Investigation on the mechanism of acupuncture in treatment of diabetes mellitus type 2 based on the network of islet macrophages-pancreatic adipose cells-islet β cells / 中国针灸

To explore the possible new mechanism of acupuncture in the treatment of diabetes mellitus type 2 (T2DM) based on the islet inflammatory response. Islet macrophages, pancreatic adipose cells and islet β cells all participate in the pathogenesis of T2DM, and the three could form a network interaction. Acupuncture could regulate the functional phenotype of islet macrophages, improve the ectopic deposition of pancreatic adipose and repair the function of islet β cells, and play a unique advantage of overall regulation. It is suggested that acupuncture can be a potential treatment strategy for T2DM.

Etiologia da hiperglicemia em crianças críticas e o impacto da disfunção de órgãos / Etiology of hyperglycemia in critically ill children and the impact of organ dysfunction

RESUMO Objetivo: Verificar a incidência da hiperglicemia de estresse em crianças em condição grave e investigar a etiologia da hiperglicemia com base em um modelo de avaliação da homeostasia. Métodos: Estudo prospectivo de coorte, conduzido em uma unidade de terapia intensiva pediátrica da Cairo University, que incluiu 60 crianças com doença grave e 21 controles saudáveis. Utilizaram-se os níveis séricos de glicose, insulina e peptídeo C, avaliados em até 24 horas após a admissão. O modelo de avaliação da homeostasia foi utilizado para analisar a função das células beta e a sensibilidade à insulina. Resultados: A hiperglicemia foi estimada em 70% dos pacientes. Valores de glicemia ≥ 180mg/dL se associaram com desfechos piores. Os níveis de glicemia se correlacionaram de forma positiva com o Pediatric Risk for Mortality (PRISM III) e o número de órgãos com disfunção (p = 0,019 e p = 0,022, respectivamente), enquanto os níveis de insulina se correlacionaram de forma negativa com o número de órgãos com disfunção (r = -0,33; p = 0,01). O modelo de avaliação da homeostasia revelou que 26 (43,3%) das crianças em condições graves tinham baixa função de células beta e 18 (30%) baixa sensibilidade à insulina. Detectou-se patologia combinada em apenas dois (3,3%) pacientes. Baixa função de células beta se associou de forma significante com a presença de disfunção de múltiplos órgãos, disfunção respiratória, cardiovascular e hematológica, e presença de sepse. Conclusões: A disfunção de células beta pareceu ser prevalente em nossa coorte e se associou com disfunção de múltiplos órgãos.

ABSTRACT Objective: This study aimed to study the incidence of stress hyperglycemia in critically ill children and to investigate the etiological basis of the hyperglycemia based on homeostasis model assessment. Methods: This was a prospective cohort study in one of the pediatric intensive care units of Cairo University, including 60 critically ill children and 21 healthy controls. Serum blood glucose, insulin, and C-peptide levels were measured within 24 hours of admission. Homeostasis model assessment was used to assess β-cell function and insulin sensitivity. Results: Hyperglycemia was estimated in 70% of patients. Blood glucose values ≥ 180mg/dL were associated with a poor outcome. Blood glucose levels were positively correlated with Pediatric Risk for Mortality (PRISM III) score and number of organ dysfunctions (p = 0.019 and p = 0.022, respectively), while insulin levels were negatively correlated with number of organ dysfunctions (r = −0.33, p = 0.01). Homeostasis model assessment revealed that 26 (43.3%) of the critically ill patients had low β-cell function, and 18 (30%) had low insulin sensitivity. Combined pathology was detected in 2 (3.3%) patients only. Low β-cell function was significantly associated with the presence of multi-organ dysfunction; respiratory, cardiovascular, and hematological dysfunctions; and the presence of sepsis. Conclusions: β-Cell dysfunction appeared to be prevalent in our cohort and was associated with multi-organ dysfunction.

Gestational diabetes reduces pancreatic beta cells in rat offspring / La diabetes gestacional reduce las células beta pancreáticas en crías de ratas

Previous study has shown the adverse effects of gestational diabetes on hippocampal and spinal cord neuronal density in animal model. This study was conducted to determine the effect of gestational diabetes on beta cells in rat pancreas in early postnatal life. In this experimental study, 10 dams randomly allocated into control and diabetic groups on day 1 of gestation. Five dams in diabetic group received 40 mg/kg/BW of streptozotocin (intraperitoneally) and control animals received normal saline. Six of 28 and 56-day-old offspring of each gestational diabetes mellitus and controls were randomly scarified and sections were taken from the pancreas and stained using Gomorra's method. The density of beta cells and number and area of pancreatic islets were evaluated by quantitative computer-assisted morphometric method. The density of beta cells of 28-day-old offspring pancreas significantly reduced from 96.23±5.0 in control group to 71.5±5.3 cells in 10000 mm2 area of islet in diabetic group (P <0.01). The number of the pancreatic islets of in gestational diabetes (15.25±3.7) significantly reduced in comparison with the controls (8.61±0.7). The density of beta cells of 56-day-old offspring pancreas significantly reduced from 105.33±8.6 in control group to 62.12±5.9 in diabetic group (P <0.01). The number of the pancreatic islets of in gestational diabetes (13.5±0.5) significantly reduced compared to controls (6.75±1.7) (P <0.01). This study revealed that gestational diabetes loss the number of the beta cells in 28 and 56-day-old rat offspring.

Estudios previos han mostrado los efectos adversos de la diabetes gestacional en la densidad neuronal del hipocampo y de la médula espinal en modelos animales. Este estudio se llevó a cabo para determinar el efecto de la diabetes gestacional en las células beta del páncreas de rata en vida postnatal temprana. En este estudio experimental, 10 ratas fueron asignadas al azar a los grupos control y diabético en el día 1 de gestación. Cinco ratas del grupo diabético recibieron 40 mg/kg/BW de estreptozotocina (intraperitonealmente), mientras que los animales del grupo control recibieron solución salina normal. Seis de los descendientes, de 28 y 56 días de edad, de cada grupo, diabetes mellitus gestacional y control, se escarificaron al azar y se tomaron secciones del páncreas, que se tiñeron usando el método de Gomorra. La densidad de las células beta y el número y área de islotes pancreáticos fueron evaluados a través de método cuantitativo asistido por computadora morfométrica. La densidad de células beta del páncreas en las crías de 28 días disminuyó significativamente de 96,23 ± 5,0 en el grupo de control a 71,5 ± 5,3 células en el grupo diabético, en 10000 mm2 de área de islote (P <0,01). El número de islotes pancreáticos de la diabetes gestacional (15,25 ± 3,7) se redujo significativamente en comparación con los controles (8,61 ± 0,7). La densidad de células beta del páncreas en las crías de 56 días de edad se redujo de 105,33 ± 8,6 en el grupo de control a 62,12 ± 5,9 en el grupo diabético (P <0,01). El número de islotes pancreáticos en el grupo de diabetes gestacional (13,5 ± 0,5) se redujo significativamente en comparación con los controles (6,75 ± 1,7) (P <0,01). Este estudio reveló que la diabetes gestacional provoca una pérdida en el número de células beta en crías de ratas de 28 y 56 días de edad.

Genetic analysis of the ELOVL6 gene polymorphism associated with type 2 diabetes mellitus

Recent animal studies have indicated that overexpression of the elongation of long-chain fatty acids family member 6 (Elovl6) gene can cause insulin resistance and β-cell dysfunction. These are the major factors involved in the development of type 2 diabetes mellitus (T2DM). To identify the relationship between single nucleotide polymorphisms (SNP) of ELOVL6 and T2DM pathogenesis, we conducted a case-control study of 610 Han Chinese individuals (328 newly diagnosed T2DM and 282 healthy subjects). Insulin resistance and islet first-phase secretion function were evaluated by assessment of insulin resistance in a homeostasis model (HOMA-IR) and an arginine stimulation test. Three SNPs of the ELOVL6 gene were genotyped with polymerase chain reaction-restriction fragment length polymorphism, with DNA sequencing used to confirm the results. Only genotypes TT and CT of the ELOVL6 SNP rs12504538 were detected in the samples. Genotype CC was not observed. The T2DM group had a higher frequency of the C allele and the CT genotype than the control group. Subjects with the CT genotype had higher HOMA-IR values than those with the TT genotype. In addition, no statistical significance was observed between the genotype and allele frequencies of the control and T2DM groups for SNPs rs17041272 and rs6824447. The study indicated that the ELOVL6 gene polymorphism rs12504538 is associated with an increased risk of T2DM, because it causes an increase in insulin resistance.

Association of TNF-α with insulin resistance in type 2 diabetes mellitus.

Background & objectives: TNF-α is an adipocytokine that has been implicated in the development of insulin resistance. Dysregulation of TNF-α production has been implicated in a variety of human diseases including type 2 diabetes mellitus. We aimed to find out the association of TNF-α levels with insulin resistance, body mass index and waist hip ratio; and to elicit its role with respect to duration of the disease, if any. Methods: 50 type-2 diabetic patients attending Narayana Medical Hospital, Nellore, were studied. Body mass index and Waist hip ratio were calculated. Homeostasis model assessment method was used to calculate insulin resistance (HOMA IR) and per cent β cell function (HOMA B) . Insulin was estimated by chemiluminescence method and TNF-α by ELISA method. The subjects were arbitrarily categorized into three groups based on duration of diabetes. Group 1 included subjects with diabetes of less than 5 yr duration, group 2 included diabetics of 6-10 yr duration and group 3 greater than 10 yr duration. Results: Our study revealed a significant correlation between TNF-α levels and BMI (P=0.006), the correlation being stronger in males when compared to females. A significant correlation was found between per cent β cell function and TNF-α (P=0.008). TNF-α correlated significantly with HOMA IR, HOMA B and insulin, in group 2 diabetes. Interpretation & conclusions: Our results suggest the possible role of TNF-α in the pathogenesis of type-2 diabetes mellitus and the importance of reducing obesity to prevent elevated levels of the cytokine and related complications.

Reduced pancreatic β-cell mass is associated with decreased FoxO1 and Erk1/2 protein phosphorylation in low-protein malnourished rats

A low-protein diet leads to functional and structural pancreatic islet alterations, including islet hypotrophy. Insulin-signaling pathways are involved in several adaptive responses by pancreatic islets. We determined the levels of some insulin-signaling proteins related to pancreatic islet function and growth in malnourished rats. Adult male Wistar rats (N = 20 per group) were fed a 17 percent protein (normal-protein diet; NP) or 6 percent protein (low-protein diet; LP), for 8 weeks. At the end of this period, blood glucose and serum insulin and albumin levels were measured. The morphometric parameters of the endocrine pancreas and the content of some proteins in islet lysates were determined. The β-cell mass was significantly reduced (≅65 percent) in normoglycemic but hypoinsulinemic LP rats compared to NP rats. Associated with these alterations, a significant 30 percent reduction in insulin receptor substrate-1 and a 70 percent increase in insulin receptor substrate-2 protein content were observed in LP islets compared to NP islets. The phosphorylated serine-threonine protein kinase (pAkt)/Akt protein ratio was similar in LP and NP islets. The phosphorylated forkhead-O1 (pFoxO1)/FoxO1 protein ratio was decreased by 43 percent in LP islets compared to NP islets (P < 0.05). Finally, the ratio of phosphorylated-extracellular signal-related kinase 1/2 (pErk1/2) to total Erk1/2 protein levels was decreased by 71 percent in LP islets compared to NP islets (P < 0.05). Therefore, the reduced β-cell mass observed in LP rats is associated with the reduction of phosphorylation in mitogenic-related signals, FoxO1 and Erk proteins. The cause/effect basis of this association remains to be determined.

Mediators and mechanisms of pancreatic beta-cell death in type 1 diabetes

Type 1 diabetes mellitus (T1D) is characterized by severe insulin deficiency resulting from chronic and progressive destruction of pancreatic beta-cells by the immune system. The triggering of autoimmunity against the beta-cells is probably caused by environmental agent(s) acting in the context of a predisposing genetic background. Once activated, the immune cells invade the islets and mediate their deleterious effects on beta-cells via mechanisms such as Fas/FasL, perforin/granzyme, reactive oxygen and nitrogen species and pro-inflammatory cytokines. Binding of cytokines to their receptors on the beta-cells activates MAP-kinases and the transcription factors STAT-1 and NFkappa-B, provoking functional impairment, endoplasmic reticulum stress and ultimately apoptosis. This review discusses the potential mediators and mechanisms leading to beta-cell destruction in T1D.

O diabetes melito tipo 1 (DM1) tem como característica uma grave deficiência de insulina que resulta da destruição da célula-beta, crônica e progressiva, pelo sistema imune. O desencadeamento da autoimunidade contra a célula-beta é causado, provavelmente, por agentes ambientais que atuam quando existe predisposição genética. Uma vez ativadas, células imunes invadem as ilhotas, e os efeitos deletérios sobre as células-beta são mediados por mecanismos relacionados a Fas/FasL, perforina/granzima, espécies reativas de oxigênio e nitrogênio, e a citocinas pró-inflamatórias. A ligação de citocinas a seus receptores na célula-beta ativa MAP-quinase e fatores de transcrição STAT-1 e NFkapaB, provocando prejuízo funcional, estresse de retículo endoplasmático e, por fim, apoptose. Esta revisão discute os mecanismos e os mediadores potenciais que levam à destruição da célula-beta no DM1.

correlation study of some methods used for insulin sensitivity assessment: the Egyptian experience

Various surrogate methods for the quantification of insulin sensitivity have been proposed. A comparative evaluation is lacking and is relevant for the standardization of investigative methods and comparability of results. A gold standard in measuring insulin sensitivity is the minimal model derived estimates of insulin sensitivity, but this method is difficult to apply in large studies. Therefore, indirect indices of insulin sensitivity were proposed, namely I, In [I], 10[4] [I x G], I/G, HOMA-IR, In [HOMA-IR], QUICKI, AIR, and HOMA-beta cell. The aim of the present study was to compare these simple indices with data from the MINMOD. Forty Egyptian subjects of whom 15 were obese and 25 were nonobese. All subjects underwent an FSIGT. Plasma glucose was determined and serum insulin was measured. The insulin sensitivity, SI was calculated with the MINMOD program. HOMA IR, beta cell function and QUICKI were calculated. In [HOMA-IR] correlated best with the MINMOD-derived SI [r = -0.401, P = 0.010]. This was followed by In [I] and QUICKI which were equally correlated with SI [r = -0.389, P = 0.013 and r = 0.388, P = 0.013, respectively]. This was followed by I/G and HOMA-IR which correlated better with the MINMOD-derived SI than 10[4] / [Insulin x G] and I, respectively [r -0.352, P = 0.026 and r = -0.350, P = 0.027 versus r = 0.343, P = 0.030 and r = -0.343, P = 0.030, respectively]. AIR and HOMA-beta cell did not show any statistically significant correlation with the MINMOD-derived SI. In both obese and nonobese subjects HOMA-IR showed a highly significant negative correlation with QUICKI [r = -0.875, P = 0.000 and r = -0.890, P = 0.000, respectively]. Also, In [HOMA-IR] showed a highly significant negative correlation with QUICKI in both obese and nonobese subjects [r = -0.968, P = 0.000 and r = -0.947, P = 0.000, respectively]. Fasting insulin-derived measures of insulin sensitivity proposed are relatively crude methods for the quantification of insulin sensitivity in comparison to the Minimal Model analysis of the FSIVGTT and are, therefore, of limited value for the assessment of the metabolic status of an individual patient. When used in epidemiologic studies, fasting insulin alone, or the widely used HOMA or QUICKI perform at least as surrogate measures of insulin sensitivity or means for the identification of individuals with the metabolic syndrome in the general population