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1.
Nat Rev Endocrinol ; 17(1): 11-30, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33188364

RESUMO

Initial studies found increased severity of coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in patients with diabetes mellitus. Furthermore, COVID-19 might also predispose infected individuals to hyperglycaemia. Interacting with other risk factors, hyperglycaemia might modulate immune and inflammatory responses, thus predisposing patients to severe COVID-19 and possible lethal outcomes. Angiotensin-converting enzyme 2 (ACE2), which is part of the renin-angiotensin-aldosterone system (RAAS), is the main entry receptor for SARS-CoV-2; although dipeptidyl peptidase 4 (DPP4) might also act as a binding target. Preliminary data, however, do not suggest a notable effect of glucose-lowering DPP4 inhibitors on SARS-CoV-2 susceptibility. Owing to their pharmacological characteristics, sodium-glucose cotransporter 2 (SGLT2) inhibitors might cause adverse effects in patients with COVID-19 and so cannot be recommended. Currently, insulin should be the main approach to the control of acute glycaemia. Most available evidence does not distinguish between the major types of diabetes mellitus and is related to type 2 diabetes mellitus owing to its high prevalence. However, some limited evidence is now available on type 1 diabetes mellitus and COVID-19. Most of these conclusions are preliminary, and further investigation of the optimal management in patients with diabetes mellitus is warranted.


Assuntos
/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , /antagonistas & inibidores , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gerenciamento Clínico , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/metabolismo , Fatores de Risco
2.
N Engl J Med ; 383(21): 2007-2017, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33207093

RESUMO

BACKGROUND: Type 1 diabetes is an autoimmune disease characterized by progressive loss of pancreatic beta cells. Golimumab is a human monoclonal antibody specific for tumor necrosis factor α that has already been approved for the treatment of several autoimmune conditions in adults and children. Whether golimumab could preserve beta-cell function in youth with newly diagnosed overt (stage 3) type 1 diabetes is unknown. METHODS: In this phase 2, multicenter, placebo-controlled, double-blind, parallel-group trial, we randomly assigned, in a 2:1 ratio, children and young adults (age range, 6 to 21 years) with newly diagnosed overt type 1 diabetes to receive subcutaneous golimumab or placebo for 52 weeks. The primary end point was endogenous insulin production, as assessed according to the area under the concentration-time curve for C-peptide level in response to a 4-hour mixed-meal tolerance test (4-hour C-peptide AUC) at week 52. Secondary and additional end points included insulin use, the glycated hemoglobin level, the number of hypoglycemic events, the ratio of fasting proinsulin to C-peptide over time, and response profile. RESULTS: A total of 84 participants underwent randomization - 56 were assigned to the golimumab group and 28 to the placebo group. The mean (±SD) 4-hour C-peptide AUC at week 52 differed significantly between the golimumab group and the placebo group (0.64±0.42 pmol per milliliter vs. 0.43±0.39 pmol per milliliter, P<0.001). A treat-to-target approach led to good glycemic control in both groups, and there was no significant difference between the groups in glycated hemoglobin level. Insulin use was lower with golimumab than with placebo. A partial-remission response (defined as an insulin dose-adjusted glycated hemoglobin level score [calculated as the glycated hemoglobin level plus 4 times the insulin dose] of ≤9) was observed in 43% of participants in the golimumab group and in 7% of those in the placebo group (difference, 36 percentage points; 95% CI, 22 to 55). The mean number of hypoglycemic events did not differ between the trial groups. Hypoglycemic events that were recorded as adverse events at the discretion of investigators were reported in 13 participants (23%) in the golimumab group and in 2 (7%) of those in the placebo group. Antibodies to golimumab were detected in 30 participants who received the drug; 29 had antibody titers lower than 1:1000, of whom 12 had positive results for neutralizing antibodies. CONCLUSIONS: Among children and young adults with newly diagnosed overt type 1 diabetes, golimumab resulted in better endogenous insulin production and less exogenous insulin use than placebo. (Funded by Janssen Research and Development; T1GER ClinicalTrials.gov number, NCT02846545.).


Assuntos
Anticorpos Monoclonais/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Área Sob a Curva , Peptídeo C/metabolismo , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobina A Glicada/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Insulina/administração & dosagem , Insulina/efeitos adversos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Proinsulina/metabolismo , Adulto Jovem
3.
Expert Opin Pharmacother ; 21(15): 1799-1803, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33108240

RESUMO

INTRODUCTION: The majority of patients with type 1 diabetes mellitus (T1DM) do not achieve glycemic targets. In addition, treatment with insulin is associated with increased risk for hypoglycemia and weight gain. Accordingly, there is an unmet need for new safe and effective glucose-lowering agents in this population. Sotagliflozin, a dual inhibitor of sodium-glucose co-transporters 1 and 2, has been recently approved for use in patients with T1DM. AREAS COVERED: The authors review the major trials that have evaluated the safety and efficacy of sotagliflozin and provide their expert opinion. EXPERT OPINION: Even though sotagliflozin reduces HbA1 c levels and does not appear to increase the risk for hypoglycemia in most patients, the substantially increased risk for diabetic ketoacidosis limits the use of this agent to a carefully selected subgroup of patients with T1DM. Based on the existing evidence, sotagliflozin should be considered only in patients who have failed to achieve adequate glycemic control despite optimal insulin therapy, are at low risk for diabetic ketoacidosis, have been adequately trained to recognize this complication and are able to be in close contact with their physician.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Glicosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/metabolismo , Cetoacidose Diabética/induzido quimicamente , Glicosídeos/administração & dosagem , Glicosídeos/efeitos adversos , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Insulina/administração & dosagem , Risco , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo
4.
Med Sci (Paris) ; 36(10): 879-885, 2020 Oct.
Artigo em Francês | MEDLINE | ID: mdl-33026330

RESUMO

Pancreatic islet transplantation is a valid cure for selected type-1 diabetic patients. It offers a minimally invasive ß-cell replacement approach and has proven its capacity to significantly enhance patients quality of life. However, these insulin-secreting mini-organs suffer from the loss of intrinsic vascularization and extra-cellular matrix occurring during isolation, resulting in hypoxic stress and necrosis. In addition, they have to face inflammatory and immune destruction once transplanted in the liver. Organoid generation represents a strategy to overcome these obstacles by allowing size and shape control as well as composition. It does offer the possibility to add supporting cells such as endothelial cells, in order to facilitate revascularization or cells releasing anti-inflammatory and/or immunomodulatory factors. This review describes the limitations of pancreatic islet transplantation and details the benefits offered by organoids as a cornerstone toward the generation of a bioartificial pancreas.


Assuntos
Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Organoides/metabolismo , Pâncreas Artificial , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/terapia , Humanos , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/citologia , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Transplante das Ilhotas Pancreáticas/métodos , Organoides/citologia , Pâncreas Artificial/provisão & distribução , Técnicas de Cultura de Tecidos/métodos
5.
PLoS One ; 15(10): e0240907, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33120406

RESUMO

Glucose metabolism is pivotal for energy and neurotransmitter synthesis and homeostasis, particularly in Glutamate and GABA systems. In turn, the stringent control of inhibitory/excitatory tonus is known to be relevant in neuropsychiatric conditions. Glutamatergic neurotransmission dominates excitatory synaptic functions and is involved in plasticity and excitotoxicity. GABAergic neurochemistry underlies inhibition and predicts impaired psychophysical function in diabetes. It has also been associated with cognitive decline in people with diabetes. Still, the relation between metabolic homeostasis and neurotransmission remains elusive. Two 3T proton MR spectroscopy studies were independently conducted in the occipital cortex to provide insight into inhibitory/excitatory homeostasis (GABA/Glutamate) and to evaluate the impact of chronic metabolic control on the levels and regulation (as assessed by regression slopes) of the two main neurotransmitters of the CNS in type 2 diabetes (T2DM) and type 1 diabetes (T1DM). Compared to controls, participants with T2DM showed significantly lower Glutamate, and also GABA. Nevertheless, higher levels of GABA/Glx (Glutamate+Glutamine), and lower levels of Glutamate were associated with poor metabolic control in participants with T2DM. Importantly, the relationship between GABA/Glx and HbA1c found in T2DM supports a relationship between inhibitory/excitatory balance and metabolic control. Interestingly, this neurometabolic profile was undetected in T1DM. In this condition we found strong evidence for alterations in MRS surrogate measures of neuroinflammation (myo-Inositol), positively related to chronic metabolic control. Our results suggest a role for Glutamate as a global marker of T2DM and a sensitive marker of glycemic status. GABA/Glx may provide a signature of cortical metabolic state in poorly controlled patients as assessed by HbA1c levels, which indicate long-term blood Glucose control. These findings are consistent with an interplay between abnormal neurotransmission and metabolic control in particular in type 2 diabetes thereby revealing dissimilar contributions to the pathophysiology of neural dysfunction in both types of diabetes.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ácido Glutâmico/metabolismo , Ácido gama-Aminobutírico/metabolismo , Idoso , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Feminino , Glucose/metabolismo , Hemoglobina A Glicada/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neurotransmissores/genética , Neurotransmissores/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Transmissão Sináptica/genética , Ácido gama-Aminobutírico/genética
6.
Biomed Environ Sci ; 33(9): 690-700, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-33106214

RESUMO

Objective: To evaluate the efficiency of silymarin (SMN) in modulating metabolic parameters and redox status in rats with type 1 diabetes mellitus (T1DM). Methods: Diabetes was induced by intraperitoneal injection of alloxan. The diabetic rats were administered with SMN at doses of 50 and 100 mg/kg body weight/d for 30 consecutive days. The rats were divided into the following four groups: vehicle control, diabetic (alloxan-treated), DS50 (alloxan + 50 mg/kg body weight/d of SMN), and DS100 (alloxan + 100 mg/kg body weight/d of SMN) groups. The bodyweight and food and water intake were evaluated. After 30 d, the animals were euthanized and the blood was collected for measuring the serum levels of glucose, triacylglycerol (TAG), urea, and creatinine. The liver and pancreas were collected for measuring the activities of superoxide dismutase (SOD) and catalase (CAT), and the levels of carbonylated protein (PC). The pancreas sample was also used for histological analysis. Results: SMN reduced hepatic ( P < 0.001) and pancreatic ( P < 0.001) protein damage and creatinine levels ( P = 0.0141) in addition to decreasing food ( P < 0.001) and water intake ( P < 0.001). However, treatment with SMN did not improve beta-cell function or decrease blood glucose levels in diabetic rats. Conclusion: SMN improved polyphagia and polydipsia, renal function, and protected the liver and pancreas against protein damage without affecting hyperglycemia in diabetic animals.


Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Experimental/metabolismo , Fígado/metabolismo , Pâncreas/metabolismo , Substâncias Protetoras/farmacologia , Silimarina/farmacologia , Aloxano/farmacologia , Animais , Diabetes Mellitus Tipo 1/metabolismo , Fígado/efeitos dos fármacos , Oxirredução , Pâncreas/efeitos dos fármacos
7.
Artigo em Inglês | MEDLINE | ID: mdl-33115820

RESUMO

INTRODUCTION: The COVID-19 pandemic forced the Italian government to issue extremely restrictive measures on daily activities since 11 March 2020 ('lockdown'), which may have influenced the metabolic control of type 1 diabetes mellitus (T1D). The aims of the study were to investigate continuous glucose monitoring (CGM) metrics in children and adults with T1D during lockdown and to identify their potentially related factors. RESEARCH DESIGN AND METHODS: We enrolled 130 consecutive patients with T1D (30 children (≤12 years), 24 teenagers (13-17 years), and 76 adults (≥18 years)) using either Dexcom or FreeStyle LibreCGM>70% during the study period, without hybrid closed-loop insulin pump. CGM metrics during the 20 days before and the 20 days after lockdown were calculated. By telephonic contact, we performed validated physical activity and perceived stress questionnaires. RESULTS: In children, significantly lower glucose SD (SDglu) (p=0.029) and time below range (TBR)<54 mg/dL (TBR2) (p=0.029) were detected after lockdown. CGM metrics were comparable in teenagers before and during lockdown. After lockdown, adults improved significantly time in range (TIR) 70-180 mg/dL (p<0.001) and remaining metrics, except percent coefficient of variation and TBR2. In adults, considering the changes in SDglu and TIR occurred before and during lockdown, we identified a group with improved TIR and SDglu who performed more physical activity, one with improved glucose variability who was younger than the other patients, and one with worsened glucose variability who showed higher perceived stress than others. CONCLUSION: In patients with T1D during lockdown, CGM metrics mostly improved in children and adults, whereas it was unchanged in teenagers. In adults, age, physical activity, and perceived stress may be relevant contributing factors.


Assuntos
Glicemia/metabolismo , Controle de Doenças Transmissíveis , Infecções por Coronavirus , Diabetes Mellitus Tipo 1/metabolismo , Pandemias , Pneumonia Viral , Adolescente , Adulto , Betacoronavirus , Automonitorização da Glicemia , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Exercício Físico , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Itália , Masculino , Pessoa de Meia-Idade , Monitorização Ambulatorial , Estresse Psicológico/metabolismo
8.
Acta Diabetol ; 57(12): 1511-1517, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33026497

RESUMO

AIMS: Billions of people have been under lockdown in an attempt to prevent COVID-19 spread. Lifestyle changes during lockdown could lead to deterioration of glycemic control in type 1 diabetes (T1D). We aimed to assess the impact of COVID-19 lockdown on the glycemic control of pediatric patients with T1D. METHODS: This observational real-life study from the AWeSoMe Group assessed continuous glucose monitoring (CGM) metrics of 102 T1D patients (52.9% males, mean age 11.2 ± 3.8 years, mean diabetes duration 4.2 ± 3.8 years) who used  Dexcom G5. The data were accessed without any interface between patients, caregivers, and the diabetes team. Study variables from CGM metrics were: mean glucose level, time-in-range (TIR, 70-180 mg/dL; 3.9-10 mmol/L), hypoglycemia (< 54 mg/dL; < 3 mmol/L), hyperglycemia (> 250 mg/dL; > 13.3 mmol/L), coefficient of variation (CV), and time CGM active before and during lockdown. Delta-variable = lockdown variable minus before-lockdown variable. RESULTS: The mean TIR was 60.9 ± 14.3% before lockdown, with no significant change during lockdown (delta-TIR was 0.9 ± 7.9%). TIR during lockdown was significantly correlated with TIR before lockdown (r = 0.855, P < 0.001). Patients with improved TIR (delta-TIR > 3%) were significantly older than patients with stable or worse TIR (P = 0.028). Children aged < 10 years had a significantly higher CV before lockdown and during lockdown than children aged ≥ 10 years (P = 0.02 and P = 0.005, respectively). Among children aged < 10 years, a multiple linear regression model revealed associations of age and lower socioeconomic cluster with delta-TIR (F = 4.416, P = 0.019) and with delta-mean glucose (F = 4.459, P = 0.018). CONCLUSIONS: CGM metrics in pediatric patients with T1D were relatively stable during a nationwide lockdown. Intervention plans should focus on younger patients with lower socioeconomic position.


Assuntos
Automonitorização da Glicemia/métodos , Glicemia/análise , Infecções por Coronavirus/epidemiologia , Diabetes Mellitus Tipo 1/metabolismo , Pneumonia Viral/epidemiologia , Adolescente , Glicemia/metabolismo , Automonitorização da Glicemia/instrumentação , Criança , Diabetes Mellitus Tipo 1/diagnóstico , Feminino , Humanos , Estudos Longitudinais , Masculino , Pandemias
9.
Am J Physiol Endocrinol Metab ; 319(6): E1074-E1083, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33044845

RESUMO

This study aimed to investigate the contributions of two factors potentially impairing glucagon response to insulin-induced hypoglycemia (IIH) in insulin-deficient diabetes: 1) loss of paracrine disinhibition by intra-islet insulin and 2) defects in the activation of the autonomic inputs to the islet. Plasma glucagon responses during hyperinsulinemic-hypoglycemic clamps ([Formula: see text]40 mg/dL) were assessed in dogs with spontaneous diabetes (n = 13) and in healthy nondiabetic dogs (n = 6). Plasma C-peptide responses to intravenous glucagon were measured to assess endogenous insulin secretion. Plasma pancreatic polypeptide, epinephrine, and norepinephrine were measured as indices of parasympathetic and sympathoadrenal autonomic responses to IIH. In 8 of the 13 diabetic dogs, glucagon did not increase during IIH (diabetic nonresponder [DMN]; ∆ = -6 ± 12 pg/mL). In five other diabetic dogs (diabetic responder [DMR]), glucagon responses (∆ = +26 ± 12) were within the range of nondiabetic control dogs (∆ = +27 ± 16 pg/mL). C-peptide responses to intravenous glucagon were absent in diabetic dogs. Activation of all three autonomic responses were impaired in DMN dogs but remained intact in DMR dogs. Each of the three autonomic responses to IIH was positively correlated with glucagon responses across the three groups. The study conclusions are as follows: 1) Impairment of glucagon responses in DMN dogs is not due to generalized impairment of α-cell function. 2) Loss of tonic inhibition of glucagon secretion by insulin is not sufficient to produce loss of the glucagon response; impairment of autonomic activation is also required. 3) In dogs with major ß-cell function loss, activation of the autonomic inputs is sufficient to mediate an intact glucagon response to IIH.NEW & NOTEWORTHY In dogs with naturally occurring, insulin-dependent (C-peptide negative) diabetes mellitus, impairment of glucagon responses is not due to generalized impairment of α-cell function. Loss of tonic inhibition of glucagon secretion by insulin is not sufficient, by itself, to produce loss of the glucagon response. Rather, impaired activation of the parasympathetic and sympathoadrenal autonomic inputs to the pancreas is also required. Activation of the autonomic inputs to the pancreas is sufficient to mediate an intact glucagon response to insulin-induced hypoglycemia in dogs with naturally occurring diabetes mellitus. These results have important implications that include leading to a greater understanding and insight into the pathophysiology, prevention, and treatment of hypoglycemia during insulin treatment of diabetes in companion dogs and in human patients.


Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/veterinária , Doenças do Cão/metabolismo , Glucagon/farmacologia , Hipoglicemia/induzido quimicamente , Hipoglicemia/metabolismo , Hipoglicemiantes , Insulina , Animais , Glicemia/metabolismo , Peptídeo C/metabolismo , Cães , Epinefrina/sangue , Células Secretoras de Glucagon/efeitos dos fármacos , Técnica Clamp de Glucose , Células Secretoras de Insulina/efeitos dos fármacos , Norepinefrina/sangue , Polipeptídeo Pancreático/metabolismo
10.
PLoS One ; 15(9): e0236921, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32986722

RESUMO

The receptor for advanced glycation endproducts (RAGE) is expressed in T cells after activation with antigen and is constitutively expressed in T cells from patients at-risk for and with type 1 diabetes mellitus (T1D). RAGE expression was associated with an activated T cell phenotype, leading us to examine whether RAGE is involved in T cell signaling. In primary CD4+ and CD8+ T cells from patients with T1D or healthy control subjects, RAGE- cells showed reduced phosphorylation of Erk. To study T cell receptor signaling in RAGE+ or-T cells, we compared signaling in RAGE+/+ Jurkat cells, Jurkat cells with RAGE eliminated by CRISPR/Cas9, or silenced with siRNA. In RAGE KO Jurkat cells, there was reduced phosphorylation of Zap70, Erk and MEK, but not Lck or CD3ξ. RAGE KO cells produced less IL-2 when activated with anti-CD3 +/- anti-CD28. Stimulation with PMA restored signaling and (with ionomycin) IL-2 production. Silencing RAGE with siRNA also decreased signaling. Our studies show that RAGE expression in human T cells is associated with an activated signaling cascade. These findings suggest a link between inflammatory products that are found in patients with diabetes, other autoimmune diseases, and inflammation that may enhance T cell reactivity.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Adolescente , Adulto , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Criança , Feminino , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Inflamação/metabolismo , Células Jurkat , Masculino , Adulto Jovem
11.
Diabetes Metab Syndr ; 14(6): 1777-1781, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32942253

RESUMO

BACKGROUND: Diabetes is recognized as an important comorbidity in patients with COVID-19 and a large amount of literature has become available regarding this. The aim of this article is to review the literature regarding various aspects of association between diabetes and COVID-19 and to highlight clinically relevant points with focus on India. METHODS: We searched Pubmed and Google Scholar databases for articles regarding diabetes and COVID-19 published between March 19, 2020 and August 30, 2020. RESULTS: Diabetes and poor glycemic control are associated with increased severity and mortality in patients with COVID-19. Several clinical scenarios about hyperglycemia and COVID-19 are identified and each of these needs specific management strategies. CONCLUSION: It is prudent to maintain good glycemic control in patients with diabetes in order to minimize the complications of COVID-19. There is a need for well conducted studies to asses the role of individual antihyperglycemic therapies in COVID-19 and also the behavior of new onset diabetes diagnosed either after COVID-19 infection or during this time.


Assuntos
/terapia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Glicemia/metabolismo , /epidemiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Hemoglobina A Glicada/metabolismo , Humanos , Índia/epidemiologia , Telemedicina
12.
Reprod Sci ; 27(12): 2211-2222, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32748223

RESUMO

Type 1 diabetes (T1D) results in decreased oocyte quality and compromised early embryonic development. Procyanidin B2 (PB2) is a natural compound extracted from grape seeds and has strong antioxidant activity in vivo. This study evaluated the effect of PB2 on oocyte maturation in diabetic mice. Diabetic mice were induced by streptozotocin (STZ) injection. PB2 was supplemented in the in vitro maturation medium, and the ratio of germinal vesicle breakdown (GVBD) and polar body extrusion (PBE), reactive oxygen species (ROS) levels, mitochondrial function, developmental ability, as well as crotonylation at H4K5 were determined in oocytes. PB2 can promote the extrusion of PBE (88.34% vs. 75.02%, P < 0.05); reduce the generation of ROS (1.12 vs. 1.96, P < 0.05); and improve the level of mitochondrial membrane potential (0.87 vs. 0.79 Δφm, P < 0.05), ATP level (1.31 vs. 0.71 pmol, P < 0.05), and mitochondria temperature (618.25 vs. 697.39 pixels, P < 0.05). The addition of PB2 also improved the level of oocyte crotonylation at H4K5 (crH4K5) (47.26 vs. 59.68 pixels, P < 0.05) and increased the blastocyst rate (61.51% vs. 36.07%, P < 0.05) after parthenogenetic activation. Our results are the first to reveal a role for PB2 in promoting the viability of oocytes by regulating the mitochondrial function. Moreover, we uncover that PB2 can improve the level of crH4K5, which provides a new strategy to combat the decline in oocyte quality of diabetic.


Assuntos
Biflavonoides/administração & dosagem , Catequina/administração & dosagem , Diabetes Mellitus Tipo 1/metabolismo , Mitocôndrias/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Oócitos/crescimento & desenvolvimento , Proantocianidinas/administração & dosagem , Animais , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Feminino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos ICR , Mitocôndrias/metabolismo , Oócitos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Estreptozocina/administração & dosagem
13.
Diabetes Res Clin Pract ; 167: 108354, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32739380

RESUMO

AIMS: Spain has been one of the worst affected countries by the COVID-19 pandemic. A very strict lockdown at home was imposed with a tough restriction of mobility. We aimed to evaluate the impact of this exceptional scenario on glucose profile of patients with T1D prone to hypoglycemia using standalone continuous glucose monitoring. METHODS: Patients with T1D prone to hypoglycemia using multiple daily injections and either a Dexcom G5® or a Free Style Libre® CGM systems for at least 6 months under the funding of National Health Service were included in an observational, retrospective study. Data were collected in two periods: pre-lockdown (PL), February 23rd-March 7th and within lockdown (WL), April 1st-14th 2020. The primary outcome was the difference in the proportion of time in target glucose range of 70-180 mg/dL (TIR). Additional glucometric data were also analysed. RESULTS: 92 patients were included: 40 women, age 42.8 ± 3.9 years, disease duration of 23.1 ± 12.6 years. Seventeen patients used Dexcom G5® and 75 Free Style Libre®. TIR 70-180 mg/dL (59.3 ± 16.2 vs 62.6 ± 15.2%), time > 180 (34.4 ± 18.0 vs 30.7 ± 16.9%), >250 (11.1 ± 10.6 vs 9.2 ± 9.7%) and Glucose Management Indicator (7.2 ± 0.8 vs 7.0 ± 0.8%) significantly improved (PL vs WL, respectively, p < 0.05). Time in hypoglycemia remained unchanged. CONCLUSIONS: Lockdown conditions imposed by the COVID-19 pandemic may be managed successfully in terms of glycemic control by population with T1D prone to hypoglycemia using CGM. The strict daily routine at home could probably explain the improvement in the time in glycemic target without increasing the time in hypoglycemia.


Assuntos
Automonitorização da Glicemia , Controle de Doenças Transmissíveis , Infecções por Coronavirus/epidemiologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Monitorização Ambulatorial , Pneumonia Viral/epidemiologia , Adulto , Betacoronavirus , Glicemia , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Humanos , Injeções , Insulina de Ação Prolongada/uso terapêutico , Insulina de Ação Curta/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pandemias , Estudos Retrospectivos , Espanha/epidemiologia , Medicina Estatal
14.
Sci Rep ; 10(1): 13656, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788632

RESUMO

An on-chip transducer, for monitoring noninvasively the insulin bio-availability in real time after administration in clinical diabetology, is proposed. The bioavailability is assessed as insulin decrease in situ after administration by means of local impedance measurement. Inter-and-intra individual reproducibility is enhanced by a personalized model, specific for the subject, identified and validated during each insulin administration. Such a real-time noninvasive bioavailability measurement allows to increase the accuracy of insulin bolus administration, by attenuating drawbacks of glycemic swings significantly. In the first part of this paper, the concept, the architecture, and the operation of the transducer, as well as details about its prototype, are illustrated. Then, the metrological characterization and validation are reported in laboratory, in vitro on eggplants, ex vivo on pig abdominal non-perfused muscle, and in vivo on a human subject, using injection as a reference subcutaneous delivery of insulin. Results of significant intra-individual reproducibility in vitro and ex vivo point out noteworthy scenarios for assessing insulin bioavailability in clinical diabetology.


Assuntos
Automonitorização da Glicemia/métodos , Glicemia/análise , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Sistemas de Infusão de Insulina , Insulina/administração & dosagem , Animais , Disponibilidade Biológica , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Humanos , Hipoglicemiantes/metabolismo , Injeções Subcutâneas , Insulina/metabolismo , Suínos
15.
Am J Pathol ; 190(11): 2237-2250, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32858016

RESUMO

The insulin and Wnt signaling pathways are involved in cell proliferation, tissue homeostasis, and tumorigenesis. However, their interrelationship in the pathophysiological process of diabetic corneal injury remains unclear. In this study, the role of insulin in the diabetic cornea was investigated in vitro, using cultured TKE2 cells and trigeminal ganglion neurons, and in vivo, by assessing corneal wound-healing responses in diabetic mice. A selective Wnt antagonist (XAV-939) and activator (BML-284) were used to regulate the interactions between insulin and the Wnt pathway. The results demonstrated that insulin promoted corneal epithelial wound healing and sensation recovery, whereas the expression of molecules involved in the Wnt/ß-catenin pathway was also up-regulated in the injured corneal epithelium. However, XAV-939 limited the insulin-induced epithelial and corneal nerve repair. By contrast, BML-284 treatment promoted the healing of the corneal epithelium and corneal nerve repair in diabetic mice. These results indicate that insulin, via Wnt signaling, contributes to diabetic corneal epithelial wound healing and nerve injury recovery and is, therefore, a potential protective factor for diabetic corneal epithelial wounds and nerve injury.


Assuntos
Lesões da Córnea , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Insulina/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Animais , Córnea/metabolismo , Córnea/patologia , Lesões da Córnea/tratamento farmacológico , Lesões da Córnea/metabolismo , Lesões da Córnea/patologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Masculino , Camundongos
16.
Curr Opin Endocrinol Diabetes Obes ; 27(4): 215-224, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32618633

RESUMO

PURPOSE OF REVIEW: Emerging data have suggested that ß-cell dysfunction may exacerbate the development and progression of type 1 diabetes (T1D). In this review, we highlight clinical and preclinical studies suggesting a role for ß-cell dysfunction during the evolution of T1D and suggest agents that may promote ß-cell health in T1D. RECENT FINDINGS: Metabolic abnormalities exist years before development of hyperglycemia and exhibit a reproducible pattern reflecting progressive deterioration of ß-cell function and increases in ß-cell stress and death. Preclinical studies indicate that T1D may be prevented by modification of pathways impacting intrinsic ß-cell stress and antigen presentation. Recent findings suggest that differences in metabolic phenotypes and ß-cell stress may reflect differing endotypes of T1D. Multiple pathways representing potential drug targets have been identified, but most remain to be tested in human populations with preclinical disease. SUMMARY: This cumulative body of work shows clear evidence that ß-cell stress, dysfunction, and death are harbingers of impending T1D and likely contribute to progression of disease and insulin deficiency. Treatment with agents targeting ß-cell health could augment interventions with immunomodulatory therapies but will need to be tested in intervention studies with endpoints carefully designed to capture changes in ß-cell function and health.


Assuntos
Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/fisiopatologia , Células Secretoras de Insulina/fisiologia , Diabetes Mellitus Tipo 1/metabolismo , Progressão da Doença , Humanos , Hiperglicemia/sangue , Hiperglicemia/complicações , Hiperglicemia/patologia , Hiperglicemia/fisiopatologia , Insulina/deficiência , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia
17.
Acta Diabetol ; 57(11): 1367-1373, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32617672

RESUMO

AIMS: A higher SGLT1 and GLUT2 gene expression was shown in the intestine of subjects with type 2 diabetes, while no data have been reported in type 1 diabetes (T1D). The purpose of our study was to evaluate the expression of glucose transporters in duodenal mucosa of subjects with T1D, compared to healthy controls (CTRL) and to patients with celiac disease (CD), as gut inflammatory disease control group. MATERIALS AND METHODS: Gene expression of GLUT1, GLUT2, SGLT1 and SGLT2 was quantified on duodenal mucosa biopsies of subjects with T1D (n = 19), CD (n = 16), T1D and CD (n = 6) and CTRL (n = 12), recruited at San Raffaele Hospital (Milan, Italy), between 2009 and 2018. SGLT2 expression was further evaluated by immunohistochemical and immunofluorescence staining. RESULTS: The expression of all four glucose transporters was detected in duodenal mucosa of all groups. A reduced GLUT2, SGLT1 and SGLT2 expression was observed in CD in comparison with T1D and CTRL, as expected; GLUT1 was significantly more expressed in T1D compared to CTRL. SGLT2 expression was quantified at much lower levels than other transporters, with no differences between groups. SGLT2 expression was confirmed by immunohistochemistry in a restricted number of enterocytes lining in the mucosa of intestinal villi, also shown on immunofluorescence. CONCLUSIONS: Our results show that glucose transporters expression in duodenal mucosa of subjects with T1D, except an increased GLUT1, is not different from that observed in healthy controls. The expression of SGLT2 in human duodenal mucosa, although at low intensity, represents a novel finding.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Duodeno/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Mucosa Intestinal/metabolismo , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Adolescente , Adulto , Idoso , Animais , Biópsia , Criança , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/metabolismo , Duodeno/patologia , Feminino , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 2/genética , Humanos , Masculino , Pessoa de Meia-Idade , Transportador 1 de Glucose-Sódio/genética , Transportador 2 de Glucose-Sódio/genética , Adulto Jovem
18.
Sci Rep ; 10(1): 12032, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694567

RESUMO

While the pathogenesis of diabetes-induced high blood pressure (BP) is not entirely clear, current evidence suggests that Toll-like receptor 4 (TLR4) is a key player in the mechanisms associated with hypertension. However, it is unknown whether this receptor affects BP under type 1 diabetes. Likewise, there is insufficient knowledge about the role of TLR4 in diabetes-associated vascular dysfunction of large arteries. To narrow these gaps, in this study, we investigated if blockade of the TLR4-MD2 complex impacts BP and vascular function in diabetic rats. We injected streptozotocin in male Sprague Dawley rats and treated them with a neutralizing anti-TLR4 antibody for 14 days. BP was directly measured in conscious animals at the end of the treatment. In another set of experiments, we excised the aorta from control and diabetic animals, and measured TLR4 and MD2-a co-receptor that confers functionality to TLR4-levels by Western blotting. We also performed functional studies and evaluated ROS levels with and without a pharmacological inhibitor for TLR4 as well as for MD2. Additionally, we scrutinized a large human RNA-Seq dataset of aortic tissue to assess the co-expression of TLR4, MD2, and subunits of the vascular NADPH oxidases under diabetes and hypertension. We report that (a) chronic blockade of the TLR4-MD2 complex lowers BP in diabetic animals; that (b) type 1 diabetes modulates the levels of MD2 expression in the aorta, but not TLR4, at least in the conditions evaluated in this study; and, that (c) acute inhibition of TLR4 or MD2 diminishes vascular contractility and reduces oxidative stress in the aorta of these animals. In summary, we show evidence that the TLR4-MD2 complex is involved in the mechanisms linking type 1 diabetes and hypertension.


Assuntos
Pressão Sanguínea , Vasos Sanguíneos/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Antígeno 96 de Linfócito/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/etiologia , Modelos Animais de Doenças , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Camundongos , Estresse Oxidativo , Ligação Proteica , Ratos , Espécies Reativas de Oxigênio/metabolismo
19.
Nat Metab ; 2(8): 744-762, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32694834

RESUMO

Metabolic memory, the persistent benefits of early glycaemic control on preventing and/or delaying the development of diabetic complications, has been observed in the Diabetes Control and Complications Trial (DCCT) and in the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study, but the underlying mechanisms remain unclear. Here, we show the involvement of epigenetic DNA methylation (DNAme) in metabolic memory by examining its associations with preceding glycaemic history, and with subsequent development of complications over an 18-yr period in the blood DNA of 499 randomly selected DCCT participants with type 1 diabetes who are also followed up in EDIC. We demonstrate the associations between DNAme near the closeout of DCCT and mean HbA1c during DCCT (mean-DCCT HbA1c) at 186 cytosine-guanine dinucleotides (CpGs) (FDR < 15%, including 43 at FDR < 5%), many of which were located in genes related to complications. Exploration studies into biological function reveal that these CpGs are enriched in binding sites for the C/EBP transcription factor, as well as enhancer/transcription regions in blood cells and haematopoietic stem cells, and open chromatin states in myeloid cells. Mediation analyses show that, remarkably, several CpGs in combination explain 68-97% of the association of mean-DCCT HbA1c with the risk of complications during EDIC. In summary, DNAme at key CpGs appears to mediate the association between hyperglycaemia and complications in metabolic memory, through modifying enhancer activity at myeloid and other cells.


Assuntos
Metilação de DNA , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Hemoglobina A Glicada/genética , Hemoglobina A Glicada/metabolismo , Adulto , Sítios de Ligação , Células Sanguíneas/metabolismo , Cromatina/metabolismo , Estudos de Coortes , Ilhas de CpG , Diabetes Mellitus Tipo 1/metabolismo , Epigênese Genética , Feminino , Células-Tronco Hematopoéticas , Humanos , Hiperglicemia/metabolismo , Masculino , Células Mieloides/metabolismo , Fatores de Transcrição
20.
Nucleosides Nucleotides Nucleic Acids ; 39(8): 1150-1161, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32643557

RESUMO

Diabetes mellitus is a debilitating health care problem affecting 382 million people around the world and one of the most common complications is diabetic nephropathy. For this reason, it is important to try to identify new mechanisms that could be involved in diabetes. A new class of receptors has been reported, called orphan receptors because the associated ligand and signaling cascades are unknown. These receptors could be an important source of targets for the treatment of many diseases such as diabetes and its associated complications like diabetic nephropathy. Therefore, the aim of this work was to study expression of the orphan receptors GPR149, GPR153, GPR176, TAAR3, TAAR5 and TAAR9 in the kidney of diabetic rats. We used male Wistar rats at 10-12 weeks of age. Diabetes was induced by a single dose of streptozotocin (60 mg/kg i.p.). After 4 weeks, tissues were obtained, and the expression of the mRNAs was measured by RT-PCR. Our results showed that the orphan receptors are expressed in a different way in the kidney. In conclusion, we suggest that orphan receptors could be involved in the development of diabetic nephropathy.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Nefropatias Diabéticas/metabolismo , Receptores Nucleares Órfãos/genética , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/induzido quimicamente , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/induzido quimicamente , Perfilação da Expressão Gênica , Masculino , Receptores Nucleares Órfãos/metabolismo , Ratos , Ratos Wistar , Estreptozocina
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