Genetics of diabetes mellitus and diabetes complications

Nature Reviews Nephrology, Journal Year: 2020, Volume and Issue: 16(7), P. 377 - 390

Published: May 12, 2020

Language: Английский

---

Molecular mechanisms and therapeutic targets for diabetic kidney disease

Kidney International, Journal Year: 2022, Volume and Issue: 102(2), P. 248 - 260

Published: June 3, 2022

Diabetic kidney disease has a high global burden and substantially increases the risk of failure cardiovascular events. Despite treatment, there is substantial residual progression with existing therapies. Therefore, an urgent need to better understand molecular mechanisms driving diabetic help identify new therapies that slow reduce associated risks. initiated by diabetes-related disturbances in glucose metabolism, which then trigger other metabolic, hemodynamic, inflammatory, fibrotic processes contribute progression. This review summarizes evidence on drivers onset progression, focusing inflammatory mediators—factors are largely unaddressed as primary treatment targets for increasing supporting key roles pathophysiology disease. Results from recent clinical trials highlight promising drug therapies, well role dietary strategies, treating Chronic (CKD), characterized albuminuria, low estimated glomerular filtration rate (eGFR), or both,1GBD Kidney Disease CollaborationGlobal, regional, national chronic disease, 1990-2017: systematic analysis Global Burden Study 2017.Lancet. 2020; 395: 709-733Abstract Full Text PDF PubMed Scopus (1156) Google Scholar affect over 840 million people worldwide.2Jager K.J. Kovesdy C. Langham R. et al.A single number advocacy communication-worldwide more than 850 individuals have diseases.Kidney Int. 2019; 96: 1048-1050Abstract (DKD), damage due diabetes, leading attributable cause CKD, occurring approximately 40% type 2 diabetes (T2D) 30% those 1 (T1D).1GBD Scholar,3Alicic R.Z. Rooney M.T. Tuttle K.R. disease: challenges, progress, possibilities.Clin J Am Soc Nephrol. 2017; 12: 2032-2045Crossref (753) The DKD expected increase parallel rise prevalence,3Alicic projected nearly 50%, 537 783 people, next 24 years.4International Diabetes FederationIDF Atlas.10th ed. International Federation, 2021Google improve diagnosis management DKD, including target related (CV) risk.1GBD Mechanisms can be broadly classified fibrotic.3Alicic Scholar,5Pérez-Morales R.E. Del Pino M.D. Valdivielso J.M. al.Inflammation disease.Nephron. 143: 12-16Crossref (57) Scholar,6Mora-Fernández Domínguez-Pimentel V. de Fuentes M.M. al.Diabetic physiology therapeutics.J Physiol. 2014; 592: 3997-4012Crossref (99) In this review, current understanding drive pathogenesis presented basis advancing therapeutic interventions. Hyperglycemia induces hyperfiltration hypertension, hemodynamic long been recognized initiate propagate diabetes.3Alicic Glomerular exacerbated levels amino acids, example, after protein overfeeding, hormonal changes poor glycemic control, level glucagon.7Rhee C.M. Kalantar-Zadeh K. Novel approaches hypoglycemia burnt-out disease.Curr Opin Nephrol Hypertens. 2022; 31: 72-81Crossref (0) Scholar, 8Tuttle Bruton J.L. Effect insulin therapy renal response acids hypertrophy non-insulin-dependent diabetes.Kidney 1992; 42: 167-173Abstract 9Tuttle Perusek M.C. al.Effect strict control enlargement insulin-dependent mellitus.N Engl Med. 1991; 324: 1626-1632Crossref (142) 10Tuttle Puhlman M.E. Cooney S.K. Short R.A. Effects glucagon hemodynamics diabetes.Am Physiol Renal 2002; 282: F103-F112Crossref These circulating mediators primarily act perfusion through afferent arteriole dilation.3Alicic Scholar,8Tuttle addition, activation renin angiotensin system local hyperfiltration. Angiotensin II production within constricts efferent arteriole, thereby, contributes higher pressure. stimulates expression proinflammatory profibrotic via barotrauma also direct cellular effects.3Alicic Scholar,10Tuttle sodium-glucose cotransporter-2 (SGLT2) now another important modulator hemodynamics. It expressed luminal surface epithelial cells proximal convoluted tubule responsible 90% filtered reabsorption.11Alicic Neumiller J.J. Johnson E.J. al.Sodium-glucose cotransporter inhibition disease.Diabetes. 68: 248-257Crossref (55) Scholar,12Vallon Gerasimova M. Rose M.A. al.SGLT2 inhibitor empagliflozin reduces growth albuminuria proportion hyperglycemia prevents Akita mice.Am 306: F194-F204Crossref (318) hyperglycemic conditions, SGLT2 activity adaptation reclaim urine, but maladaptive consequence worsening hyperglycemia.11Alicic Scholar,13Heerspink H.J. Perkins B.A. Fitchett D.H. al.Sodium inhibitors mellitus: effects, potential mechanisms, applications.Circulation. 2016; 134: 752-772Crossref Therapeutically, lowers blood decreasing reabsorption at resulting glucosuria.13Heerspink restore tubuloglomerular feedback distal delivery sodium chloride macula densa, where solute generates adenosine by-product triphosphate utilization. Adenosine acts paracrine manner enhance arteriolar vasoconstriction, suppress release juxtaglomerular cells, perhaps constriction.11Alicic Scholar,14Kidokoro Cherney D.Z.I. Bozovic A. al.Evaluation function mice using vivo imaging.Circulation. 140: 303-315Crossref (124) 15Ortiz-Capisano Atchison D.K. Harding P. al.Adenosine inhibits A1 receptor-TRPC-mediated pathway.Am 2013; 305: F1209-F1219Crossref 16Heerspink H.J.L. Perco Mulder S. al.Canagliflozin inflammation fibrosis biomarkers: mechanism action beneficial effects disease.Diabetologia. 62: 1154-1166Crossref (145) 17Vallon Thomson S.C. tubular hypothesis nephron disease.Nat Rev 16: 317-336Crossref (102) relative balance between constriction may vary age. physiological studies humans normal GFR, younger T1D demonstrated constriction, whereas older T2D had dilation.18van Bommel E.J.M. Lytvyn Y. al.Renal hyperfiltering function.Kidney 97: 631-635Abstract (17) Irrespective precise vasoregulatory whole, restoration hypertension and, hyperfiltration.14Kidokoro Scholar,18van prompts series intracellular promote (Figure 1).3Alicic Scholar,19Zhao L. Zou Liu F. Transforming factor-beta1 disease.Front Cell Dev Biol. 8: 187Crossref (34) Scholar,20Reidy Kang H.M. Hostetter T. Susztak Molecular disease.J Clin Invest. 124: 2333-2340Crossref (448) Altered metabolism advanced glycation end products (AGEs), reactive oxygen species, kinase C Janus (JAK)-signal transducer activator transcription (STAT) pathways.20Reidy Podocytes exposed AGE nuclear factor κB–associated upregulation messenger RNA variety much 25-fold.21Pichler Afkarian Dieter B.P. Immunity translating biomarkers targets.Am 312: F716-F731Crossref (108) Scholar,22Anderberg R.J. Meek R.L. Hudkins K.L. al.Serum amyloid A podocytes.Lab 2015; 95: 250-262Crossref podocytes endothelial AGEs bind receptor (RAGE), produce nucleotide-binding oligomerization domain–like pyrin domain containing 3 inflammasome.21Pichler Scholar,23Shahzad Bock Dong W. al.Nlrp3-inflammasome non-myeloid-derived aggravates nephropathy.Kidney 87: 74-84Abstract (234) Scholar,24Sakai N. Wada Revisiting nephropathy: Nlrp3 inflammasome resident cells.Kidney 12-14Abstract Together, κB induce interleukins (IL), IL-1β IL-18, respectively.24Sakai Moreover, serum A, RAGE activator, perpetuates feed-forward cycle gene 1).21Pichler signals lead ongoing mediators, factors, immune cell recruitment.19Zhao Scholar,21Pichler Notably, newer glucose-lowering agents, glucagon-like peptide-1 agonists (GLP-1 RAs), prevent CKD T2D, independent their effects.25Neuen B.L. Young Heerspink prevention patients diabetes: meta-analysis.Lancet Endocrinol. 7: 845-854Abstract (339) 26Cannon C.P. Perkovic Agarwal al.Evaluating canagliflozin events mellitus according baseline HbA1c, HbA1c <7%: CREDENCE trial.Circulation. 141: 407-410Crossref (65) 27Mann J.F.E. Buse J.B. Idorn al.Potential protection liraglutide semaglutide: Exploratory mediation analysis.Diabetes Obes Metab. 2021; 23: 2058-2066Crossref (3) 28Tuttle Lakshmanan Rayner B. al.Dulaglutide versus glargine moderate-to-severe (AWARD-7): multicentre, open-label, randomised trial.Lancet 2018; 6: 605-617Abstract (233) 29Kang Jardine M.J. offer benefit beyond diabetes.Nat 17: 83-84Crossref (12) By ameliorating glucotoxicity influx into potent anti-inflammatory effects. preclinical models suppresses hyperglycemia-induced species generation formation attenuates surrounding tubulointerstitial fibrosis.11Alicic Scholar,30Ojima Matsui Nishino al.Empagliflozin, exerts antifibrotic experimental nephropathy partly suppressing AGEs-receptor axis.Horm Metab Res. 47: 686-692Crossref Scholar,31Eleftheriadis Pissas G. Tsogka unifying model human effect dapagliflozin.Int Urol 52: 1179-1189Crossref GLP-1 RAs downregulate pathways nonpancreatic organs.32Alicic Cox Incretin drugs biological evidence.Nat 227-244Crossref (27) rodent RA decreased oxidative stress, transforming factor-beta (TGF-β1), intercellular adhesion molecule-1, tumor necrosis factor-α, IL-1β, macrophages kidney.32Alicic stress nicotinamide adenine dinucleotide phosphatase oxidase cyclic monophosphate–dependent heme oxygenase-1.33Kawanami D. Takashi outcomes mechanisms.Front Pharmacol. 11: 967Crossref (22) Scholar,34Yang H. Li Wang Z. al.Exendin-4 ameliorates ischemia-reperfusion injury rat.J Surg 182: 825-832Abstract (25) Inhibition signaling proposed suppression cytokine chemokine expression.32Alicic exposure occur diet hyperglycemia.20Reidy Scholar,35Uribarri J. Woodruff Goodman al.Advanced foods practical guide reduction diet.J Diet Assoc. 2010; 110: 911-916.e912Abstract (746) Dietary escape gastrointestinal absorption interact colonic microbiota,36Yacoub Nugent Cai restriction bacterial gut microbiota peritoneal dialysis patients; randomized open label controlled trial.PLoS One. 12e0184789Crossref (63) Scholar,37Snelson Coughlan products: digestion, modulation microbial ecology.Nutrients. 22: 215Crossref (82) triggering mediators.38Garay-Sevilla Beeri M.S. la Maza M.P. al.The endproducts development non-infectious diseases: narrative review.Nutr Res Rev. 33: 298-311Crossref (6) Activation RAGE-dependent causes mucosal barrier dysfunction translocation systemic circulation.39Raman K.G. Sappington P.L. Yang intestinal hemorrhagic shock.Am Gastrointest Liver 2006; 291: G556-G565Crossref Scholar,40Snelson Tan S.M. Clarke al.Processed permeability microvascular diseases.Sci Adv. 7eabe4841Crossref As progresses, greater amounts ammonia urea shift toward Gram-negative bacteria gut. Lipopolysaccharides walls toll-like receptor-4 production, recruitment lipopolysaccharides.41Zhang Meng microbiome mellitus.Diabetes Pract. 172: 108645Abstract Scholar,42Ramezani Raj D.S. microbiome, targeted interventions.J 25: 657-670Crossref (397) Exposure podocytes, these lipopolysaccharides injury, inflammation, fibrosis.43Ma Chadban S.J. Zhao C.Y. al.TLR4 promotes podocyte interstitial nephropathy.PLoS 9: e97985Crossref Diabetes-associated protective short-chain fatty disruption.41Zhang Scholar,44Mosterd Kanbay van den Born al.Intestinal derived metabolites inmodulation progression.Best Pract Endocrinol 35: 101484Crossref 45Reichardt Duncan S.H. al.Phylogenetic distribution three propionate microbiota.ISME 1323-1335Crossref (530) 46Diener Reyes-Escogido M.L. Jimenez-Ceja L.M. al.Progressive shifts reflect prediabetes treatment-naive Mexican cohort.Front (Lausanne). 602326Crossref (2) Complex especially essentially "diseases diseases," such present major challenges deciphering reproducible genetic contributions susceptibility severity.47Cole Florez J.C. Genetics complications.Nat 377-390Crossref (163) Advances acquiring large datasets genome-wide association yielded insights shed light predisposition DKD. Missense mutations COL4A3 gene, encodes structural component basement membrane (GBM), known Alport syndrome.48Salem R.M. Todd J.N. Sandholm al.Genome-wide study highlights biology involved collagen.J 30: 2000-2016Crossref Recently, variant (rs55703767) linked "diabetic nephropathy" T1D, suggesting disordered collagen expression.48Salem was most evident glycated hemoglobin. less GBM thickening glomerulosclerosis among either who biopsy data. Thus, "second-hit" phenomenon operative consequences hyperglycemia, damage. Variants genes (DDR1, COLEC11, BMP7) various phenotypes.48Salem contrast variants, APOL-l G1/G2 alleles observed African ancestry nondiabetic often when accompanied "second hit," viral illness interferon state.49Friedman D.J. Pollak M.R. APOL1 genetics applications.Clin 294-303Crossref (11) Another APOL-1 (rs9622363) recently reported meta-analysis American it progression.50Guan Keaton Dimitrov identifies novel loci diabetes-attributed end-stage Americans.Hum Genomics. 13: 21Crossref Among European cohort GABRR1 (rs9942471) highly microalbuminuria.51van Zuydam N.R. Ahlqvist E. subjects diab

Language: Английский

---

The tubular hypothesis of nephron filtration and diabetic kidney disease

Nature Reviews Nephrology, Journal Year: 2020, Volume and Issue: 16(6), P. 317 - 336

Published: March 9, 2020

Language: Английский

---

Molecular pathways that drive diabetic kidney disease

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(4)

Published: Feb. 14, 2023

Kidney disease is a major driver of mortality among patients with diabetes and diabetic kidney (DKD) responsible for close to half all chronic cases. DKD usually develops in genetically susceptible individual as result poor metabolic (glycemic) control. Molecular genetic studies indicate the key role podocytes endothelial cells driving albuminuria early diabetes. Proximal tubule changes show strong association glomerular filtration rate. Hyperglycemia represents cellular stress by altering metabolism imposing an excess workload requiring energy oxygen proximal cells. Changes induce adaptive hypertrophy reorganization actin cytoskeleton. Later, mitochondrial defects contribute increased oxidative activation inflammatory pathways, causing progressive function decline fibrosis. Blockade renin-angiotensin system or sodium-glucose cotransporter associated protection slowing decline. Newly identified molecular pathways could provide basis development much-needed novel therapeutics.

Language: Английский

---

Complexities of the glomerular basement membrane

Nature Reviews Nephrology, Journal Year: 2020, Volume and Issue: 17(2), P. 112 - 127

Published: Aug. 24, 2020

Language: Английский

---

The glomerular filtration barrier: a structural target for novel kidney therapies

Nature Reviews Drug Discovery, Journal Year: 2021, Volume and Issue: 20(10), P. 770 - 788

Published: July 14, 2021

Language: Английский

---

Genetics in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Kidney International, Journal Year: 2022, Volume and Issue: 101(6), P. 1126 - 1141

Published: April 21, 2022

Numerous genes for monogenic kidney diseases with classical patterns of inheritance, as well complex that manifest in combination environmental factors, have been discovered. Genetic findings are increasingly used to inform clinical management nephropathies, and led improved diagnostics, disease surveillance, choice therapy, family counseling. All these steps rely on accurate interpretation genetic data, which can be outpaced by current rates data collection. In March 2021, Kidney Diseases: Improving Global Outcomes (KDIGO) held a Controversies Conference "Genetics Chronic Disease (CKD)" review the state understanding (polygenic) diseases, processes applying medicine, use genomics defining stratifying CKD. Given important contribution variants CKD, practitioners CKD patients advised "think genetic," specifically involves obtaining history, collecting detailed information age onset, performing examination extrarenal symptoms, considering testing. To improve genetics nephrology, meeting participants developing an advanced training or subspecialty track nephrologists, crafting guidelines testing treatment, educating patients, students, practitioners. Key areas future research, including genome variation, electronic phenotyping, global representation, kidney-specific molecular polygenic scores, translational epidemiology, open resources, were also identified.

Language: Английский

---

The Type 2 Diabetes Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(4), P. 695 - 710.e6

Published: March 23, 2023

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories these data seek to be disease-agnostic therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is public resource datasets genomic annotations dedicated type diabetes (T2D) related traits. Here, we make the T2DKP more accessible prospective users useful existing users. First, evaluate T2DKP's comprehensiveness by comparing its with those other repositories. Second, describe how researchers unfamiliar can begin using correctly interpreting them via T2DKP. Third, extend their current workflows use full suite tools offered We finally discuss lessons toward goal democratizing access complex disease results.

Language: Английский

---

Protective Factors and the Pathogenesis of Complications in Diabetes

Endocrine Reviews, Journal Year: 2023, Volume and Issue: 45(2), P. 227 - 252

Published: Aug. 25, 2023

Chronic complications of diabetes are due to myriad disorders numerous metabolic pathways that responsible for most the morbidity and mortality associated with disease. Traditionally, divided into those microvascular macrovascular origin. We suggest revising this antiquated classification vascular, parenchymal, hybrid (both vascular parenchymal) tissue origin, since profile ranges from involving only tissues mostly parenchymal organs. A major paradigm shift has occurred in recent years regarding pathogenesis complications, which focus shifted studies on risks interplay between risk protective factors. While factors clearly important development chronic diabetes, have established equally significant modulating severity complications. These responses may help explain differential even lack pathologies, some tissues. Nevertheless, despite growing number field, comprehensive reviews their mechanisms action not available. This review thus focused clinical, biochemical, molecular support idea endogenous factors, roles initiation progression diabetes. In addition, also aimed identify main needs field future studies.

Language: Английский

---

Diabetes mellitus—Progress and opportunities in the evolving epidemic

Cell, Journal Year: 2024, Volume and Issue: 187(15), P. 3789 - 3820

Published: July 1, 2024

Language: Английский

---