Diabetes and cancer: A 2013 synopsis

Diabetes, in particular type 2 diabetes, and cancer are two diseases that appear to be associated. Numerous epidemiological studies indicate indeed that diabetes increases the incidence of several tumors. Chronic hyperglycemia and/or insulin resistance with compensatory hyperinsulinemia could account for the association. On the other hand, the interpretation of the link between diabetes and cancer could be influenced by therapeutical interferences. Considering all these data together, cancer should be considered as a “new potential complication” of diabetes and integrated in the follow-up of diabetic subjects.     

Pathophysiology of prediabetes

Prediabetes encompasses conventional diagnostic categories of impaired fasting glucose and impaired glucose tolerance but is a band of glucose concentrations and a temporal phase over a continuum extending from conventional normal glucose tolerance to overt type 2 diabetes. Insulin resistance and defective glucose sensing at the β-cell are the central pathophysiologic determinants that together cause hyperglycemia. Regardless of the cellular origin of insulin resistance, excessive tissue fat utilization is a consistent metabolic mechanism. Although genetic influences affect β-cell function, becoming overweight is the main acquired challenge to insulin action. The phenotype of prediabetes includes dyslipidemia and higher arterial blood pressure.     

Early phase insulin secretion is increased in subjects with normal fasting glucose and metabolic syndrome: a premature feature of beta-cell dysfunction

Background and Aims

Metabolic syndrome (MS) has been mainly related to insulin resistance, but the role of changes in insulin secretion has not been thoroughly investigated.

Methods and Results

Using an oral glucose tolerance test (OGTT) we studied beta-cell function and insulin sensitivity in subjects with normal fasting glucose with and without MS, and their relationship to fatty liver which was evaluated by abdominal-ultrasonography. In MS early phase insulin secretion, as measured by insulinogenic index (IG₃₀), was increased (p < 0.05) independently from insulin sensitivity. Furthermore IG₃₀ was progressively higher as the number of factors needed for the diagnosis of MS increased (p < 0.01). Insulin and C-peptide AUC were also increased (p < 0.01 and p < 0.05, respectively) but, in contrast to IG_30, these differences disappeared when ISI was used as a covariate. After OGTT, 51% of the subjects with MS had altered post-load glucose tolerance compared to 24.9% without MS (p < 0.01). In both groups, the altered glucose tolerance was associated with a similar IG₃₀ reduction. In normo-tolerant subjects with MS the IG₃₀ was higher (+54.1%, p < 0.01), and this elevation occurred irrespective of ISI; however, the beta-cell compensatory capacity for insulin resistance (disposition index) was impaired (p < 0.001). Fatty liver was more frequent (p < 0.001) and more severe (p < 0.01) in MS, and it was significantly related to total AUC-insulin (p < 0.001), independently from ISI.

Conclusion

These findings indicate that the prevalence of altered tolerance is more frequent in subjects with normal fasting glucose and MS. The hyperinsulinemia might not only be an adaptive response to insulin resistance, but a primary defect of beta-cell function contributing to glucose intolerance.     

CD4+CD28 null T lymphocytes are expanded in young women with polycystic ovary syndrome

Women affected by polycystic ovary syndrome (PCOS) have an increased risk of cardiovascular disease. We demonstrated that women with PCOS showed an expansion of CD4(+)CD28(null) T cells, an aggressive population of T lymphocytes that has been recently associated with recurrent coronary instability and type 2 diabetes mellitus. This sheds new light on possible mechanisms responsible for the higher rate of cardiovascular disease among women with PCOS.     

高胰岛素血症:因还是果?

2011年美国糖尿病协会(ADA)年会Banting科学成就奖获得者为波士顿大学的Barbara E.Corkey.她提出2型糖尿病的先决原因是高胰岛素血症,而胰岛素抵抗是其后的代偿.基础胰岛素分泌过剩的原因在于环境因素.其提出2型糖尿病的发病模型是:环境因素造成了高基础胰岛素血症.而环境因素导致胰岛素分泌过剩的共同路径是氧化还原反应的紊乱.     

糖尿病与恶性肿瘤风险的相关性

糖尿病与恶性肿瘤作为全球性的健康威胁备受关注,二者的发病率及患病率逐年攀升.近年来研究发现,糖尿病与恶性肿瘤的发生、发展密切相关,糖尿病患者恶性肿瘤的患病率明显高于非糖尿病者,且愈后更差,二者存在很多共同的危险因素,糖尿病可能通过高胰岛素血症、高血糖和慢性炎性反应等机制影响恶性肿瘤的发生、发展.     

The predictive value of preoperative fluorine-18-L-3,4-dihydroxyphenylalanine positron emission tomography-computed tomography scans in children with congenital hyperinsulinism of infancy

Background/Purpose

In congenital hyperinsulinism (CHI) of infancy, the use of preoperative fluorine-18-l-3,4-dihydroxyphenylalanine-positron emission tomography-computed tomography (¹⁸F-DOPA-PET-CT) scan has recently been reported. The aim of this study was to evaluate the accuracy of this technique in discriminating between diffuse and focal CHI and the anatomical localization of focal lesions.

Methods

Between 2006 and 2010, ¹⁸F-DOPA-PET scan was performed in 19 children with CHI (median age, 2 months; range, 1-12 months) who were not responding to medical therapy and underwent laparoscopic or open surgery. The findings of ¹⁸F-DOPA-PET scan were correlated with histology.

Results

In 5 children, ¹⁸F-DOPA-PET scan showed diffuse pancreatic uptake, confirmed at histology and supporting the genetic suspicion of diffuse disease. In 14 children, ¹⁸F-DOPA-PET scan indicated focal pancreatic uptake, which corresponded to histology. However, in 5 patients (36%), ¹⁸F-DOPA-PET scan was inaccurate in defining the location of the lesion (n = 3), size of the lesion (n = 1), or both location and size (n = 1), leading to an inaccurate pancreatic resection.

Conclusions

Fluorine-18-l-3,4-dihydroxyphenylalanine-positron emission tomography-computed tomography scan discriminates between diffuse and focal forms of CHI. In focal forms, ¹⁸F-DOPA-PET scan is useful in 2/3 of patients in defining the site and dimension of the focal lesion. Intraoperative histologic confirmation of complete focal lesion resection is needed.     

糖负荷后胰岛素与空腹胰岛素在心血管危险因素评估中的比较

目的 通过比较糖负荷后胰岛素(2hINS)和空腹胰岛素(FINS)在评估心血管危险因素中的差异,探讨联合应用2hINS和FINS评估胰岛素抵抗的可行性.方法 研究对象为2008年5月经口服葡萄糖耐量试验(OGTT)进行糖尿病筛查的北京某院校员工,检测空腹和糖负荷后2 h血糖(2hPG)、胰岛素.分别以空腹胰岛素或2hINs胰岛素≥95%分位点判定高胰岛素血症(HINS).结果 筛查共1148名,FINS、2hINS在性别间分布无差异.糖代谢异常人群合并糖负荷后高胰岛素血症(2 hHINS)的比例为40.8%,显著高于合并空腹高胰岛素血症(FHINS)的比例(18.4%,P＜0.01).2 hHINS人群聚集心血管危险因素的数目较FHINS人群无差异.偏相关分析显示在调整了性别、年龄、体质指数和腰围变量后,2hINS与2hPG的相关强度(r=0.370)高于FINS与空腹血糖(r=0.104);FINS与TG、HDL-C的相关强度高于2hINS,而2hINS与舒张压、总胆固醇、低密度脂蛋白胆固醇的相关强度高于FINS.Logistic回归分析显示FHINS、2hHINS均是发生代谢综合征的独立危险因素,其OR(95%CI)分别为5.11(2.953～8.842)、3.46(2.109～5.687).结论 2hINS和FINS均与心血管病危险因素密切相关,与不同心血管危险因素的相关性有所不同.联合应用FINS和2hINS评估胰岛素抵抗更有益.

Abstract：

Objective To study the feasibility of using postprandial insulin (2hINS) and fasting insulin (FINS) on evaluation of insulin resistance, comparison was conducted between 2hINS and FINS on evaluation of cardiovascular risk factors. Methods A survey were conducted among individuals in the community in May 2008 and data of routine clinical examination were collected. All subjects were investigated and received 75 g oral glucose tolerance test (OGTT), and fasting and OGTT2 h blood glucose as well as insulin concentrations were determined. Hyperinsulinemia was defined as a FINS or 2bINS concentration at or above the 95th percentile of the distribution among normal glucose tolerance individuals. Results 1148 individuals were investigated and insulin concentration in male was similar to female. Prevalence of 2hHINS (40.8%) in individuals with abnormal glucose metabolism was higher than FHINS ( 18. 4%, P ＜0. 01 ). The number of metabolic risk factors in subjects with 2hHINS was similar to subjects with FHINS. After adjustment by sex, age, BMI and waist circumference, partial correlation analysis showed that the correlation between 2hINS and 2hPG(r=0.370) was higher than that of FINS and FPG(r =0. 104); FINS was higher correlated with TG and HDL- cholesterol than 2hINS, however, 2hINS was higher correlated with diastolic blood pressure, total cholesterol and LDL-cholesterol than FINS. Logistic regression analysis showed that FHINS and 2hHINS were both the independent risk factor of metabolic syndrome, the OR (95% CI) were 5. 11 (2.953 - 8. 842) and 3.46 (2. 109 - 5.687). Conclusion 2hINS and FINS were both closely associated with cardiovascular risk factors. The correlation was inconsistent when 2bINS and FINS were related to different risk factors. The combination of 2hINS and FINS might be more helpful on evaluation of insulin resistance.     

Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer's-like changes

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Pharmacological treatments presently available can slow down the progression of symptoms but can not cure the disease. Currently there is widening recognition that AD is closely associated with impaired insulin signaling and glucose metabolism in brain, suggesting it to be a brain-specific form of diabetes and so also termed as “type 3 diabetes”. Hence investigating the role of pharmacological agents that could ameliorate neuronal insulin resistance merit attention in AD therapeutics, however the therapeutics for pathophysiological condition like neuronal insulin resistance itself is largely unknown. In the present study we have determined the effect of metformin on neuronal insulin resistance and AD-associated characteristics in an in vitro model of “type 3 diabetes” by differentiating neuronal cell line Neuro-2a under prolonged presence of insulin. We observed that prolonged hyperinsulinemic conditions in addition to generating insulin resistance also led to development of hallmark AD-associated neuropathological changes. Treatment with metformin sensitized the impaired insulin actions and also prevented appearance of molecular and pathological characteristics observed in AD. The results thus demonstrate possible therapeutic efficacy of peripheral insulin-sensitizer drug metformin in AD by its ability to sensitize neuronal insulin resistance. These findings also provide direct evidences linking hyperinsulinemia and AD and suggest a unique opportunity for prevention and treatment of “type 3 diabetes”.     

Polycystic ovary syndrome and its developmental origins

The prenatal testosterone (T)-treated adult female rhesus monkey is one animal model of polycystic ovary syndrome (PCOS) in women, with early prenatal T excess programming a permanent PCOS-like phenotype characterized by luteinizing hormone (LH) hypersecretion from reduced hypothalamic sensitivity to steroid negative feedback and relative insulin excess from increased abdominal adiposity. These combined reproductive and metabolic abnormalities are associated with ovarian hyperandrogenism and follicular arrest in adulthood, as well as premature follicle differentiation and impaired embryo development during gonadotropin therapy for in vitro fertilization (IVF). A second animal model for PCOS, the prenatal T-treated sheep also is characterized by LH hypersecretion from reduced hypothalamic sensitivity to steroid negative feedback, persistent follicles and insulin resistance, but also is associated with intrauterine growth retardation and compensatory growth after birth. The ability of prenatal T excess in both species to alter the developmental trajectory of multiple organ systems in utero provides evidence that the hormonal environment of intrauterine life programs target tissue differentiation, raising the possibility that T excess in human fetal development promotes PCOS in adulthood. Such a hypothesis must include data from clinical studies of PCOS women to clarify the homology between these PCOS-like animal models and PCOS per se in reproductive and metabolic function. Future studies should develop new clinical strategies that improve pregnancy outcome and minimize pregnancy loss in women with disorders of insulin action, including PCOS, obesity and diabetes mellitus as well as minimize transgenerational susceptibility to adult PCOS and its metabolic derangements in male close relatives.