Rastreamento de cardiopatias congênitas associadas ao diabetes mellitus por meio da concentração plasmática materna de frutosamina

OBJETIVO: avaliar a importância da concentração plasmática materna de frutosamina como indicador de cardiopatias congênitas fetais, em gestações complicadas pelo diabetes mellitus. MÉTODOS: o estudo retrospectivo incluiu 91 gestantes portadoras de diabetes mellitus, as quais foram submetidas à ecocardiografia fetal de rotina em centro universitário de referência em Medicina Fetal. Foram selecionadas 65 pacientes que apresentavam diabete pré-gestacional e registro em prontuário médico de frutosamina plasmática anterior ao exame ultrassonográfico. A primeira dosagem registrada foi confrontada com o resultado da ecocardiografia fetal de rotina, realizada por médico especialista do serviço. A presença ou ausência de achados ecográficos de cardiopatia congênita (AECC) foi relacionada aos níveis plasmáticos de frutosamina, por meio de teste de médias, e sua acuidade para AECC verificada por curva ROC. Foram discutidos como pontos de corte os valores da concentração plasmática materna de frutosamina de 2,68, 2,9 e 2,23 mmol/L, que são, respectivamente, o valor de referência local do laboratório, o do kit de dosagem empregado e o de maior acurácia global. RESULTADOS: o AECC foi encontrado em 52,3% dos fetos. A primeira dosagem de frutosamina durante o pré-natal aconteceu em média com 20,4±8,0 semanas de gestação. A capacidade da concentração materna de frutosamina em identificar fetos com AECC foi significante (p<0,0001) e apresentou área sob a curva ROC de 0,78 (IC95%=0,66-0,89). A concentração plasmática de frutosamina de 2,9 mmol/L apontou AECC com maior especificidade e, porém, com maior porcentual de falso-negativo (96,8 e 55,9%). Valores acima de 2,68 mmol/L associam-se à probabilidade de 4,6 em identificar fetos com AECC em relação a valores inferiores, com sensibilidade de 58,8% e especificidade de 87,1%. O valor de 2,23 mmol/L mostrou-se de maior acurácia global entre os três pontos sugeridos, com sensibilidade de 88,2% na identificação de fetos com anormalidades à ecocardiografia. CONCLUSÕES: é possível utilizar a dosagem plasmática de frutosamina materna, obtida no segundo trimestre, para direcionar gestantes de risco aos centros de referência em ecocardiografia fetal. Os achados são relevantes no seguimento de gestantes portadoras de diabetes mellitus que iniciam tardiamente o pré-natal.

A importância do teste de tolerância à glicose oral no diagnóstico da intolerância à glicose e diabetes mellitus do tipo 2 em mulheres com síndrome dos ovários policísticos

OBJETIVO: Avaliar a importância do teste de tolerância à glicose oral (TTGO) no diagnóstico da intolerância à glicose (IG) e diabetes mellitus do tipo 2 (DM-2) em mulheres com SOP. MÉTODOS: Estudo retrospectivo em que foram incluídas 247 pacientes portadoras de SOP, selecionadas de forma aleatória. O diagnóstico de IG foi obtido por meio do TTGO de duas horas com 75 gramas de glicose de acordo com os critérios do World Health Organization (WHO) (IG: glicemia plasmática aos 120 minutos >140 mg/dL e <200 mg/dL); e o de DM-2 tanto pelo TTGO (DM: glicemia plasmática aos 120 minutos >200 mg/dL) quanto pela glicemia de jejum segundo os critérios da American Diabetes Association (glicemia de jejum alterada: glicemia plasmática >100 e <126 mg/dL; DM: glicemia de jejum >126 mg/dL). Para comparar o TTGO com a glicemia de jejum foi aplicado o modelo de regressão logística para medidas repetidas. Para a análise das características clínicas e bioquímicas das pacientes com e sem IG e/ou DM-2 foi utilizada a ANOVA seguida do teste de Tukey. O valor p<0,05 foi considerado estatisticamente significante. RESULTADOS: As pacientes com SOP apresentaram média etária de 24,8±6,3 e índice de massa corpórea (IMC) entre 18,3 e 54,9 kg/m² (32,5±7,6). O percentual de pacientes obesas foi de 64%, de sobrepeso 18,6%, e peso saudável 17,4%. O TTGO identificou 14 casos de DM-2 (5,7%), enquanto a glicemia de jejum detectou somente três casos (1,2%), sendo que a frequência destes distúrbios foi maior com o aumento da idade e IMC. CONCLUSÕES: Os resultados do presente estudo demonstram a superioridade do TTGO em relação à glicemia de jejum em diagnosticar DM-2 em mulheres jovens com SOP e deve ser realizado neste grupo de pacientes.

Estudo do perfil hemodinâmico da artéria oftálmica em gestantes com diabetes mellitus gestacional

OBJETIVOS: Avaliar os padrões hemodinâmicos da artéria oftálmica, por meio da doplervelocimetria, em portadoras de diabetes mellitus gestacional (DMG), e comparar os achados com os obtidos em gestantes normais. MÉTODOS: Estudo prospectivo caso-controle que analisou os índices doplervelocimétricos das artérias oftálmicas. Foram constituídos dois grupos: um com 40 gestantes com diagnóstico de DMG e o outro por 40 gestantes normais. Foram incluídas gestantes com DMG segundo critérios da American Diabetes Association - 2012, com gravidez de 27 semanas até o termo, e excluídas gestantes hipertensas, em uso de drogas vasoativas ou com diagnóstico prévio de diabetes. O estudo foi realizado em um olho com transdutor linear de 10 MHz Sonoace 8000 Live Medison ®. As variáveis analisadas foram: índice de pulsatilidade (IP), índice de resistência (IR), razão entre picos de velocidade (RPV), pico de velocidade sistólica (PVS) e velocidade diastólica final (VDF). Para análise de normalidade das amostras foi empregado o teste de Lillefors, e os testes t de Student e Mann-Whitney, para comparação entre as médias e medianas conforme normalidade dos dados, e adotado nível de significância de 95%. RESULTADOS: As medianas e médias com desvio padrão das variáveis doplervelocimétricas da artéria oftálmica dos grupos de DMG e gestantes normais foram, respectivamente: IP=1,7±0,6 e 1,6±0,4 (p=0,7); IR=0,7 e 0,7 (p=0,9); RPV=0,5±0,1 e 0,5±0,1 (p=0,1); PVS=33,6 e 31,9 cm/seg (p=0,7); VDF=6,3 e 7,9 cm/seg (p=0,4). Não houve diferença significante entre as médias e medianas das variáveis analisadas entre os dois grupos de gestantes. CONCLUSÕES: Os padrões hemodinâmicos das artérias oftálmicas permaneceram inalterados no grupo de gestantes com DMG em relação ao grupo de gestantes normais, sugerindo que o tempo de exposição à doença durante a gestação é curto para causar vasculopatias importantes no território materno central.

Correlação das dosagens de frutosamina e de hemoglobina glicosilada com o perfil glicêmico em gestantes com diabetes mellitus

Objetivo Avaliar se há correlação das dosagens de frutosamina e de hemoglobina glicosilada (HbA1c) com as frequências de desvios de glicemia capilar em gestantes com diabetes mellitus. Métodos estudo observacional, retrospectivo, de corte transversal, incluindo todas as gestantes comdiabetes que iniciaram o pré-natal emhospital terciário de ensino durante o ano de 2014 e que apresentavam pelo menos 20 dias de auto monitoramento glicêmico previamente às dosagens séricas de frutosamina e de HbA1c. Os desvios de glicemia capilar foram considerados "hipoglicemias" quando menores que 70mg/dL ou "hiperglicemias" quando acima do alvo glicêmico terapêutico para o horário. Foram testadas as correlações lineares par a par das dosagens de frutosamina e de HbA1c com as frequências de hipoglicemias e de hiperglicemias capilares pelo teste Tau-b de Kendall. Na sequência, foi avaliada a regressão linear entre as dosagens de HbA1c e de frutosamina e as frequências de hipoglicemias e de hiperglicemias. Resultados Foram incluídas 158 gestantes que contribuíram com 266 amostras para dosagem sérica de frutosamina e HbA1c. As dosagens de frutosamina e de HbA1c apresentaram, respectivamente, coeficientes τ de Kendall de 0,29 (p < 0,001) e 0,5 (p < 0,001) com a frequência de hiperglicemias, e de 0,09 (p = 0,04) e 0,25 (p < 0,001) com a frequência de hipoglicemias capilares. No modelo de regressão linear, as dosagens de frutosamina e de HbA1c apresentaram, respectivamente, coeficientes de determinação R2 = 0,26 (p < 0,001) e R2 = 0,51 (p < 0,001) para a predição de hiperglicemias, e R2 = 0,03 (p = 0,003) e R2 = 0,059 (p < 0,001) para a predição de hipoglicemias. Conclusão As dosagens de frutosamina e de HbA1c apresentam correlação fraca a moderada com as frequências de hiperglicemias e hipoglicemias capilares no auto monitoramento glicêmico e não são capazes de traduzir com precisão os desvios da meta glicêmica no tratamento de gestantes com diabetes.

Estudo comparativo das estruturas do segmento anterior de olhos de cães normais e com catarata, portadores ou não de Diabetes mellitus, avaliados por biomicroscopia ultrassônica

A catarata representa uma das principais causas de cegueira em cães, sendo que as alterações metabólicas provocadas pelo Diabetes mellitus (DM), constituem a segunda causa mais comum de catarata nesta espécie. A biomicroscopia ultrassônica (UBM) é um método ultrassonográfico de alta frequência (50 MHz) que permite a obtenção de imagens do modo B de qualidade microscópica. Este estudo objetivou, por meio do uso da UBM, comparar as estruturas do segmento anterior de olhos de cães com catarata, diabética e não-diabética, às de cães normais, para verificar possíveis alterações decorrentes do DM. Os parâmetros avaliados foram espessura da córnea, profundidade da câmara anterior, aumento de celularidade no interior da câmara anterior e medida do ângulo iridocorneal. Foram realizados exames de 87 olhos de 47 animais da espécie canina, divididos em 3 grupos: grupo controle (GCO), grupo de portadores de catarata não-diabéticos (GCAT) e o grupo dos diabéticos (GDM). Os resultados revelam que o grupo dos diabéticos apresentou maiores espessuras de córnea que os demais grupos enquanto o grupo controle apresentou maiores câmaras anteriores. Encontrou-se aumento de celularidade em câmara anterior apenas nos grupos com catarata. Quando analisadas as medidas do ângulo iridocorneal, não houve diferença entre os 3 grupos. Com base no que foi aferido, permite-se concluir que olhos de cães diabéticos com catarata apresentam maior espessura de córnea central que olhos de cães com catarata de outras etiologias e de cães normais, que há diminuição da câmara anterior, com aumento de celularidade, em olhos de cães com catarata, quando comparados a cães normais e que não há diferença na medida do ângulo iridocorneal em olhos de cães com catarata, diabética ou não, e de cães normais.

Factors predicting mortality in type 2 diabetes. With special reference to physical exercise, blood pressure, proteinuria, inflammation and P wave duration

Background: Type 2 diabetes patients have a 2-4 fold risk of cardiovascular disease (CVD) compared to the general population. In type 2 diabetes, several CVD risk factors have been identified, including obesity, hypertension, hyperglycemia, proteinuria, sedentary lifestyle and dyslipidemia. Although much of the excess CVD risk can be attributed to these risk factors, a significant proportion is still unknown. Aims: To assess in middle-aged type 2 diabetic subjects the joint relations of several conventional and non-conventional CVD risk factors with respect to cardiovascular and total mortality. Subjects and methods: This thesis is part of a large prospective, population based East-West type 2 diabetes study that was launched in 1982-1984. It includes 1,059 middle-aged (45-64 years old) participants. At baseline, a thorough clinical examination and laboratory measurements were performed and an ECG was recorded. The latest follow-up study was performed 18 years later in January 2001 (when the subjects were 63-81 years old). The study endpoints were total mortality and mortality due to CVD, coronary heart disease (CHD) and stroke. Results: Physically more active patients had significantly reduced total, CVD and CHD mortality independent of high-sensitivity C-reactive protein (hs-CRP) levels unless proteinuria was present. Among physically active patients with a hs-CRP level >3 mg/L, the prognosis of CVD mortality was similar to patients with hs-CRP levels ≤3 mg/L. The worst prognosis was among physically inactive patients with hs-CRP levels >3 mg/L. Physically active patients with proteinuria had significantly increased total and CVD mortality by multivariate analyses. After adjustment for confounding factors, patients with proteinuria and a systolic BP <130 mmHg had a significant increase in total and CVD mortality compared to those with a systolic BP between 130 and 160 mmHg. The prognosis was similar in patients with a systolic BP <130 mmHg and ≥160 mmHg. Among patients without proteinuria, a systolic BP <130 mmHg was associated with a non-significant reduction in mortality. A P wave duration ≥114 ms was associated with a 2.5-fold increase in stroke mortality among patients with prevalent CHD or claudication. This finding persisted in multivariable analyses. Among patients with no comorbidities, there was no relationship between P wave duration and stroke mortality. Conclusions: Physical activity reduces total and CVD mortality in patients with type 2 diabetes without proteinuria or with elevated levels of hs-CRP, suggesting that the anti-inflammatory effect of physical activity can counteract increased CVD morbidity and mortality associated with a high CRP level. In patients with proteinuria the protective effect was not, however, present. Among patients with proteinuria, systolic BP <130 mmHg may increase mortality due to CVD. These results demonstrate the importance of early intervention to prevent CVD and to control all-cause mortality among patients with type 2 diabetes. The presence of proteinuria should be taken into account when defining the target systolic BP level for prevention of CVD deaths. A prolongation of the duration of the P wave was associated with increased stroke mortality among high-risk patients with type 2 diabetes. P wave duration is easy to measure and merits further examination to evaluate its importance for estimation of the risk of stroke among patients with type 2 diabetes.

Metformin in gestational diabetes mellitus

METFORMIININ KÄYTTÖ RASKAUSDIABETEKSESSA Raskausdiabeteksella tarkoitetaan sokeriaineenvaihdunnan häiriötä, joka todetaan ensimmäisen kerran raskauden aikana. Hoidolla voidaan vähentää raskausdiabetekseen liittyviä äidin ja vastasyntyneen haittoja. Lääkitystä tarvitaan, jos ruokavaliohoidolla ei saavuteta hyvää sokeritasapainoa. Perinteisesti lääkityksenä on käytetty insuliinia, mutta metformii¬nin käyttöä insuliinin vaihtoehtona on ehdotettu. Metformiini läpäisee istukan, mutta sen läpäisymekanismi ei ole selvillä. Tämän tutkimuskokonaisuuden pääasiallisin tarkoitus oli verrata metformiinin tehokkuutta ja turvallisuutta insuliiniin raskausdiabeteksen hoidossa selvittämällä lääkkeen vaiku¬tusta äitiin ja vastasyntyneeseen. Lisäksi haluttiin tutkia, mitkä tekijät ennustavat insulii¬nin tarvetta metformiinin lisänä, jotta saavutettaisiin hyvä sokeritasapaino. Metformiinin annoksen vaikutus äitiin ja vastasyntyneeseen arvioitiin mittaamalla metformiinin pitoisuus äidistä, ja sikiön puolelta napanuoran veressä. Tässä tutkimuksessa selvitettiin myös aktiivisen kuljetusproteiinin (OCT) merkitystä metformiinin kulkeutumiseen istukan läpi perfusiomalla istukkaa ex vivo . Ex vivo istukkaperfuusiotutkimuksen tulokset viittasivat siihen, että OCT-kuljetusproteiinilla ei ollut todennäköisesti merkittävää osuutta metformiinin kulkeutumisessa istukan läpi. Metformiinin pitoisuusmittaukset synnytyksen yhteydessä osoittivat metformiinin siirtyvän sikiöön istukan läpi suuressa määrin (96 %) kertymättä kuitenkaan sikiön verenkiertoon. Metformiinin pitoisuudella ei ollut vaikutusta vastasyntyneen hyvinvointiin. Maksi¬maalisella metformiinin annostuksella ja korkealla metformiinipitoisuudella todettiin olevan suotuisa vaikutus äidin painon nousuun raskauden aikana. Insuliiniin verrattuna metformiini ei lisännyt äidin, sikiön tai vastasyntyneen haittatapahtumia, eikä sillä ollut vaikutusta synnytystapaan. Sokeritasapaino insuliini- ja metformiinilääkityksen aikana oli yhtäläinen arvioitaessa sitä HbA1c- ja fruktosamiinimittauksilla, mutta 21 % metformiinin käyttäjistä tarvitsi lisäksi insuliinia hyvän sokeritasapainon saavuttamiseksi. Tutkimuksesssa todettiin, että mitä iäkkäämpi äiti oli, mitä varhaisemmassa raskauden vaiheessa sokerirasitus oli tehty ja lääkitys aloitettu, ja mitä korkeammat HbA1c ja fruktosamiinipitoisuudet olivat, sitä suuremmalla todennäköisyydellä metformiinin lisänä tarvittiin insuliinia.

Standardization of a computerized method for calculating autonomic function test responses in healthy subjects and patients with diabetes mellitus

The objectives of the present study were 1) to compare results obtained by the traditional manual method of measuring heart rate (HR) and heart rate response (HRR) to the Valsalva maneuver, standing and deep breathing, with those obtained using a computerized data analysis system attached to a standard electrocardiograph machine; 2) to standardize the responses of healthy subjects to cardiovascular tests, and 3) to evaluate the response to these tests in a group of patients with diabetes mellitus (DM). In all subjects (97 healthy and 143 with DM) we evaluated HRR to deep breathing, HRR to standing, HRR to the Valsalva maneuver, and blood pressure response (BPR) to standing up and to a sustained handgrip. Since there was a strong positive correlation between the results obtained with the computerized method and the traditional method, we conclude that the new method can replace the traditional manual method for evaluating cardiovascular responses with the advantages of speed and objectivity. HRR and BPR of men and women did not differ. A correlation between age and HRR was observed for standing (r = -0.48, P<0.001) and deep breathing (r = -0.41, P<0.002). Abnormal BPR to standing was usually observed only in diabetic patients with definite and severe degrees of autonomic neuropathy.

Pituitary-thyroid axis in short- and long-term experimental diabetes mellitus

Short-term experimental diabetes mellitus (DM) produces a significant decrease in serum thyroid hormones, a decreased or normal serum thyroid-stimulating hormone (TSH) and a reduction in hepatic and renal T4-5'-deiodination. However, little is known about the effects of chronic diabetes mellitus on the pituitary-thyroid axis function. We evaluated the changes induced by very short-term (6 days), short-term (15 days) and chronic (6 months) streptozotocin-induced diabetes mellitus in 3-month old female Dutch-Miranda rat serum T4, serum TSH and T4-5'-deiodinase activity in the thyroid and pituitary glands. Serum hormones were determined by specific radioimmunoassays. Iodothyronine-5'-deiodinase activities were assayed in the thyroid and pituitary microsomal fractions using 2 µM T4 as substrate. Mean serum T4 was significantly decreased from 3.3 to 2.0 µg/dl 6 days after diabetes mellitus induction, and from 2.2 to 1.5 µg/dl after 15 days of DM, with no significant changes in serum TSH, indicating a decreased pituitary TSH responsiveness to the diminished suppression by T4, even though pituitary T4-5'-deiodinase activity was unchanged. Thyroid T4-5'-deiodinase was unchanged after 6 days of diabetes mellitus, but was significantly increased from 20.6 to 37.0 pmol T3/mg protein after 15 days. Six months after diabetes mellitus induction, both serum T4 and thyroid T4-5'-deiodinase returned to normal ranges and serum TSH was unchanged, although pituitary T4-5'-deiodinase was now significantly decreased from 2.7 to 1.7 pmol T3/mg protein. These findings indicate that some kind of adaptation to chronic insulinopenia may occur at the thyroid level, but this does not seem to be true for the pituitary

Autoradiographic thyroid evaluation in short-term experimental diabetes mellitus

Previous studies have shown that in vitro thyroid peroxidase (TPO) iodide oxidation activity is decreased and thyroid T4-5'-deiodinase activity is increased 15 days after induction of experimental diabetes mellitus (DM). In the present study we used thyroid histoautoradiography, an indirect assay of in vivo TPO activity, to determine the possible parallelism between the in vitro and in vivo changes induced by experimental DM. DM was induced in male Wistar rats (about 250 g body weight) by a single ip streptozotocin injection (45 mg/kg), while control (C) animals received a single injection of the vehicle. Seven and 30 days after diabetes induction, each diabetic and control animal was given ip a tracer dose of 125I (2 µCi), 2.5 h before thyroid excision. The glands were counted, weighed, fixed in Bouin's solution, embedded in paraffin and cut. The sections were stained with HE and exposed to NTB-2 emulsion (Kodak). The autohistograms were developed and the quantitative distribution of silver grains was evaluated with a computerized image analyzer system. Thyroid radioiodine uptake was significantly decreased only after 30 days of DM (C: 0.38 ± 0.05 vs DM: 0.20 ± 0.04%/mg thyroid, P<0.05) while in vivo TPO activity was significantly decreased 7 and 30 days after DM induction (C: 5.3 and 4.5 grains/100 µm2 vs DM: 2.9 and 1.6 grains/100 µm2, respectively, P<0.05 ). These data suggest that insulin deficiency first reduces in vivo TPO activity during short-term experimental diabetes mellitus

Distribution of HLA-DRB1 alleles in a mixed population with insulin-dependent diabetes mellitus from the Southeast of Brazil

HLA class II genes are strongly associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). The present study reports the HLA-DRB1 genotyping of 41 IDDM patients and 99 healthy subjects from the Southeast of Brazil (Campinas region). Both groups consisted of an ethnic mixture of Caucasian, African Negro and Amerindian origin. HLA-DRB1*03 and *04 alleles were found at significantly higher frequencies among IDDM patients compared to the controls (DRB1*03: 48.8% vs 18.2%, P<0.005, RR = 4.27; DRB1*04: 43.9% vs 15.1%, P<0.008, RR = 4.37) and were associated with a susceptibility to the disease. DRB1*03/*04 heterozygosity conferred a strong IDDM risk (RR = 5.44). In contrast, the HLA-DRB1*11 allele frequency was lower among IDDM patients (7.3% vs 26.3% in controls), but the difference was not significant. These data agree with those described for other populations and allow genetic characterization of IDDM in Brazil

Residual ß-cell function and microvascular complications in type 1 diabetic patients

To determine the influence of residual ß-cell function on retinopathy and microalbuminuria we measured basal C-peptide in 50 type 1 diabetic outpatients aged 24.96 ± 7.14 years, with a duration of diabetes of 9.1 ± 6.2 years. Forty-three patients (86%) with low C-peptide (<0.74 ng/ml) had longer duration of diabetes than 7 patients (14%) with high C-peptide (³0.74 ng/ml) (9 (2-34) vs 3 (1-10) years, P = 0.01) and a tendency to high glycated hemoglobin (HBA1) (8.8 (6-17.9) vs 7.7 (6.9-8.7)%, P = 0.08). Nine patients (18%) had microalbuminuria (two out of three overnight urine samples with an albumin excretion rate (AER) ³20 and <200 µg/min) and 13 (26%) had background retinopathy. No association was found between low C-peptide, microalbuminuria and retinopathy and no difference in basal C-peptide was observed between microalbuminuric and normoalbuminuric patients (0.4 ± 0.5 vs 0.19 ± 0.22 ng/ml, P = 0.61) and between patients with or without retinopathy (0.4 ± 0.6 vs 0.2 ± 0.3 ng/ml, P = 0.43). Multiple regression analysis showed that duration of diabetes (r = 0.30, r2 = 0.09, P = 0.031) followed by HBA1 (r = 0.41, r2 = 0.17, P = 0.01) influenced basal C-peptide, and this duration of diabetes was the only variable affecting AER (r = 0.40, r2 = 0.16, P = 0.004). In our sample of type 1 diabetic patients residual ß-cell function was not associated with microalbuminuria or retinopathy.

Pancreatic nitric oxide and oxygen free radicals in the early stages of streptozotocin-induced diabetes mellitus in the rat

The objective of the present study was to explore the regulatory mechanisms of free radicals during streptozotocin (STZ)-induced pancreatic damage, which may involve nitric oxide (NO) production as a modulator of cellular oxidative stress. Removal of oxygen species by incubating pancreatic tissues in the presence of polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) (1 U/ml) produced a decrease in nitrite levels (42%) and NO synthase (NOS) activity (50%) in diabetic but not in control samples. When NO production was blocked by N G-monomethyl-L-arginine (L-NMMA) (600 µM), SOD activity increased (15.21 ± 1.23 vs 24.40 ± 2.01 U/mg dry weight). The increase was abolished when the NO donor, spermine nonoate, was added to the incubating medium (13.2 ± 1.32). Lipid peroxidation was lower in diabetic tissues when PEG-SOD was added (0.40 ± 0.02 vs 0.20 ± 0.03 nmol/mg protein), and when L-NMMA blocked NOS activity in the incubating medium (0.28 ± 0.05); spermine nonoate (100 µM) abolished the decrease in lipoperoxide level (0.70 ± 0.02). We conclude that removal of oxygen species produces a decrease in pancreatic NO and NOS levels in STZ-treated rats. Moreover, inhibition of NOS activity produces an increase in SOD activity and a decrease in lipoperoxidation in diabetic pancreatic tissues. Oxidative stress and NO pathway are related and seem to modulate each other in acute STZ-induced diabetic pancreas in the rat.

Is pancreas development abnormal in the non-obese diabetic mouse, a spontaneous model of type I diabetes?

Despite extensive genetic and immunological research, the complex etiology and pathogenesis of type I diabetes remains unresolved. During the last few years, our attention has been focused on factors such as abnormalities of islet function and/or microenvironment, that could interact with immune partners in the spontaneous model of the disease, the non-obese diabetic (NOD) mouse. Intriguingly, the first anomalies that we noted in NOD mice, compared to control strains, are already present at birth and consist of 1) higher numbers of paradoxically hyperactive ß cells, assessed by in situ preproinsulin II expression; 2) high percentages of immature islets, representing islet neogenesis related to neonatal ß-cell hyperactivity and suggestive of in utero ß-cell stimulation; 3) elevated levels of some types of antigen-presenting cells and FasL+ cells, and 4) abnormalities of extracellular matrix (ECM) protein expression. However, the colocalization in all control mouse strains studied of fibroblast-like cells (anti-TR-7 labeling), some ECM proteins (particularly, fibronectin and collagen I), antigen-presenting cells and a few FasL+ cells at the periphery of islets undergoing neogenesis suggests that remodeling phenomena that normally take place during postnatal pancreas development could be disturbed in NOD mice. These data show that from birth onwards there is an intricate relationship between endocrine and immune events in the NOD mouse. They also suggest that tissue-specific autoimmune reactions could arise from developmental phenomena taking place during fetal life in which ECM-immune cell interaction(s) may play a key role.

Insulin secretion, insulin sensitivity, and hepatic insulin extraction in first-degree relatives of type 2 diabetic patients

To identify early metabolic abnormalities in type 2 diabetes mellitus, we measured insulin secretion, sensitivity to insulin, and hepatic insulin extraction in 48 healthy normal glucose-tolerant Brazilians, first-degree relatives of type 2 diabetic patients (FH+). Each individual was matched for sex, age, weight, and body fat distribution with a person without history of type 2 diabetes (FH-). Both groups were submitted to a hyperglycemic clamp procedure (180 mg/dl). Insulin release was evaluated in its two phases. The first was calculated as the sum of plasma insulin at 2.5, 5.0, 7.5, and 10.0 min after the beginning of glucose infusion, and the second as the mean plasma insulin level in the third hour of the clamp procedure. Insulin sensitivity index (ISI) was the mean glucose infusion rate in the third hour of the clamp experiment divided by the mean plasma insulin concentration during the same period of time. Hepatic insulin extraction was determined under fasting conditions and in the third hour of the clamp procedure as the ratio between C-peptide and plasma insulin levels. FH+ individuals did not differ from FH- individuals in terms of the following parameters [median (range)]: a) first-phase insulin secretion, 174 (116-221) vs 207 (108-277) µU/ml, b) second-phase insulin secretion, 64 (41-86) vs 53 (37-83) µU/ml, and c) ISI, 14.8 (9.0-20.8) vs 16.8 (9.0-27.0) mg kg-1 min-1/µU ml-1. Hepatic insulin extraction in FH+ subjects was similar to that of FH- ones at basal conditions (median, 0.27 vs 0.27 ng/µU) and during glucose infusion (0.15 vs 0.15 ng/µU). Normal glucose-tolerant Brazilian FH+ individuals well-matched with FH- ones did not show defects of insulin secretion, insulin sensitivity, or hepatic insulin extraction as tested by hyperglycemic clamp procedures.