Short-term dietary adjustment with a hydrolyzed casein-based diet postpones diabetes development in the diabetes-prone BB rat

From earlier studies it appears that weaning associated changes in the animal's physiology and that of the pancreas in particular, render diabetes-prone Bio-Breeding (DP-BB) rats susceptible to the induction and development of insulin-dependent diabetes mellitus (IDDM). In this study we tested whether a short-term dietary adjustment at weaning would influence the development of diabetes later in life. For this purpose a diet in which the protein source was replaced with hydrolyzed casein (HC) was given to the rats from weaning to 60 days of age and from weaning to 130 days of age. The control group received the cereal-based standard diet throughout the experiment. The short-term dietary adjustment resulted in a significant delay of diabetes development. The rats fed the HC diet from weaning to 130 days of age showed a lower incidence of diabetes at 130 days of age. No differences were seen in the histological insulitis scores between the rats of the different treatment groups. Interestingly, when testing (mucosal) immune functions of short-term HC-fed rats, their mesenteric lymph node cells (MLNC) showed increased interferon-gamma (IFN-gamma) and reduced interleukin-10 (IL-10) production after in vitro stimulation. These results demonstrate that short-term dietary adjustments at a young age can influence the course of diabetes later in life. The shift in cytokine profile of MLNC of the HC-fed rats suggests that mechanisms involved can be at the level of both the (mucosal) immune system and the beta cell.     

D-乳酸与I-FABP在肠屏障功能受损中作用的研究进展

肠道是人体消化吸收的器官,同时具有对肠道细菌及其毒素阻挡入侵的屏障作用。在手术、感染、休克、创伤等应激下肠黏膜最易受损,当其受损后,将会造成一系列的病理生理变化,甚至导致系统性炎症反应综合征(SIRS)和多器官功能不全综合征(MODS)的发生,给患者带来难以承受的不良结局。因此早期预警肠黏膜屏障功能对于预防肠黏膜屏障功能受损导致的临床不良结局就显得尤为重要。目前国内外学者报道了许多与肠黏膜屏障受损相关的标志物,并将其用于临床评估。该文对D-乳酸和I-FABP在肠屏障功能受损中作用的研究进展进行综述。     

The role of diet in the prevention of type 2 diabetes

Type 2 diabetes mellitus is an important preventable disease and a growing public health problem. Epidemiologic and interventional studies suggest that weight loss is the main driving force to reduce diabetes risk. Landmark clinical trials of lifestyle changes in subjects with prediabetes have shown that diet and exercise leading to weight loss consistently reduce the incidence of diabetes. However, from these studies it cannot be established whether dietary changes alone play a significant role in preventing diabetes. Here we review epidemiologic and clinical trial evidence relating nutrients, foods and dietary patterns to diabetes risk and the possible mechanisms involved. The differential effects of carbohydrate and fat quantity and quality, and those of specific foods and whole diets are discussed. Importantly, most dietary components influencing diabetes risk have similar effects on biomarkers of cardiovascular risk and inflammation. The conclusion is that there is no universal dietary strategy to prevent diabetes or delay its onset. Together with the maintenance of ideal body weight, the promotion of the so-called prudent diet (characterized by a higher intake of food groups that are generally recommended for health promotion, particularly plant-based foods, and a lower intake of red meat, meat products, sweets, high-fat dairy and refined grains) or a Mediterranean dietary pattern rich in olive oil, fruits and vegetables, including whole grains, pulses and nuts, low-fat dairy, and moderate alcohol consumption (mainly red wine) appears as the best strategy to decrease diabetes risk, especially if dietary recommendations take into account individual preferences, thus enabling long-time adherence.     

Cyclophosphamide inhibits the development of diabetes in the diabetes-prone BB rat

Abstract Aims/hypothesis. Cyclophosphamide has been shown to augment the diabetic process in NOD mouse and BB rat models of Type I (insulin-dependent) diabetes mellitus. Because cyclophosphamide has, however, been shown to increase immunoregulatory cell activity, we examined if cyclophosphamide treatment increases immunoregulatory cell activity and inhibits the diabetic process in BB rats. Methods. The development of insulitis and diabetes was explored in BB rats treated with saline and cyclophosphamide (60 to 175 mg/kg body weight). Subsets of spleen cells were assessed by flow cytometry and cytokine gene expression by RT-PCR. To determine if cyclophosphamide induces immunoregulatory cell activity, the development of diabetes was assessed in BB rats injected with spleen cells from rats treated with saline and cyclophosphamide. Results. All dosages of cyclophosphamide decreased the development of diabetes. The degree of insulitis was lower in pancreata from 55-day-old rats treated with cyclophosphamide than those from controls. Cyclophosphamide caused no alterations in the numbers of NK cells, T-cell subsets, or RT6.1⁺ T cells. The adoptive transfer of spleen cells from cyclophosphamide-treated rats to BB rats inhibited the development of diabetes. Cyclophosphamide treatment decreased IL-12, IL-1β, IL-2, IFN-γ and TNF-α gene expressions in mononuclear spleen cells but IL-4 gene expression increased. Conclusion/interpretation. These findings show that cyclophosphamide treatment decreases the development of diabetes by inhibiting the development of insulitis. This inhibitory action of cyclophosphamide on the diabetic process seems to be mediated by the induction of immunoregulatory cell activity. The suppression of cytokines that promote Th1 cell differentiation by cyclophosphamide treatment could also play a part in the diabetes sparing effect of cyclophosphamide. [Diabetologia (2000) 43: 986–994] Received: 10 December 1999 and in revised form: 13 April 2000     

Evaluation of type 2 diabetes prevention through diet modification in people with impaired glucose regulation: A population-based study

PurposeA few interventional studies to date have specifically assessed the association between dairy products and/or sugar consumption and the risk of type 2 diabetes mellitus (T2D) incidence. The aim of this study was to assess the effectiveness of diet modification in people with impaired glucose regulation (IGR) as defined by a glucose tolerance test (GTT).MethodsA quasi-experimental study design was used for this study. A total of 318 randomly selected 18-year-old or older participants from the rural area of the Kyiv region of Ukraine who had not been registered as T2D patients before underwent GTT between June 2013 and June 2017. For those who had been diagnosed with IGR, World Health Organization (WHO)/International Diabetes Federation criteria were used. Of 318 participants screened for T2D, 123 (74% of them females) were diagnosed with IGR. They were aged 18 to 79 years old with a median (Q_I – Q_III) age of 62 (52–68) years. They were repeatedly tested during the study and completed a questionnaire on average 2.8 (1.1) years (standard deviation [SD]), after they had received their lifestyle-based T2D prevention recommendations. In addition to basic recommendations, they were advised to consume approximately 200 g of low-fat dairy products and less than 25 g of sugar daily. Cases of screen-detected diabetes mellitus (SDDM) were diagnosed and reported as an outcome variable if a fast capillary blood glucose level reached 6.1 mmol/L and above. To define the association between implementation of recommendations and the risk of SDDM, the Cox proportional-hazards regression analysis was used.ResultsDuring the study observation period, 56 (45.5%) of 123 IGR-positive participants were recognized as SDDM cases. Those individuals with IGR (n = 111) who confirmed their adherence to preventive recommendations had a significantly lower risk of identifying SDDM, age- and gender-adjusted hazard ratio (HR) 0.26 (95% C?; 0.09–0.72). This effect appears to be related to the recommendation to reduce the daily intake of sugar to less than 25 g (n = 99), corresponding to age- and gender-adjusted HR 0.44 (95% C?; 0.2–0.99). We cannot prove that increasing consumption of dairy products, vegetables, and fruit or increased physical activity had similar effectiveness.ConclusionsAfter 2.8 years of follow-up, the individuals who are IGR-positive and who confirmed their adherence to lifestyle-based preventive recommendations had a significantly lower risk of identifying SDDM. This effect appears to be related to recommendations to reduce the daily intake of sugar to less than 25 g.     

Neonatal oral administration of DiaPep277, combined with hydrolysed casein diet,protects against Type 1 diabetes in BB-DP rats. An experimental study

Aims/hypothesis Environmental factors such as diet and bacterial antigens play an important role in the onset of Type 1 diabetes. Different self-antigens are suggested to play a role in the development of diabetes. Antibodies against the 60-kDa heat shock protein 60, which have a high homology to bacterial heat shock protein 65, have been found in the circulation at the onset of diabetes in humans and in pre-diabetic NOD-mice. One of the immunodominant epitopes in autoimmune diabetes is p277, a specific peptide of human heat shock protein 60 corresponding to positions 437–460. In this study we investigated whether neonatal oral administration of DiaPep277 (a synthetic peptide analogue of p277) affected the development of diabetes in the BioBreeding-Diabetes Prone (BB-DP) rat, and whether this could potentiate the effect of a protective hydrolysed casein-diet.Methods BB-DP rats were orally inoculated once per day with placebo or DiaPep277 at days 4, 5, 6 and 7 of life. At the age of 21 days rats were weaned on to a conventional, cereal-based diet or on to the hydrolysed casein-diet.Results The development of diabetes in animals receiving DiaPep277 in combination with the hydrolysed casein-diet was delayed by 17 days, and a relative reduction of the incidence by 64% was seen. Non-diabetic animals did not show any sign of insulitis.Conclusions/interpretation Short-term neonatal feeding with p277 in early life, combined with diet adaptation, appears to provide a procedure to significantly reduce the development of Type 1 diabetes in later life.Abbreviations BB-DP BioBreeding diabetes-prone - HC hydrolysed casein - hsp60/65 heat shock protein 60/65 - ICA-69 islet cell antigen 69 - NOD non-obese diabetic     

Approaches to type 1 diabetes prevention by intervention in cytokine immunoregulatory circuits

Type 1 (insulin-dependent) diabetes mellitus, like other organ specific autoimmune diseases, results from a disorder of immunoregulation. T cells specific for pancreatic islet beta cell constituents (autoantigens) exist normally but are restrained by regulatory mechanisms (self-tolerant state). When regulation fails, beta cell-specific autoreactive T cells become activated and expand clonally. Current evidence indicates that islet beta cell-specific autoreactive T cells belong to a T helper 1 (Th1) subset, and these Th1 cells and their characteristic cytokine products, IFNgamma and IL-2, are believed to cause islet inflammation (insulitis) and beta cell destruction. Immune-mediated destruction of beta cells precedes hyperglycemia and clinical symptoms by many years because these become apparent only when most of the insulin-secreting beta cells have been destroyed. Therefore, several approaches are being tested or are under consideration for clinical trials to prevent or arrest complete autoimmune destruction of islet beta cells and insulin-dependent diabetes. Approaches that attempt to correct underlying immunoregulatory defects in autoimmune diabetes include interventions aimed at i) deleting beta cell autoreactive Th1 cells and cytokines (IFNgamma and IL-2) and/or ii) increasing regulatory Th2 cells and/or Th3 cells and their cytokine products (IL-4, IL-10 and TGFbeta1).     

二甲双胍和食物纤维在糖耐量低减人群向2型糖尿病发展中的干预作用

目的　观察二甲双胍和食物纤维预防糖耐量低减 (IGT)人群进展为 2型糖尿病 (DM)的作用。　方法　以口服 75 g葡萄糖耐量试验 (OGTT)确诊 (WHO标准 )的 IGT2 93例中男 2 16例 ,女 77例。入选者年龄 35岁以上 ,体重指数 (BMI)在 19kg/ m2以上。随机分为对照组 72例 ,教育组 5 7例 ,食物纤维组 84例 ,二甲双胍组 80例。对照组进行一般的健康教育 ;教育组进行饮食指导 ,每半年1次 ;食物纤维组除健康教育外 ,每日口服食物纤维 12 g;二甲双胍组每日口服二甲双胍 0 .75 g,分 3次餐后口服。对四组参试者每半年作 1次 OGTT,同时测身高、体重、BMI、12 h尿白蛋白 ,复查日当天不服干预药物或食物纤维。共观察 3年。若 2次 OGTT或最后 1次复查结果为 DM,则判断为已发展为 DM。　结果　 2 93例 IGT在观察中有 2 3例 (7.8% )退出。空腹血糖 (FBS)和服糖后 1h血糖 (1hPBS)在对照组、教育组和食物纤维组均较治疗前略有升高 ,但在二甲双胍治疗组均有下降。四组间FBS比较 F=8.118,P<0 .0 1,四组间 1h PBS比较 F=3.6 97,P=0 .0 12。观察期末对照组 16例 (2 5 .0 % )、教育组 11例 (2 1.6 % )、食物纤维组 13例 (16 .3% )、二甲双胍组 7例 (9.3% )转化为 DM,二甲双胍组在治疗后 DM转化率明显低于对照组 (χ2 =6 .318,P<0 .0     

A plant-based diet for the prevention and treatment of type 2 diabetes

The prevalence of type 2 diabetes is rising worldwide, especially in older adults. Diet and lifestyle, particularly plant-based diets, are effective tools for type 2 diabetes prevention and management. Plant-based diets are eating patterns that emphasize legumes, whole grains, vegetables, fruits, nuts, and seeds and discourage most or all animal products. Cohort studies strongly support the role of plant-based diets, and food and nutrient components of plant-based diets, in reducing the risk of type 2 diabetes. Evidence from observational and interventional studies demonstrates the benefits of plant-based diets in treating type 2 diabetes and reducing key diabetes-related macrovascular and microvascular complications. Optimal macronutrient ratios for preventing and treating type 2 diabetes are controversial; the focus should instead be on eating patterns and actual foods. However, the evidence does suggest that the type and source of carbohydrate (unrefined versus refined), fats (monounsaturated and polyunsaturated versus saturated and trans), and protein (plant versus animal) play a major role in the prevention and management of type 2 diabetes. Multiple potential mechanisms underlie the benefits of a plant-based diet in ameliorating insulin resistance, including promotion of a healthy body weight, increases in fiber and phytonutrients, food-microbiome interactions, and decreases in saturated fat, advanced glycation endproducts, nitrosamines, and heme iron.     

1型糖尿病的二级预防临床研究进展

1型糖尿病是一种器官特异性自身免疫性疾病,目前尚无根治方法,患者需要终身胰岛素替代治疗。将1型糖尿病防患于未然,是患者和医师的梦想。近年来,易感基因和胰岛自身抗体检测方面的进展为1型糖尿病前期的预测和预防提供了理论依据和技术可能。此外,1型糖尿病二级预防的免疫干预治疗也取得了一定的成效。现对1型糖尿病二级预防的最新研究...     

Mechanisms of impaired bone strength in type 1 and 2 diabetes

Diabetes and osteoporosis are common and complex disorders with an enormous health burden that can be often associated especially in middle-age and elderly individuals. Although there is raising awareness of the higher fractures rates among patients with type 1 (DM1) and 2 (DM2) diabetes, there are few data available on the pathogenetic mechanisms responsible for this increased risk. Importantly, several experimental and clinical observations suggest that bone abnormalities associated with diabetes may differ, at least in part, from those associated with senile or post-menopausal osteoporosis. This implies that specific preventive and therapeutic strategies have to be developed and tested to prevent fractures in DM1 and DM2 patients. It is also likely that shared (i.e. due to glucose-toxicity) as well as different (i.e. due to insulin levels or other hormones) mechanisms may be associated with bone fragility in DM1 and DM2. Moreover, the hypothesis of an endocrine role of the skeleton in the regulation of glucose metabolism and insulin sensitivity has been recently proposed by experimental observations. This review summarizes the recent clinical and experimental advances on glucose tolerance, bone fragility and osteoporosis associated with diabetes.     

Induction and prevention of type 1 diabetes mellitus by viruses.

Genetic factors and environmental factors are thought to be involved in the pathogenesis of insulin-dependent diabetes mellitus Type 1. Viruses, as one environmental factor, may act as primary injurious agents to beta cells or as triggering agents for autoimmunity. Some viruses such as EMC-D and Coxsackie B4 can induce Type 1 diabetes by infecting and destroying beta cells in genetically susceptible mice. In addition, certain species of monkey, such as Patas, show elevated blood glucose levels and depressed insulin secretion after infection with Coxsackie B4 virus. An occasional case of Type 1 diabetes mellitus appears to be associated with the infection of beta cells with Coxsackie B viruses. In addition, Coxsackie B4 virus may also generate viral antigen-specific cytotoxic T cells which may cross-react with a beta cell-specific autoantigen leading to autoimmune Type 1 diabetes. In the case of viral triggering of autoimmune Type 1 diabetes, certain viruses (eg, retrovirus in NOD mice and rubella virus in hamsters and humans) may alter a normally existing beta cell antigen into an immunogenic form or might induce a new antigen, leading to beta cell-specific autoimmune insulin dependent diabetes mellitus. In addition, other viruses (eg, Kilham's rat virus in DR-BB rats) could generate antigen-specific T effector cells which may cross-react with a beta cell-specific autoantigen. In contrast to the induction of diabetes, viruses can prevent the development of diabetes. Inoculation of DP-BB or NOD mice with lymphocytic choriomeningitis virus reduced the incidence of diabetes or prevented the disease by disordering particular lymphocyte subsets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Recent advances in the prevention of hypoglycemia in type 1 diabetes

Iatrogenic hypoglycemia is one of the chief barriers to optimal glycemic control in people with type 1 diabetes (T1D). As a common contributor to morbidity and mortality in T1D, severe hypoglycemia (SH) is also a major fear for people with T1D and their families. Consequently, fear of hypoglycemia and hypoglycemia-avoidant behaviors are predominant limiting factors in achieving euglycemia in people with T1D. Nocturnal SH and hypoglycemia unawareness are prevalent obstacles in the detection of hypoglycemia which further impair the prevention and treatment of SH. Various strategies and technologies have already been developed to help detect and prevent hypoglycemia, including improved patient education, frequent self-monitoring of blood glucose levels, the use of rapid-acting and basal insulin analogs, continuous subcutaneous insulin infusion therapy, exercise-related insulin modifications, and continuous glucose monitors. The efficacy of these methods is well established, but further advances are still needed. The purpose of this review is to describe these currently available methods and to emphasize recent progress related to the prevention of hypoglycemia in T1D.     

己酮可可碱预防NOD鼠1型糖尿病的机理研究

目的 探讨己酮可可碱（Pentoxifylline,PTX)对非肥胖糖尿病（NOD）小鼠1型糖尿病发病率，胰岛素的影响及其机制。方法 采用动物模型NOD鼠，注射环磷酰胺（CP）加速其发病。给PTX药物后计算糖尿病发病率，HE染色观察胰岛炎，并用逆转录（RT）PCR法检测脾细胞干扰素γ（IFN－γ），肿瘤坏死因子α（TNF－α），白介素10（IL－10）mRNA的表达。结果 PTX组糖尿病发生率（30．00％）明显低于对照组（67．86％）（P＜0．1）；胰岛炎程度也明显减轻（P＜0．001）；脾细胞IFN－γ，TNF－αmRNA的表达较对照组明显降低（P＜0．05），IL－10mRNA的表达无明显改变。结论 PTX可预防NOD鼠发生糖尿病，其机制可能与纠正Th1与Th2型细胞因子比例失衡有关。     

Disruption of intestinal motility by a calcium channel-stimulating autoantibody in type 1 diabetes

BACKGROUND & AIMS: Autonomic neuropathy, including gastrointestinal dysfunction, is a common complication of type 1 diabetes; however, its cause is uncertain. This study aimed to test whether functional autoantibodies cause the gastrointestinal dysfunction. METHODS: We used isolated mouse colon undergoing colonic migrating motor complex (MMC) activity to test for autoantibodies that disrupt colonic motility. Purified immunoglobulin G (IgG) from patients with type 1 diabetes or from controls was tested either in vitro or after passive transfer. Pharmacological studies of the interaction between the IgG and L-type calcium channel activator (Bay K8644) and inhibitors (nicardipine and verapamil) were performed. The effect of IgG on nerve-evoked contraction of the vas deferens longitudinal smooth muscle was also assessed. RESULTS: MMC activity was disrupted by IgG (0.2 mg/mL) from 8 of 16 patients with type 1 diabetes but not by control IgG. Passive transfer of diabetic IgG to mice also disrupted MMCs, showing access to the antigen in vivo. The acute effect of the autoantibody was mimicked by the dihydropyridine agonist, Bay K8644 (2-10 nmol/L), and both Bay K8644 and the autoantibody competitively inhibited the effect on MMC contraction of the dihydropyridine antagonist, nicardipine. Diabetic IgG, but not control IgG, altered the nerve-evoked contractile activity of vas deferens smooth muscle effects mimicked by Bay K8644. CONCLUSIONS: A novel functional autoantibody that activates smooth muscle L-type calcium channels at the dihydropyridine binding site is produced specifically by patients with type 1 diabetes and may mediate gastrointestinal and autonomic dysfunction in these patients.     

Enteropathy precedes type 1 diabetes in the BB rat

BACKGROUND AND AIMS: There is increasing evidence implicating intestinal immune responses to dietary proteins in the pathogenesis of type 1 autoimmune diabetes (T1D). Here we investigated the association between intestinal pathology and dietary factors in T1D by examining the mucosal architecture in the BB rat model. METHODS: BB control (BBc) and diabetes prone (BBdp) rats were fed either a diabetes retardant hydrolysed casein based diet or one of two cereal based diets that promote the development of diabetes. Intestinal architecture was assessed in the jejunum by microdissection, histology, and immunohistology, and by measuring peroxidase activity and brush border invertase levels. RESULTS: Enteropathy was present in BBdp rats soon after weaning, as assessed by increases in crypt length and in the proliferative activity of crypt epithelial cells in the jejunum, and this remained constant until 120 days of age. There was also a decrease in invertase activity, as well as increased numbers of intraepithelial lymphocytes, increased levels of mucosal peroxidase activity, and infiltration of the mucosa by CD4(+) T lymphocytes. Equivalent enteropathy was present at all times in BBdp rats and was not influenced by the nature of the diet or by thymectomy at three weeks at age, procedures which prevent the development of diabetes. CONCLUSION: Enteropathy is a consistent feature in the diabetes prone BB rat but it precedes the onset of insulitis and appears to be due to mechanisms distinct from those which cause diabetes. The beneficial effects of the diabetes retardant hydrolysed casein diet on diabetes are not due to an effect on intestinal architecture per se but mucosal damage may be necessary for the development of autoreactivity in the pancreas.