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1.
Eur J Endocrinol ; 185(6): 831-840, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34636745

RESUMO

Objective: To identify determinants associated with insulin resistance and to assess the association between insulin resistance and cardiovascular events, vascular interventions and mortality in people with type 1 diabetes at high risk of cardiovascular disease. Design: Prospective cohort study. Methods: One hundred and ninety-five people with type 1 diabetes from the Secondary Manifestations of ARTerial disease (SMART) cohort were included. Insulin resistance was quantified by the estimated glucose disposal rate (eGDR) with higher eGDR levels indicating higher insulin sensitivity (i.e. lower eGDR levels indicating higher insulin resistance). Linear regression models were used to evaluate determinants associated with eGDR. The effect of eGDR on cardiovascular events, cardiovascular events or vascular interventions (combined endpoint) and on all-cause mortality was analysed using Cox proportional hazards models adjusted for confounders. Results: In 195 individuals (median follow-up 12.9 years, IQR 6.7-17.0), a total of 25 cardiovascular events, 26 vascular interventions and 27 deaths were observed. High eGDR as a marker for preserved insulin sensitivity was independently associated with a lower risk of cardiovascular events (HR: 0.75; 95% CI: 0.61-0.91), a lower risk of cardiovascular events and vascular interventions (HR: 0.74; 95% CI: 0.63-0.87) and a lower risk of all-cause mortality (HR: 0.81; 95% CI: 0.67-0.98). Conclusions: Insulin resistance as measured by eGDR is an additional risk factor for cardiovascular disease in individuals with type 1 diabetes. Modification of insulin resistance by lifestyle interventions or pharmacological treatment could be a viable therapeutic target to lower the risk of cardiovascular disease.


Assuntos
Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 1/metabolismo , Resistência à Insulina , Infarto do Miocárdio/epidemiologia , Revascularização Miocárdica/estatística & dados numéricos , Acidente Vascular Cerebral/epidemiologia , Hemorragia Subaracnóidea/epidemiologia , Adulto , Amputação/estatística & dados numéricos , Aneurisma da Aorta Abdominal/mortalidade , Ruptura Aórtica/mortalidade , Doenças Cardiovasculares/epidemiologia , Causas de Morte , Estudos de Coortes , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Insuficiência Cardíaca/mortalidade , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Mortalidade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Procedimentos Cirúrgicos Vasculares/estatística & dados numéricos , Adulto Jovem
2.
Int J Mol Sci ; 22(17)2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34502413

RESUMO

Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon's secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans' islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (ß) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to ß cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy.


Assuntos
Comunicação Autócrina , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Glucagon/metabolismo , Células Secretoras de Insulina/metabolismo , Comunicação Parácrina , Animais , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/antagonistas & inibidores , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células Secretoras de Glucagon/patologia , Humanos , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/patologia
3.
Int J Mol Sci ; 22(17)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34502562

RESUMO

Diabetic kidney disease (DKD) is a progressive disorder, which is increasing globally in prevalence due to the increased incidence of obesity and diabetes mellitus. Despite optimal clinical management, a significant number of patients with diabetes develop DKD. Hence, hitherto unrecognized factors are likely to be involved in the initiation and progression of DKD. An extensive number of studies have demonstrated the role of microbiota in health and disease. Dysregulation in the microbiota resulting in a deficiency of short chain fatty acids (SCFAs) such as propionate, acetate, and butyrate, by-products of healthy gut microbiota metabolism, have been demonstrated in obesity, type 1 and type 2 diabetes. However, it is not clear to date whether such changes in the microbiota are causative or merely associated with the diseases. It is also not clear which microbiota have protective effects on humans. Few studies have investigated the centrality of reduced SCFA in DKD development and progression or the potential therapeutic effects of supplemental SCFAs on insulin resistance, inflammation, and metabolic changes. SCFA receptors are expressed in the kidneys, and emerging data have demonstrated that intestinal dysbiosis activates the renal renin-angiotensin system, which contributes to the development of DKD. In this review, we will summarize the complex relationship between the gut microbiota and the kidney, examine the evidence for the role of gut dysbiosis in diabetes and obesity-related kidney disease, and explore the mechanisms involved. In addition, we will describe the role of potential therapies that modulate the gut microbiota to prevent or reduce kidney disease progression.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , Disbiose/metabolismo , Microbioma Gastrointestinal/fisiologia , Obesidade/metabolismo , Animais , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/fisiopatologia , Ácidos Graxos Voláteis/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Obesidade/fisiopatologia
4.
Am J Physiol Heart Circ Physiol ; 321(4): H751-H755, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34533402

RESUMO

Lack of glucose uptake compromises metabolic flexibility and reduces energy efficiency in the diabetes mellitus (DM) heart. Although increased use of fatty acid to compensate glucose substrate has been studied, less is known about ketone body metabolism in the DM heart. Ketogenic diet reduces obesity, a risk factor for T2DM. How ketogenic diet affects ketone metabolism in the DM heart remains unclear. At the metabolic level, the DM heart differs from the non-DM heart because of altered metabolic substrate and the T1DM heart differs from the T2DM heart because of insulin levels. How these changes affect ketone body metabolism in the DM heart are poorly understood. Ketogenesis produces ketone bodies by using acetyl-CoA, whereas ketolysis consumes ketone bodies to produce acetyl-CoA, showing their opposite roles in the ketone body metabolism. Cardiac-specific transgenic upregulation of ketogenesis enzyme or knockout of ketolysis enzyme causes metabolic abnormalities leading to cardiac dysfunction. Empirical evidence demonstrates upregulated transcription of ketogenesis enzymes, no change in the levels of ketone body transporters, very high levels of ketone bodies, and reduced expression and activity of ketolysis enzymes in the T1DM heart. Based on these observations, I hypothesize that increased transcription and activity of cardiac ketogenesis enzyme suppresses ketolysis enzyme in the DM heart, which decreases cardiac energy efficiency. The T1DM heart exhibits highly upregulated ketogenesis compared with the T2DM heart because of the lack of insulin, which inhibits ketogenesis enzyme.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Cardiomiopatias Diabéticas/etiologia , Metabolismo Energético , Insulina/metabolismo , Corpos Cetônicos/metabolismo , Miocárdio/metabolismo , Animais , Coenzima A-Transferases/genética , Coenzima A-Transferases/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Cetoacidose Diabética/etiologia , Cetoacidose Diabética/metabolismo , Dieta Cetogênica , Feminino , Humanos , Hidroximetilglutaril-CoA Sintase/genética , Hidroximetilglutaril-CoA Sintase/metabolismo , Masculino
5.
Elife ; 102021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34515636

RESUMO

Laboratory HbA1c does not always predict diabetes complications and our aim was to establish a glycaemic measure that better reflects intracellular glucose exposure in organs susceptible to complications. Six months of continuous glucose monitoring data and concurrent laboratory HbA1c were evaluated from 51 type 1 diabetes (T1D) and 80 type 2 diabetes (T2D) patients. Red blood cell (RBC) lifespan was estimated using a kinetic model of glucose and HbA1c, allowing the calculation of person-specific adjusted HbA1c (aHbA1c). Median (IQR) RBC lifespan was 100 (86-102) and 100 (83-101) days in T1D and T2D, respectively. The median (IQR) absolute difference between aHbA1c and laboratory HbA1c was 3.9 (3.0-14.3) mmol/mol [0.4 (0.3-1.3%)] in T1D and 5.3 (4.1-22.5) mmol/mol [0.5 (0.4-2.0%)] in T2D. aHbA1c and laboratory HbA1c showed clinically relevant differences. This suggests that the widely used measurement of HbA1c can underestimate or overestimate diabetes complication risks, which may have future clinical implications.


Assuntos
Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Eritrócitos/fisiologia , Hemoglobina A Glicada/química , Hemoglobina A Glicada/provisão & distribuição , Adulto , Idoso , Glicemia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Pessoa de Meia-Idade
6.
Arch Biochem Biophys ; 710: 109000, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34343486

RESUMO

Impaired endothelium-mediated vasodilation and/or increased sensitivity to vasoconstrictors lead to vascular smooth muscle cell (VSMC) dysfunction in individuals with diabetes. Diabetic nephropathy is associated with a considerably higher risk of cardiovascular disease and death than their nondiabetic counterparts. We studied the activity of Cullin 3 RING ubiquitin ligase (CRL3) and its substrates in mice using an intraperitoneal injection of streptozotocin (STZ) and db/db mice. The levels of CRL3 adaptors, including Kelch-like 2/3 (KLHL2/3) and Rho-related BTB domain-containing protein 1, were significantly decreased in the aortic tissues and heart of the STZ group, whereas the levels of Cullin 3 (CUL3) and its neddylated derivatives were substantially increased. Decreased KLHL3 expression and significantly increased expression of NEDD8 conjugates were observed in the kidneys of db/db mice. The neddylation inhibitor MLN4924 decreased the degradation of KLHL2/KLHL3 under high-glucose conditions with/without insulin, and transfection with KLHL2 promoted the degradation of its substrates with-no-lysine (WNK) kinases. Increased abundance of WNK3, RhoA/ROCK activity and phosphodiesterase 5 enhanced the sensibility to vasoconstrictors and impaired vasodilation. Moreover, WNK3 localized in VSMCs undergoing cell division, and high-glucose medium increased WNK3 signaling in VSMCs undergoing mitosis, which might explain the increased thickness of aortic tissues in subjects with diabetes. Increases in WNK4 abundance resulted in increased sodium reabsorption in the distal renal tubules. Thus, KLHL2/RhoBTB1/KLHL3 inactivation in the aortic tissues and kidney is a result of excessive activation of neddylation in hyperglycemia and hyperinsulinemia, which affects vascular tone and sodium reabsorption.


Assuntos
Proteínas Culina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Sódio/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Vasoconstrição/fisiologia , Animais , Aorta/metabolismo , Aorta/patologia , Células Cultivadas , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/fisiopatologia , Humanos , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Proteínas dos Microfilamentos/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
7.
Nat Commun ; 12(1): 5110, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433824

RESUMO

HLA-DQ8, a genetic risk factor in type I diabetes (T1D), presents hybrid insulin peptides (HIPs) to autoreactive CD4+ T cells. The abundance of spliced peptides binding to HLA-DQ8 and how they are subsequently recognised by the autoreactive T cell repertoire is unknown. Here we report, the HIP (GQVELGGGNAVEVLK), derived from splicing of insulin and islet amyloid polypeptides, generates a preferred peptide-binding motif for HLA-DQ8. HLA-DQ8-HIP tetramer+ T cells from the peripheral blood of a T1D patient are characterised by repeated TRBV5 usage, which matches the TCR bias of CD4+ T cells reactive to the HIP peptide isolated from the pancreatic islets of a patient with T1D. The crystal structure of three TRBV5+ TCR-HLA-DQ8-HIP complexes shows that the TRBV5-encoded TCR ß-chain forms a common landing pad on the HLA-DQ8 molecule. The N- and C-termini of the HIP is recognised predominantly by the TCR α-chain and TCR ß-chain, respectively, in all three TCR ternary complexes. Accordingly, TRBV5 + TCR recognition of HIP peptides might occur via a 'polarised' mechanism, whereby each chain within the αßTCR heterodimer recognises distinct origins of the spliced peptide presented by HLA-DQ8.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Antígenos HLA-DQ/metabolismo , Insulina/metabolismo , Peptídeos/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Sequência de Aminoácidos , Linfócitos T CD4-Positivos/química , Linfócitos T CD4-Positivos/metabolismo , Diabetes Mellitus Tipo 1/genética , Antígenos HLA-DQ/química , Antígenos HLA-DQ/genética , Humanos , Insulina/química , Insulina/genética , Peptídeos/química , Ligação Proteica , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética
8.
Exp Eye Res ; 210: 108710, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34339682

RESUMO

Diabetes is a significant risk factor for meibomian gland dysfunction (MGD), but its mechanism is poorly understood. The main function of the meibomian glands (MGs) is to synthesize, store, and secrete lipids. In this study, we found that the amount of lipids in the meibomian acini in STZ-induced type 1 diabetic mice decreased, and the lipid droplets became larger and irregular. In all, 31 lipid subclasses were identified in the mouse MGs, which contained 1378 lipid species in total through lipidomics analysis based on LC-MS/MS. Diabetes caused a significant increase in the content of ceramides (Cer) in the MGs but a significant decrease in the ration of sphingomyelin to ceramides (SM/Cer). The quantity of meibocytes in diabetic mice was dramatically decreased, and the proliferation activity was alleviated, which may be associated with cell cycle arrest caused by diabetes-induced abnormal Cer metabolism in MGs. We found an increase in macrophage and neutrophils infiltration in the diabetic MGs, which may be related to the significant reduction of AcCa in diabetic MGs. Taken together, the results of the present study demonstrated that diabetes induced disruption of lipid homeostasis in MGs, which may mediate the decreased cell proliferation and increased inflammation caused by diabetes in MGs.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Doenças Palpebrais/metabolismo , Metabolismo dos Lipídeos/fisiologia , Glândulas Tarsais/metabolismo , Animais , Glicemia/metabolismo , Cromatografia Líquida , Diabetes Mellitus Experimental/metabolismo , Técnica Indireta de Fluorescência para Anticorpo , Inflamação/metabolismo , Lipidômica , Macrófagos/fisiologia , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Infiltração de Neutrófilos/fisiologia , Espectrometria de Massas em Tandem
9.
Nat Rev Nephrol ; 17(11): 740-750, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34363037

RESUMO

Diabetic nephropathy has been traditionally diagnosed based on persistently high albuminuria and a subsequent decline in glomerular filtration rate (GFR), which is widely recognized as the classical phenotype of diabetic kidney disease (DKD). Several studies have emphasized that trajectories of kidney function in patients with diabetes (specifically, changes in GFR and albuminuria over time) can differ from this classical DKD phenotype. Three alternative DKD phenotypes have been reported to date and are characterized by albuminuria regression, a rapid decline in GFR, or non-proteinuric or non-albuminuric DKD. Although kidney biopsies are not typically required for the diagnosis of DKD, a few studies of biopsy samples from patients with DKD have demonstrated that changes in kidney function associate with specific histopathological findings in diabetes. In addition, various clinical and biochemical parameters are related to trajectories of GFR and albuminuria. Collectively, pathological and clinical characteristics can be used to predict trajectories of GFR and albuminuria in diabetes. Furthermore, cohort studies have suggested that the risks of kidney and cardiovascular outcomes might vary among different phenotypes of DKD. A broader understanding of the clinical course of DKD is therefore crucial to improve risk stratification and enable early interventions that prevent adverse outcomes.


Assuntos
Albuminúria/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , Taxa de Filtração Glomerular , Insuficiência Renal Crônica/metabolismo , Albuminúria/etiologia , Albuminúria/patologia , Albuminúria/fisiopatologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Humanos , Rim/patologia , Fenótipo , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia , Índice de Gravidade de Doença , Fatores de Tempo
10.
Diabetes ; 70(9): 1915-1925, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34417266

RESUMO

Completion of the Human Genome Project enabled a novel systems- and network-level understanding of biology, but this remains to be applied for understanding the pathogenesis of type 1 diabetes (T1D). We propose that defining the key gene regulatory networks that drive ß-cell dysfunction and death in T1D might enable the design of therapies that target the core disease mechanism, namely, the progressive loss of pancreatic ß-cells. Indeed, many successful drugs do not directly target individual disease genes but, rather, modulate the consequences of defective steps, targeting proteins located one or two steps downstream. If we transpose this to the T1D situation, it makes sense to target the pathways that modulate the ß-cell responses to the immune assault-in relation to signals that may stimulate the immune response (e.g., HLA class I and chemokine overexpression and/or neoantigen expression) or inhibit the invading immune cells (e.g., PDL1 and HLA-E expression)-instead of targeting only the immune system, as it is usually proposed. Here we discuss the importance of a focus on ß-cells in T1D, lessons learned from other autoimmune diseases, the "alternative splicing connection," data mining, and drug repurposing to protect ß-cells in T1D and then some of the initial candidates under testing for ß-cell protection.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Redes Reguladoras de Genes , Células Secretoras de Insulina/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Humanos
11.
Cells ; 10(8)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34440644

RESUMO

Mast cells are highly differentiated, widely distributed cells of the innate immune system, that are currently considered as key regulators of both innate and adaptive immunity. Mast cells play a key role in health and survival mechanisms, especially as sentinel cells that can stimulate protective immune responses. On the other hand, it has been shown that mast cells are involved in the pathogenesis of several diseases, and recently a possible pathogenetic role of mast cells in diabetes has been proposed. In this review we summarize the evidence on the increased presence of mast cells in the pancreas of subjects with type 1 diabetes, which is due to the autoimmune destruction of insulin secreting beta cells, and discuss the differences with type 2 diabetes, the other major form of diabetes. In addition, we describe some of the pathophysiological mechanisms through which mast cells might exert their actions, which could be targeted to potentially protect the beta cells in autoimmune diabetes.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/sangue , Mastócitos/metabolismo , Animais , Comunicação Celular , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/patologia , Humanos , Resistência à Insulina , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Mastócitos/imunologia
12.
Sci Rep ; 11(1): 13627, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34211074

RESUMO

Corneal innervation plays a major role in the pathobiology of diabetic corneal disease. However, innervation impact has mainly been investigated in the context of diabetic epitheliopathy and wound healing. Further studies are warranted in the corneal stroma-nerve interactions. This study unravels the nerve influence on corneal stroma metabolism. Corneal stromal cells were isolated from healthy (HCFs) and diabetes mellitus (Type1DM and Type2 DM) donors. Cells were cultured on polycarbonate membranes, stimulated by stable Vitamin C, and stroma-only and stroma-nerve co-cultures were investigated for metabolic alterations. Innervated compared to stroma-only constructs exhibited significant alterations in pyrimidine, glycerol phosphate shuttle, electron transport chain and glycolysis. The most highly altered metabolites between healthy and T1DMs innervated were phosphatidylethanolamine biosynthesis, and pyrimidine, methionine, aspartate metabolism. Healthy and T2DMs main pathways included aspartate, glycerol phosphate shuttle, electron transport chain, and gluconeogenesis. The metabolic impact on T1DMs and T2DMs was pyrimidine, purine, aspartate, and methionine. Interestingly, the glucose-6-phosphate and oxaloacetate was higher in T2DMs compared to T1DMs. Our in vitro co-culture model allows the examination of key metabolic pathways corresponding to corneal innervation in the diabetic stroma. These novel findings can pave the way for future studies to fully understand the metabolic distinctions in the diabetic cornea.


Assuntos
Doenças da Córnea/metabolismo , Substância Própria/inervação , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Linhagem Celular , Células Cultivadas , Doenças da Córnea/etiologia , Doenças da Córnea/patologia , Substância Própria/metabolismo , Substância Própria/patologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Metabolismo Energético , Glucose/metabolismo , Humanos , Redes e Vias Metabólicas , Metaboloma , Tecido Nervoso/metabolismo , Tecido Nervoso/patologia
13.
PLoS One ; 16(7): e0254859, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34329330

RESUMO

BACKGROUND: Glycocalyx lines the inner surface of the capillary endothelium. Capillaroscopy enables visualization of the sublingual capillaries and measurement of the Perfused Boundary Region (PBR) as an estimate of the glycocalyx. Novel software enables assessment of the PBR estimated at a fixed high flow level (PBR-hf) and an overall microvascular assessment by the MicroVascular Health Score (MVHS). Damaged glycocalyx may represent microvascular damage in diabetes and assessment of its dimension might improve early cardio-renal risk stratification. AIM: To assess the associations between PBR, PBR-hf and MVHS and cardio-renal risk factors in persons with type 1 diabetes (T1D); and to compare these dimensions in persons with T1D and controls. METHODS: Cross-sectional study including 161 persons with T1D stratified according to level of albuminuria and 50 healthy controls. The PBR, PBR-hf and MVHS were assessed by the GlycoCheck device (valid measurements were available in 136 (84.5%) with T1D and in all the controls). Higher PBR and PBR-hf indicate smaller glycocalyx width. Lower MVHS represents a worse microvascular health. RESULTS: There were no associations between PBR, PBR-hf or MVHS and the cardio-renal risk factors in persons with T1D, except for higher PBR-hf and lower MVHS in females (p = 0.01 for both). There was no difference in PBR, PBR-hf or MVHS in persons with normo-, micro- or macroalbuminuria. The PBR was higher (2.20±0.30 vs. 2.03±0.18µm; p<0.001) and MVHS lower (3.15±1.25 vs. 3.53±0.86µm; p = 0.02) in persons with T1D compared to controls (p≤0.02). After adjustment for cardio-renal risk factors the difference in PBR remained significant (p = 0.001). CONCLUSIONS: The endothelial glycocalyx dimension was impaired in persons with T1D compared to controls. We found no association between the endothelial glycocalyx dimension and the level of albuminuria or cardio-renal risk factors among persons with T1D. The use of the GlycoCheck device in T1D may not contribute to cardio-renal risk stratification.


Assuntos
Albuminúria/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Glicocálix/metabolismo , Idoso , Estudos Transversais , Endotélio Vascular , Feminino , Humanos , Masculino , Microcirculação , Pessoa de Meia-Idade , Fatores de Risco
14.
Biomolecules ; 11(6)2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205061

RESUMO

BACKGROUND: The main goal of our study was to explore the wound-healing property of a novel cerium-containing N-acethyl-6-aminohexanoate acid compound and determine key molecular targets of the compound mode of action in diabetic animals. METHODS: Cerium N-acetyl-6-aminohexanoate (laboratory name LHT-8-17) as a 10 mg/mL aquatic spray was used as wound experimental topical therapy. LHT-8-17 toxicity was assessed in human skin epidermal cell culture using (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A linear wound was reproduced in 18 outbred white rats with streptozotocin-induced (60 mg/kg i.p.) diabetes; planar cutaneous defect was modelled in 60 C57Bl6 mice with streptozotocin-induced (200 mg/kg i.p.) diabetes and 90 diabetic db/db mice. Firmness of the forming scar was assessed mechanically. Skin defect covering was histologically evaluated on days 5, 10, 15, and 20. Tissue TNF-α, IL-1ß and IL-10 levels were determined by quantitative ELISA. Oxidative stress activity was detected by Fe-induced chemiluminescence. Ki-67 expression and CD34 cell positivity were assessed using immunohistochemistry. FGFR3 gene expression was detected by real-time PCR. LHT-8-17 anti-microbial potency was assessed in wound tissues contaminated by MRSA. RESULTS: LHT-8-17 4 mg twice daily accelerated linear and planar wound healing in animals with type 1 and type 2 diabetes. The formulated topical application depressed tissue TNF-α, IL-1ß, and oxidative reaction activity along with sustaining both the IL-10 concentration and antioxidant capacity. LHT-8-17 induced Ki-67 positivity of fibroblasts and pro-keratinocytes, upregulated FGFR3 gene expression, and increased tissue vascularization. The formulation possessed anti-microbial properties. CONCLUSIONS: The obtained results allow us to consider the formulation as a promising pharmacological agent for diabetic wound topical treatment.


Assuntos
Aminocaproatos/administração & dosagem , Cério/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Administração Tópica , Aminocaproatos/metabolismo , Animais , Cério/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Cicatrização/fisiologia
15.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299114

RESUMO

Type 1 Diabetes (T1D) results from autoimmune destruction of insulin producing pancreatic ß-cells. This disease, with a peak incidence in childhood, causes the lifelong need for insulin injections and necessitates careful monitoring of blood glucose levels. However, despite the current insulin therapies, it still shortens life expectancy due to complications affecting multiple organs. Recently, the incidence of T1D in childhood has increased by 3-5% per year in most developed Western countries. The heterogeneity of the disease process is supported by the findings of follow-up studies started early in infancy. The development of T1D is usually preceded by the appearance of autoantibodies targeted against antigens expressed in the pancreatic islets. The risk of T1D increases significantly with an increasing number of positive autoantibodies. The order of autoantibody appearance affects the disease risk. Genetic susceptibility, mainly defined by the human leukocyte antigen (HLA) class II gene region and environmental factors, is important in the development of islet autoimmunity and T1D. Environmental factors, mainly those linked to the changes in the gut microbiome as well as several pathogens, especially viruses, and diet are key modulators of T1D. The aim of this paper is to expand the understanding of the aetiology and pathogenesis of T1D in childhood by detailed description and comparison of factors affecting the progression from the islet autoimmunity to T1D in children.


Assuntos
Autoanticorpos/imunologia , Autoimunidade , Diabetes Mellitus Tipo 1/patologia , Microbioma Gastrointestinal , Predisposição Genética para Doença , Ilhotas Pancreáticas/patologia , Criança , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Fatores de Risco
16.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209306

RESUMO

Diabetic foot ulcer (DFU) is a diabetes complication which greatly impacts the patient's quality of life, often leading to amputation of the affected limb unless there is a timely and adequate management of the patient. DFUs have a high economic impact for the national health system. Data have indeed shown that DFUs are a major cause of hospitalization for patients with diabetes. Based on that, DFUs represent a very important challenge for the national health system. Especially in developed countries diabetic patients are increasing at a very high rate and as expected, also the incidence of DFUs is increasing due to longevity of diabetic patients in the western population. Herein, the surgical approach focused on the targeted use of the acellular dermal matrix has been integrated with biochemical and morphological/histological analyses to obtain evidence-based information on the mechanisms underlying tissue regeneration. In this research report, the clinical results indicated decreased postoperative wound infection levels and a short healing time, with a sound regeneration of tissues. Here we demonstrate that the key biomarkers of wound healing process are activated at gene expression level and also synthesis of collagen I, collagen III and elastin is prompted and modulated within the 28-day period of observation. These analyses were run on five patients treated with Integra® sheet and five treated with the injectable matrix Integra® Flowable, for cavitary lesions. In fact, clinical evaluation of improved healing was, for the first time, supported by biochemical and histological analyses. For these reasons, the present work opens a new scenario in DFUs treatment and follow-up, laying the foundation for a tailored protocol towards complete healing in severe pathological conditions.


Assuntos
Derme Acelular , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Pé Diabético , Cicatrização , Idoso , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/terapia , Pé Diabético/metabolismo , Pé Diabético/patologia , Pé Diabético/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Science ; 373(6554): 516-522, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34326233

RESUMO

Technological advancements in blood glucose monitoring and therapeutic insulin administration have improved the quality of life for people with type 1 diabetes. However, these efforts fall short of replicating the exquisite metabolic control provided by native islets. We examine the integrated advancements in islet cell replacement and immunomodulatory therapies that are coalescing to enable the restoration of endogenous glucose regulation. We highlight advances in stem cell biology and graft site design, which offer innovative sources of cellular material and improved engraftment. We also cover cutting-edge approaches for preventing allograft rejection and recurrent autoimmunity. These insights reflect a growing understanding of type 1 diabetes etiology, ß cell biology, and biomaterial design, together highlighting therapeutic opportunities to durably replace the ß cells destroyed in type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/terapia , Imunomodulação , Células Secretoras de Insulina/transplante , Transplante das Ilhotas Pancreáticas , Animais , Autoimunidade , Glicemia/metabolismo , Diferenciação Celular , Engenharia Celular , Microambiente Celular , Diabetes Mellitus Tipo 1/metabolismo , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Tolerância Imunológica , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/fisiologia , Células-Tronco Pluripotentes/transplante , Transplante de Células-Tronco
19.
Front Endocrinol (Lausanne) ; 12: 690222, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34326814

RESUMO

Aims: The purpose of the study was to evaluate the impact of the lockdown established by the Italian government to limit the spread of Coronavirus disease (COVID-19) on glycemic control in a large sample of patients with type 1 diabetes (T1D) based on age, type of insulin therapy, number of telemedicine visits and physical activity. Material and Methods: We retrospectively evaluated glycemic control in young T1D patients using the DexcomG6® system before the Italian lockdown (February 10-23, 2020-Time 0) and during lockdown (April 17-30, 2020-Time 1). Data on age, type of insulin therapy, number of telemedicine visits and physical activity of 202 patients with T1D and a median age of 18.2 years (range: 6-39) were collected. Results: Data showed a significant improvement of TIR from 54.58% at T0 to 59.09% at T1 (p ≤0.0001). Glycemic control improved significantly in patients ≥14 years old, showing the best outcome in the "university students and young adults" group (55.40% at T0 and 61.37% at T1, p ≤0.001). All patients reduced physical activity during lockdown; in the 56 patients of "intense physical activity" group both at T0 and T1 TIR increased from ±56.91 to 64.11% (p ≤0.0001). Conclusions: Overall, the lockdown led to an unexpected improvement in glycemic control of young patients with T1D. A healthier and stressless lifestyle changes in association with the maintenance of physical activity resulted in a significant age-proportional improvement in glycemic control.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Exercício Físico , Adolescente , Adulto , COVID-19/epidemiologia , Criança , Pré-Escolar , Feminino , Controle Glicêmico , Humanos , Itália/epidemiologia , Estilo de Vida , Masculino , Quarentena , Estudos Retrospectivos , Adulto Jovem
20.
Sci Rep ; 11(1): 14614, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272437

RESUMO

We evaluated trajectories of glycated hemoglobin (HbA1c) levels and body mass index z-scores (BMIz) for 5 years after diagnosis among Korean children and adolescents with type 1 diabetes (T1D) or type 2 diabetes (T2D) using the common data model. From the de-identified database of three hospitals, 889 patients < 15 years of age diagnosed with T1D or T2D (393 boys, 664 T1D patients) were enrolled. Diagnosis was defined as first exposure to antidiabetic drug at each center. Compared with T2D patients, T1D patients had lower BMIz at diagnosis (- 0.4 ± 1.2 vs. 1.5 ± 1.4, p < 0.001) and 3 months (- 0.1 ± 1.0 vs. 1.5 ± 1.5, p < 0.001), and higher HbA1c levels at diagnosis (10.0 ± 2.6% vs. 9.5 ± 2.7%, p < 0.01). After 3 months, HbA1c levels reached a nadir of 7.6% and 6.5% in T1D and T2D patients, respectively, followed by progressive increases; only 10.4% of T1D and 29.7% of T2D patients achieved the recommended HbA1c target (< 7.0%) at 60 months. T1D patients showed consistent increases in BMIz; T2D patients showed no significant change in BMIz during follow-up. Peri-pubertal girls with T1D had higher HbA1c and BMIz values. Achieving optimal glycemic control and preventing obesity should be emphasized in pediatric diabetes care.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hemoglobina A Glicada/metabolismo , Adolescente , Índice de Massa Corporal , Criança , Pré-Escolar , Elementos de Dados Comuns , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Insulina/uso terapêutico , Masculino , Metformina/uso terapêutico
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