira, T.C.; Afeche, S.C.; Cipolla-Neto, J. Early-stage retinal melatonin synthesis impairment in streptozotocin-induced diabetic wistar rats. Investig. Ophthalmol. Vis. Sci. 2011, 52, 7416–7422.
Uhlemeyer, C.; Müller, N.; Rieck, M.; Kuboth, J.; Schlegel, C.; Grieß, K.; Dorweiler, T.F.; Heiduschka, S.; Eckel, J.; Roden, M.; et al. Selective ablation of P53 in pancreatic beta cells fails to ameliorate glucose metabolism in genetic, dietary and pharmacological models of diabetes mellitus. Mol. Metab. 2022, 67, 101650.
Tao, S.; Yang, Y.; Fan, Y.; Chu, K.; Sun, J.; Wu, Q.; Wang, A.; Wan, J.; Tian, H. Melatonin protects against nonylphenol caused pancreatic β-cells damage through MDM2-P53-P21 axis. Toxicol. Res. 2022, 11, 391–401.
Ivanov, D.O.; Evsyukova, I.I.; Mazzoccoli, G.; Anderson, G.; Polyakova, V.O.; Kvetnoy, I.M.; Carbone, A.; Nasyrov, R.A. The Role of Prenatal Melatonin in the Regulation of Childhood Obesity. Biology 2020, 9, 72.
Rutters, F.; Nefs, G. Sleep and Circadian Rhythm Disturbances in Diabetes: A Narrative Review. Diabetes Metab. Syndr. Obes. 2022, 15, 3627–3637.
Hjortkjær, H.Ø.; Persson, F.; Theilade, S.; Winther, S.A.; Tofte, N.; Ahluwalia, T.S.; Rossing, P. Non-dipping and higher nocturnal blood pressure are associated with risk of mortality and development of kidney disease in type 1 diabetes. J. Diabetes Complicat. 2022, 36, 108270.
Chiriacò, M.; Sacchetta, L.; Forotti, G.; Leonetti, S.; Nesti, L.; Taddei, S.; Natali, A.; Solini, A.; Tricò, D. Prognostic value of 24-hour ambulatory blood pressure patterns in diabetes: A 21-year longitudinal study. Diabetes Obes. Metab. 2022, 24, 2127–2137.
Kulecki, M.; Naskret, D.; Kaminski, M.; Kasprzak, D.; Lachowski, P.; Klause, D.; Kozlowska, M.; Flotynska, J.; Uruska, A.; Zozulinska-Ziolkiewicz, D. Association between central non-dipping pattern and platelet morphology in adults with type 1 diabetes without cardiovascular disease: A cross-sectional study. Sci. Rep. 2021, 11, 15416.
Lee, J.S.; Lee, Y.J.; Lee, Y.A.; Shin, C.H. Effects of circadian blood pressure patterns on development of microvascular complications in pediatric patients with type 1 diabetes mellitus. Ann. Pediatr. Endocrinol. Metab. 2022, 27, 44–51.
Beam, C.A.; Beli, E.; Wasserfall, C.H.; Woerner, S.E.; Legge, M.T.; Evans-Molina, C.; McGrail, K.M.; Silk, R.; Grant, M.B.; Atkinson, M.A.; et al. Peripheral immune circadian variation, synchronisation and possible dysrhythmia in established type 1 diabetes. Diabetologia 2021, 64, 1822–1833.
Pallayova, M.; Breznoscakova, D. The altered circadian pattern of basal insulin Requirements—An early marker of autoimmune polyendocrine syndromes in type 1 diabetes mellitus. Endocr. Regul. 2020, 54, 126–132.
Anderson, G.; Seo, M.; Berk, M.; Carvalho, A.F.; Maes, M. Gut Permeability and Microbiota in Parkinson’s Disease: Role of Depression, Tryptophan Catabolites, Oxidative and Nitrosative Stress and Melatonergic Pathways. Curr. Pharm. Des. 2016, 22, 6142–6151.
Bankole, T.; Winn, H.; Li, Y. Dietary Impacts on Gestational Diabetes: Connection between Gut Microbiome and Epigenetic Mechanisms. Nutrients 2022, 14, 5269.
Wang, W.; Wang, Y.; Chi, J.; Tan, X.; Hu, J.; Ma, X.; Sun, X.; Che, K.; Lv, W.; Wang, Y. hUCMSCs carrying exenatide prevent T1DM by improving intestinal microflora composition and islet tissue damage repair. Mol. Med. 2022, 28, 155.
Teixeira, L.D.; Harrison, N.A.; da Silva, D.R.; Mathews, C.E.; Gonzalez, C.F.; Lorca, G.L. Nanovesicles From Lactobacillus johnsonii N6.2 Reduce Apoptosis in Human Beta Cells by Promoting AHR Translocation and IL10 Secretion. Front. Immunol. 2022, 13, 899413.
Teixeira, L.D.; Kling, D.N.; Lorca, G.L.; Gonzalez, C.F. Lactobacillus johnsonii N6.2 diminishes caspase-1 maturation in the gastrointestinal system of diabetes prone rats. Benef. Microbes 2018, 9, 527–539.
Kingma, S.D.; Li, N.; Sun, F.; Valladares, R.B.; Neu, J.; Lorca, G.L. Lactobacillus johnsonii N6.2 stimulates the innate immune response through Toll-like receptor 9 in Caco-2 cells and increases intestinal crypt Paneth cell number in biobreeding diabetes-prone rats. J. Nutr. 2011, 141, 1023–1028.
Lau, K.; Benitez, P.; Ardissone, A.; Wilson, T.D.; Collins, E.L.; Lorca, G.; Li, N.; Sankar, D.; Wasserfall, C.; Neu, J.; et al. Inhibition of type 1 diabetes correlated to a Lactobacillus johnsonii N6.2-mediated Th17 bias. J. Immunol. 2011, 186, 3538–3546.
Marcial, G.E.; Ford, A.L.; Haller, M.J.; Gezan, S.A.; Harrison, N.A.; Cai, D.; Meyer, J.L.; Perry, D.J.; Atkinson, M.A.; Wasserfall, C.H.; et al. Lactobacillus johnsonii N6.2 Modulates the Host Immune Responses: A Double-Blind, Randomized Trial in Healthy Adults. Front. Immunol. 2017, 8, 655.
He, T.; Zhu, Y.H.; Yu, J.; Xia, B.; Liu, X.; Yang, G.Y.; Su, J.H.; Guo, L.; Wang, M.L.; Wang, J.F. Lactobacillus johnsonii L531 reduces pathogen load and helps maintain short-chain fatty acid levels in the intestines of pigs challenged with Salmonella enterica Infantis. Vet. Microbiol. 2019, 230, 187–194.
Zhang, Y.; Wang, S.; Zhang, L.; Zhou, F.; Zhu, K.; Zhu, Q.; Liu, Q.; Liu, Y.; Jiang, L.; Ning, G.; et al. Protein acetylation derepresses Serotonin Synthesis to potentiate Pancreatic Beta-Cell Function through HDAC1-PKA-Tph1 signaling. Theranostics 2020, 10, 7351–7368.
Jin, C.J.; Engstler, A.J.; Sellmann, C.; Ziegenhardt, D.; Landmann, M.; Kanuri, G.; Lounis, H.; Schröder, M.; Vetter, W.; Bergheim, I. Sodium butyrate protects mice from the development of the early signs of non-alcoholic fatty liver disease: Role of melatonin and lipid peroxidation. Br. J. Nutr. 2016, 116, 1682–1693.
Gavin, P.G.; Kim, K.W.; Craig, M.E.; Hill, M.M.; Hamilton-Williams, E.E. Multi-omic interactions in the gut of children at the onset of islet autoimmunity. Microbiome 2022, 10, 230.
Zhao, G.; Vatanen, T.; Droit, L.; Park, A.; Kostic, A.D.; Poon, T.W.; Vlamakis, H.; Siljander, H.; Härkönen, T.; Hämäläinen, A.M.; et al. Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children. Proc. Natl. Acad. Sci. USA 2017, 114, E6166–E6175.
Shilo, S.; Godneva, A.; Rachmiel, M.; Korem, T.; Bussi, Y.; Kolobkov, D.; Karady, T.; Bar, N.; Wolf, B.C.; Glantz-Gashai, Y.; et al. The Gut Microbiome of Adults With Type 1 Diabetes and Its Association With the Host Glycemic Control. Diabetes Care 2022, 45, 555–563.
van Heck, J.I.P.; Gacesa, R.; Stienstra, R.; Fu, J.; Zhernakova, A.; Harmsen, H.J.M.; Weersma, R.K.; Joosten, L.A.B.; Tack, C.J. The Gut Microbiome Composition Is Altered in Long-standing Type 1 Diabetes and Associates With Glycemic Control and Disease-Related Complications. Diabetes Care 2022, 45, 2084–2094.
Zheng, P.; Li, Z.; Zhou, Z. Gut microbiome in type 1 diabetes: A comprehensive review. Diabetes Metab. Res. Rev. 2018, 34, e3043.
Tetz, G.; Brown, S.M.; Hao, Y.; Tetz, V. Type 1 Diabetes: An Association Between Autoimmunity, the Dynamics of Gut Amyloid-producing E. coli and Their Phages. Sci. Rep. 2019, 9, 9685.
Park, A.; Zhao, G. Mining the Virome for Insights into Type 1 Diabetes. DNA Cell Biol. 2018, 37, 422–425.
Alnek, K.; Talja, I.; Laht, B.; Metsküla, K.; Mandel, M.; Reppo, I.; Lubi, M.; Uibo, R. IgA-Type Enterovirus Antibodies Are Increased among Adults and Children with Recently Diagnosed Type 1 Diabetes. BioMed Res. Int. 2022, 2022, 7603062.
Gürsoy, S.; Koçkar, T.; Atik, S.U.; Önal, Z.; Önal, H.; Adal, E. Autoimmunity and intestinal colonization by Candida albicans in patients with type 1 diabetes at the time of the diagnosis. Korean J. Pediatr. 2018, 61, 217–220.
Vazquez-Munoz, R.; Thompson, A.; Russell, J.T.; Sobue, T.; Zhou, Y.; Dongari-Bagtzoglou, A. Insights From the Lactobacillus johnsonii Genome Suggest the Production of Metabolites With Antibiofilm Activity Against the Pathobiont Candida albicans. Front. Microbiol. 2022, 13, 853762.
Janssen, A.W.M.; Stienstra, R.; Jaeger, M.; van Gool, A.J.; Joosten, L.A.B.; Netea, M.G.; Riksen, N.P.; Tack, C.J. Understanding the increased risk of infections in diabetes: Innate and adaptive immune responses in type 1 diabetes. Metabolism 2021, 121, 154795.
Charlet, R.; Le Danvic, C.; Sendid, B.; Nagnan-Le Meillour, P.; Jawhara, S. Oleic Acid and Palmitic Acid from Bacteroides thetaiotaomicron and Lactobacillus johnsonii Exhibit Anti-Inflammatory and Antifungal Properties. Microorganisms 2022, 10, 1803.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Integrative & Complementary Medicine

Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

George Anderson

View Times: 264

Update Date: 15 Feb 2023

Table of Contents

Video Upload Options

Confirm

1. Introduction

2. Classical Type 1 Diabetes Mellitus Pathoetiology

3. Wider T1DM Pathophysiology

References