Deterioration of plasticity and metabolic homeostasis in the brain of the UCD-T2DM rat model of naturally occurring type-2 diabetes

The rising prevalence of type-2 diabetes is becoming a pressing issue based on emerging reports that T2DM can also adversely impact mental health. We have utilized the UCD-T2DM rat model in which the onset of T2DM develops spontaneously across time and can serve to understand the pathophysiology of diabetes in humans. An increased insulin resistance index and plasma glucose levels manifested the onset of T2DM. There was a decrease in hippocampal insulin receptor signaling in the hippocampus, which correlated with peripheral insulin resistance index along the course of diabetes onset (r = − 0.56, p < 0.01). T2DM increased the hippocampal levels of 4-hydroxynonenal (4-HNE; a marker of lipid peroxidation) in inverse proportion to the changes in the mitochondrial regulator PGC-1α. Disrupted energy homeostasis was further manifested by a concurrent reduction in energy metabolic markers, including TFAM, SIRT1, and AMPK phosphorylation. In addition, T2DM influenced brain plasticity as evidenced by a significant reduction of BDNF–TrkB signaling. These results suggest that the pathology of T2DM in the brain involves a progressive and coordinated disruption of insulin signaling, and energy homeostasis, with profound consequences for brain function and plasticity. All the described consequences of T2DM were attenuated by treatment with the glucagon-like peptide-1 receptor agonist, liraglutide. Similar results to those of liraglutide were obtained by exposing T2DM rats to a food energy restricted diet, which suggest that normalization of brain energy metabolism is a crucial factor to counteract central insulin sensitivity and synaptic plasticity associated with T2DM.     

岩藻多糖在2型糖尿病大鼠模型的作用及机制研究

目的:研究岩藻多糖(Fucoidan)对链脲佐菌素诱导实验性2型糖尿病大鼠的治疗作用.方法:在SD大鼠建立2型糖尿病动物模型,随机分为5组,分别用生理盐水、岩藻多糖高、中、低剂量(600mg/kg、400mg/kg、150mg/kg)、二甲双胍(200mg/kg)灌胃给药30天,同时采用正常SD大鼠为正常对照.测定各组大鼠体重、空腹血糖、血脂和血清胰岛素水平.结果:高、中剂量岩藻多糖能够明显降低模型动物空腹血糖水平,降低空腹胰岛素水平,改善胰岛素抵抗,降低血清胆固醇、甘油三酯、低密度脂蛋白胆固醇含量(P<0.05),升高高密度脂蛋白胆固醇含量(P<0.05),其作用效果与阳性对照药二甲双胍效果相当.低剂量岩藻多糖作用效果不明显.结论:岩藻多糖有降血糖、调节血脂紊乱的功能,时实验性2型糖尿病大鼠有治疗作用.     

The BBZDR/Wor rat model for investigating the complications of type 2 diabetes mellitus

Congenic and inbred strains of rats offer researchers invaluable insight into the etiopathogenesis of diabetes and associated complications. The inbred Bio-Breeding Zucker diabetic rat (BBZDR)/Wor rat strain is a relatively new and emerging model of type 2 diabetes. This strain was created by classical breeding methods used to introgress the defective leptin receptor gene (Lepr(fa)) from insulin-resistant Zucker fatty rats into the inbred BBDR/Wor strain background. The diabetic male BBZDR/Wor rat is homozygous for the fatty mutation and shares the genetic background of the original BB strain. Although lean littermates are phenotypically normal, obese juvenile BBZDR/Wor rats are hyperlipidemic and hyperleptinemic, become insulin resistant, and ultimately develop hyperglycemia. Furthermore, the BBZDR/Wor rat is immune competent and does not develop autoimmunity. Similar to patients with clinical diabetes, the BBZDR/Wor rat develops complications associated with hyperglycemia. The BBZDR/Wor rat is a model system that fully encompasses the ability to study the complications that affect human type 2 diabetic patients. In this review, recent work that has evaluated type 2 diabetic complications in BBZDR/Wor rats is discussed, including the authors' preliminary unpublished studies on cardiovascular disease.     

Longitudinal ultrastructure study of islet amyloid in the HIP rat model of type 2 diabetes mellitus

In 2004, the human islet amyloid polypeptide (HIP) rat model was created by transfecting the Sprague-Dawley rat with the human islet amyloid polypeptide (hIAPP)-amylin gene. The objective of this study is to utilize the transmission electron microscope to study the longitudinal cellular and extracellular morphological changes within the islets of this model at 4, 8, and 14 months of age. It has been previously demonstrated that the 2-, 5-, and 10-month HIP models have no diabetes, impaired fasting glucose, and diabetes, respectively. The 4-month HIP model (FBS 123 mg/dl) demonstrated an abundance of beta-cells and insulin secretory granules with significant pericapillary and inter-beta-cell islet amyloid deposition. The 8-month model (FBS 187 mg/dl) demonstrated extensive islet amyloid deposition and marked changes of beta-cell apoptosis. The 14-month-old model (FBS 244 mg/dl) demonstrated islet and beta-cell atrophy with even greater amounts of extracellular islet amyloid compared to the 4-month-old and 8-month-old models. Functional beta cells were sparse and were associated with intra islet adipose deposition. These findings of ultrastructure cellular and extracellular morphological longitudinal remodeling changes in this novel animal model of type 2 diabetes may provide investigators with a better understanding regarding the role of islet amyloid in human islet.     

2型糖尿病鼠类模型的研究进展

小鼠、大鼠糖尿病模型对基础与临床防治研究十分重要,不同的研究目标对应不同的动物模型载体。本文就目前常用的2型糖尿病鼠类模型的构建、主要疾病特征及应用等进行评述,为研究者了解、选择适合的动物模型提供参考。     

Cardiovascular disease in diabetes mellitus type 2: a potential role for novel cardiovascular risk factors

A major consequence of diabetes mellitus type 2 is the accelerated development of atherosclerosis. Assessment of conventional risk factors such as plasma lipids, lipoproteins and hypertension only partly account for the excessive risk of developing cardiovascular disease in this population. Increasing evidence has emerged suggesting that conditions associated with diabetes mellitus type 2, such as insulin resistance, hyperinsulinemia and hyperglycemia, may also play a significant role in regulating 'novel' cardiovascular risk factors. These factors and their potential roles in the development of atherosclerosis and cardiovascular events are discussed in this review.     

Discovery of a novel phenylethyl benzamide glucokinase activator for the treatment of type 2 diabetes mellitus

Novel benzamide derivatives were synthesized and tested at in vitro assay by measuring fold increase of glucokinase activity at 5.0 mM glucose concentration. Among the prepared compounds, YH-GKA was found to be an active glucokinase activator with EC₅₀ of 70 nM. YH-GKA showed similar glucose AUC reduction of 29.6% (50 mg/kg) in an OGTT study with C57BL/J6 mice compared to 29.9% for metformin (300 mg/kg). Acute treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity. In subchronic study with ob/ob mice, YH-GKA showed significant decrease in blood glucose levels and no adverse effects on serum lipids or body weight. In addition, YH-GKA exhibited high bioavailability and moderate elimination in preclinical species.     

Mitochondrial pathophysiology and type 2 diabetes mellitus

Over the last decades, substantial progress has been made in defining the molecular events and relevant tissues controlling insulin action and the potential defects that lead to insulin resistance and later on Type 2 diabetes mellitus (T2DM). Mitochondrial dysfunction has been postulated as a common mechanism implicated in the development of insulin resistance and T2DM aetiology. Since then there has been growing interest in this area of research and many studies have addressed whether mitochondrial function/dysfunction is implicated in the progression of T2DM or if it is just a consequence. Mitochondria are adjusted to the specific needs of the tissue and to the environmental interactions or pathophysiological state that it encounters. This review offers a current state of the subject in a tissue specific approach. We will focus our attention on skeletal muscle, liver, and white adipose tissue as the main insulin sensitive organs. Hypothalamic mitochondrial function will be also discussed.     

Bisphenol A exposure and type 2 diabetes mellitus risk: a meta-analysis

Background

This meta-analytic study explored the relationship between the risk of type 2 diabetes mellitus (T2DM) and bisphenol A concentrations.

Methods

The Embase and Medline (PubMed) databases were searched, using relevant keywords, for studies published between 1980 and 2018. A total of 16 studies, twelve cross-sectional, two case-control and one prospective, were included in the meta-analysis. The odds ratio (OR) and its 95% confidence interval (CI) were determined across the sixteen studies. The OR and its 95% CI of diabetes associated with bisphenol A were estimated using both fixed-effects and random-effects models.

Results

A total of 41,320 subjects were included. Fourteen of the sixteen studies included in the analysis provided measurements of urine bisphenol A levels and two study provided serum bisphenol A levels. Bisphenol A concentrations in human bio-specimens showed positive associations with T2DM risk (OR 1.28, 95% CI 1.14, 1.44). A sensitivity analysis indicated that urine bisphenol A concentrations were positively associated with T2DM risk (OR 1.20, 95% CI 1.09, 1.31).

Conclusions

This meta-analysis indicated that Bisphenol A exposure is positively associated with T2DM risk in humans.

     

Capn10, a candidate gene responsible for type 2 diabetes mellitus in the OLETF rat

The rat strain Otsuka Long-Evans Tokushima Fatty (OLETF) is an animal model for type 2 diabetes mellitus. Nidd8/of has been identified as one of 14 quantitative trait loci (QTLs) involved in the diabetes by a whole genome search in 160 F2 progenies obtained by mating the OLETF and F344 rats. Comparative mapping between human and rat indicated that the Nidd8/of genomic region, near D9rat21 on rat chromosome 9, contains the calpain10 (Capn10) gene, which is putative type 2 diabetes-susceptibility gene in humans. In this study, we found no difference in Capn10 mRNA expression in the heart, liver, skeletal muscle and pancreas between OLETF and F344 rats at 5 and 10 weeks of age. However, we found a single nucleotide polymorphism (SNP) (A/A genotype in OLETF and G/G genotype in F344 and LETO rats) at the base 583 downstream from the translation start site in the rat Capn10 cDNA sequence. This SNP was deduced to substitute serine (OLETF) for glycine (F344 and LETO) at the 195 amino acid residue within the protease domain of rat Capn10. Because serine is generally not interchangeable with glycine in respect of the protein structure and function, it was deduced that the A/A genotype in OLETF is not a 'safe' mutation. This non-conservative amino acid substitution might be associated with susceptibility to type 2 diabetes in OLETF rats.     

Renal production of thromboxane and prostaglandins in a rat model of type 2 diabetes

In an investigation of the involvement of prostanoids in the pathogenesis of nephropathy in type 2 diabetes, we repeatedly measured the urinary excretion of prostanoids in both diabetic and healthy rats as the rats aged. Seven rats of the Otsuka Long-Evans Tokushima Fatty strain were used as rats with a model of type 2 diabetes and seven rats of the Long-Evans Tokushima Otsuka strain were used as rats without diabetes. Thromboxane (TX) B2 and 6-keto-prostaglandin (PG) F1alpha, the amounts of which reflect renal production of TXA2 and PGI2, respectively, and PGE2 in urine collected in metabolic cages were assayed when rats were 14, 30, 46, and 54 weeks old. Plasma glucose and urinary protein excretion also were measured periodically. The mean plasma glucose concentration of the diabetic rats was higher than that of the healthy rats throughout the study. At 30 weeks and later, urinary protein excretion by the diabetic rats was greater than that of the healthy rats, and it increased with age. Urinary excretion of TXB2 by the diabetic rats was higher than that of the healthy rats at 14 weeks (52.4+/-23.5 vs. 27.0+/-2.6 ng/day; mean +/- SD, P = .015) and the difference continued to the end of the experiment. Urinary excretion of 6-keto-PGF1alpha by the diabetic rats was high at 14 weeks (52.3+/-12.8 vs. 26.9+/-4.6 ng/day; mean +/- SD, P<.001) but decreased with age and was the same as that of the healthy rats at 54 weeks. The urinary excretion of PGE2 by the two groups of rats was not significantly different. These results suggest that altered renal production of TXA2 and PGI2 is involved in the pathogenesis of diabetic nephropathy in rats with type 2 diabetes.     

2型糖尿病兼抑郁症大鼠模型的建立与评价

目的：用体重检测、空腹血糖检测、宏观表征、旷场实验行为学评价糖尿病兼抑郁症的大鼠模型。方法采用高脂饲料喂养加腹腔注射小剂量链脲佐菌素（ STZ）的方法制备2型糖尿病模型,在其基础上再用21 d慢性束缚的方法建立糖尿病兼抑郁症大鼠模型。将32只Wistar大鼠随机分为3组（ n ＝8）：正常组（N组）,2型糖尿病组（T组）,2型糖尿病兼抑郁症组（T＋D组）。2型糖尿病模型建立后,在慢性束缚的第0、7、14、21天检测大鼠的空腹血糖和体重,并对大鼠的宏观表征、饮食量、粪便、小便、精神状态进行观察,在第21天利用行为学设备分析软件,对大鼠旷场实验进行分析,检测大鼠的抑郁程度,验证评价2型糖尿病兼抑郁症大鼠模型是否成功。结果给予高脂饲料及腹腔注射STZ制备2型糖尿病模型后,T＋D组大鼠的毛发散乱,无光泽,活动迟缓,进食量、饮水量增加,粪便尿量增加,精神萎靡。第0、7、14、21天T组和T＋D组组大鼠体重均下降,与N组比较差异有显著性（P＜0.05;P＜0.01）,21d慢性束缚刺激后,T＋D组体重比T组大鼠体重增加较慢,差异有显著性（P＜0.05）;第0、7、14、21天,T组和T＋D组大鼠血糖均升高,与N组比较差异有显著性（ P＜0.01）,21 d慢性束缚刺激后,第21天T＋D组大鼠血糖比T组较高,差异有显著性（P＜0.01）,大鼠5 min内总移动距离有变化,与N组相比,T组差异没有显著性（P＞0.05）,T＋D组差异有显著性（P＜0.05）;与N组相比,T组大鼠5 min内移动速度减慢,差异有显著性（P＜0.05）,T＋D组差异有显著性（ P＜0.01）。结论利用高脂饲料喂养加腹腔注射小剂量STZ及21天慢性束缚的方法,可以成功复制2型糖尿病兼抑郁症大鼠模型,适用于后续研究。     

Discovery and optimization of a novel series of GPR142 agonists for the treatment of type 2 diabetes mellitus

The discovery and initial optimization of a series of phenylalanine based agonists for GPR142 is described. The structure-activity-relationship around the major areas of the molecule was explored to give agonists 90 times more potent than the initial HTS hit in a human GPR142 inositol phosphate accumulation assay. Removal of CYP inhibition by exploration of the pyridine A-ring is also described.     

Genetic analysis for diabetes in a new rat model of nonobese type 2 diabetes,Spontaneously Diabetic Torii rat

The Spontaneously Diabetic Torii (SDT) rat has recently been established as a new rat model of nonobese type 2 diabetes. In this study, we characterized diabetic features in SDT rats, and performed quantitative trait locus (QTL) analysis for glucose intolerance using 319 male (BNxSDT)xSDT backcrosses. Male SDT rats exhibited glucose intolerance at 20 weeks, and spontaneously developed diabetes with the incidence of 100% at 38 weeks, and glucose intolerance is well associated with the development of diabetes. The QTL analysis identified three highly significant QTLs (Gisdt1, Gisdt2, and Gisdt3) for glucose intolerance on rat chromosomes 1, 2, and X, respectively. The SDT allele for these QTLs significantly exacerbated glucose intolerance. Furthermore, synergistic interactions among these QTLs were detected. These findings indicate that diabetic features in SDT rats are inherited as polygenic traits and that SDT rats would provide insights into genetics of human type 2 diabetes.     

The rat model of type 2 diabetic mellitus and its glycometabolism characters.

To develop a rat model of type 2 diabetic mellitus that simulated the common manifestation of the metabolic abnormalities and resembled the natural history of a certain type 2 diabetes in human population, male Sprague-Dawley rats (4 months old) were injected with low-dose (15 mg/kg) STZ after high fat diet (30% of calories as fat) for two months (L-STZ/2HF). The functional and histochemical changes in the pancreatic islets were examined. Insulin-glucose tolerance test, islet immunohistochemistry and other corresponding tests were performed and the data in L-STZ/2HF group were compared with that of other groups, such as the model of type 1 diabetes (given 50 mg/kg STZ) and the model of obesity (high fat diet). The body weight of rats in the group of rats given 15 mg/kg STZ after high fat diet for two months increased significantly more than that of rats in the group of rats given 50 mg/kg STZ (the model of type 1 diabetes) (595 +/- 33 g vs. 352 +/- 32 g, p<0.05). Fast blood glucose levels for L-STZ/2HF group were 16.92 +/- 1.68 mmol/l, versus 5.17 +/- 0.55 mmol/l in normal control and 5.59 +/- 0.61 mmol/l in rats given high fat diet only. Corresponding values for fast serum insulin were 0.66 +/- 0.15 ng/ml, 0.52 +/- 0.13 ng/ml, 0.29 +/- 0.11 ng/ml, respectively. Rats of type 2 diabetes (L-STZ/2HF) had elevated levels of triglyceride (TG, 3.82 +/- 0.88 mmol/l), and cholesterol(Ch, 2.38 +/- 0.55 mmol/l) compared with control (0.95 +/- 0.15 mmol/l and 1.31 +/- 0.3 mmol/l, respectively) (p<0.05). The islet morphology as examined by immunocytochemistry using insulin antibodies in the L-STZ/2HF group was affected and quantitative analysis showed the islet insulin content was higher than that of rats with type 1 diabetes (P<0.05). We concluded that the new rat model of type 2 diabetes established with conjunctive treatment of low dose of STZ and high fat diet was characterized by hyperglycemia and light impaired insulin secretion function accompanied by insulin resistance, which resembles the clinical manifestation of type 2 diabetes. Such a model, easily attainable and inexpensive, would help further elucidation of the underlying mechanisms of diabetes and its complications.     

Mucosal inflammation in a genetic model of spontaneous type I diabetes mellitus

The BioBreeding (BB) rat provides a model of spontaneous type I diabetes mellitus that closely resembles the human disease. Diabetes-prone BB rats demonstrate increased intestinal permeability prior to the development of insulinitis. Studies suggest that alterations in intestinal permeability can lead to increased intestinal inflammatory activity. Diabetes-prone (BBdp) and diabetes-resistant (BBdr) BB rats were examined at 45 days and at >70 days of age following the development of clinical disease (BBd). In separate experiments, tissue was assayed for myeloperoxidase (MPO) or fixed for histological assessment and immunohistochemistry. Blood was obtained for leukocyte MPO measurements and morphological assessment of circulating leukocytes. MPO activity was significantly elevated in the distal small intestine of 45-day-old BBdp rats. In contrast, at >70 days of age, MPO activity was significantly increased throughout the small intestine of BBd and non-diabetic BBdp rats. Subsequently, all measurements were performed in >70-day-old rats. An increase in inflammatory infiltrate was noted in the distal small intestine of BBd rats by light microscopy. Infiltrating cells were identified as bands (a maturing cell type of the neutrophil lineage) and mature neutrophils. The findings suggest diabetes susceptibility is associated with an increase in intestinal inflammatory activity.     

Plasma bicarbonate and risk of type 2 diabetes mellitus

Background:

Several biomarkers of metabolic acidosis, including lower plasma bicarbonate and higher anion gap, have been associated with greater insulin resistance in cross-sectional studies. We sought to examine whether lower plasma bicarbonate is associated with the development of type 2 diabetes mellitus in a prospective study.

Methods:

We conducted a prospective, nested case–control study within the Nurses’ Health Study. Plasma bicarbonate was measured in 630 women who did not have type 2 diabetes mellitus at the time of blood draw in 1989–1990 but developed type 2 diabetes mellitus during 10 years of follow-up. Controls were matched according to age, ethnic background, fasting status and date of blood draw. We used logistic regression to calculate odds ratios (ORs) for diabetes by category of baseline plasma bicarbonate.

Results:

After adjustment for matching factors, body mass index, plasma creatinine level and history of hypertension, women with plasma bicarbonate above the median level had lower odds of diabetes (OR 0.76, 95% confidence interval [CI] 0.60–0.96) compared with women below the median level. Those in the second (OR 0.92, 95% CI 0.67–1.25), third (OR 0.70, 95% CI 0.51–0.97) and fourth (OR 0.75, 95% CI 0.54–1.05) quartiles of plasma bicarbonate had lower odds of diabetes compared with those in the lowest quartile (p for trend = 0.04). Further adjustment for C-reactive protein did not alter these findings.

Interpretation:

Higher plasma bicarbonate levels were associated with lower odds of incident type 2 diabetes mellitus among women in the Nurses’ Health Study. Further studies are needed to confirm this finding in different populations and to elucidate the mechanism for this relation.Resistance to insulin is central to the pathogenesis of type 2 diabetes mellitus.¹ Several mechanisms may lead to insulin resistance and thereby contribute to the development of type 2 diabetes mellitus, including altered fatty acid metabolism, mitochondrial dysfunction and systemic inflammation.² Metabolic acidosis may also contribute to insulin resistance. Human studies using the euglycemic and hyperglycemic clamp techniques have shown that mild metabolic acidosis induced by the administration of ammonium chloride results in reduced tissue insulin sensitivity.³ Subsequent studies in rat models have suggested that metabolic acidosis decreases the binding of insulin to its receptors.^4,5 Finally, metabolic acidosis may also increase cortisol production,⁶ which in turn is implicated in the development of insulin resistance.⁷Recent epidemiologic studies have shown an association between clinical markers of metabolic acidosis and greater insulin resistance or prevalence of type 2 diabetes mellitus. In the National Health and Nutrition Examination Survey, both lower serum bicarbonate and higher anion gap (even within ranges considered normal) were associated with increased insulin resistance among adults without diabetes.⁸ In addition, higher levels of serum lactate, a small component of the anion gap, were associated with higher odds of prevalent type 2 diabetes mellitus in the Atherosclerosis Risk in Communities study⁹ and with higher odds of incident type 2 diabetes mellitus in a retrospective cohort study of the risk factors for diabetes in Swedish men.¹⁰ Other biomarkers associated with metabolic acidosis, including higher levels of serum ketones,¹¹ lower urinary citrate excretion¹² and low urine pH,¹³ have been associated in cross-sectional studies with either insulin resistance or the prevalence of type 2 diabetes mellitus. However, it is unclear whether these associations are a cause or consequence. We sought to address this question by prospectively examining the association between plasma bicarbonate and subsequent development of type 2 diabetes mellitus in a nested case–control study within the Nurses’ Health Study.