Circulating RNAs as predictive markers for the progression of type 2 diabetes

Type 2 Diabetes Mellitus (T2DM) is the most prevalent form of diabetes in the USA, thus, the identification of biomarkers that could be used to predict the progression from prediabetes to T2DM would be greatly beneficial. Recently, circulating RNA including microRNAs (miRNAs) present in various body fluids have emerged as potential biomarkers for various health conditions, including T2DM. Whereas studies that examine the changes of miRNA spectra between healthy controls and T2DM individuals have been reported, the goal of this study is to conduct a baseline comparison of prediabetic individuals who either progress to T2DM, or remain prediabetic. Using an advanced small RNA sequencing library construction method that improves the detection of miRNA species, we identified 57 miRNAs that showed significant concentration differences between progressors (progress from prediabetes to T2DM) and non‐progressors. Among them, 26 have been previously reported to be associated with T2DM in either body fluids or tissue samples. Some of the miRNAs identified were also affected by obesity. Furthermore, we identified miRNA panels that are able to discriminate progressors from non‐progressors. These results suggest that upon further validation these miRNAs may be useful to predict the risk of conversion to T2DM from prediabetes.     

Natural course of preclinical type 1 diabetes

The clinical presentation of type 1 diabetes is preceded by an asymptomatic latent period characterized by the presence of diabetes-associated autoantibodies in the peripheral circulation, reflecting beta-cell damage. This prediabetic period may last for months and years. Several studies observing genetically susceptible subjects from birth have shown that insulin autoantibodies (IAA) are the first or among the first autoantibodies to appear in young children, implying that insulin may be the primary autoantigen in most cases of childhood type 1 diabetes. About 12-16% of siblings of children with type 1 diabetes have been observed to test positive for at least one diabetes-associated autoantibody, whereas the risk of diabetes among siblings has been estimated to be 6-8%. In parallel, close to 4% of Finnish schoolchildren tested positive for at least one diabetes-associated autoantibody; the lifetime risk of type 1 diabetes in the Finnish population has been estimated to be close to 1%. These observations suggest that only 25-50% of those with signs of beta-cell autoimmunity eventually progress to clinical type 1 diabetes. Accordingly there is a considerable proportion of children in whom beta-cell autoimmunity remains subclinical or is aborted. Positivity for only one diabetes-associated autoantibody may actually represent innocent beta-cell autoimmunity, while positivity for two or more autoantibodies seems to mark a point of no return. The autoimmune response is very dynamic in the early phase of prediabetes, with spreading from one antigen to another and from one epitope to another within a given antigen. In addition both isotype spreading and switching can be observed in early prediabetes. This indicates that the early prediabetic process may be a suitable target for immunomodulation aimed at delaying or preventing progression to clinical diabetes.     

Proinflammatory cytokine profiles in prediabetic Saudi patients

Prediabetes is an increase-risk state for diabetes that is associated with an increase in blood glucose levels to more than normal, but not increased enough to be termed as type 2 diabetes mellitus (T2DM). A timely intervention and management of prediabetes can stop its further progression to the diabetic state. Many cytokines are involved in diseases including diabetes, however, their role in prediabetes is unknown. In this study, we attempted to analyze numerous proinflammatory cytokines in prediabetic patients. A total of 60 adult Saudi prediabetes patients and healthy control individuals were included in this study. To better understand the role of the proinflammatory cytokines in prediabetes patients and its potential link to the disease outcome, the variations in the levels of these cytokines were investigated using Multi-Analyte ELISA technique. The T helper cells (Th1 and Th2) immune response expression profiling of 84 genes was done using Real Time-quantitative PCR (RT-qPCR) technique. The present finding showed that serum Interleukin IL-2, IL-1β, and IL-1α levels of all prediabetes patients were increased when compared with healthy control cases (P < 0.05). Inductions of proinflammatory cytokines and upregulation of Th1 and Th2 immune genes might play a potential role during prediabetes status and may be linked to the disease outcome. Further studies are needed to investigate the underlying mechanism of these proinflammatory cytokines in diabetes development. A strong positive correlation was found between IL and 1α with glucose levels than with IL-1β and IL-2. In conclusion, cytokines, especially IL-1, may play a critical role in the development of diabetes.     

Is Serum Zinc Level Associated with Prediabetes and Diabetes?: A Cross-Sectional Study from Bangladesh

Aims

To determine serum zinc level and other relevant biological markers in normal, prediabetic and diabetic individuals and their association with Homeostasis Model Assessment (HOMA) parameters.

Methods

This cross-sectional study was conducted between March and December 2009. Any patient aged ≥30 years attending the medicine outpatient department of a medical university hospital in Dhaka, Bangladesh and who had a blood glucose level ordered by a physician was eligible to participate.

Results

A total of 280 participants were analysed. On fasting blood sugar results, 51% were normal, 13% had prediabetes and 36% had diabetes. Mean serum zinc level was lowest in prediabetic compared to normal and diabetic participants (mean differences were approximately 65 ppb/L and 33 ppb/L, respectively). In multiple linear regression, serum zinc level was found to be significantly lower in prediabetes than in those with normoglycemia. Beta cell function was significantly lower in prediabetes than normal participants. Adjusted linear regression for HOMA parameters did not show a statistically significant association between serum zinc level, beta cell function (P = 0.07) and insulin resistance (P = 0.08). Low serum zinc accentuated the increase in insulin resistance seen with increasing BMI.

Conclusion

Participants with prediabetes have lower zinc levels than controls and zinc is significantly associated with beta cell function and insulin resistance. Further longitudinal population based studies are warranted and controlled trials would be valuable for establishing whether zinc supplementation in prediabetes could be a useful strategy in preventing progression to Type 2 diabetes.     

Diabetes,Prediabetes and the Survival of Nasopharyngeal Carcinoma: A Study of 5,860 Patients

Background

The incidence of diabetes is increasing. But the impact of diabetes and prediabetes on survival of patients with nasopharyngeal carcinoma (NPC) has received little evaluation.

Methods

In a cohort of 5,860 patients, we compared the disease specific survival (DSS), locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS) of patients with diabetes, prediabetes and normoglycemia defined by pretreatment fasting plasma glucose (FPG) using Kaplan–Meier method, log-rank test and Cox proportional hazards model.

Results

Comparing to normoglycemic patients, the diabetic and the prediabetic were generally older, fatter, had hypertension, heart diseases and hyperlipaemia and usually received radiotherapy alone. But both the diabetic and the prediabetic had similar DSS, LRFS and DMFS to normoglycemic patients, even adjusting for such important factors as age, gender, smoking, drinking, hypertension, heart diseases, body mass index, hyperlipaemia, titer of VCA-IgA and EA-IgA, pathology, T-stage, N-stage, chemotherapy and radiotherapy (P>0.05 for all). Additionally, the findings remained unchanged in sensitivity analysis by excluding patients with known diabetes history and in subgroups of the various factors.

Conclusions

The diabetic and prediabetic NPC patients had similar survival to normoglycemic NPC patients. These data, in the largest reported cohort, are the first to evaluate the association between diabetes, prediabetes and the survival in NPC. The findings are relevant to patient management and provided evidence of the effect on this disease exerted by comorbidities.     

Risk of complications of pregnancy in women with type 1 diabetes: nationwide prospective study in the Netherlands

Objective To investigate maternal, perinatal, and neonatal outcomes of pregnancies in women with type 1 diabetes in the Netherlands.Design Nationwide prospective cohort study.Setting All 118 hospitals in the Netherlands.Participants 323 women with type 1 diabetes who became pregnant between 1 April 1999 and 1 April 2000.Main outcome measures Maternal, perinatal, and neonatal outcomes of pregnancy.Results 84% (n = 271) of the pregnancies were planned. Glycaemic control early in pregnancy was good in most women (HbA_1c ≤ 7.0% in 75% (n = 212) of the population), and folic acid supplementation was adequate in 70% (n = 226). 314 pregnancies that went beyond 24 weeks'' gestation resulted in 324 infants. The rates of pre-eclampsia (40; 12.7%), preterm delivery (101; 32.2%), caesarean section (139; 44.3%), maternal mortality (2; 0.6%), congenital malformations (29; 8.8%), perinatal mortality (9; 2.8%), and macrosomia (146; 45.1%) were considerably higher than in the general population. Neonatal morbidity (one or more complications) was extremely high (260; 80.2%). The incidence of major congenital malformations was significantly lower in planned pregnancies than in unplanned pregnancies (4.2% (n = 11) v 12.2% (n = 6); relative risk 0.34, 95% confidence interval 0.13 to 0.88).Conclusion Despite a high frequency of planned pregnancies, resulting in overall good glycaemic control (early) in pregnancy and a high rate of adequate use of folic acid, maternal and perinatal complications were still increased in women with type 1 diabetes. Neonatal morbidity, especially hypoglycaemia, was also extremely high. Near optimal maternal glycaemic control (HbA_1c ≤ 7.0%) apparently is not good enough.     

Intimal redox stress: Accelerated atherosclerosis in metabolic syndrome and type 2 diabetes mellitus. Atheroscleropathy

Metabolic syndrome, insulin resistance, prediabetes, and overt type 2 diabetes mellitus are associated with an accelerated atherosclerosis (atheroscleropathy). This quartet is also associated with multiple metabolic toxicities resulting in the production of reactive oxygen species. The redox stress associated with these reactive oxygen species contribute to the development, progression, and the final fate of the arterial vessel wall in prediabetic and diabetic atheroscleropathy. The prevention of morbidity and mortality of these intersecting metabolic diseases can be approached through comprehensive global risk reduction.     

Alveolar bone of BB/W rats: a morphometric and histochemical study

The present study reported histochemical changes in alveolar bone glycosaminoglycans (GAG) (using Safranin O) and in interdental bone height in three groups of BB/W rats: diabetic, diabetes prone, and diabetes resistant. Safranin O staining intensity suggested that total GAG levels were highest in diabetic bone (p less than 0.05 compared to diabetes resistant, p less than 0.005 compared to diabetes prone) but not significantly different between diabetes prone and resistant groups. Following chondroitinase AC and ABC digestion, staining reactions suggested that the highest levels of dermatan sulfate were in the diabetes resistant group (p less than 0.001 compared to diabetic, p less than 0.001 compared to diabetes prone) and the highest levels of chondroitin sulfates were in the diabetes prone group (p less than 0.001). Coincidently the mean height of diabetes prone interdental septum was significantly less than that of diabetes resistant or diabetic groups (p less than 0.05). The study suggested that 1) diabetes and "prediabetes" produce significant changes in levels of chondroitin 4, 6, and dermatan sulfates within alveolar bone, 2) in "prediabetic" animals, interdental bone loss occurs prior to the onset of clinical symptoms and in the absence of local irritating factors, the bone height appears to return to normal levels, and 3) there may be a correlation between alveolar bone height and relative levels of dermatan sulfate.     

常用口服降糖药的药物基因组学研究进展

近年来,中国 2 型糖尿病(T2DM)发病率呈快速增长趋势。T2DM 是一种慢性代谢性疾病,涉及全身各个系统,甚至可能引起严 重的并发症。大多数 T2DM 患者需长期口服降糖药物。口服降糖药的药物基因组学研究可指导个体化治疗,改善疗效,降低用药成本,减 少不良反应和并发症风险,已成为当前研究的热点。综述常用口服降糖药药效学和药代动力学参数的相关基因多态性研究进展,为更加合理、 有效地进行糖尿病临床个体化治疗提供参考。     

Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion

The adult Goto-Kakizaki (GK) rat is characterized by impaired glucose-induced insulin secretion in vivo and in vitro, decreased beta-cell mass, decreased insulin sensitivity in the liver, and moderate insulin resistance in muscles and adipose tissue. GK rats do not exhibit basal hyperglycemia during the first 3 wk after birth and therefore could be considered prediabetic during this period. Our aim was to identify the initial pathophysiological changes occurring during the prediabetes period in this model of type 2 diabetes (T2DM). To address this, we investigated beta-cell function, insulin sensitivity, and body composition in normoglycemic prediabetic GK rats. Our results revealed that the in vivo secretory response of GK beta-cells to glucose is markedly reduced and the whole body insulin sensitivity is increased in the prediabetic GK rats in vivo. Moreover, the body composition of suckling GK rats is altered compared with age-matched Wistar rats, with an increase of the number of adipocytes before weaning despite a decreased body weight and lean mass in the GK rats. None of these changes appeared to be due to the postnatal nutritional environment of GK pups as demonstrated by cross-fostering GK pups with nondiabetic Wistar dams. In conclusion, in the GK model of T2DM, beta-cell dysfunction associated with increased insulin sensitivity and the alteration of body composition are proximal events that might contribute to the establishment of overt diabetes in adult GK rats.     

High-risk pregnancy and hypoluteoidism in the bitch

High-risk pregnancies are those in which the prevalence of maternal, fetal and/or perinatal morbidity or mortality is likely to be higher than that of the general obstetrical population. Some maternal characteristics associated with risk to maternal, fetal and/or perinatal health are readily identifiable prior to conception, such as advanced maternal age, brachycephalic breed, or a previous history of pregnancy loss. Others, such as gestational diabetes or a singleton litter, are recognized after conception. Early recognition of the problem (i.e. the risk), anticipation of the potential sequelae, and development of an aggressive management scheme are essential for a successful outcome of a high-risk pregnancy. A previous history of pregnancy loss is a high-risk factor for recurrence during subsequent pregnancies. Infection is a common cause. In some instances, recurrent pregnancy loss is associated with low serum concentrations of progesterone. Although the mechanism(s) by which this occurs is not fully understood, the situation has been called hypoluteoidism. Whatever the cause of the risks to pregnancy, the goals of managing high-risk pregnancies are to optimize maternal, fetal and perinatal health, so as to maintain maternal health throughout pregnancy and lactation and maximize the number of healthy pups surviving to weaning age.     

High-risk pregnancy and hypoluteoidism in the bitch

High-risk pregnancies are those in which the prevalence of maternal, fetal and/or perinatal morbidity or mortality is likely to be higher than that of the general obstetrical population. Some maternal characteristics associated with risk to maternal, fetal and/or perinatal health are readily identifiable prior to conception, such as advanced maternal age, brachycephalic breed, or a previous history of pregnancy loss. Others, such as gestational diabetes or a singleton litter, are recognized after conception. Early recognition of the problem (i.e. the risk), anticipation of the potential sequelae, and development of an aggressive management scheme are essential for a successful outcome of a high-risk pregnancy. A previous history of pregnancy loss is a high-risk factor for recurrence during subsequent pregnancies. Infection is a common cause. In some instances, recurrent pregnancy loss is associated with low serum concentrations of progesterone. Although the mechanism(s) by which this occurs is not fully understood, the situation has been called hypoluteoidism. Whatever the cause of the risks to pregnancy, the goals of managing high-risk pregnancies are to optimize maternal, fetal and perinatal health, so as to maintain maternal health throughout pregnancy and lactation and maximize the number of healthy pups surviving to weaning age.     

Animal models of type 2 diabetes: clinical presentation and pathophysiological relevance to the human condition

The prevalence of diabetes throughout the world has increased dramatically over the recent past, and the trend will continue for the foreseeable future. One of the major concerns associated with diabetes relates to the development of micro- and macrovascular complications, which contribute greatly to the morbidity and mortality associated with the disease. Progression of the disease from prediabetic state to overt diabetes and the development of complications occur over many years. Assessment of interventions designed to delay or prevent disease progression or complications in humans also takes years and requires tremendous resources. To better study both the pathogenesis and potential therapeutic agents, appropriate animal models of type 2 diabetes (T2D) mellitus are needed. However, for an animal model to have relevance to the study of diabetes, either the characteristics of the animal model should mirror the pathophysiology and natural history of diabetes or the model should develop complications of diabetes with an etiology similar to that of the human condition. There appears to be no single animal model that encompasses all of these characteristics, but there are many that provide very similar characteristics in one or more aspects of T2D in humans. Use of the appropriate animal model based on these similarities can provide much needed data on pathophysiological mechanisms operative in human T2D.     

High-Throughput Sequencing of Islet-Infiltrating Memory CD4+ T Cells Reveals a Similar Pattern of TCR Vβ Usage in Prediabetic and Diabetic NOD Mice

Autoreactive memory CD4⁺ T cells play a critical role in the development of type 1 diabetes, but it is not yet known how the clonotypic composition and TCRβ repertoire of the memory CD4⁺ T cell compartment changes during the transition from prediabetes to diabetes. In this study, we used high-throughput sequencing to analyze the TCRβ repertoire of sorted islet-infiltrating memory CD4⁺CD44^high T cells in 10-week-old prediabetic and recently diabetic NOD mice. We show that most clonotypes of islet-infiltrating CD4⁺CD44^high T cells were rare, but high-frequency clonotypes were significantly more common in diabetic than in prediabetic mice. Moreover, although the CD4⁺CD44^high TCRβ repertoires were highly diverse at both stages of disease development, dominant use of TRBV1 (Vβ2), TRBV13-3 (Vβ8.1), and TRBV19 (Vβ6) was evident in both prediabetic and diabetic mice. Our findings strongly suggest that therapeutic targeting of cells specifically expressing the dominant TCRβ might reduce pancreatic infiltration in prediabetic mice and attenuate the progression to diabetes.     

Is Serum Zinc Associated with Pancreatic Beta Cell Function and Insulin Sensitivity in Pre-Diabetic and Normal Individuals? Findings from the Hunter Community Study

Aim

To determine if there is a difference in serum zinc concentration between normoglycaemic, pre-diabetic and type-2 diabetic groups and if this is associated with pancreatic beta cell function and insulin sensitivity in the former 2 groups.

Method

Cross sectional study of a random sample of older community-dwelling men and women in Newcastle, New South Wales, Australia. Beta cell function, insulin sensitivity and insulin resistance were calculated for normoglycaemic and prediabetes participants using the Homeostasis Model Assessment (HOMA-2) calculator.

Result

A total of 452 participants were recruited for this study. Approximately 33% (N = 149) had diabetes, 33% (N = 151) had prediabetes and 34% (N = 152) were normoglycaemic. Homeostasis Model Assessment (HOMA) parameters were found to be significantly different between normoglycaemic and prediabetes groups (p<0.001). In adjusted linear regression, higher serum zinc concentration was associated with increased insulin sensitivity (p = 0.01) in the prediabetic group. There was also a significant association between smoking and worse insulin sensitivity.

Conclusion

Higher serum zinc concentration is associated with increased insulin sensitivity. Longitudinal studies are required to determine if low serum zinc concentration plays a role in progression from pre-diabetes to diabetes.     

Effect of Dexamethasone on Glucose Homeostasis In Normal and Prediabetic Subjects With A First-Degree Relative With Type 2 Diabetes Mellitus

ObjectiveTo determine the effect of a single 8-mg orally administered dose of dexamethasone or placebo on glucose and insulin homeostasis, during an oral glucose tolerance test (OGTT) performed before and 24 hours after the administered dose.MethodsIn a randomized, double-blind, placebo controlled study, we conducted experiments in subjects with normal glucose tolerance (NGT) or prediabetes, all of whom had at least one first-degree relative with type 2 dia betes mellitus. Measures of glucose and insulin homeosta sis derived from an OGTT before and 24 hours after admin istration of dexamethasone or placebo were compared in 21 placebo-treated versus 23 dexamethasone-treated sub jects with NGT as well as in 23 placebo-treated versus 20 dexamethasone-treated subjects with prediabetes.ResultsBefore administration of dexamethasone or placebo, area under the curve (AUC) for glucose and homeostasis model assessment of insulin resistance were higher, and the Matsuda and disposition indices were lower, in the prediabetic versus the NGT group. In both NGT and prediabetic groups treated with dexamethasone, glu cose and insulin values at fasting and during OGTT were increased in comparison with placebo-treated groups at 24 hours (P = .001). Dexamethasone treatment in both study groups increased homeostasis model assessment of insulin resistance and AUC glucose and decreased the Matsuda index (P = .001). No significant changes were observed in AUC insulin/AUC glucose or homeostasis model assess ment of beta-cell function after dexamethasone treatment in either the NGT or the prediabetic group. The disposition index decreased and was lowest in the prediabetic group after dexamethasone treatment.ConclusionIn a study population in which all sub jects had at least one first-degree relative with type 2 dia betes mellitus, those with prediabetes were more insulin resistant and had a lower disposition index than did sub jects with NGT. Subjects with prediabetes also had a pro nounced decrease in disposition index when challenged with a single 8-mg orally administered dose of dexametha sone. (Endocr Pract. 2012;18:855-863)     

L'hyperglycémie et les complications du diabète de type adulte.

In this paper the principal investigations into the effects of glycemia and its treatment on the complications associated with maturity-onset diabetes are analysed. Two points are stressed. First, a consensus is lacking on the diagnostic levels of blood glucose; some diabetologists recommend a return to the use of fasting blood glucose values. Second, a definite causal relation between hyperglycemia (and its control) and the main complications of diabetes has not been established. Until the natural history of the condition and the effectiveness of hypoglycemic treatment on the long-term prognosis are better understood, systematic screening for maturity-onset diabetes in asymptomatic adults is not justified. In addition, patients with mildly abnormal blood glucose levels should be followed yearly to monitor the development of overt diabetes or other cardiovascular risk factors. They should be neither labelled as diabetics nor compelled to comply with a strict therapeutic regimen.     

Birth defects in infants of diabetic mothers: A historical review

Background: Over the past 80+ years, outcomes in diabetic pregnancies have improved remarkably. In the preinsulin era, both fetal and maternal deaths were common. After insulin was discovered, the likelihood of a successful pregnancy increased, but fetal losses were still common. By the end of the 20th century, a number of medical advances allowed women with diabetes to reasonably expect to deliver a healthy infant, although the perinatal mortality rate was twice that reported for women without diabetes. The excess losses were attributable to birth defects.Objective: The purpose of this article was to use the recognition of, and approach to, birth defects in infants of mothers with diabetes as an example of the gradual evolution of clinical care and research from the dawn of the insulin era to the age of molecular biology.Methods: Archival material from the Joslin Diabetes Center (Boston, Massachusetts) was used to document the early history of the problem. Particular emphasis was given to the writings of Priscilla White, MD. Illustrative articles, especially those cited in textbooks, were chosen to highlight developments over the mid to late 20th century.Results: Before the discovery of insulin, maternal death was the primary issue in diabetic pregnancies. With the availability of insulin, the maternal death rate decreased sharply and fetal deaths became the preeminent problem. Many of these losses were due to iatrogenic prematurity complicated by respiratory distress syndrome; early deliveries avoided stillbirth in late gestation. In the last quarter of the 20th century, methods of assessing fetal well-being and lung maturity allowed pregnancies to proceed nearer to term. Birth defects then emerged as the leading cause of perinatal mortality. The risk for birth defects was linked to diabetes control early in the first trimester, and the mechanism was related to free oxygen radicals from excess glucose. Preconception programs have been shown to reduce the risk.Conclusions: Clinical advances often are not dramatic. This article illustrates how resolution of a problem may evolve incrementally over decades. Birth defects, once unnoticed in infants of diabetic mothers, became a leading concern. It is now possible to reduce the incidence of these defects to levels seen in nondiabetic pregnancies. Epigenetic mechanisms responsible for malformations have been elucidated.     

Antidiabetic potential of saffron and its active constituents

The prevalence of diabetes mellitus is growing rapidly worldwide. This metabolic disorder affects many physiological pathways and is a key underlying cause of a multitude of debilitating complications. There is, therefore, a critical need for effective diabetes management. Although many synthetic therapeutic glucose-lowering agents have been developed to control glucose homeostasis, they may have unfavorable side effects or limited efficacy. Herbal-based hypoglycemic agents present an adjunct treatment option to mitigate insulin resistance, improve glycemic control and reduce the required dose of standard antidiabetic medications. Saffron (Crocus sativus L.), whilst widely used as a food additive, is a natural product with insulin-sensitizing and hypoglycemic effects. Saffron contains several bioactive β carotenes, which exert their pharmacological effects in various tissues without any obvious side effects. In this study, we discuss how saffron and its major components exert their hypoglycemic effects by induction of insulin sensitivity, improving insulin signaling and preventing β-cell failure, all mechanisms combining to achieve better glycemic control.