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Accumulation of advanced glycation endproducts (AGEs) is linked to decline in renal function, particularly in patients with diabetes. Major forms of AGEs in serum are protein-bound AGEs and AGE free adducts. In this study, we assessed levels of AGEs in subjects with and without diabetes, with normal renal function and stages 2 to 4 chronic kidney disease (CKD), to identify which AGE has the greatest progressive change with decline in renal function and change in diabetes. We performed a cross-sectional study of patients with stages 2-4 CKD, with and without diabetes, and healthy controls (n = 135). Nine protein-bound and free adduct AGEs were quantified in serum. Most protein-bound AGEs increased moderately through stages 2-4 CKD whereas AGE free adducts increased markedly. Methylglyoxal-derived hydroimidazolone MG-H1 free adduct was the AGE most responsive to CKD status, increasing 8-fold and 30-fold in stage 4 CKD in patients without and with diabetes, respectively. MG-H1 Glomerular filtration flux was increased 5-fold in diabetes, likely reflecting increased methylglyoxal glycation status. We conclude that serum MG-H1 free adduct concentration was strongly related to stage of CKD and increased in diabetes status. Serum MG-H1 free adduct is a candidate AGE risk marker of non-diabetic and diabetic CKD.
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Diabetes Mellitus , Nefropatias Diabéticas , Insuficiência Renal Crônica , Humanos , Reação de Maillard , Aldeído Pirúvico , Produtos Finais de Glicação Avançada , Estudos TransversaisRESUMO
BACKGROUND: Advances in information communications technology (ICT) provide opportunities for enhanced diabetes care. Knowledge of the more acceptable communication modalities in patients of different ages will help to inform the direction of future innovations. METHODS: An anonymous ICT survey (examining access and use of mobile phones, computers, tablets, and the Internet and attitudes toward e-mail, Web-based consultations, and online peer-support) was conducted at the Royal Prince Alfred Hospital Diabetes Centre in Sydney, Australia. Survey deployment occurred during 4-month periods in 2012 and 2017. Respondents were stratified by current age (<40 or ≥40 years). RESULTS: A total of 614 unselected patients (20% with type 1 diabetes, 55% with type 2 diabetes, 13% with gestational diabetes mellitus, and 12% with an undisclosed type of diabetes) completed the survey. Access to ICT increased from 89% in 2012 to 97% in 2017. The most commonly owned device was a mobile phone (87% ownership in 2017). Increase in mobile Internet usage in the <40 years of age subgroup was significant (P = 0.04). Significant increases in Internet access and smartphone feature use were observed in patients aged ≥40 years (P ≤0.001 for all). Overall use of short message service (SMS, or text messaging) was high (90 and 80% for ages <40 and ≥40 years, respectively). Use of digital applications was low, even among the young (45% in 2017). Comfort with online consultations (40%) and support groups (32%) was also low. CONCLUSION: Access to and acceptance and use of ICT is high, especially in those <40 years of age; however, the greatest increases were seen in those aged ≥40 years. High penetrance of mobile phones and text messaging in all age-groups would suggest that innovations involving an SMS platform have the greatest potential to enhance diabetes care.
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Increasingly, we recognise that type 2 diabetes in youth is a disease with an aggressive time course and a significant complication risk. On the other hand, outcomes for youth with type 1 diabetes appear generally to be improving. With increasing numbers of both types of diabetes in youth, it is timely that a comparative perspective is offered to help clinicians prognosticate more appropriately. Contemporary comparative studies add a new perspective to a consistent story, that for youth-onset type 2 diabetes, the development and progression of cardio-renal complications are increased and the survival prognosis is significantly worse than for type 1 diabetes. Here, we review this mounting evidence, highlight the importance of metabolic syndrome factors in the excess risk and underscore that there remains a significant mortality gap for youth with either type of diabetes, to be addressed as a matter of urgency.
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Albuminúria/mortalidade , Complicações do Diabetes/mortalidade , Diabetes Mellitus Tipo 1/mortalidade , Diabetes Mellitus Tipo 2/mortalidade , Adolescente , Idade de Início , Albuminúria/etiologia , Doenças Cardiovasculares/mortalidade , Criança , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/mortalidade , Nefropatias Diabéticas/mortalidade , Neuropatias Diabéticas/mortalidade , Progressão da Doença , Humanos , Fatores de RiscoRESUMO
The coexistence of depression with diabetes significantly increases the likelihood of developing complications. This study aimed to describe the presence and severity of depression in immigrant Chinese Australian people with diabetes and explore its relationship to sociodemographic and diabetes-related factors. This study found that approximately one-fifth of immigrant Chinese Australian people with diabetes had symptoms consistent with moderate to severe depression and that individuals who are socially isolated and have more complex treatment and complications of diabetes are particularly at risk.
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Monocytes express many cell surface markers indicative of their inflammatory and activation status. Whether these markers are affected by diabetes and its complications is not known and was investigated in this study. Blood was obtained from 22 nondiabetic and 43 diabetic subjects with a duration of diabetes >10 years, including 25 without and 18 with clinically significant complications. The number of CD45(+)CD14(+) monocytes and the percentage expressing the proinflammatory marker CD16 were determined by flow cytometry. Other markers of monocyte activation and expression of chemokine receptors were also examined. The relationship between monocyte CD16 and clinical data, selected cytokines, and chemokines was also investigated. Diabetes had no effect on total white cell number but increased monocyte number. Diabetes also significantly decreased the number of CD16(+) monocytes but only in those with diabetic complications. Other markers of monocyte activation status and chemokine receptors were not affected by diabetes or complications status. Diabetes induced plasma proinflammatory cytokines and they were lower in diabetic subjects with complications compared to those without complications. These results suggest that the circulating monocyte phenotype is altered by diabetic complications status. These changes may be causally related to and could potentially be used to predict susceptibility to diabetic complications.
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Complicações do Diabetes/sangue , Monócitos/química , Receptores de IgG/análise , Adulto , Idoso , Biomarcadores/análise , Feminino , Proteínas Ligadas por GPI/análise , Proteínas Ligadas por GPI/fisiologia , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Receptores de IgG/fisiologiaRESUMO
BACKGROUND & AIMS: While type 2 diabetes is an independent risk factor for worsening of human non-alcoholic steatohepatitis (NASH) in clinical studies, it has not been systematically reported in any model whether diabetes exacerbates NASH. The study aim was to determine if diabetes causes NASH progression in a mouse model of diet induced obesity. METHODS: C57BL/6 mice were fed a high fat diet (HFD: 45% kcal fat) or standard chow (CHOW: 12% kcal fat) for 20 weeks and some animals (HFD+DM or CHOW+DM) were also rendered diabetic by low dose streptozotocin for the final 5 weeks, to model type 2 diabetes. Serum assays included circulating insulin, triglyceride, ALT and AST, glucose, and ultrasensitive CRP and results of insulin tolerance tests. Intrahepatic lipid, triglyceride, macrophage infiltration, and fibrosis were determined. Fibrosis markers collagen-I, collagen-III, CTGF, TIMP-1, and FAP were assessed by qPCR and CTGF and collagen-I by immunostaining. RESULTS: HFD mice were obese, insulin resistant and hyperinsulinaemic, with NASH features of elevated intrahepatic lipid and macrophages, but without fibrosis. In contrast, the HFD+DM mice exhibited fibrosis in addition to these NASH features. By ANOVA, Sirius red staining at perisinusoidal, portal tract and central vein sites, collagen-I, collagen-III, FAP, and TIMP-1 transcripts and collagen-I and CTGF protein were each significantly increased in HFD+DM, compared with CHOW alone. In a further experiment, insulin treatment protected against fibrosis and CRP increases in HFD+DM, showing that diabetes, not streptozotocin, causes the fibrosis. CONCLUSIONS: This novel model indicates that diet-induced NASH fibrosis is exacerbated by diabetes and attenuated by insulin therapy.
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Diabetes Mellitus Experimental/complicações , Fígado Gorduroso/etiologia , Animais , Colágeno/genética , Colágeno/metabolismo , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Gorduras na Dieta/administração & dosagem , Modelos Animais de Doenças , Progressão da Doença , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Humanos , Insulina/uso terapêutico , Metabolismo dos Lipídeos , Glicogênio Hepático/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Obesidade/complicações , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: Young-onset type 2 diabetes is an aggressive disease characterized by development of diabetic complications, including nephropathy, early in the disease course. However, within the cohort of young-onset type 1 and type 2 diabetes there are limited comparative data regarding progression to ESKD requiring renal replacement therapy or renal-related death (RRT/RRD). METHODS: Probabilistic linkage of data from the RPAH Diabetes Centre, National Death Index and Australian and New Zealand Dialysis and Transplant Registry was undertaken. Cumulative Incidence Competing Risk and Cox Proportional Hazards Modelling approaches were utilized to examine progression to ESKD in young-onset type 1 and type 2 diabetes (age of diagnosis 15-35 years). FINDINGS: Unadjusted incidence rates (95% CI) of RRT/RRD in young-onset type 1 and type 2 diabetes were 3.1 (2.3-4.0) and 4.6 (3.7-5.7) per 1000 person years respectively. After adjustment for gender, ethnicity and duration of diabetes, the HR (95% CI) of RRT/RRD in young-onset type 2 diabetes was 2.0 (1.4-2.9). The HR remained higher after further adjustment for first available cholesterol, HbA1c and systolic blood pressure but not BMI. For those who progressed to RRT, prognosis was similar irrespective of diabetes type; cumulative incidence of mortality was 40% in both young-onset type 1 and type 2 diabetes after 6 years of dialysis. INTERPRETATION: Progression to RRT/RRD is greater in young-onset type 2 diabetes than in young-onset type 1 diabetes. The increased progression is associated with increased BMI. However, once ESKD is reached, individuals with young-onset type 1 and type 2 diabetes do equally poorly.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Falência Renal Crônica , Terapia de Substituição Renal , Adolescente , Adulto , Austrália/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Humanos , Incidência , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/terapia , Sistema de Registros , Taxa de Sobrevida , Adulto JovemRESUMO
Infiltration of macrophages to the kidney is a feature of early diabetic nephropathy. For this to happen monocytes must become activated, migrate from the circulation, and infiltrate the mesangium. This process involves degradation of extracellular matrix, a process mediated by matrix metalloproteinases (MMPs). In the present study we investigate the expression of proinflammatory cytokines TNF-alpha, IL-6, and MMP-9 in glomeruli of control and diabetic rodents and use an in vitro coculture system to examine whether factors secreted by mesangial cells in response to a diabetic milieu can induce monocyte MMP-9 expression and infiltration. After 8 wk of diabetes, the glomerular level of TNF-alpha, IL-6, and macrophage number and colocalization of MMP-9 with macrophage were increased (P < 0.01). Coculture of THP1 monocytes and glomerular mesangial cells in 5 or 25 mM glucose increased MMP-9 (5 mM: 65% and 25 mM: 112%; P < 0.05) and conditioned media degradative activity (5 mM: 30.0% and 25 mM: 33.5%: P < 0.05). These effects were reproduced by addition of mesangial cell conditioned medium to THP1 cells. High glucose (25 mM) increased TNF-alpha, IL-6, and monocyte chemoattractant protein-1 in mesangial cell conditioned medium. These cytokines all increased adhesion and differentiation of THP1 cells (P < 0.05), but only TNF-alpha and IL-6 increased MMP-9 expression (50- and 60-fold, respectively; P < 0.05). Our results show that mesangial cell-secreted factors increase monocyte adhesion, differentiation, MMP expression, and degradative capacity. High glucose could augment these effects by increasing mesangial cell proinflammatory cytokine secretion. This mesangial cell-monocyte interaction may be important in activating monocytes to migrate from the circulation to the kidney in the early stages of diabetic nephropathy.
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Nefropatias Diabéticas/patologia , Inflamação/patologia , Células Mesangiais/fisiologia , Monócitos/fisiologia , Animais , Antígeno CD11b/biossíntese , Adesão Celular , Linhagem Celular , Células Cultivadas , Quimiotaxia de Leucócito/fisiologia , Citocinas/metabolismo , Diabetes Mellitus Experimental/patologia , Citometria de Fluxo , Humanos , Contagem de Leucócitos , Macrófagos/fisiologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Inibidores Teciduais de Metaloproteinases/metabolismoRESUMO
BACKGROUND: A number of previous studies exploring family history of type 2 diabetes have reported a predominance of maternal diabetes. These studies have not explicitly compared parental history of diabetes across the spectrum of disease onset from youth to later adulthood. METHODS: Family history data from 11,467 patients with type 2 diabetes were extracted from the RPA Diabetes Centre database. Parental histories of diabetes were compared across a range of age of diagnosis strata (15-<30, 30-<40, 40-<50, 50-<60 and 60-<70â¯years). For the young-onset group (diagnosed between 15 and 30â¯years of age), associations between parental history of diabetes and the presence of cardio-metabolic risk factors and diabetic complications were also explored. RESULTS: For the total cohort and within each age of diagnosis strata, more individuals reported maternal history than paternal history of diabetes. The young-onset group demonstrated the highest prevalence of any parental history of diabetes (60.7%), the highest combined maternal and paternal history (15.8%) and the smallest differential between maternal (25.1%) and paternal (19.7%) history of diabetes. Within the young-onset group, no significant association between parental history and cardio-metabolic risk factors or diabetic complications were identified after a median of 15.0â¯years of diabetes exposure. CONCLUSION: Overall, our results demonstrate a consistent maternal excess of diabetes which could be consistent with an underlying epigenetic effect. However, the differential between maternal and paternal history is significantly lower in the young-onset group. Earlier emergence of type 2 diabetes may therefore reflect a different interaction and impact of genetic and environmental factors.
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Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Pai/estatística & dados numéricos , Anamnese/estatística & dados numéricos , Mães/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Idade de Início , Idoso , Estudos de Coortes , Diabetes Mellitus Tipo 2/genética , Diabetes Gestacional/epidemiologia , Feminino , Humanos , Padrões de Herança/genética , Masculino , Pessoa de Meia-Idade , Gravidez , Fatores de Risco , Adulto JovemRESUMO
Foot ulcers and poor wound healing are problematic for patients with diabetes. The beehive protectant Propolis can improve wound healing but whether it can improve healing in diabetic wounds has not been investigated. In this study, the effect of a single application of Propolis on epithelial closure, wound morphology, cellular infiltrate, and blood vessel density were investigated. Diabetes was induced in rats using streptozocin. After 6 weeks, diabetic and control animals were wounded and the wounds were treated with Propolis or saline as control. At days 6 and 12 animals were sacrificed and wounds were excised. Compared with controls, diabetes decreased epithelial closure and reepithelialization but had no effect on wound contraction. These delays were prevented by Propolis. At day 12, the impaired macrophage infiltration (C:1.49+/-0.09 vs. D:0.25+/-0.14), persistent neutrophil infiltration (C:0.22+/-0.19 vs. D:1.33+/-0.81), and increased myeloperoxidase activity (fourfold) in diabetic wounds were prevented by Propolis. Diabetes had no effect on wound volume, vessel number, or branch points. These novel data indicate that Propolis can accelerate wound healing in diabetes. As neutrophil infiltration is normalized, its mechanism of action may be through anti-inflammatory pathways. This result and the established safety profile of Propolis provide a rationale for studying topical application of this agent in a clinical setting.
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Anti-Inflamatórios/uso terapêutico , Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus Experimental , Própole/uso terapêutico , Úlcera Cutânea/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
The significance of the metabolic syndrome in type 1 diabetes is not well understood. This study aimed to estimate its prevalence and attendant complications. Four hundred twenty-seven type 1 diabetic subjects were grouped according to the presence or absence of metabolic syndrome (WHO criteria). Macro- and microvascular complications were compared between the groups as individual and as composite endpoints. Data were analyzed for the total cohort and in subgroups according to duration of diabetes quartiles (<6.9, 7-12.9, 13-19.9, and >20 years) and year of presentation. Fifteen percent of individuals fulfilled the WHO criteria for metabolic syndrome, and of these, 26.9% were insulin resistant, as compared with 3.4% of those without metabolic syndrome [odds ratio (OR)=8.9, P=.001]. Both BMI and metabolic syndrome showed an increasing trend from 1992 to 2003. Those with metabolic syndrome required significantly higher insulin dosage [0.9 (0.7-1.2) vs. 0.6 (0.5-0.9) units/kg, P=.03], were older [35.0 (26.2-47.3) vs. 29.7 (23.4-36.4) years, P=.002], and had longer duration of diabetes [19.7 (10.7-25.6) vs. 12.1 (6.3-17.9) years, P=.0001]. They also had a significantly higher macrovascular composite endpoint (OR=3.3, P=.02) as well as higher macrovascular and microvascular composite endpoint (OR=3.1, P=.0001). The prevalence of stroke (OR=22.8, P=.008), peripheral vascular disease (OR=7.3, P=.05), and severe retinopathy (OR=3.7, P=.01) is higher in subjects with metabolic syndrome in the >or=20-year quartile group; in addition, these subjects have higher macrovascular composite endpoint (OR=3.9, P=.03) and macrovascular and microvascular composite endpoint (OR=2.9, P=.03). This remained so even when subjects with albuminuria were excluded. Some individuals with type 1 diabetes can also have metabolic syndrome. They are more prone to complications and require even more intensive glycemic control and reduction of macrovascular risk factors.
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Diabetes Mellitus Tipo 1/complicações , Síndrome Metabólica/complicações , Adulto , Diabetes Mellitus Tipo 1/fisiopatologia , Dislipidemias/complicações , Dislipidemias/fisiopatologia , Feminino , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Resistência à Insulina/fisiologia , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/fisiopatologia , Prevalência , Estudos Retrospectivos , Fatores de Risco , Doenças Vasculares/etiologiaRESUMO
PURPOSE: This article aims to study the effects of ruboxistaurin (RBX) on skin microvascular blood flow (SkBF) and evaluate the relationship between endothelial and neural control of SkBF in patients with diabetic peripheral neuropathy (DPN). METHODS: We studied 11 placebo- and 9 RBX (32 mg/day)-treated patients who participated in a 1-year, double-masked, randomized, Phase 3 study of RBX for treatment of DPN sensory symptoms. Patients had type 1 or type 2 diabetes, a detectable sural sensory nerve action potential, and Neuropathy Total Symptom Score-6 (NTSS-6) >6 points. SkBF was measured by laser Doppler velocimetry, combined with iontophoresis of acetylcholine and sodium nitroprusside, at baseline, 3 months, and 1 year. Sensory symptoms and electrophysiology were also evaluated during the study. The relationship between endothelial and neural control of SkBF at baseline was assessed using linear regression. RESULTS: No significant differences (RBX vs. placebo) were demonstrable for post-iontophoresis SkBF [fold increase from basal state (1 year): endothelium-dependent, 3.6 vs. 8.6; endothelium-independent, 3.7 vs. 2.0; C fiber-mediated, 1.7 vs. 2.0; P>.05] or sensory symptoms [NTSS-6 total score (1 year): 7.7 vs. 6.0 points; P=.4]. There were also no significant between-group differences in nerve conduction parameters, except for placebo peroneal nerve conduction velocity, which demonstrated a statistically significant improvement of unknown clinical importance (Z=2.1; P=.034). At baseline, C fiber-mediated vasodilatation correlated well with endothelium-dependent vasodilation (r=.7, P<.01) but not with endothelium-independent vasodilatation (r=-.1, P=.7). CONCLUSIONS: RBX demonstrated no effect on SkBF or sensory symptoms after 1 year in this cohort. The correlation between C fiber-mediated and endothelium-dependent SkBF at baseline suggests that improving endothelial function could affect the microcirculation not only locally but also via the neurovascular arcade.
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Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Neuropatias Diabéticas/tratamento farmacológico , Endotélio Vascular/fisiopatologia , Inibidores Enzimáticos/uso terapêutico , Indóis/uso terapêutico , Maleimidas/uso terapêutico , Microcirculação/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Pele/irrigação sanguínea , Adulto , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Eletrofisiologia , Endotélio Vascular/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/fisiologia , Proteína Quinase C beta , Análise de Regressão , Pele/inervaçãoRESUMO
The aim of this study was to characterise microvascular blood flow in the skin and to compare it with biomarkers of endothelial dysfunction and tissue inflammation in patients with type 2 diabetes with (n=20) or without (n=20) microvascular complications and 20 control subjects. Microvascular function was measured by laser Doppler velocimetry in combination with iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). Blood was collected for measurement of biomarkers including plasminogen activator inhibitor-1 (PAI-1), soluble intercellular adhesion molecule (sICAM), soluble vascular cell adhesion molecule (sVCAM) and high-sensitivity C-reactive protein (hsCRP). Both ACh and SNP responses fall progressively with the development of diabetes and microvascular complications. For the total cohort, there was a significant overall correlation between ACh and SNP response (r=0.7, p<0.0001), and this relationship was particularly strong in those with microvascular complications. There was a trend towards higher hsCRP levels across the three groups, but no difference in other biomarkers. Abnormalities of microvascular blood flow are evident in diabetes and become more marked with the development of microvascular complications. This relationship was similar to that shown by the marker of inflammation (hsCRP), but stronger than that pertaining to biomarkers of endothelial function. As both ACh and SNP responses are attenuated, the disturbance is not characteristic of endothelial dysfunction alone.
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Biomarcadores/sangue , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/diagnóstico , Endotélio Vascular/fisiopatologia , Microcirculação/fisiopatologia , Pele/irrigação sanguínea , Acetilcolina , Adulto , Idoso , Proteína C-Reativa/metabolismo , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/sangue , Feminino , Humanos , Iontoforese , Fluxometria por Laser-Doppler , Masculino , Pessoa de Meia-Idade , Nitroprussiato , VasodilatadoresRESUMO
Abnormalities of endothelial function have been demonstrated in diabetes and are thought to play a role in the pathogenesis of diabetic complications. The aims of this study were to determine whether aminoguanidine, an inhibitor of glycation, can prevent endothelial and microcirculation abnormalities in a primate model of type 1 diabetes. Male baboons (Papio hamadryas) were assigned to one of the four groups: control, diabetes, control treated with aminoguanidine or diabetes treated with aminoguanidine. Diabetes was induced by streptozocin (60 mg/kg) and treated with once daily injection of insulin. Aminoguanidine was given subcutaneously (10 mg/kg), once a day. Diabetic animals had a mean duration of diabetes of 8.9 +/- 3.4 years and HbA1c of 8.9 +/- 1.1%. Microvascular function was measured by laser Doppler velocimetry, with examination of endothelium-dependent increase in skin blood flow (SkBF) following iontophoresis of acetylcholine (ACh) and endothelium-independent increase in SkBF in response to the nitric oxide (NO) donor sodium nitroprusside (SNP). Multiple regression analysis identified diabetes (P = 0.049) and aminioguanidine treatment (P = 0.026) as significant determinants of ACh response. The diabetic baboons treated with aminoguanidine had less Ach-mediated SkBF response compared with controls (1.39 +/- 0.32 vs. 2.26 +/- 0.61, F = 3.3, P = 0.04), but there was no difference between groups in SkBF response to SNP. We conclude that endothelial dysfunction can be demonstrated in this primate model of type 1 diabetes at a stage when overt diabetic complications are not present. This occurred in the absence of insulin resistance or significant hypercholesterolemia. Administration of aminoguanidine from the onset of diabetes was not able to prevent this abnormality and in fact aggravated the endothelial response. Effects of aminoguanidine on NO synthase may contribute to this phenomenon.
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Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Guanidinas/farmacologia , Animais , Modelos Animais de Doenças , Endotélio Vascular/fisiologia , Masculino , Papio hamadryas , Fatores de Tempo , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
OBJECTIVE: Many individuals with diabetes experience neuropathic pain, often without objective signs of large-fiber neuropathy. We examined intraepidermal nerve fibers (IENFs) to evaluate the role of small nerve fibers in the genesis of neuropathic pain. RESEARCH DESIGN AND METHODS: Twenty-five diabetic subjects with neuropathic pain and 13 without were studied. The pain was present for at least 6 months for which no other cause could be found. Punch skin biopsies were obtained from the distal leg. IENFs were stained using antibody to protein gene product 9.5 and counted with confocal microscopy. Neuropathy was graded by vibration perception and cold detection thresholds and the Michigan Neuropathy Screening Instrument. RESULTS: In the total cohort, IENF density was significantly lower in those with pain compared with those without (3 [1-6] vs. 10 [3-19], respectively, P = 0.02). There were significant inverse correlations between IENF and severity of neuropathy, with the pain group having a flatter gradient than their pain-free counterparts (P < 0.02). The difference in IENF density was greatest in subjects with less objective evidence of neuropathy (P < or = 0.01). CONCLUSIONS: More severe loss of IENF is associated with the presence of neuropathic pain only in those with little or no objective sign of neuropathy. Thus, loss of IENF cannot explain pain in all cases, suggesting that different mechanisms underpin the genesis of pain at various stages of neuropathy.
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Neuropatias Diabéticas/patologia , Epiderme/inervação , Fibras Nervosas/patologia , Dor/patologia , Idoso , Biópsia , Neuropatias Diabéticas/diagnóstico , Feminino , Pé , Humanos , Masculino , Pessoa de Meia-Idade , Tato , VibraçãoRESUMO
OBJECTIVE: The U.K. Prospective Diabetes Study (UKPDS) has demonstrated that metformin is as effective as sulfonylureas in obese subjects and is associated with less weight gain, fewer hypoglycemic episodes, and better cardiovascular outcomes. It is hence the pharmacological therapy of choice in this subgroup. However, a gap in our present knowledge is the long-term response to metformin in nonobese individuals. In this study, we compared metformin therapy in normal, overweight, and obese individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: A database of patients treated at a referral center in Sydney, Australia, were analyzed. Patients with type 2 diabetes and complete HbA(1c) (A1C) data and treated with metformin or sulfonylurea monotherapy for at least three visits before receiving dual oral therapy were included (n = 644). Analysis by BMI and the type of oral agent was performed. Individuals were categorized as normal, overweight, or obese (BMI <25, 25-29.9, and >/=30 kg/m(2), respectively). RESULTS: There were no differences between the initial, follow-up, and last A1C between the three metformin-treated groups. The duration of successful glycemic control with metformin monotherapy in the normal and overweight individuals and their incidences of diabetes-related complications for the entire duration of follow-up were not inferior to those of the obese individuals. The nonobese patients performed better regardless of the type of oral hypoglycemic agent used. CONCLUSIONS: We conclude that metformin is at least as efficacious in normal and overweight individuals as it is in those who are obese. Our study provides evidence-based data to support metformin use in nonobese individuals with type 2 diabetes.
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Peso Corporal , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Administração Oral , Idoso , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , Bases de Dados Factuais , Complicações do Diabetes/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Seguimentos , Humanos , Incidência , Pessoa de Meia-Idade , Obesidade/complicações , Resultado do TratamentoRESUMO
OBJECTIVE: To determine the effect of sulfonylurea-related hypoglycemia on cardiac repolarization and ectopy in the setting of well-controlled type 2 diabetes. RESEARCH DESIGN AND METHODS: Thirty subjects with sulfonylurea-treated type 2 diabetes underwent 48 h of concurrent continuous glucose monitoring and ambulatory electrocardiography. Ventricular repolarization (QTc) and QT dynamicity were analyzed during periods of hypoglycemia (<3.5 mmol/L for >20 min) and compared with periods of euglycemia and hyperglycemia combined. Cardiac ectopy rates during hypoglycemia were compared with ectopy rates when blood glucose was 4-10 mmol/L. RESULTS: Mean HbA1c was 6.9% (52 mmol/mol). Hypoglycemia was detected in 9 of 30 subjects (30%); episodes were typically nocturnal (67%) and asymptomatic (73%). Hypoglycemia-associated QTc prolongation was seen in five of nine subjects with a large variation in individual response. Higher QT dynamicity, a poor prognostic factor in cardiac disease, was seen in subjects who experienced hypoglycemia compared with subjects who did not (0.193 vs. 0.159 for the nocturnal period; P = 0.01). This finding persisted after the hypoglycemic event. The rates of ventricular and supraventricular ectopy demonstrated a nonsignificant trend toward an increase during hypoglycemia (median rate ratio 1.58 and 1.33, respectively). Similar, nonsignificant results were observed in a separate insulin-treated cohort. CONCLUSIONS: Hypoglycemia, often unrecognized, is a frequent finding in well-controlled sulfonylurea-treated type 2 diabetes. It is associated with the novel finding of increased QT dynamicity and QTc prolongation in some individuals. Our findings suggest sulfonylurea-related hypoglycemia can have detrimental cardiovascular sequelae. Similar effects are also seen in the setting of insulin therapy.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Coração/efeitos dos fármacos , Hipoglicemia/induzido quimicamente , Hipoglicemia/fisiopatologia , Hipoglicemiantes/efeitos adversos , Compostos de Sulfonilureia/efeitos adversos , Idoso , Arritmias Cardíacas/fisiopatologia , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Eletrocardiografia Ambulatorial , Feminino , Coração/fisiopatologia , Frequência Cardíaca/fisiologia , Humanos , Hipoglicemia/sangue , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Compostos de Sulfonilureia/uso terapêuticoRESUMO
OBJECTIVE: To test whether the rate of diabetic retinopathy development in a population calculated from the prevalence of retinopathy and duration of diabetes can be used to assess their prior glycemic control. RESEARCH DESIGN AND METHODS: 9281 patients with type 2 diabetes (T2DM) were grouped by duration of diabetes and plotted against the % of retinopathy in each band. The slope was used to calculate retinopathy development/year (RD/y). We correlated the RD/y with updated HbA1c within groups of different ethnicity, age of diabetes onset, year of the eye examination, socio-economic status and fluency in English. RESULTS: Differences in ethnicity, age of diabetes onset and year of the eye examination affect RD/y to a degree predictable from their respective updated HbA1c. No such relationship with updated HbA1c was evident when a factor has no apparent effect on RD/y. CONCLUSIONS: This relationship between prevalence of retinopathy and duration of diabetes can be used to assess future retinopathy burden. Perhaps more intriguing, the camera can be reversed to allow an estimate of prior glycemic control of a population from its retinopathy prevalence. Health care organizations can use this method to project future needs and to assess adequacy of prior glycemic control.
Assuntos
Diabetes Mellitus Tipo 2/terapia , Retinopatia Diabética/prevenção & controle , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Modelos Cardiovasculares , Vigilância em Saúde Pública/métodos , Adulto , Austrália/epidemiologia , Estudos de Coortes , Terapia Combinada , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Retinopatia Diabética/epidemiologia , Progressão da Doença , Registros Eletrônicos de Saúde , Feminino , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos RetrospectivosRESUMO
OBJECTIVES: To determine whether small nerve fiber dysfunction predicts pain in diabetic neuropathy using quantitative sensory testing of thermal thresholds. METHODS: Diabetic patients with or without painful neuropathy (n=191) were studied. Small nerve fiber function was assessed by quantitative sensory testing of cold detection and heat pain thresholds. Subjects were also categorized as being hyperalgesic (<10th percentile) or hyposensitive (>90th percentile) by comparing with normative data. Vibration perception threshold, a large nerve fiber function, was measured using a biothesiometer (Bio-medical Instrument, Newbury, OH). RESULTS: In the patients with pain, cold stimulus was detected after a greater reduction in temperature from baseline (-3.7 degrees C vs. -0.6 in the no-pain group, P<0.0001). There were no differences between the pain and painless groups in the heat pain tests, with hyperalgesia noted in about 60% of subjects. Vibration perception threshold and loss of ankle reflexes were significant determinants of pain, but together they accounted for only 6.8% of the variance. If these were removed from the model, cold detection threshold became a significant determinant of pain but accounted for only 3.0% of the variance. CONCLUSIONS: Quantitative sensory testing of small nerve fiber function is a useful test to detect the presence of neuropathy, and overall diabetic patients with neuropathic pain have more sensory loss. However, small nerve fiber abnormalities detected by quantitative sensory testing do not predict the presence of pain in diabetic neuropathy.