Methods for the Assessment of Insulin Resistance / 임상당뇨병

Insulin resistance is one of the major aggravating factors for metabolic disease. There are many methods available for estimation of insulin resistance which range from complex techniques down to simple indices. For all methods of assessing insulin resistance, it is essential that their validity and reliability be established before using them in clinical investigations. The reference techniques of hyperinsulinemic euglycemic clamp and its alternative,the frequently sampled intravenous glucose tolerance test, are the most reliable methods available for estimating insulin resistance. However, there are many simple methods from which indices can be derived that have been assessed and validated, which include homeostasis model assessment (HOMA) and the quantitative insulin sensitivity check index (QUICKI). Given the increasing number of simple indices of insulin resistance, it may be difficult for clinicians and researchers to select the most appropriate index for their studies. In planning studies on insulin resistance and selecting a suitable index, a number of important factors need to be considered by investigators, the principle one being the nature of the study to be undertaken.

O envelhecimento do pâncreas endócrino: fisiopatologia de diabetes mellitus tipo 2 e a caracterização da incretinopatia com início na senectude / The aging of endocrine pancreas: physiopathology of diabetes mellitus type 2 and characterization of incretinpathy starting on senescence

Objetivo: Estimar o impacto do envelhecimento e do diabetes na sensibilidade à insulina, função da célula beta, adipocitocinas e produção de incretina Métodos: Foram realizados clamps hiperglicêmicos, testes de arginina e testes de refeição padrão em 50 pacientes não obesos para medir a sensibilidade à insulina e secreção de insulina, assim como os níveis plasmáticos do glucagon, GLP-1 e GIP. Os pacientes com diabetes e do grupo controle saudáveis foram divididos nos seguintes grupos: meia idade com diabetes tipo 2 (MI-DM2), idosos com diabetes tipo 2 (I-DM2), meia idade ou idosos com tolerância normal à glicose (MI-TNG, I-TNG). Resultados: A sensibilidade à insulina (SI), determinada pelo modelo de avaliação da homeostase, taxa de infusão de glicose e pela sensibilidade à insulina a glicose oral, foi reduzida no grupo de idosos e nos grupos com DM2, comparados com o grupo de meia idade com tolerância normal à glicose, mas foi similar no grupo MI-DM2 e grupo I-DM2. O índice insulinogênico, a primeira e segunda fase de secreção de insulina e o índice de disposição, com exceção da resposta da insulina à arginina, foram reduzidos com o envelhecimento e nos grupos com DM2. A produção pós-prandial média de glucagon no tempo total de 0 - 180 minutos foram maiores no grupo de DM2 comparado ao grupo de TNG, sendo que na primeira hora da produção de glugagon o grupo de I-DM2 apresentou uma média mais elevado em relação ao grupo de MI-DM2. Embora a produção de GLP-1 tenha sido reduzida no grupo I-DM2, nenhuma diferença entre os grupos foi observada em relação à produção de GIP. Conclusão: O diabetes e o envelhecimento desencadearam uma redução da sensibilidade à insulina em pacientes não obesos. A produção de insulina foi reduzida com o envelhecimento e exacerbada pela condição do diabetes. As deficiências associadas ao envelhecimento se sobrepõe a fisiopatologia do diabetes, particularmente relacionada à produção de GLP-1...

Objective: To estimate the impact of aging and diabetes on insulin sensitivity, beta-cell function, adipocytokines, and incretin production. Methods: Hyperglycemic clamps, arginine tests and meal tolerance tests were performed in 50 non-obese subjects to measure insulin sensitivity (IS) and insulin secretion as well as plasma levels of glucagon, GLP-1 and GIP. Patients with diabetes and healthy control subjects were divided into the following groups: middle-aged type 2 diabetes (MA-DM), elderly Type 2 diabetes (E-DM) and middle-aged or elderly subjects with normal glucose tolerance (MA-NGT or E-NGT). Results: IS (insulin sensitivity), as determined by the homeostasis model assessment glucose infusion rate and oral glucose insulin sensitivity, was reduced in the aged and DM groups compared with MA-NGT, but similar in MA-DM and E-DM groups. Insulinogenic index, first and second phase of insulin secretion and the disposition indices, except insulin response to arginine, were reduced in the elderly and DM groups. The average postprandial glucagon production on the interval of 0-180 min was higher in DM groups compared to NGT groups, furthermore noticed that in the first hour of glucagon secretion, group E-DM had a higher average value compared to group MA-DM. Whereas the GLP-1 production was reduced in A-DM, no differences between groups were observed in GIP production. Conclusions: In non-obese subjects, diabetes and aging impair insulin sensitivity. Insulin production is reduced by aging, and diabetes exacerbates this condition. Aging associated defects superimposed diabetic physiopathology, particularly regarding GLP-1 production. On the other hand, the glucose-independent secretion of insulin was preserved. The knowledge of the complex relationship between aging and diabetes could support the development of physiopathological and pharmacological based therapies.

Síndrome da apnéia do sono na acromegalia: impacto do tratamento sobre o metabolismo dos carboidratos / Sleep apnea syndrome on acromegaly: treatment impact on carbohydrates metabolism

Introdução: A acromegalia é uma doença rara, caracterizada pela produção aumentada de hormônio do crescimento, causada geralmente por um adenoma hipofisário, ocasionando uma série de comorbidades como apneia do sono e resistência insulínica que acarretam um aumento na mortalidade e redução da expectativa de vida. Objetivo: O objetivo deste estudo foi avaliar o impacto da terapêutica da apneia do sono com um dispositivo de pressão positiva contínuas nas vias aéreas (CPAP) e avaliar o impacto desta terapêutica na resistência insulínica pela realização do clamp euglicêmico hiperinsulinêmico (CEH). Pacientes: De 156 acromegálicos regularmente atendidos na unidade de Neuroendocrinologia do HC-FMUSP, foram selecionados 12 indivíduos com apneia do sono de moderada a grave em uso de análogos da somatostatina (AS). Método: Os pacientes foram randomizados em dois grupos com seis integrantes. O grupo A iniciou o tratamento com CPAP, e o grupo B, um adesivo dilatador nasal com efeito de placebo. A avaliação basal incluiu a polissonografia, determinação do GH, IGF-1, HbA1c, ácidos graxos livres, lípides, CEH, bem como os índices de resistência periférica à insulina (HOMA, HOMA2 e QUICKI). Após 3 meses de tratamento, os pacientes foram reavaliados pelos mesmos exames, sendo trocado o tratamento entre os grupos e feita nova avaliação, após mais 90 dias. Resultados: Analisando os resultados finais de todos os pacientes que fizeram uso do CPAP, foi observada uma redução significante na resistência periférica à insulina, verificada pelo índice de sensibilidade derivado do clamp (ISCLAMP, pré e pós- CPAP, 3,83 versus 6,11, p=0,032). Esta redução não foi observada no grupo que fez uso do adesivo nasal (ISCLAMP, pré e pós-adesivo, 5,53 versus 5,19, p=0,455). Não houve diferença significante nos níveis de lípides, HbA1c nem nos índices de resistência periférica à insulina. Conclusão: O tratamento da apneia do sono moderada a grave com CPAP, em pacientes acromegálicos em uso de...

Introduction: Acromegaly is a rare disease, characterized by the production of high GH levels usually by pituitary adenoma leading to comorbidities as sleep apnea and insulin resistance, bringing increase of mortality and life span reduction. Objective: This study aims to assess the impact of treatment of sleep apnea with a continuous positive air pressure device (CPAP) on the insulin resistance by performing the hyperinsulinemic euglycemic clamp (HEC). Patients: From 156 acromegalic patients regularly attended on Neuroendocrine Unit of the Hospital das Clínicas, University of São Paulo Medical School, 12 subjects on somatostatin analogs (SA) harboring moderate to severe sleep apnea were selected. Methods: Patients were randomized in two groups of six subjects. Group A started treatment with CPAP while group B started treatment using a nasal dilator adhesive with placebo effect. Basal assessment included polysomnography, determination of GH, IGF-1, HbA1c, free fat acids, lipids assays, HEC as well as insulin resistance indexes (HOMA, HOMA2 and QUICKI). Patients were reevaluated after three months of treatment by the same tests and then the treatment was switched between groups with new assessment 90 days later. Results: A significant reduction on insulin resistance determined by the clamp derived sensibility index was observed after assessing the final data of all patients on CPAP (SICLAMP, pre and post CPAP, 3,83 versus 6,11, p=0,032). This reduction was not seen in the nasal dilator adhesive group (SICLAMP, pre and post adhesive, 5,53 versus 5,19, p=0,455). There was no significant difference on lipids, HbA1c or on peripheral insulin resistance indexes. Conclusion: CPAP treatment of acromegalic patients on AS with moderate to severe sleep apnea leaded to significant reduction on peripheral insulin resistance assessed by the HEC. HOMA, HOMA2 and QUICK did not detect this data.

Usefulness of Oral Glucose Insulin Sensitivity Index in Women with Polycystic Ovary Syndrome / 이화의대지

OBJECTIVES: Insulin resistance is a major pathophysiology in polycystic ovary syndrome (PCOS), and assessment of insulin sensitivity is important. Various insulin sensitivity indices from fasting state or oral glucose tolerance test (OGTT) have been compared with euglycemic hyperinsulinemic clamp. We aimed to evaluate the usefulness of these indices in young Korean women with PCOS. METHODS: Euglycemic hyperinsulinemic clamp test and 75 g OGTT were performed in 290 women with PCOS. Insulin mediated glucose uptake (IMGU), the insulin sensitivity index from clamp, was compared with various insulin sensitivity indices such as composite insulin sensitivity index (ISIcomp), estimated metabolic clearance rate (MCRest) of glucose and estimated insulin sensitivity index (ISIest), area under the curve of glucose and insulin ratio (AUC-GIR), OGTT-derived Belfiore index, and oral glucose insulin sensitivity index (OGSI) by Kazama. Fasting state indices such as glucose insulin ratio (GIR), homeostasis model assessment for insulin resistance (HOMA-IR), fasting Belfiore index, and quantitative insulin sensitivity check index (QUICKI) were also compared with IMGU. RESULTS: The correlation coefficients of ISIcomp, MCRest, ISIest, AUC-GIR, OGTT-Belfiore index, and OGSI with IMGU were all about 0.5 (Ps'<0.001) in PCOS women as a whole. The MCRest and ISIest were significantly correlated with IMGU in both obese (r=0.58 and 0.58, P<0.0001) and non-obese subjects (r=0.33 and 0.32, P<0.001). Fasting glucose and insulin-derived indices showed worse correlation with IMGU than OGTT-derived ones. CONCLUSION: The MCRest and ISIest from OGTT might be the best replacement for the insulin sensitivity index from hyperinsulinemic euglycemic clamp independent of obesity.

Chronic intermittent hypoxia from pedo-stage decreases glucose transporter 4 expression in adipose tissue and causes insulin resistance / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The persistence of sleep disordered breathing (SDB) symptoms after tonsil and/or adenoid (T&A) surgery are common in children with obstructive sleep apnea (OSA). We tested the hypothesis that disturbances of glucose transporters (GLUTs) in intraabdominal adipose tissue caused by chronic intermittent hypoxia (CIH) from the pedo-period could facilitate the appearance of periphery insulin resistance in Sprague-Dawley (SD) rats. We tested the hypothesis that the changes of GLUTs in adipose tissue may be one of the reasons for persistent SDB among clinical OSA children after T&A surgery.</p><p><b>METHODS</b>Thirty 21-day-old SD rats were randomly divided into a CIH group, a chronic continuous hypoxia (CCH) group, and a normal oxygen group (control group) and exposed for 40 days. The changes of weight, fasting blood glucose and fasting blood insulin levels were measured. Hyperinsulinemic-euglycemic clamp techniques were used to measure insulin resistance in each animal. Real-time quantitative PCR and Western blotting were used to measure GLUT mRNA and proteins in intraabdominal adipose tissue. Additional intraabdomial white adipose tissue (WAT) was also processed into paraffin sections and directly observed for GLUTs1-4 expression.</p><p><b>RESULTS</b>When compared with control group, CIH increased blood fasting insulin levels, (245.07 +/- 53.89) pg/ml vs. (168.63 +/- 38.70) pg/ml, P = 0.038, and decreased the mean glucose infusion rate (GIR), (7.25 +/- 1.29) mg x kg(-1) x min(-1) vs. (13.34 +/- 1.54) mg x kg(-1) x min(-1), P < 0.001. GLUT-4 mRNA and protein expression was significantly reduced after CIH compared with CCH or normal oxygen rats, 0.002 +/- 0.002 vs. 0.039 +/- 0.009, P < 0.001; 0.642 +/- 0.073 vs. 1.000 +/- 0.103, P = 0.035.</p><p><b>CONCLUSIONS</b>CIH in young rats could induce insulin resistance via adverse effects on glycometabolism. These findings emphasize the importance of early detection and treatment of insulin insensitivity in obese childhood OSA.</p>

Association between four adipokines and insulin sensitivity in patients with obesity, type 1 or type 2 diabetes mellitus, and in the general Chinese population / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Hyperinsulinemic euglycemic clamp is the gold standard to evaluate the insulin sensitivity, but it is too complicated and expensive to use in clinic. We tried to find an alternative indicator to reflect insulin sensitivity. To evaluate the association between the four adipokines, adiponectin, leptin, resistin and tumor necrosis factor-alpha (TNF-alpha) with insulin sensitivity, we used a hyperinsulinemic euglycemic clamp to test insulin sensitivity in Chinese patients with obesity and type 1 or type 2 diabetes mellitus versus controls.</p><p><b>METHODS</b>In this parallel control study, we tested insulin sensitivity using a hyperinsulinemic euglycemic clamp in different groups, then examined levels of adiponectin, leptin, resistin and TNF-alpha in serum, and the relationship between the different adipokines and glucose disposal rate (M value), as well as insulin sensitivity index (M value/insulin, M/I), which are the "gold standard" indices of insulin sensitivity.</p><p><b>RESULTS</b>There were significant differences in mean leptin values in the four adipokines from the four different groups (P < 0.001; comparison of the variation between different groups was analyzed by variance analysis). Compared to controls (using multiple comparison two-way Dunnett t test), only the leptin level showed significant differences in the four adipokines from the four different groups at the same time (P < 0.001). The association analysis between the different adipokines and M or M/I values also showed that only leptin negatively correlated with M (r = -0.64, P < 0.001) or M/I values (r = -0.56, P < 0.001); there was no relationship between the other three adipokines and M or M/I values.</p><p><b>CONCLUSION</b>Only leptin was associated with M or M/I values. Therefore, leptin might be one of the predictive factors of the degree of insulin resistance and risk of the accompanying disease.</p>

Respuesta del sistema antioxidante en varones sanos, frente a hiperglicemia aguda inducida / Healthy males' antioxidant system response in induced acute hyperglycemia

Objetivo: determinar la respuesta del sistema antioxidante en varones sanos, frente a la hiperglicemia aguda inducida. Diseño: estudio prospectivo, descriptivo, longitudinal, experimental. Lugar: Instituto Nacional de Biología Andina, Facultad de Medicina, Universidad Nacional Mayor de San Marcos, Lima, Perú. Material biológico: Sangre y suero de sujetos aparentemente sanos. Intervenciones: A 13 sujetos adultos clínicamente sanos, entre 20 y 41años, después de 10 horas de ayuno, se administró glucosa vía endovenosa, mediante el método de clamp hiperglicémico, a 125 mg/dL por encima del valor basal, durante 120 minutos. Se realizó mediciones de la glicemia a 0, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 y 120 minutos. Se tomó la muestra sanguínea con anticoagulante EDTA y otra de sangre total, para obtención de suero, para las pruebas bioquímicas a los 0, 60 y 120 minutos. Principales medidas de resultados: Modificaciones de la glicemia y lipoperoxidación en suero, glutatión y actividad superóxido dismutasa en glóbulos rojos lisados e índices de estrés oxidativo. Resultados: El nivel de glucosa durante el clamp hiperglicémico, luego de alcanzar el æequilibrioÆ, fue 197±17,58 mg/dL. La lipoperoxidación aumentó de 2,54 + 0,51 a 2,90 + 0,58 umol/L, de 0 a 60 minutos, y a 2,66 + 0,55 umol/L a los 120 minutos. El glutatión se redujo en 8,10 por ciento a la hora, aumentando 7,08 por ciento a los 120 minutos. La actividad superóxido dismutasa se elevó 0,54 por ciento a los 60 minutos y 5,66 por ciento a los 120 minutos, sobre el basal. Los índices de valoración del estrés oxidativo tuvieron correlación r Pearson positiva, en nivel alto a muy alto. Conclusiones: la hiperglicemia aguda inducida hasta 2 horas elevó el estrés oxidativo, promoviendo generación de defensa antioxidante, con síntesis de glutatión reducido de novo y mayor actividad de la superóxido dismutasa.

Objective: To determine healthy malesÆ antioxidant system response in induced acute hyperglycemia. Design: Prospective, descriptive, longitudinal, experimental study. Setting: National Institute of Andean Biology, Faculty of Medicine, Universidad Nacional Mayor de San Marcos, Lima, Peru. Biological materials: Whole blood and serum of apparently healthy men. Interventions: After 10 hour fasting, intravenous glucose was administered to thirteen healthy 20-41 year-old adult men using the hyperglycemic clamp method at 125 mg/dL above basal value during 120 minutes. Glycemia was measured at 0, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, and 120 minutes. Blood sampling was obtained with EDTA anticoagulant and whole blood to obtain blood serum for biochemistry tests at 0, 60 and 120 minutes. Main outcome measures: Blood serum glycemia and lipoperoxidation variation, glutathione and superoxide dismutase activity in lysed red blood cells and oxidative stress index. Results: After achieving æbalanceÆ, glucose levels during hyperglycemic clamp was 197 ± 17,58 mg/dL. Lipoperoxidation increased from 2,54 + 0,51 to 2,90 + 0,58umol/L, from 0 to 60 minutes, and to 2,66 + 0,55 umol/L at 120 minutes. Glutathione was reduced in 8,10 per cent at one hour, rising 7,08 per cent at 120 minutes. Superoxide dismutase activity rose above basal 0,54 per cent at 60 min and 5,66 per cent at 120 min. Oxidative stress valuation index had high level to very high level positive Pearson r correlation. Conclusions: Acute induced hyperglycemia up to 2 hours increased oxidative stress, promoting generation of antioxidant defence with de novo synthesis of reduced glutathione and greater activity of superoxide dismutase.

A pilot study on hyperinsulinaemic euglycaemic clamp based insulin sensitivity in young adult Indian males with low body mass index.

Background & objectives: Indians have decreased insulin sensitivity (IS) and a greater adiposity at a lower body mass index (BMI) when compared with other ethnic groups. Despite this, IS has not been studied in Indians of low BMI. This study thus used the hyperinsulinaemic euglycaemic clamp (HEC) technique to compare IS in young normal weight (NW) and low BMI (LBMI) Indian males. Clamp IS was also compared with convenient indices of insulin sensitivity such as the homeostatic model assessment (HOMA). In the NW group, clamp IS was compared with published data of similarly measured IS in other studies and ethnic groups. Methods: Ten NW [body mass index (BMI): 18.5-25 kg/m2] and ten LBMI (BMI < 18.5 kg/m2) young healthy Indian males aged between 19-32 yr were recruited through advertisements from Bangalore slums. Fasting plasma glucose and insulin, glucose disposal rates (GDR) and IS were the parameters measured during the HEC technique. Results: The NW group had a Clamp IS of 4.5 (3.8, 5.3) (median, lower, upper quartile, mg/(kg. min)/μU/ml) that was close to half that of the LBMI group; 9.9 (7.1, 13.4: P<0.001). Clamp IS in the NW group was significantly lower than that observed in published studies involving other ethnic groups (P<0.05). Clamp IS and per cent body fat (% BF), were significantly and negatively correlated (n=20, ρ = -0.7, P<0.001). Correlations between Clamp IS and other IS indices ranged from ρ = -0.5 for HOMA2-%B to ρ = 0.5 for HOMA2-%S (P<0.05); however, the correlation with HOMA1-IR was not significant (ρ = 0.4). Interpretation & conclusions: The significantly lower Clamp IS of the NW group compared with the LBMI group and other ethnic groups indicated that IS was impaired in Indians at relatively low BMIs. Most of the convenient indices of IS were significantly correlated with Clamp IS, however, the Clamp IS was more sensitive method with greater discriminatory power, since IS differences between LBMI and NW groups were only apparent with Clamp IS.

Overcoming metabolic syndrome in severe obesity: adiponectin as a marker of insulin sensitivity and HDL-cholesterol improvements after gastric bypass / Reversão da síndrome metabólica na obesidade mórbida: adiponectina como um marcador da sensibilização à insulina e do aumento do HDL-colesterol após o bypass gástrico

OBJECTIVE: To assess the relationship between adiponectin and metabolic parameters in severely obese women during surgical-induced weight loss. METHODS: Nineteen lean (CT - BMI:21.2 ± 0.3 kg.m²), 14 overweight/class II obese (OB/OW - BMI: 29.7 ± 0.7 kg/m²) and 8 morbidly obese (OBIII - BMI: 56.4 ± 3.6 kg/m²) were evaluated by hyperinsulinemic-euglycemic clamp, adiponectin, and lipids. OBIII were evaluated at 5th and 16th month post-operatively. RESULTS: Compared to lean, obese groups had lower adiponectin (OB/OW: 9.4 ± 0.9, OBIII: 7.1 ± 1.3 versus 12.2 ± 0.9 ng/dL; p < 0.01), lower HDL-cholesterol (OB/OW:1.05 ± 0.05, OBIII: 0.88 ± 0.04 versus 1.22 ± 0.07 mmol/L; p < 0.01) and insulin resistance-IR (glucose uptake, M-value - OB/OW: 43.6 ± 2.7, OBIII: 32.4 ± 3.2 versus 20.0 ± 1.8 umol/kgFFM.min; p < 0.001). Considering all subjects, adiponectin levels were inversely correlated to BMI and waist circumference, and directly to M-value and HDL-cholesterol (p < 0.01). During weight loss, improvements in IR (Study III: 36.1 ± 3.9 umol/kg/FFM.min, p < 0.0001), adiponectin (11.8 ± 1.4 ng/dL, p = 0.006) and HDL-cholesterol were observed (1.10 ± 0.04 mmol/L, p = 0.007). Moreover, HDL-cholesterol improvement was significantly and independently related to variations of adiponectin and BMI (r² = 0.86; p < 0.0002). CONCLUSIONS: The improvements of IR and adiponectin were related to surgical-induced weight loss, suggesting an important role of adiponectin in HDL-cholesterol regulation.

OBJETIVO: Identificar a relação entre adiponectina e parâmetros metabólicos em mulheres obesas mórbidas durante o emagrecimento por bypass gástrico. MÉTODOS: Dezenove magras (CT - IMC: 21,2 ± 0,3 kg/m²), 14 com sobrepeso/obesidade classe II (OB/OW - IMC: 29,7 ± 0,7 kg/m²) e oito obesas classe III (OBIII - IMC:56,4 ± 3,6 kg/m²) foram avaliadas pelo clamp euglicêmico-hiperinsulinêmico, adiponectina e lípides. OBIII submeteram-se aos mesmos testes no quinto e décimo-sexto mês pós-operatório. RESULTADOS: comparados a CT, os grupos obesos tiveram menor adiponectinemia (OB/OW: 9,4 ± 0,9, OBIII: 7,1 ± 1,3 versus 12,2 ± 0,9 ng/dL; p < 0,01), menor HDL-colesterol (OB/OW: 1,05 ± 0,05, OBIII: 0,88 ± 0,04 versus 1,22 ± 0,07 mmol/L; p < 0,01) e resistência insulínica - RI (captação de glicose, M - OB/OW:43,6 ± 2,7, OBIII:32,4 ± 3,2 versus 20,0 ± 1,8 umol/kgFFM.min; p < 0,001). Analisando todos os voluntários: adiponectina correlacionou-se negativamente com IMC, circunferência da cintura e positivamente ao M-clamp e HDL-colesterol (p < 0,01). No emagrecimento, houve melhora da RI (Estudo III:36,1 ± 3,9 umol/kgFFM.min, p < 0,0001), adiponectina (11,8 ± 1,4 ng/dL, p = 0,006) e HDL-colesterol (1,10 ± 0,04 mmol/L, p = 0,007). Aumentos do HDL-colesterol foram significativa e independentemente relacionados às variações da adiponectina e IMC (r² = 0,86; p < 0,0002). CONCLUSÕES: A melhora da RI e adiponectina no emagrecimento induzido por bypass gástrico sugerem um importante papel da adiponectina na regulação do HDL-colesterol.

Nitric Oxide Increases Insulin Sensitivity in Skeletal Muscle by Improving Mitochondrial Function and Insulin Signaling / 당뇨병

BACKGROUND: Accumulating evidence has suggested that nitric oxide (NO) is involved in the regulation of insulin sensitivity in skeletal muscle. Recent studies also suggested NO as an important molecule regulating mitochondrial biogenesis. This study examined the effect of the NO donor, 3-morpholinosydnonimine (SIN-1), on glucose metabolism in skeletal muscle and tested the hypothesis that NO's effect on glucose metabolism is mediated by its effect on mitochondrial function. METHODS: In Sprague-Dawley (SD) rats treated with SIN-1 for 4 weeks, insulin sensitivity was measured by a glucose clamp study. Triglyceride content and fatty acid oxidation were measured in the skeletal muscle. In addition, mitochondrial DNA content and mRNA expression of mitochondrial biogenesis markers were assessed by real-time polymerase chain reaction and expression of insulin receptor substrate (IRS)-1 and Akt were examined by Western blot analysis in skeletal muscle. In C2C12 cells, insulin sensitivity was measured by 2-deoxyglucose uptake and Western blot analysis was used to examine the expression of IRS-1 and Akt. RESULTS: SIN-1 improved insulin sensitivity in C2C12 cells and skeletal muscles of SD rats. In addition, SIN-1 decreased triglyceride content and increased fatty acid oxidation in skeletal muscle. Mitochondrial DNA contents and biogenesis in the skeletal muscle were increased by SIN-1 treatment. Moreover, SIN-1 increased the expression of phosphor-IRS-1 and phosphor-Akt in the skeletal muscle and muscle cells. CONCLUSION: Our results suggest that NO mediates glucose uptake in skeletal muscle both in vitro and in vivo by improving mitochondrial function and stimulating insulin signaling pathways.

Categorización del síndrome metabólico de acuerdo con las variables que lo constituyen y su relación con la insulino-resistencia / Consensus definition of the metabolic syndrome and diagnostic criteria for identification and its relationshipo with the insulin-resistance syndrome

In recent years, the cardiovascular prevention has found a new clinical tool: the metabolic syndrome (MS). Arised in the observation of associations between risk factors, it is recognized as the clinical manifestation of insulin resistance. In the course of time, it was demonstrated that the presence of MS possess a prognostic value to predict death, nonfatal acute myocardial infarction, vascular stroke and the development of diabetes... The relationshipo to insulin resistance and diagnostic criteria for identification of the metabolic syndrome are given in the article.

Insulin sensitivity and cardiac autonomic function in young male practitioners of yoga.

BACKGROUND: While yoga is thought to reduce the risk of chronic non-communicable diseases such as diabetes, there are no studies on insulin sensitivity in long term practitioners of yoga. We assessed insulin sensitivity and cardiac autonomic function in long term practitioners of yoga. METHODS: Fifteen healthy, young, male practitioners of yoga were compared with 15 young, healthy males who did not practice yoga matched for body-mass index. Fasting insulin sensitivity was measured in the fasting state by the hyperinsulinaemic-euglycaemic clamp. RESULTS: There were no significant differences between the groups in their anthropometry or body composition. However, the fasting plasma insulin was significantly lower in the yoga group. The yoga group was also more insulin sensitive (yoga 7.82 [2.29] v. control 4.86 [11.97] (mg/[kg.min])/(microU/ml), p < 0.001). While the body weight and waist circumference were negatively correlated with glucose disposal rate in the controls, there were no similar correlations in the yoga group. The yoga group had significantly higher low-frequency power and lower normalized high-frequency power. CONCLUSION: Long term yoga practice (for 1 year or more) is associated with increased insulin sensitivity and attenuates the negative relationship between body weight or waist circumference and insulin sensitivity.

Índices de sensibilidad insulínica (homa y quicki): en escolares y adolescentes sanos en Valera: estado Trujillo-Venezuela / Insuline sensibility index among healthy children and adolescents in Valera: Trujillo state-Venezuela

La resistencia a la insulina contribuye a la fisiopatología de la diabetes tipo 2 y es la antesala de la obesidad, el síndrome metabólico y muchas enfermedades cardiovasculares, de allí la importancia de su detección temprana. Evaluar el grado de sensibilidad insulinica mediante los índices HOMA y QUICKI y la asociación de la insulinosensibilidad basal con algunas variables biológicas (edad, sexo, estado nutricional). Se realizó un estudio descriptivo de corte transversal en escolares y adolescentes entre 6 y 18 años, entre marzo y julio de 2005. Se calculó el IMC y se emplearon las curvas percentiles de FUNDACREDESA para su categorización. Se extranjeron 5mL de sangre para detectar los valores de glucosa e insulina. La sensibilidad insulínica basal se calculó mediante los índices HOMA [glicemia en ayunas (mmol/l) x insulina en ayunas (mU/l)]/22,5 y QUICKI (1/(Log glicemia ayuno (mg/dl)+Log insulina ayuno (µU/ml). Se calcularon los estadísticos descriptivos y las diferencias fueron estudiadas mediante la prueba Chi², considerando significativo a todo valor de p<0,05. 269 niños tenían peso normal (84,5 por ciento), 29 presentaron sobrepeso (9,11 por ciento) y 20 eran obesos (6,28 por ciento). No se encontró asociación significativa entre la sensibilidad insulínica y el estado nutricional. Hubo diferencia significativa en las glicemias en ayunas entre escolares y adolescentes eutróficos y con sobrepeso (p<0.001). No hubo insulino resistencia en escolares ni adolescentes. El índice HOMA alcanzó un valor cercano a 1, y el índice de QUICKI se mantuvo alrededor de 0,40 independientemente del estado nutricional.

Insulin resistance contributes to the physiopathology of diabetes and is the previous step to obesity, metabolic syndrome and many cardiovascular disease, therefore the importance of its early detection. To evaluate the degree of insulin sensitivity by means of the indexes HOMA and QUICKI and the association with some biological variables (age, gender, nutritional state). The study is descriptive of transverse cut type and included children and adolescents between 6 and 18 years. Body Mass Index was calculated and the categorization was performed by Fundacredesa's charts. Glucose and insulin were measured in blood. Basal insulin sensitivity was calculated by means of the indexes HOMA, [blood fasting sugar (mmol/1) x fasting insulin (mU/1)]/22,5 and QUICKI (1/(Log fasting blood sugar (mg/dl) + Log fasting blood insulin (µU/ml). Descriptive statistic were calculated and differences were studied by means of the test X², considering as significant, values under 0.05. There were 269 children with normal weight (84,5%), 29 were overweight (9,11%) and obese (6,28%). There was no significant association between insulin sensitivity and nutritional state. There were significant differences in fasting blood sugar between normal and overweight children and adolescents (p<0,001). There were neither children nor adolescents with insulin resistance the HOMA index reached a value of 1 and the QUICKI index was near 0,40 independently of the nutritional state.

Análise crítica do uso dos índices do Homeostasis Model Assessment (HOMA) na avaliação da resistência à insulina e capacidade funcional das células-beta pancreáticas: [revisão] / Critical analysis on the use of the homeostasis hodel assessment (HOMA) indexes in the evaluation of the insulin resistance and the pancreatic beta cells functional capacity: [review]

A disfunção das células-beta e a resistência insulínica são anormalidades metabólicas inter-relacionadas na etiologia do diabetes tipo 2. Em diversos países, tem sido observado o aumento da prevalência de obesidade e diabetes em associação com a presença da resistência insulínica. Nesse contexto, é útil a mensuração da resistência insulínica e da capacidade funcional das células-beta nos indivíduos. Os índices Homeostasis Model Assessment (HOMA) têm sido amplamente utilizados, representando uma das alternativas para avaliação desses parâmetros, principalmente por figurarem um método rápido, de fácil aplicação e de menor custo. Esta revisão discute sobre a origem e a evolução dos índices HOMA, bem como as particularidades do método, abordando aspectos relacionados à sua validação e aos pontos de corte existentes para sua interpretação.

Beta-cell dysfunction and insulin resistance are interrelated metabolic abnormalities in the aetiology of Type 2 Diabetes. In several countries, increases in the prevalence of obesity and diabetes have been observed in association with the presence of insulin resistance. In this context, measurement of insulin resistance and beta-cell function is useful. The HOMA indexes (Homeostasis Model Assessment) have been widely used, representing an alternative for the evaluation of these parameters, particularly as a fast, easy and cheap method. This review discusses the origin and evolution of the HOMA index, as well as details of the method, analyzing features related to its validation and the cutoff limits for its interpretation.

Nova técnica para pesquisa de viabilidade miocárdica com 18F-fluoro-desoxi-glicose utilizando dieta restrita em carboidratos: estudo comparativo com o clamp hiperinsulínico euglicêmico / New method in myocardial viability detection with 18F-fluoro-desoxi-glucose using a low-carbohydrate diet: a comparative study with euglycemic hyperinsulinemic clamp

INTRODUÇÃO: Em pacientes com infarto do miocárdio (IM) e disfunção cardíaca, a evidência de viabilidade miocárdica é primordial, e o exame tomográfico por emissão de pósitrons com 18F-fluoro-desoxi-glicose (18FDG-PET) é o padrão-ouro para essa identificação. Existe preferência, na literatura, pela realização do clamp hiperínsulínico euglicêmico (CLAMP) antes da injeção de 18FDG para estimular todo o miocárdio a consumir glicose (GLI), garantindo assim a sua captação pelas áreas de miocárdio hibernado (MH). No entanto, essa técnica é trabalhosa, além do risco de hipoglicemia durante a realização. Desenvolvemos uma nova técnica na qual o paciente é submetido a uma dieta restrita em carboidratos (DIETA) por 24 horas antes do exame, sem a necessidade de CLAMP, com o objetivo de diminuir os níveis de insulina e aumentar ácidos graxos livres (AGL), estimulando o miocárdio normal a consumir AGL, e não GLI. A área de MH, porém, não consegue realizar o metabolismo oxidativo de AGL, mantendo o consumo de GLI. OBJETIVOS: comparar o PET após DIETA (PET-DIETA) com o PET após CLAMP (PET-CLAMP), para a pesquisa de viabilidade miocárdica. MÉTODOS: Trinta pacientes com IM prévio e hipocinesia na área infartada foram submetidos à cintilografia de perfusão miocárdica com 99mTc-sestamibi (MIBI), PET-CLAMP e PET-DIETA. A DIETA limitava-se a 15-20g de carboidratos por dia. Os exames foram submetidos à análise visual e classificados por escores (0 a 4). Foram consideras áreas de mismatch (MH) aquelas com hipoperfusão ao MIBI e captação presente no PET-CLAMP ou no PET-DIETA, em um modelo de 17 segmentos, além da análise por parede, território arterial e por paciente. A análise por segmentos foi realizada ainda dividindo-se os pacientes em diabéticos (DM) e não diabéticos (NDM). O PET-DIETA também foi submetido à análise automática (por percentual de captação) RESULTADOS: Durante o CLAMP, seis (20%) pacientes apresentaram hipoglicemia. Nenhum paciente apresentou hipoglicemia...

BACKGROUND: In patients with myocardial infarction and left ventricular dysfunction, the evidence of myocardial viability has important clinical implications. Positron emission tomography (PET) using 18F-fluoro-desoxi-glucose (18FDG) is considered the gold standard for viability detection. The euglycemic hyperinsulinemic clamping (CLAMP) before 18FDG injection stimulates uptake of both glucose and 18FDG in the myocardium, including areas of hibernating myocardium (MH), and it is the most used protocol. However, this imaging protocol has an increased risk for hypoglycemia and is relatively time-consuming. We developed a new protocol using a 24 hours low-carbohydrate diet (DIET), aiming to reduce insulin levels and increase free fatty acids (FFA). This protocol stimulates the normal myocardium to use FFA, not glucose, but the area of hibernating myocardium (viable area) may not use oxidative metabolism with FFA, keeping glucose uptake and becoming a hot spot at PET images. The aim of this study was to compare both techniques by segments, regions, vascular territories and patients. METHODS: Thirty patients with previous myocardial infarction and left ventricular dysfunction were studied. All of them underwent into a SPECT perfusion scan with 99mTc-sestamibi and two 18FDG PET studies to asses myocardial viability, one with CLAMP (PET-CLAMP) and another using a 24 hours low-carbohydrate diet (PET-DIET). For the analysis, the myocardium was divided into 17 segments, 5 regions and 3 vascular territories. A visual and an automatic semi-quantitative analysis (only for PET-DIET) were carried out according to the following score indicating radiotracer uptake: 0 = normal to 4 = absent. Myocardial viability was defined as the presence of normal or mildly reduced FDG uptake in an area with reduced perfusion (99mTc-sestamibi uptake). We also performed subgroup analyses in diabetes (DM) and non-diabetic patients (NDM). RESULTS: While using CLAMP protocol, six (20%) patients...

Secreção de insulina e sensibilidade à insulina em indivíduos de risco para o Diabetes Mellitus Tipo 2 / Secretion of insulin and insulin sensitivity in individuals at risk for Diabetes Mellitus Type 2

O diabetes mellitus tipo 2 (DMT2) é das principais doenças do século atual, com repercussões importantes à sociedade e ao indivíduo. Para o melhor tratamento e até mesmo a prevenção, faz-se necessário melhor compreensão do DMT2. Embora haja evidência crescente quanto à superposição de um ou mais fatores que causam resistência à insulina, às células f3 com capacidade de compensação geneticamente limitada o(s) fator (es) primário(s) patogenético(s) do DMT2 ainda é (são) controverso(s). O objetivo foi portanto, compreender melhor a patogênese do DMT2 avaliando-se: 1) parentes em primeiro grau de portadores de DMT2 após cerca de 9 anos; 2) indivíduos que progrediram da TGN para TGD ou DMT2. Indivíduos e Métodos: Dos 130 indivíduos que participaram do 10 estudo (há 9 anos) 79 puderam ser reavaliados atualmente. Todos foram submetidos ao teste oral de tolerância à glicose (TOTG), com dosagem da glicose e insulina a cada 30 minutos por 120 minutos após a carga oral de 75 g de glicose. Observou-se que 17 participantes progrediram na tolerância à glicose. Assim, foram estudados os indivíduos progressores (P) versus os não­ progressores (NP) (IA e IB) e os com parentes em primeiro grau de portadores de DMT2 (HF mais) versus não-parentes (HF menos), ambos com TGN (IIA e IIB), numa abordagem transversal e prospectiva, respectivamente. Para cada um dos estudos, os grupos foram comparados quanto: a) às características clínicas e bioquímicas basais; b) parâmetros obtidos durante o TOTG; c) parâmetros obtidos do clamp hiperglicêmico. A glicose foi determinada pelo método da glicose oxidase; a insulina, por radioimunoensaio de fase sólida e 3 pró-insulina, pelo ensaio imuno-enzimático. A análise estatística dos resultados foi realizada pelo teste t de Student e Mann-Whitney para as variáveis paramétricas e não-paramétricas, respectivamente. E análise da variância de medidas repetidas para as variáveis estudadas nos estudos prospectivos (RMANOVA)...

comparative study of three brands of biosynthetic human insulin

To compare the activity of three brands of regular biosynthetic human insulin [BHI] in healthy normal subjects with the glucose clamp technique. A comparative study. CMH Lahore from May 2007 to July 2007. Thirty healthy normal male volunteers who met the inclusion criteria were tested. Each insulin preparation was sequentially infused through intravenous route at 0.02 U/kg/h for 2 hour, 0.032 U/kg/h for 2 hour and finally at 0.05 U/kg/h for 2 hours. A simultaneous 25% glucose infusion was maintained and the amount the glucose consumed was calculated. All subjects were studied on three different occasions with the three brands' of insulin. Blood glucose was monitored at regular intervals and its level was kept constant [clamped] at a baseline. The amount of glucose infused was calculated for each insulin dose for the three brands of BHI. Mean values of glucose administered during the six hour infusion period for the three brands ranged between 162 to 190g. The mean glucose consumed with 0.02 units/kg/hr of Zansulin, Actrapid and Humulin were 26.7gm, 30.6gm and 31.2gm respectively Similarly the mean glucose consumed with 0.032 units/kg/hr of Zansulin, Actrapid and Humulin were 53gm, 59.7gm and 62.1gm respectively and a similar pattern of glucose consumption was observed for insulin dose of 0.05 units/kg/hr. Glucose administered during the 6 hour infusion differed significantly among the three brands of insulin, [p<0.05]. Post hoc test for multiple comparison showed significantly more glucose consumption with Humulin R and Actrapid as compared to Zansulin R [p value <0.05].There was no significant difference in biological activity of Humulin R and Actrapid [p value >0.05] Humulin R and Actrapid had greater biological activity as compared to Zansulin R when glucose consumption was measured for each using glucose clamp technique

Avaliação da secreção e resistência insulínica em indivíduos com diferentes graus de tolerância à glicose - do metabolismo normal ao diabetes mellitus / Insulin resistance and secretion assessment across a range of glucose tolerance from normal individuals through diabetes

OBJETIVO: Os principais objetivos são determinar a associação entre os parâmetros clínicos e demográficos e os diferentes índices de secreção e resistência insulínica em indivíduos aparentemente saudáveis, sem conhecimento prévio de seu grau de tolerância à glicose. PACIENTES E MÉTODOS: Submetemos ao teste oral de tolerância à glicose (TOTG), no período de fevereiro a agosto de 2003, 105 indivíduos com média de idade de 33,4 ± 1,4 anos, sendo 57,1 por cento do sexo feminino, subdividindo-os em 4 grupos: grupo 0 (normais): indivíduos com IMC < 25 e metabolismo glicídico normal, grupo 1 (obesos): IMC > 25 e metabolismo glicídico normal, grupo 2 (IFG): glicemia de jejum alterada e grupo 3 (IOG): intolerância oral à glicose. RESULTADOS: Encontramos diferença estatística para todas as variáveis analisadas durante o TOTG dentre os 4 grupos de indivíduos: glicemias de jejum e em 2 horas (p < 0,05; p < 0,05), valor de pico (p < 0,05), delta (p = 0,02), percentual de incremento (p = 0,047), área sob a curva (p < 0,05) e tempo de pico da glicose (p = 0,022). Não encontramos diferença para a velocidade de incremento da glicose, assim como para nenhuma variável da curva de insulina. Em relação aos índices de secreção insulínica, não houve significância estatística para os índices insulinogênico ou delta, porém estes tornaram-se significantes após correção da secreção pela resistência insulínica (p = 0,008). Quanto aos índices de resistência insulínica, os índices HOMA e QUICKI foram estatisticamente significativos (p = 0,005; p = 0,005, respectivamente), assim como a relação glicose/insulina em jejum (p = 0,053). CONCLUSÃO: Apesar do tamanho limitado da amostra, podemos inferir que indivíduos com intolerância à glicose em jejum e pós-prandial possivelmente estão em momentos diferentes da história natural da doença. Nossos dados demonstram que os melhores índices para a avaliação de resistência insulínica são o HOMA e o QUICKI, e que os...

AIM AND METHODS: Our main aim was to determine the association between clinical, demographical parameters and different insulin resistance and secretion indices in apparently healthy subjects, without previous knowledge of their own level of glucose tolerance. For that purpose, we evaluated 105 individuals from February to August 2003 by means of OGTT, aged 33.4 ± 1.4 years old, 57.1 percent female. We allocated them in four groups: group 0 (normal): individuals with BMI < 25 Kg/m² and normal glucose metabolism, group 1 (obese): BMI > 25 Kg/m² and normal glucose metabolism, group 2 (IFG): impaired fasting glucose and group 3 (IGT): impaired glucose tolerance. RESULTS: We have found statistical difference on all variables during OGTT between all groups: fasting glucose (p < 0.05), 2-hour glucose (p < 0.05), glucose peak value (p < 0.05), glucose delta (p = 0.02), glucose incremental percentage (p = 0.047), area under curve (p < 0.05), and glucose peak time (p = 0.022). We have not found difference on any variable in insulin curves or on glucose incremental velocity. Regarding insulin secretion indices there were no statistical significance in insulinogenic or delta indices, but they became significant after being corrected by insulin resistance (p = 0.008). When we evaluated insulin resistance alone, by using HOMA and QUICKI indices and the fasting glucose to insulin index, we have found statistical significance (p = 0.005; p = 0.005; p = 0.053). CONCLUSION: Although studying a small sample, we could suggest that individuals with impaired fasting glucose and impaired glucose tolerance are in different stages of diabetes natural history disease. We found out that the best indices of insulin resistance are both HOMA and QUICKI. We also suggest that pancreatic secretion indices should be corrected by the insulin resistance, which could best reflect type 2 diabetes natural history.

Correlation between change in serum homocysteine levels during hyperinsulinemia and insulin sensitivity.

OBJECTIVE: To study the correlation between the changes in homocysteine (Hcy) levels during hyperinsulinemia and insulin sensitivity. MATERIAL AND METHOD: Forty-five subjects who underwent hyperinsulinemic euglycemic clamp were studied. Twenty-five subjects had normal glucose tolerance, seven had impaired glucose tolerance, and 13 had type 2 diabetes mellitus. Serum Hcy was measured before (Hcy 0) and at 120 minutes (Hcy 120) of glucose clamp. The change in Hcy levels during hyperinsulinemia was expressed as absolute difference between Hcy 0 and Hcy 120 (deltaHcy) and percentage difference over Hcy 0 (%deltaHcy). Insulin sensitivity index (ISI) was used to correlate with variables of interest. RESULTS: The ISI was not correlated with Hcy 0 and Hcy 120 but was correlated with deltaHcy and %deltaHcy. The deltaHcy and %deltaHcy were not significantly different between subjects with normal and abnormal glucose tolerance, whereas they were significantly different between subjects whose ISI were above and below the mean value. CONCLUSION: Although the change in Hcy levels during hyperinsulinemia was correlated with insulin sensitivity, the Hcy levels per se were not found to be correlated with insulin sensitivity. The change in Hcy levels during hyperinsulinemia was significantly different in subjects whose ISI was above and below the mean value but not in subjects with normal and abnormal glucose tolerance. This indicated that insulin resistance, not the glucose tolerance status, affected Hcy metabolism.