Experimental Diabetes Research最新文献

Salivary factors have been studied for their effects on the process of dental caries in patients of diabetes mellitus type 2. In this study, protective role of salivary pH, salivary flow rate, and salivary calcium is assessed in the patients of diabetes mellitus type 2 with dental caries. The samples of saliva were collected from 400 patients of diabetes mellitus type 2 and 300 age- and sex- matched controls after getting informed consent. All the subjects were classified into four groups according to age. The severity of dental caries was counted by decayed, missed, and filled teeth (DMFT) score. The salivary pH, flow rate, and calcium levels were found to be low in patients as compared to controls. The levels of fasting blood sugar, HbA1c, and DMFT score were found to be significantly high in patients than controls. The glycemic factors were significantly correlated with salivary factors indicating their influence on progression of caries in diabetes. On the basis of findings, it is concluded that the suitable salivary pH and flow rate may be regarded as main protective factors against dental caries in diabetes. Optimum level of salivary calcium may be responsible for continuous supply of calcium to arrest the demineralization and help reduce the occurrence of dental caries.

The metabolic syndrome affects 30% of the US population with increasing prevalence. In this paper, we explore the relationship between the metabolic syndrome and the incidence and severity of cardiovascular disease in general and coronary artery disease (CAD) in particular. Furthermore, we look at the impact of metabolic syndrome on outcomes of coronary revascularization therapies including CABG, PTCA, and coronary collateral development. We also examine the association between the metabolic syndrome and its individual component pathologies and oxidative stress. Related, we explore the interaction between the main external sources of oxidative stress, cigarette smoke and air pollution, and metabolic syndrome and the effect of this interaction on CAD. We discuss the apparent lack of positive effect of antioxidants on cardiovascular outcomes in large clinical trials with emphasis on some of the limitations of these trials. Finally, we present evidence for successful use of antioxidant properties of pharmacological agents, including metformin, statins, angiotensin II type I receptor blockers (ARBs), and angiotensin II converting enzyme (ACE) inhibitors, for prevention and treatment of the cardiovascular complications of the metabolic syndrome.

Prostate cancer and the androgen deprivation therapy (ADT) thereof are involved in diabetes in terms of diabetes-associated carcinogenesis and ADT-related metabolic disorder, respectively. The aim of this study is to systematically review relevant literature. About 218,000 men are estimated to be newly diagnosed with prostate cancer every year in the United States. Approximately 10% of them are still found with metastasis, and in addition to them, about 30% of patients with nonmetastatic prostate cancer recently experience ADT. Population-based studies have shown that dissimilar to other malignancies, type 2 diabetes is associated with a lower incidence of prostate cancer, whereas recent large cohort studies have reported the association of diabetes with advanced high-grade prostate cancer. Although the reason for the lower prevalence of prostate cancer among diabetic men remains unknown, the lower serum testosterone and PSA levels in them can account for the increased risk of advanced disease at diagnosis. Meanwhile, insulin resistance already appears in 25-60% of the patients 3 months after the introduction of ADT, and long-term ADT leads to a higher incidence of diabetes (reported hazard ratio of 1.28-1.44). Although the possible relevance of cytokines such as Il-6 and TNF-α to ADT-related diabetes has been suggested, its mechanism is poorly understood.

The endoplasmic reticulum (ER) is a cellular organelle responsible for multiple important cellular functions including the biosynthesis and folding of newly synthesized proteins destined for secretion, such as insulin. The ER participates in all branches of metabolism, linking nutrient sensing to cellular signaling. Many pathological and physiological factors perturb ER function and induce ER stress. ER stress triggers an adaptive signaling cascade, called the unfolded protein response (UPR), to relieve the stress. The failure of the UPR to resolve ER stress leads to pathological conditions such as β-cell dysfunction and death, and type II diabetes. However, much less is known about the fine details of the control and regulation of the ER response to hyperglycemia (glucotoxicity), hyperlipidemia (lipotoxicity), and the combination of both (glucolipotoxicity). This paper considers recent insights into how the response is regulated, which may provide clues into the mechanism of ER stress-mediated β-cell dysfunction and death during the progression of glucolipotoxicity-induced type II diabetes.

Objective: Adiponectin has anti-atherogenic and anti-inflammatory properties. We investigated the influence of adiponectin on glucose tolerance status, adiposity and cardiovascular risk factors (CVRFs).

Design and patients: Study consisted of 107 subjects: 55 with normal glucose tolerance (NGT) and 52 with impaired glucose regulation (IGR) who were divided into two groups: 24 subjects with impaired fasting glucose (IFG Group) and 28 patients with type 2 diabetes mellitus (DM Group). In additional analysis, study participants were divided into two groups, according to CVRFs: low and high risk.

Measurements: Patients were evaluated for glucose, HbA1C, insulin, lipids, CRP, HOMA-IR and adiponectin.

Results: Adiponectin was significantly higher in NGT group than in IFG (P = 0.003) and DM (P = 0.01) groups. Adiponectin was significantly, positively associated with HDL and inversely associated with glucose, HbA1c, ALT, AST, TG, HOMA-IR. Patients with higher CVRFs load have lesser adiponectin compared to patients with low cardiovascular risk P < 0.0001). Adiponectin was inversely associated with the number of risk factors (r = -0.430, P = 0.0001).

Conclusions: Circulating adiponectin was significantly lower in subjects with different degree of IGR compared to subjects with normal glucose homeostasis. Adiponectin was significantly lower in high risk group than low risk group and decreased concurrently with increased number of CVRFs.

The purpose of this study was to determine whether levels of interleukin-6 (IL-6) in childhood are related to insulin resistance in adolescence. Further, to explore how fatness and cardiorespiratory fitness (VO(2peak)) moderate this relationship. Methods. 292 nine-year-old children (n = 292) were followed for 4 years. Anthropometrics and VO(2peak) were measured. Fasting blood samples were analyzed for IL-6, insulin, and glucose. Homeostasis model assessment (HOMA-IR) was used as a measure of insulin resistance. Results. For girls but not boys, levels of IL-6 at age 9 yrs correlated with HOMA-IR at age 13 yrs: r = 0.223, P = 0.008. Girls with IL-6 levels within the highest quartile at age 9 yrs had an odds ratio of 3.68 (CI = 1.58-8.57) being in the highest quartile of HOMA-IR four years later. Conclusion. In this cohort, IL-6 levels in childhood were related to insulin resistance in adolescence, but only for girls.

Diabetes mellitus (DM) alters circulating progenitor cells relevant for the pathophysiology of coronary artery disease (CAD). While endothelial progenitor cells (EPCs) are reduced, there is no data on procalcific polarization of circulating progenitors, which may contribute to vascular calcification in these patients. In a cohort of 107 subjects with and without DM and CAD, we analyzed the pro-calcific versus endothelial differentiation status of circulating CD34+ progenitor cells. Endothelial commitment was determined by expression of VEGFR-2 (KDR) and pro-calcific polarization by expression of osteocalcin (OC) and bone alkaline phosphatase (BAP). We found that DM patients had significantly higher expression of OC and BAP on circulating CD34+ cells than control subjects, especially in the presence of CAD. In patients with DM and CAD, the ratio of OC/KDR, BAP/KDR, and OC+BAP/KDR was about 3-fold increased than in other groups. EPCs cultured from DM patients with CAD occasionally formed structures highly suggestive of calcified nodules, and the expression of osteogenic markers by EPCs from control subjects was significantly increased in response to the toll-like receptor agonist LPS. In conclusion, circulating progenitor cells of diabetic patients show a phenotypic drift toward a pro-calcific phenotype that may be driven by inflammatory signals.

Aims: The aim of this study was to evaluate the effect of acute glycemia increase on microvasculature and endothelium in Type 1 diabetes during hyperinsulinemic clamp.

Patients and methods: Sixteen patients (51 ± 7 yrs) without complications were examined during iso- and hyperglycemic clamp (glucose increase 5.5 mmol·L(-1)). Insulin, lipid parameters, cell adhesion molecules and fibrinogen were analyzed. Microvascular reactivity (MVR) was measured by laser Doppler flowmetry.

Results: Maximum perfusion and the velocity of perfusion increase during PORH were higher in hyperglycemia compared to baseline (47 ± 16 versus 40 ± 16 PU, P < 0.01, and 10.4 ± 16.5 versus 2.6 ± 1.5 PU·s(-1), P < 0.05, resp.). Time to the maximum perfusion during TH was shorter and velocity of perfusion increase during TH higher at hyperglycemia compared to isoglycemic phase (69 ± 15 versus 77 ± 16 s, P < 0.05, and 1.4 ± 0.8 versus 1.2 ± 0.7 PU·s(-1), P < 0.05, resp.). An inverse relationship was found between insulinemia and the time to maximum perfusion during PORH (r = -0.70, P = 0.007).

Conclusion: Acute glycemia did not impair microvascular reactivity in this clamp study in Type 1 diabetic patients. Our results suggest that insulin may play a significant role in the regulation of microvascular perfusion in patients with Type 1 diabetes through its vasodilation effect and can counteract the effect of acute glucose fluctuations.

Altered expression of oxidative metabolism genes has been described in the skeletal muscle of individuals with type 2 diabetes. Pancreatic beta cells contain low levels of antioxidant enzymes and are particularly susceptible to oxidative stress. In this study, we explored the effect of hyperglycemia-induced oxidative stress on a panel of oxidative metabolism genes in a rodent beta cell line. We exposed INS-1 rodent beta cells to low (5.6 mmol/L), ambient (11 mmol/L), and high (28 mmol/L) glucose conditions for 48 hours. Increases in oxidative stress were measured using the fluorescent probe dihydrorhodamine 123. We then measured the expression levels of a panel of 90 oxidative metabolism genes by real-time PCR. Elevated reactive oxygen species (ROS) production was evident in INS-1 cells after 48 hours (P < 0.05). TLDA analysis revealed a significant (P < 0.05) upregulation of 16 of the 90 genes under hyperglycemic conditions, although these expression differences did not reflect differences in ROS. We conclude that although altered glycemia may influence the expression of some oxidative metabolism genes, this effect is probably not mediated by increased ROS production. The alterations to the expression of oxidative metabolism genes previously observed in human diabetic skeletal muscle do not appear to be mirrored in rodent pancreatic beta cells.

Diabetes is associated with impairment of angiogenesis such as reduction of myocardial capillary formation. Our previous studies demonstrate that disruption of Angiopoietin-1 (Ang-1)/Tie-2 signaling pathway contributes to the diabetes-associated impairment of angiogenesis. Protein tyrosine phosphatase (PTP) has a critical role in the regulation of insulin signal by inhibition of tyrosine kinase phosphorylation. In present study, we examined the role of protein tyrosine phosphatase-1 (SHP-1) in diabetes-associated impairment of Ang-1/Tie-2 angiogenic signaling and angiogenesis. SHP-1 expression was significantly increased in diabetic db/db mouse hearts. Furthermore, SHP-1 bond to Tie-2 receptor and stimulation with Ang-1 led to SHP-1 dissociation from Tie-2 in mouse heart microvascular endothelial cell (MHMEC). Exposure of MHMEC to high glucose (HG, 30 mmol/L) increased SHP-1/Tie-2 association accompanied by a significant reduction of Tie-2 phosphorylation. Exposure of MHMEC to HG also blunted Ang-1-mediated SHP-1/Tie-2 dissociation. Knockdown of SHP-1 significantly attenuated HG-induced caspase-3 activation and apoptosis in MHMEC. Treatment with PTP inhibitors restored Ang-1-induced Akt/eNOS phosphorylation and angiogenesis. Our data implicate a critical role of SHP-1 in diabetes-associated vascular complications, and that upregulation of Ang-1/Tie-2 signaling by targeting SHP-1 should be considered as a new therapeutic strategy for the treatment of diabetes-associated impairment of angiogenesis.