Soluble insulin receptor and metabolic syndrome

The metabolic syndrome describes a group of signs that increase the likelihood for developing type 2 diabetes mellitus, cardiovascular diseases and some types of cancer. The action of insulin depends on its binding to membrane receptors on its target cells. We wonder if blood insulin could travel bound to proteins and if, in the presence of hyperinsulinemia, a soluble insulin receptor might be generated. We used young adult Wistar rats (which have no predisposition to obesity or diabetes), whose drinking water was added 20 % of sugar and that were fed a standard diet ad libitum for two and six months. They were compared with control rats under the same conditions, but that had running water for consumption. At two months, the rats developed central obesity, moderate hypertension, high triglyceride levels, hyperinsulinemia, glucose intolerance and insulin resistance, i.e., metabolic syndrome. Electrophoresis of the rats’ plasma proteins was performed, followed by Western Blot (WB) for insulin and for the outer portion of the insulin receptor. The bands corresponding to insulin and to the receptor external part were at the same molecular weight level, 25-fold higher than that of free insulin. We demonstrated that insulin, both in control animals and in those with hyperinsulinemia, travels bound to the receptor outer portion (ectodomain), which we called soluble insulin receptor, and that is released al higher amounts in response to plasma insulin increase; in rats with metabolic syndrome and hyperinsulinemia, plasma levels are much higher than in controls. Soluble insulin receptor increase in blood might be an early sign of metabolic syndrome.

Obesity, insulin resistance and comorbidities ? Mechanisms of association / Obesidade, resistência à insulina e comorbidades ? Mecanismos de associação

Overall excess of fat, usually defined by the body mass index, is associated with metabolic (e.g. glucose intolerance, type 2 diabetes mellitus (T2DM), dyslipidemia) and non-metabolic disorders (e.g. neoplasias, polycystic ovary syndrome, non-alcoholic fat liver disease, glomerulopathy, bone fragility etc.). However, more than its total amount, the distribution of adipose tissue throughout the body is a better predictor of the risk to the development of those disorders. Fat accumulation in the abdominal area and in non-adipose tissue (ectopic fat), for example, is associated with increased risk to develop metabolic and non-metabolic derangements. On the other hand, observations suggest that individuals who present peripheral adiposity, characterized by large hip and thigh circumferences, have better glucose tolerance, reduced incidence of T2DM and of metabolic syndrome. Insulin resistance (IR) is one of the main culprits in the association between obesity, particularly visceral, and metabolic as well as non-metabolic diseases. In this review we will highlight the current pathophysiological and molecular mechanisms possibly involved in the link between increased VAT, ectopic fat, IR and comorbidities. We will also provide some insights in the identification of these abnormalities. Arq Bras Endocrinol Metab. 2014;58(6):600-9.

Excesso de gordura, geralmente definido pelo índice de massa corporal, está associado a distúrbios metabólicos (p. ex., intolerância à glicose, diabetes melito tipo 2 (DM2), dislipidemia) e não metabólicos (p. ex., neoplasias, síndrome dos ovários policísticos, esteatose hepática não alcoólica, glomerulopatia, fragilidade óssea etc.). No entanto, mais do que sua quantidade total, a forma da distribuição corporal de tecido adiposo constitui-se em um melhor indicador de risco para o desenvolvimento de tais doenças. O acúmulo de gordura na região abdominal e em tecido não adiposo (gordura ectópica), por exemplo, está associado ao aumento de risco para distúrbios metabólicos e não metabólicos. Por outro lado, observações sugerem que os indivíduos que apresentam adiposidade periférica, caracterizada por aumento das circunferências dos quadris e da coxas, têm melhor tolerância à glicose, redução das incidências de DM2 e da síndrome metabólica. Uma das alterações subjacentes na relação entre a obesidade, particularmente a visceral, e os distúrbios citados é a resistência à insulina. Nesta revisão, enfatizaremos os mecanismos fisiopatológicos e moleculares possivelmente implicados na ligação entre o aumento das gorduras visceral e ectópica, IR e comorbidades. Também mencionaremos os métodos diagnósticos mais frequentemente usados na identificação dessas anormalidades. Arq Bras Endocrinol Metab. 2014;58(6):600-9.

Fat and muscle component of body mass index (BMI): relation with hyperinsulinemia.

Currently there is tremendous interest in obesity and its harmful donsequences. Height, weight and body mass index (BMI) along with waist girth are routinely used parameters. One snag in the interpretation of BMI >25 as a measure of obesity is the assumption that the increase is mainly due to fat. This review emphasizes the importance of assessing the muscle component of BMI (by simple somatoscopy or somatotyping). 75 percent of Indian T2DM patients have a normal or low BMI, only 25 percent have BMI >25, wherein muscle mass also contributes as well as fat. Hyperinsulinemia is anabolic to both fat and muscle. Since skeletal muscle is a primary site of insulin resistance, greater the muscle mass, greater the importance of physical exercise to overcome the insulin resistance and greater the importance of dietary supplement of n3-PUFA to optimize the phospholipid composition of the muscle membrane (increasing membrane fluidity and thereby permitting longer residence of GLUT-4 in the plasma membrane). I propose three testable hypotheses: (1) Brown fat (FDG-PET imaging) and UCP2 and UCP3 expression in muscle are positively correlated with ectomorphy and mesomorphy, and negatively correlated with endomorphy and obesity. BAT is absent in obese people. (2) Indian T2DM patients with normal or low BMI have increased UCP2 and UCP3 expession in their muscle, as well as increased high molecular weight adiponectin which promote fatty acid oxidation and prevent obesity. (3) Indian T2DM with BMI >25 and obesity have dysfunction of UCP2 and UCP3. They have high leptin with leptin resistance (induced by hyperinsulinemia) and low adiponectin. There is inverse relationship between adipose mass and adiponectin production.

Insulin resistance and hypertension / 华中科技大学学报（医学）（英德文版）

The insulin sensitivity in hypertensive patients with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM) and the insulin resistance (IR) under the disorder of glucose metabolism and hypertension were studied. By glucose tolerance test and insulin release test, insulin sensitivity index (ISI) and the ratio of area under glucose tolerance curve (AUCG) to area under insulin release curve (AUCI) were calculated and analyzed. The results showed that ISI was decreased to varying degrees in the patients with hypertension, the mildest in the group of NGT with hypertension, followed by the group of IGT without hypertension, the group of IGT with hypertension and DM (P = 0). There was very significant difference in the ratio of AUCG/AUCI between the hypertensive patients with NGT and controls (P = 0). It was concluded that a significant IR existed during the development of IGT both in hypertension and nonhypertension. The increase of total insulin secretion (AUCI) was associated with nonhypertension simultaneously. IR of the hypertensive patients even existed in NGT and was worsened with the deterioration of glucose metabolism disorder, but the AUCI in the HT group changed slightly. A relative deficiency of insulin secretion or dysfunction of beta-cell of islet existed in IGT and DM of the hypertensive patients.

Respuesta glucémica e insulinémica y niveles de lípidos en pacientes con hipopituitarismo / Glucaemic and insulinaemic response and lipid levels in patients with hypopituitarism

Con el objetivo de identificar la respuesta glucémica e insulinémica y los niveles de lípidos en sangre de pacientes con hipopituitarismo, bajo tratamiento sustitutivo hormonal, según las causas de la insuficiencia hipofisaria, se evaluaron 51 pacientes de la consulta clínica de hipófisis de nuestra institución con ese diagnóstico, reclutados en un período de 6 meses. Al momento del estudio los pacientes estaban en tratamiento sustitutivo hormonal o habían recibido cirugía o radioterapia hipofisaria según causa de la hipofunción hipofisaria. Se excluyeron los pacientes con insuficiencia hipofisaria secundaria a enfermedad de Cushing o acromegalia. Se realizaron determinaciones de colesterol total, triglicéridos, HDL-colesterol y lipoproteína (a) y simultáneo a la extracción de sangre se insertó trocar para determinar glucemia e insulinemia basales y post-sobrecarga de 75 g de dextrosa oral. Se precisó el índice insulinemia/glucemia por cada grupo etiológico. Se realizó el cálculo del área bajo la curva y se compararon empleando el test de Wilcoxom y para someter a prueba la igualdad de las medias se empleó el análisis de varianza (ANOVA), con un nivel de significación estadística de p < 0,05. La media en años de duración del hipopituitarismo de los pacientes fue de 14,8 ± 9,9 y un promedio de edad al diagnóstico de 22,7 ± 12,6 años, con una talla media de 150,9 ± 11,3 cm. Se halló elevada proporción de pacientes con tratamiento de sustitución hormonal, pero ninguno había recibido tratamiento con hormona de crecimiento. Los valores de glucemia estuvieron en la normoglucemia baja con respuestas aplanadas, mientras que la insulinemia post-sobrecarga de glucosa estuvo elevada, con rangos amplios en todos los grupos etiológicos. El índice insulinémico glucémico medio más elevado lo presentó el grupo de pacientes con síndrome de Sheehan, que también manifestaron los niveles más altos de colesterol y triglicéridos. Se concluyó que la respuesta insulinémica ante una sobrecarga de glucosa oral está considerablemente elevada en los pacientes con diferentes causas de hipopituitarismo, pero que el síndrome de Sheehan presenta los valores más altos de hiperinsulinemia así como los trastornos lipídicos más manifiestos, como expresión de una mayor severidad del daño hipofisario.(AU)

In order to identify the glucaemic and insulinemic response and the levels of lipids in blood of patients with hypopituitarism under hormonal replacement treatment, according to the causes of hypophyseal insuficiency, 51patients with this diagnosis that were registered in a period of 6 months and were attended at the consulting room of hypophysis of our institution were evaluated. At the time of the study the patients were under hormonal replacement therapy or they have undergone surgery or hypophyseal radiotherapy according to the cause of hypophyseal hypofucntion. Patients with hypophyseal insuficiency secondary to Cushing disease or acromegaly were excluded. Total cholesterol, triglycerides, HDL-cholesterol and lipoprotein (a) were determined. Blood was extracted and at the same time a trocar was inserted to determine basal glucaemia and insulinaemia and post-overload of 75 g of oral dextrose. The insulinaemia/glucaemia index was found out for each etiologic group.The area under the curve was calculated and a comparison was made by using Wilconxom's test. To put to the test the equality of the means it was used the variance analysis (ANOVA) with a level of statistical signification of p < 0.05. The average duration of hypopituitarism among the patients was l4.8 ± 9.9 with an average age at the time of diagnosis of 22.7 ± 12.6, and an average height of 150.9 ±11.3 cm. The proportion of patients under hormonal replacement therapy was elevated, but none of them have received treatment with growth hormone. The values of glucaemia were within the low normoglucaemia with even responses, whereas insulinaemia after the overload of glucose was elevated with wide ranges in all the etiologic groups. The highest insulinaemic average index was observed in the group of patients witn Sheehan syndrome that also showed the highest levels of cholesterol and triglycerides. It was concluded that the insulinaemic response to an overload of oral glucose is considerably elevated in patients with different causes of hypopituitarism, but that the Sheehan syndrome presents the highest levels of hyperinsulinaemia as well as the most manifest lipid disorders, as an expression of a greater severity of the hypophyseal damage(AU)

Sindrome dos ovarios policisticos e resistencia a insulina / Polycystic ovary syndrome and insulin resistance

A sindrome dos ovarios policisticos e uma sindrome heterogenea, cuja etiologia ainda nao e totalmente conhecida. A hiperinsulinemia e achado bastante frequente nesta sindrome e foi relacionada a aumento da morbidade em mulheres portadoras da afeccao. O objetivo deste trabalho foi de estudar os aspectos mais relevantes da associacao entre a sindrome e a...

Sindrome dos ovarios policisticos: contribuicao para o estudo da resistencia a insulina / Polycystic ovary syndrome: contribution for the study of insulin resistance

Apos uma avaliacao inicial, 25 pacientes com sindrome dos ovarios policisticos (SOP) foram submetidas a teste de tolerancia a glicose oral com dosagens de glicose e insulina. Treze pacientes foram tratadas com espironolactona, 200 mg/dia por 6 meses e reavaliadas aos 3 e 6 meses. Concluimos que : 1- a SOP esta associada com a resistencia a insulina; 2- insulinemia de jejum nao e suficiente para o diagnostico; 3- mulheres obesas com acanthosis nigricans sao mais resistentes a insulina e 4- o uso de um antiandrogenio melhora a...

Insulin resistance and urinary excretion of sodium in hypertensive patients with non-insulin dependent diabetes mellitus.

BACKGROUND: Hyperinsulinemia has been implicated in the pathogenesis of hypertension both in non-diabetic and diabetic patients. A causal relationship between renal sodium retention and hyperinsulinemia is speculated to play role in the development of hypertension in diabetes mellitus. MATERIAL AND METHODS: Twenty patients (12 males; 8 females) with hypertension and non-insulin dependent diabetes mellitus (NIDDM) and twenty normotensive patients (11 males, 9 females) with NIDDM were included in the present study. Blood samples for glucose and immunoreactive insulin (IRI) assay were collected at 0, 30, 60 and 120 minutes after 75 g of glucose per oral. Urinary sodium excretion in 24 hrs was estimated by flame photometry. Insulin response to glucose and correlation between basal insulin secretion and urinary sodium excretion were evaluated. RESULTS: Mean fasting plasma glucose value was significantly raised in hypertensive group in comparison with normotensive group of diabetic patients. Patients with diabetes and hypertension and significantly higher level of serum IRI than normotensive patients with diabetes mellitus. Urinary sodium excretion was significantly lower in diabetic patients with hypertension than in diabetic patients without hypertension. A negative correlation between basal insulin level and urinary Na+ excretion was observed in hypertensive patients with NIDDM. CONCLUSION: A negative correlation between hyperinsulinemia and 24 hrs urinary Na+ excretion was observed in patients with diabetes and hypertension. The study highlights that patients with diabetes mellitus have tendency to retain sodium under the influence of insulin but this needs further evaluation.

Obesidad, hipertensión y sindrome metabólico / Obesity, hypertension and metabolic syndrome

Introducción. Si bien la asociación entre insulinorresistencia (IR) e hipertensión (HTA) existe, puede ser fuertemente afectada por la obesidad, factor que explicaría la relación. Objetivo. La obesidad, medida por el índice de masa corporal (IMC), puede identificar a una población con mayor prevalencia de hipertensión y alteraciones del síndrome metabólico. Método. Análisis de la base de datos de Tucumán del Estudio Multicéntrico de Factores de Riesgo SAC '88 que incluye a 186 personas, 94 mujeres y 92 varones, entre 30 y 60 años. Cálculo del índice de sensibilidad insulínica (ISI) mediante fórmula de Berglund y Lithell y del peso mediante IMC. Se consideran significativas P< 0.05, realizándose análisis uni y multivariado. Resultados. En Tucumán el 67.7 por ciento de 186 trabajadores tienen sobrepeso y 22 por ciento son obesos. La obesidad se asocia a la hipertensión arterial, P .000, OR 0.14 (0.04-0.45); hiperglucemia, P. 0.12, OR 0.19 (0.04-0.84), y a un patrón dislipidémico de hipertrigliceridemia, P. 000, OR 0.09 (0.03-0.26) con incremento de la relación C/HDLc, P .006, OR 0.32 (0.13-0.80)...

Ovarian activity before and after gonadal suppression by GnRH-a in patients with polycystic ovary syndrome, hyperandrogenism, hyperinsulinism and acanthosis nigricans

Objective. To investigate the ovarian activity before and after gonadal suppression with GnRH-analog in patients with PCO, hyperandrogenism, hyperinsulinism and ancathosis nigricans. Design: Controlled clinical study. Setting: Tertiary academic medical center. Patients: Six patients with clinical findings of PCO, hirsutism and acanthosis nigricans. Interventions. Morning blood samples in the follicular phase to determine the seteroid levels, glucose and insulin curve, comparing to a control group. Administration for 2 consecutive months of a GnRH-analog, comparing, in the study group, the free testosterone levels before and after ovarian suppression. Main Outcome Measure. Determination of insulin levels in PCO, hirsutism and acanthotic patients and the free-testosterone levels before and after gonadal suppression. Results. Insulin levels were significantly higher in the study group when compared to normal women during the glycemic test. We also found a significant decrease in the free-testosterone levels after 2 months of gonadal suppression with GnRH-analog when compared to the initial time. Conclusions. Patients with PCO, hirsutism and acanthosis nicrigans present high levels of in sulin, suggesting an ovarian hyperesponsiveness, which is not sustained when gonadotrophic blockage was achieved.

Reduced renal sodium excretion in primary hypertensive patients after an oral glucose load

This study was designed to determine urinary sodium excretion in response to an oral glucose load in hypertensive patients. Fifteen hypertensive patients and eighteen normotensive subjects were studied after an overnight fast and for 4 h after the ingestion of 100 g glucose. A subgroup of intreated, nonobese, primary hypertensive patients (five of the 15 hypertensive patients) became hyperinsulinemic (total area under the insulin curve[TAUC]:33,080 + 3349 muU ml(-1) 120 min(-1) in response to an oral glucose load compared to normotensive subjects (TAUC: 3670<13.731<23,693 muU ml(-1) 120 min(-1) or to the other subgroup of normoinsulinemic hypertensive individuals (TAUC:10,221 + 1615 muU ml(-1) 120 min(-1) despite a similar serum glucose concentration in both groups. A significant decrease in renal sodium excretion in the entire hypertensive group (47.1 + 4.7 per cent, P<0.019) compared to the normotensive (20.0 + 10.5 per cent) subjects was also observed during the oral glucose tolerance test. Decreased renal sodium excretion was followed by a transient increase in urinary acid excretion. We speculate that the increase in insulin secretion may be responsible for the sodium-dependent increase in intracellular Ca2+, cellular H+ output and blood pressure in a subgroup of salt-sensitive patients with hypertension. New studies should be designed to identify the precise mechanisms involved in the interaction between hypertension, serum insulin-glucose levels and the magnitude of the renal tubule reabsorption abnormality.

Síndrome metabólico de riesgo vascular e hipertensión arterial / Vascular risk metabolic syndrome and arterial hypertension

La hipertensión se asocia a alteraciones metabólicas vinculables a hiperinsulinemia, como posibles resultantes de nuestros hábitos de vida. Las relaciones entre obesidad central, hiperinsulinemia, actividad simpática, dislipemia, aterosclerosis, retención de sodio, reactividad vascular alterada e hipertensión, permiten estabelecer nexos fisiopatológicos que no son exhaustivamente comprendidos en la actualidad, pero con probable implicación etiológica. Aun sin estabelecer un puente entre la obesidad y la hipertensión a través de la hiperinsulinemia, el síndrome metabólico condiciona incremento tanto del riesgo vascular como de la presión arterial, y nos hace reconsiderar la definición esencial en estos pacientes.

Portal hyperinsulinemia after partial hepatectomy combined with vagotomy

In order to study the changes in portal insulin levels after partial hepatectomy plus vagotomy with and without preservation of the hepatic branches of the left vagus nerve, portal insulin levels were measured in 57 male Wistar rats 4 and 24 hours after surgery. Partial hepatectomy caused an early reduction in portal insulin levels providing evidence that reduced regenerative capacity observed in the liver after trunkal vagotomy is not due to a reduction in portal insulinemia