c-Jun氨基末端激酶抑制剂减轻烫伤后胰岛素抵抗的实验研究

目的探讨c-Jun氨基末端激酶(JNK)抑制剂SP600125对烫伤后胰岛素抵抗的作用及机制。方法24只SD大鼠以表格随机法分为假伤组、烫伤对照组和烫伤 SP600125组。将大鼠制成30％TBSAⅢ度烫伤模型(其中假伤组以常温模拟烫伤过程)。伤后第4天进行葡萄糖钳夹实验(烫伤 SP600125组在实验开始前2 h给予拮抗剂SP600125),检测肌肉组织胰岛素受体底物(IRS)1磷酸化丝氨酸307(Ser307)和酪氨酸的活性变化,并比较各组磷酸化JNK表达水平。结果(1)葡萄糖钳夹实验:假伤组、烫伤对照组和烫伤 SP600125组100 g／L葡萄糖输注率分别为(12．33±0．42)、(6．61±0．27)、(11．11±0．68)mg·kg-1·min-1,各组间比较,差异有统计学意义(P< 0．01)。(2)烫伤对照组与假伤组比较,肌肉组织IRS-1磷酸化Ser307和磷酸化JNK活性明显升高, IRS-1磷酸化酪氨酸活性明显降低(P<0．05)。烫伤 SP600125组与烫伤对照组比较,肌肉组织中IRS-1磷酸化Ser307和磷酸化JNK活性降低而IRS-1磷酸化酪氨酸活性增加。结论SP600125通过抑制JNK磷酸化而降低IRS-1磷酸化Ser307活性,可部分减轻烫伤后胰岛素抵抗发生。     

K(ATP) channels "vingt ans après": ATG to PDB to Mechanism

A multidisciplinary effort over twenty years has provided deep insight into the nature of K(ATP) channels. First discovered in cardiomyocytes and pancreatic beta-cells, as ubiquitous sensors of the ADP/ATP ratio they are implicated in multiple disorders characterized by the uncoupling of excitation from metabolism. Composed of two disparate subunits these large octameric channels present a formidable challenge to scientists interested in understanding mechanism in physical, chemical, and structural terms. Post-cloning studies have defined the domains and interactions, within and between the nucleotide-inhibited K(IR) pore and nucleotide-stimulated, drug-binding core of the ATP-Binding Cassette (ABC) regulatory subunits, that control channel assembly and gating. Determination of the three-dimensional structures of the bacterial prototypes of the channel subunits allowed homology modeling and has provided increasingly detailed mechanistic understanding. Here I review the early electrophysiology and molecular biology of K(ATP) channels, cover biophysical principles governing their single channel kinetics, integrate this with current efforts to understand ligand-recognition and gating within the pore and SUR core, and propose a mechanism of coupling based on recent identification of a SUR gatekeeper module and first composite models of (SUR/K(IR) 6.0)(4) complexes. This mechanism, based on interactions between inter-K(IR) subunit ATP-binding pockets and a unique bi-directional regulatory apparatus comprised of elements from the gatekeeper and K(IR) amino terminus, provides a molecular perspective for understanding the biophysical basis underlying the polar effects of pathogenic mutations in K(ATP) channel subunits.     

磺脲类药物受体基因多态性与2型糖尿病高危人群血清胰岛素水平相关性研究

目的　了解磺脲类药物受体(SUR)基因多态性与中国汉族人糖尿病高危人群血清胰岛素浓度的关系。方法采用多聚酶链式反应-限制性酶切片段长度多态性分析技术(PCR-RFLP)对SUR基因第24内含子的多态性进行分析,采用放射免疫法(RIA)测定血清胰岛素浓度。结果　SUR基因第24内含子的“c”等位基因频率在206例有2型糖尿病家族史而彼此间无血缘关系的糖耐量试验正常人(A组)中较110例正常对照者(B组)显著升高(64%vs54%,P=0.004),且“cc”纯合子基因型的频率亦在此人群中显著升高(38%vs24%,P=0.002)。A组人群中纯合子“cc”基因型者BMI(27.27±6.37vs24.99±3.43kg/m2,P＜0.05;27.27±6.37vs25.28±2.78kg/m2,P＜0.05)、空腹及口服75g葡萄糖后2小时血清胰岛素(15.52±10.72vs9.27±5.03U/ml,P＜0.01;15.52±10.72vs10.79±7.80U/ml,P＜0.05及76.41±54.02vs55.43±49.60U/ml,P＜0.01;76.41±54.02vs55.71±40.39,P＜0.05)、HOMA(Ri)(4.00±3.09vs2.79±1.32,P＜0.01;4.00±3.09vs2.82±2.94,P＜0.01)及ISI(-4.22±0.75vs-3.69±0.57,P＜0.01;-4.22±0.75vs-3.75±0.94,P＜0.01)均显著高于其它基因型者。结论　本研究表明SUR基因的缺陷可能导致胰岛素的高分泌,而后者可能是后继的体重增加及胰岛素敏感性降低的原因之一。本研究结果支持在糖尿病发病的自然病程中高胰岛素分泌为初始病因的假说。     

Recent advances in hyperinsulinemic hypoglycemia of infancy

Hyperinsulinemia-induced hypoglycemia is the most common cause of persistent hypoglycemia in adults, children, and infants. Our understanding of the disorders responsible for this type of hypoglycemia has been increasing due to the recent discoveries in the molecular and biochemical regulation of insulin secretion. In this article, we review the current knowledge of the pathophysiology, clinical presentation, and diagnosis of disorders that cause hyperinsulinemic hypoglycemia of infancy. We highlight the distinction between the diffuse and focal forms of the disease, especially the promising results with ¹⁸F-L-dopa positive emission tomography (PET) scanning for preoperative localization and distinction to guide the extent of surgical removal of pancreatic tissue that may result in cure rather than persistence of disturbed carbohydrate metabolism.

Conclusion: Despite all these discoveries, much remains to be learned, as currently about one third of infants with hyperinsulinemic hypoglycemia have no identifiable cause.     

Insulin promotes HER2 signaling activation during Barrett’s Esophagus carcinogenesis

BackgroundInsulin-resistance and hyperinsulinemia could have a role in the growing incidence of esophageal adenocarcinoma (EAC) and its pre-cancerous lesion Barrett’s Esophagus (BE). HER2 activation has also a pivotal role in EAC carcinogenesis but no data correlate these two phenomena in this disease context.AimsTo investigate the role of hyperinsulinemia in BE-dysplasia-adenocarcinoma sequence and the possible relationship between insulin-mediated and HER2 signaling in EAC development.MethodsSerum insulin, C-peptide, IGF1, glucagon, IL-6, TNF-alpha, leptin, adiponectin and Insulin-Resistance-index were analyzed in 19 patients with gastro-esophageal reflux disease, 51 with BE, 24 with dysplastic-BE and 14 with EAC. Insulin/IGF1/HER2 pathways were analyzed in esophageal biopsies using Luminex^® Technology. Insulin effect was also evaluated in EAC-derived OE19 cells.Data were analyzed by Fisher’s exact test, Kruskal–Wallis test, Mann–Whitney U-test, Cuzick’s test and Spearman correlation coefficient calculation.ResultsInsulin-Resistance-index, insulin and C-peptide levels increased along with disease progression (p = 0.019, p = 0.002, p < 0.0001, respectively) and correlated with HER2 expression and with downstream mediators phospho-Akt and phospho-mTOR in esophageal tissue.In vitro, insulin was also able to induce cell proliferation through HER2 activation.ConclusionsOur data pinpoint a possible role of hyperinsulinemia in the Barrett’s Esophagus metaplasia-dysplasia-adenocarcinoma sequence through HER2 activation in esophageal epithelial cells.     

Insulin resistance and clinical aspects of non-alcoholic steatohepatitis (NASH).

Non-alcoholic steatohepatitis (NASH) is one of the most common liver disorders. This is highly prevalent in obese and diabetic subjects. Persons with central obesity are at particular risk. Other clinical predictors are age more than 40-50 years and hyperlipidemias, but none of these factors is invariable for causation of NASH. Other reported associations are, celiac disease, Wilson's Disease and few other metabolic diseases. Drugs, particularly amiodarone, tamoxifen, nucleoside analogues and methotrxate have also been linked to NASH. The disease is evenly distributed in both sexes but advanced disease is more common in women. Ethnic variation exists and African Americans are less affected than Hispanic Americans. Specific clinical features of NASH are infrequent. Patients usually come to clinical attention by elevated liver enzymes found on routine evaluation but on history, about two third of patients will admit to have mild fatigue and about half will report right upper quadrant pain. Rarely, patient may present with a complication of cirrhosis. Physical examination may reveal hepatomegaly and splenomegaly. Research in last few years has stressed that development of steatosis, stetohepatitis, fibrosis with subsequent cirrhosis are most probably the result of insulin resistance. Therefore, clinical features may reflect existence of insulin resistance. Obesity, particularly central obesity is most important of these. Patients may have sleep apnea syndrome. Hypertension and manifestations of diabetes mellitus like polyuria, polydypsia, and neurological deficits may occur. Patients may have varying combination of obesity, diabetes, hyperlipidemia, hypertension and impaired fibrinolysis (syndrome X). Children with insulin resistance may show acanthosis nigricance. Patients with polycystic ovary syndrome, which consists of insulin resistance, diabetes, obesity, hirsutism, oligo or polymenorrha and hyperlipidemia may have NASH. Other rare manifestations of insulin resistance, which can be seen in patients of NASH are lipomatosis, lipoatrophy/lipodystrophy and panniculitis. Most other rare conditions known to cause NASH like peroxisomal diseases, mitochondialpathies, Weber-Christian disease, Mauriac syndrome, Madelung's lipomatosis and abetaliopprotenemia also have insulin resistance. This is believed that primary defect underlying insulin resistance is impairment in postreceptor pathways (through tyrosine kinase activity) of insulin action. Primary defect in insulin receptors appear uncommon. This results in down regulation of insulin receptor substance 1 (IRS-1) signaling by excess free fatty acids. In muscle, activated IRS-1 promotes translocation of glucose transporter protein 4 (GLUT4) to cell membrane. As a result, monocyte glucose uptake by GLUT4 increases glucose disposal from blood and reduced need for insulin. PKC-0 is a likely candidate as serine kinase in muscle regulated by fatty acids that can impair the activation of IRS-1. Insulin resistance is usually evaluated by fasting insulin levels, Quantitative Insulin Check Index (QUICKI) and Homeostasis Model Assessment of Insulin Resistance (HOMA), C-peptid/insulin ratio oral glucose tolerance test and hyper insulinemic euglycemic clamp. The clamp technique is considered the gold standard.     

Adult focal β-cell nesidioblastosis: A case report

BACKGROUNDNesidioblastosis usually refers to a series of clinical manifestations caused by the proliferation of β-cells in pancreatic islets, and these clinical manifestations are hyperinsulinemia and persistent hypoglycemia. According to the size of the lesion, nesidioblastosis is divided into focal nesidioblastosis, diffuse nesidioblastosis and atypical nesidioblastosis, and its pathogenesis is still unclear. Nesidioblastosis is mainly seen in infants and rarely reported in adults, especially focal nesidioblastosis, which is difficult to distinguish from insulinoma.CASE SUMMARYWe report a case of adult focal β-cell nesidioblastosis in which the preoperative diagnosis was insulinoma. The patient was a 48-year-old male who suffered from repeated morning and fasting palpitations, sweating, and severe disturbance of consciousness for 5 years. His blood glucose was found to be as low as 1.79 mmol/L during an attack. However, abdominal computed tomography showed no abnormalities. Magnetic resonance imaging and endoscopic ultrasonography demonstrated a nodular mass in the head of the pancreas, combined with hyperinsulinemia and high serum C-peptide. The patient was diagnosed with insulinoma and underwent Beger surgery; however, the postoperative pathological results showed nesidioblastosis.CONCLUSIONAlthough surgical resection is the preferred option for nesidioblastosis, some cases can be treated non-surgically. In order to increase clinicians'' understanding of nesidioblastosis, it is necessary to review the pathogenesis, diagnosis and treatment of this disease.     

Chronic effects of clozapine administration on insulin resistance in rats: Evidence for adverse metabolic effects

Chronic treatment with the atypical antipsychotics clozapine has been associated with an increased risk for deterioration of glucose homeostasis, leading to hyperglycemia and insulin resistance diabetes. The present study mainly aimed to investigate possible mechanisms underlying clozapine-induced hyperglycemia. Male Wistar albino rats were randomly divided into two groups (each consists of 12 rats). The first group received clozapine orally at a dose of 10 mg/kg body weight daily for 6 weeks, while the other group received the drug vehicle only and served as the control group. At the end of the six weeks, hyperglycemia, hyperinsulinemia and insulin resistance, as indicated by Homeostatic model assessment of insulin resistance (HOMA-IR), were observed in the clozapine group as compared with the control group. This disturbance in glucose regulation was associated with non-significant changes in body weight, serum cortisol level, and hepatic glycogen content. The Clozapine group showed a significant increase in hepatic phosphorylase activity and in the gene expression level of hepatic glucose-6-phosphatse (G6Pase) enzymes compared to the control group. It can be concluded that clozapine-induced hyperglycemia and insulin resistance occur in a manner mostly independent of weight gain, and may be attributed to an increase in hepatic phosphorylase activity and increased expression level of G6Pase.