Effects of T2DM on cancer progression: pivotal precipitating factors and underlying mechanisms.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder affecting people worldwide. It is characterized by several key features, including hyperinsulinemia, hyperglycemia, hyperlipidemia, and dysbiosis. Epidemiologic studies have shown that T2DM is closely associated with the development and progression of cancer. T2DM-related hyperinsulinemia, hyperglycemia, and hyperlipidemia contribute to cancer progression through complex signaling pathways. These factors increase drug resistance, apoptosis resistance, and the migration, invasion, and proliferation of cancer cells. Here, we will focus on the role of hyperinsulinemia, hyperglycemia, and hyperlipidemia associated with T2DM in cancer development. Additionally, we will elucidate the potential molecular mechanisms underlying their effects on cancer progression. We aim to identify potential therapeutic targets for T2DM-related malignancies and explore relevant directions for future investigation.

Whole fresh fruit intake and risk of incident diabetes in different glycemic stages: a nationwide prospective cohort investigation.

PURPOSE: Fruit intake is beneficial to several chronic diseases, but controversial in diabetes. We aimed to investigate prospectively the associations of whole fresh fruit intake with risk of incident type 2 diabetes (T2D) in subjects with different glucose regulation capacities. METHODS: The present study included 79,922 non-diabetic participants aged ≥ 40 years from an ongoing nationwide prospective cohort in China. Baseline fruit intake information was collected by a validated food frequency questionnaire. Plasma HbA1c, fasting and 2 h post-loading glucose levels were measured at both baseline and follow-up examinations. Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% confidence intervals (CI) for incident diabetes among participants with normal glucose tolerance (NGT) and prediabetes, after adjusted for multiple confounders. Restricted cubic spline analysis was applied for dose-response relation. RESULTS: During a median 3.8-year follow-up, 5886 (7.36%) participants developed diabetes. Overall, we identified a linear and dose-dependent inverse association between dietary whole fresh fruit intake and risk of incident T2D. Each 100 g/d higher fruit intake was associated with 2.8% lower risk of diabetes (HR 0.972, 95%CI [0.949-0.996], P = 0.0217), majorly benefiting NGT subjects with 15.2% lower risk (HR 0.848, 95%CI [0.766-0.940], P = 0.0017), while not significant in prediabetes (HR 0.981, 95%CI 0.957-4.005, P = 0.1268). Similarly, the inverse association was present in normoglycemia individuals with a 48.6% lower risk of diabetes when consuming fruits > 7 times/week comparing to those < 1 time/week (HR 0.514, 95% CI [0.368-0.948]), but not in prediabetes (HR 0.883, 95% CI [0.762-1.023]). CONCLUSION: These findings suggest that higher frequency and amount of fresh fruit intake may protect against incident T2D, especially in NGT, but not in prediabetes, highlighting the dietary recommendation of higher fresh fruit consumption to prevent T2D in normoglycemia population.

The Association Between Leucine and Diabetic Retinopathy in Different Genders: A Cross-Sectional Study in Chinese Patients With Type 2 Diabetes.

Objective: To explore the association between serum leucine (leu) and diabetic retinopathy (DR) in patients with type 2 diabetes (T2D) and then to analyze the influence of gender on the association. Method: The electronic medical records of 1,149 T2D patients who met inclusion and exclusion criteria were retrieved from the Second Affiliated Hospital of Dalian Medical University and the First Affiliated Hospital of Jinzhou Medical University. Serum leu levels of all subjects were measured by liquid chromatography-mass spectrometry. Logistic regression was used to obtain the odds ratio (OR) and CI of leu-DR risk in multiple models. When using these models, restricted cubic spline (RCS) was used to test the potential non-linear relationship between multiple continuous independent variables, such as leu and DR (classification), and dependent variables. We also used the additive interaction method to evaluate the interaction effect between leu and gender on DR. Results: Leu was a protective factor of DR [0.78 (0.66, 0.92)]. When gender was divided into male and female, the above relationship was statistically significant only in men [0.73 (0.58, 0.94)]. Three indicators of additive interaction-RERI, AP, and S-suggested that there is no interaction between gender and leu on the risk of DR. Conclusions: Male T2D patients with high leu levels may have a lower risk of DR.

Inverted U-Shaped Associations between Glycemic Indices and Serum Uric Acid Levels in the General Chinese Population: Findings from the China Cardiometabolic Disease and Cancer Cohort (4C) Study.

OBJECTIVE: The relationship between serum uric acid (SUA) levels and glycemic indices, including plasma glucose (FPG), 2-hour postload glucose (2h-PG), and glycated hemoglobin (HbA1c), remains inconclusive. We aimed to explore the associations between glycemic indices and SUA levels in the general Chinese population. METHODS: The current study was a cross-sectional analysis using the first follow-up survey data from The China Cardiometabolic Disease and Cancer Cohort Study. A total of 105,922 community-dwelling adults aged ≥ 40 years underwent the oral glucose tolerance test and uric acid assessment. The nonlinear relationships between glycemic indices and SUA levels were explored using generalized additive models. RESULTS: A total of 30,941 men and 62,361 women were eligible for the current analysis. Generalized additive models verified the inverted U-shaped association between glycemic indices and SUA levels, but with different inflection points in men and women. The thresholds for FPG, 2h-PG, and HbA1c for men and women were 6.5/8.0 mmol/L, 11.0/14.0 mmol/L, and 6.1/6.5, respectively (SUA levels increased with increasing glycemic indices before the inflection points and then eventually decreased with further increases in the glycemic indices). CONCLUSION: An inverted U-shaped association was observed between major glycemic indices and uric acid levels in both sexes, while the inflection points were reached earlier in men than in women.

Luteolin attenuates angiotensin II­induced renal damage in apolipoprotein E­deficient mice.

Renal damage is a common and severe condition encountered in the clinic. Luteolin (Lut) exhibits anti­inflammatory, anti­fibrotic and anti­apoptotic effects. Thus, the present study aimed to investigate the pharmacological effects of Lut on angiotensin II (AngII)­induced renal damage in apolipoprotein E­deficient (ApoE­/­) mice. Male ApoE­/­ mice (age, 8 weeks) were randomly divided into the following three groups: i) Control group (n=6); ii) AngII group (n=6); and iii) AngII + Lut group (n=6). Lut was administered by gavage (100 mg/kg/d). ApoE­/­ mice were implanted with Alzet osmotic minipumps, filled with either saline vehicle or AngII solution for a maximum period of 4 weeks. After 4 weeks, metabolic characteristics were measured and the histopathological alterations in the kidney tissue were observed. The metabolic characteristics of blood creatinine (CRE) levels were lower in the AngII + Lut group compared with in the AngII group. The expression levels of collagen I and III were lower in the kidney tissues of the AngII + Lut group compared with the corresponding tissues of the AngII group. The gene expression levels of IL­1ß, IL­6, TNF­α and IL­10 were also suppressed in the kidney tissues of the AngII + Lut group compared with those in the corresponding tissues of the AngII group. Furthermore, the AngII + Lut group exhibited markedly increased LC3 protein expression and notably decreased p62 protein expression in the kidney tissues compared with the expression levels in the AngII group. The data demonstrated that Lut attenuated AngII­induced collagen deposition and inflammation, while inducing autophagy. Collectively, the results suggested that Lut treatment exhibited a exerted effect on AngII­induced renal injury in ApoE­/­ mice.

Elevated triglycerides rather than other lipid parameters are associated with increased urinary albumin to creatinine ratio in the general population of China: a report from the REACTION study.

BACKGROUND: Dyslipidaemia has always been regarded as the cornerstone of arteriosclerosis and is related to the pathogenesis of renal insufficiency. However, it is unclear which routinely available lipid parameter is related to urinary albumin to creatinine ratio (UACR). The purpose of this study was to examine the lipid abnormalities associated with UACR in the general population in China. METHODS: The present study was nested in an ongoing Risk Evaluation of cAncers in Chinese diabetic Individuals: A lONgitudinal (REACTION) study, which was designed to demonstrate the association of abnormal glucose metabolism with the risk of cancer in the Chinese population. This cross-sectional study included 34, 569 subjects (11, 390 males and 23, 179 females) from 8 different regional community cohorts, with an average age of 57.9 years. The UACR data were divided into the < 25% group, the 25-49% group, the 50-74% group, and the ≥ 75% group according to the quartile division of the centre where the subjects visited. The lipid classes were defined according to the guidelines for the prevention and treatment of dyslipidaemia in Chinese adults. Multiple logistic regression analysis was used to evaluate the association of the lipid parameters and UACR. RESULTS: Multivariable regression analysis revealed that compared with the other lipid parameters, triglycerides (TG) showed an adjusted odds ratio that was significant in model 1-4. This relationship was attenuated after adjusting for Haemoglobin A1c (HbA1c) and blood pressure (BP), but TG ≥ 2.3 mmol/L was still significantly associated with UACR in total subjects and in both men and women (OR: 1.131, 95% CI 1.065-1.203, P < 0.001 in total subjects; OR: 1.134, 95% CI 1.022-1.258, P = 0.017 in men; OR: 1.129, 95% CI 1.046-1.219, P = 0.002 in women). In the stratified analysis, elevated TG was significantly associated with increased urinary albumin in subjects with eGFR ≥ 90 mL/min per 1.73 m2, 5.6 ≤ FBG < 7.0 or 7.8 ≤ PBG < 11.1 mmol/L, 24 ≤ BMI < 28 kg/m2, 120 ≤ SBP < 140 and/or 80 ≤ DBP < 90 mmHg. CONCLUSIONS: We conclude that high TG levels rather than total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or non-high-density lipoprotein cholesterol levels are associated with UACR in the general population in China.

Cutoff Point of HbA1c for Diagnosis of Diabetes Mellitus in Chinese Individuals.

BACKGROUND: The purpose of the present study was to find the optimal threshold of glycated hemoglobin (HbA1c) for diagnosis of diabetes mellitus in Chinese individuals. METHODS: A total of 8 391 subjects (including 2 133 men and 6 258 women) aged 40-90 years with gradable retinal photographs were recruited. The relationship between HbA1c and diabetic retinopathy (DR) was examined. Receiver operating characteristic (ROC) curves were used to find the optimal threshold of HbA1c in screening DR and diagnosing diabetes. RESULTS: HbA1c values in patients with DR were significantly higher than in those with no DR. The ROC curve for HbA1c had an area under the curve of 0.881 (95%CI 0.857-0.905; P = 0.000). HbA1c at a cutoff of 6.5% had a high sensitivity (80.6%) and specificity (86.9%) for detecting DR. CONCLUSIONS: HbA1c can be used to diagnose diabetes in a Chinese population, and the optimal HbA1c cutoff point for diagnosis is 6.5%.

[Regulations of berberine on gene expression of BMP4 transcriptional pathways to improve visceral white adipose tissues insulin resistance in type 2 diabetic hamsters].

To study the effects of berberine on the gene mRNA expressions of BMP4 transcriptional pathways and brown/white adipose tissue conversion transcriptional pathways in visceral white adipose tissues(VWAT) in type 2 diabetic hamsters and explore the relevant mechanisms. The obese insulin-resistant hamster model were induced by using high-fat diet, and then the type 2 diabetic hamster model was created through injection with low-dose streptozotocin in the obese insulin-resistant hamster model. After the modeling, the hamsters were randomly divided into normal control, obese insulin-resistant, type 2 diabetic and berberine-treated diabetic groups. After the nine-week treatment, real-time quantitative PCR was used to measure the changes in gene mRNA expressions of VWAT BMP4 transcriptional pathways, brown/white adipose tissue conversion transcriptional pathways and their target genes in different groups. The results showed that the gene mRNA expressions of BMP4, BMPRⅡ, BMPRlA, Smad1, Smad5, Smad8, p38/MAPK, ATF2, PRDM16, C/EBPß, PGC1α, PPARγ and brown adipose tissue-specific genes was decreased and that of Smad6, Smurf1 and white adipose tissue-specific genes was increased in VWAT of model hamsters. Treatment with berberine regulated BMP4 transcriptional pathways and brown adipose tissue transcriptional pathways and induced the gene mRNA expression of brown adipose tissue-specific genes in VWAT to develop browning gene phenotype of white adipose tissues, and then improved fat-induced insulin resistance. These findings indicated that BMP4 transcriptional pathways involved in the formation of fat-induced visceral white adipose tissues insulin resistance (FIVWATIR) and the browning molecular mechanism of white adipose tissues induced by berberine.

[The safety and effectiveness of once daily detemir in patients with type 2 diabetes previously failing oral agents: the Chinese cohort from SOLVE(TM) observational study].

OBJECTIVE: Study of Once-daily LeVEmir(®) (SOLVE(TM)) was a 24-week international observational study to evaluate the safety and effectiveness of initiating once-daily insulin detemir (Levemir) as add-on therapy in patients with type 2 diabetes mellitus (T2DM) who failed treatment of oral anti-diabetic drugs (OAD). METHODS: The present study was derived from the data of Chinese cohort. A total of 3272 patients with T2DM failing OAD were enrolled in the study. Determir were prescribed to the patients by the decision of the physician. Clinical data were collected at baseline, week 12 and week 24 to evaluate the safety and effectiveness of detemir. RESULTS: The age of the patients was (56.2 ± 10.8) years with a diabetes duration of (7.1 ± 5.2) years. Their BMI was (25.3 ± 3.3) kg/m(2). No patient experienced any major or nocturnal hypoglycaemic event during the study. After 24 weeks of treatment, the glycosylated hemoglobin A1c (HbA1c) decreased from (8.33 ± 1.69)% to (7.16 ± 1.18)% with a mean change of -1.17%, the fasting plasma glucose decreased from (9.52 ± 2.59) mmol/L to (6.84 ± 1.42) mmol/L with a mean change of -2.7 mmol/L, and the 7-point blood glucose profile improved overall. Totally 49.1% of patients achieved HbA1c < 7%. The mean body weight decreased by 0.15 kg. CONCLUSIONS: Insulin detemir administered once daily as add-on therapy in patients with T2DM failing OAD regimen significantly reduces the risk of major hypoglycemia, improves glycemic control, increases the percentage of patients achieving treatment target with neutral effect on body weight.

[The baseline characteristics of patients with type 2 diabetes initiating insulin detemir : the Chinese cohort from the SOLVE(TM) study].

OBJECTIVE: To characterize the baseline status of Chinese diabetic patients based on data derived from Chinese cohort from SOLVE(TM) study. METHODS: Patients with type 2 diabetes initiating basal insulin detemir at the decision of the physician were eligible for the study. Data on demographics, medical history, glycemic profile and treatment regimen at baseline were collected by physicians. RESULTS: A total of 3272 patients [female 42%, male 58%, mean age (56.2 ± 10.8) years] were included in the study. Their BMI was (25.3 ± 3.3) kg/m(2). The duration of diabetes was 4.0 (0.1 - 27.0) years, and the duration of treatment with oral antidiabetic drugs (OADs) was 3.0 (0.0 - 20.2) years. The proportions of subjects with diabetic macro- and micro-vascular complications were 15.8% (515 cases) and 27.1% (866 cases), respectively. The hemoglobin A1c (HbA1c) at baseline was (8.33 ± 1.70)%, and the fasting blood glucose (FPG) was (9.5 ± 2.6) mmol/L. CONCLUSIONS: A large proportion of patients with type 2 diabetes remain in poor glycemic control, and the prevalence of diabetic complications is high, which requires optimal therapeutic strategy for the patients with suboptimal glycemic control.

[Activation of liver X receptor regulates fatty acid synthase expression in diabetic liver].

OBJECTIVE: To investigate the effects of liver X receptor (LXR) on the expression of fatty acid synthase (FAS) in diabetic liver. METHODS: Sixteen-week-old male db/db mice with C57BL/6 background were administered via gavaging of T0901317 (TO), a LXR synthetic agonist, at the dose of 3 mg x kg(-1) x d(-1) or dimethyl sulfide (DMSO), a vehicle alone for 7 days. Then the mice were killed with their livers taken out to undergo immunohistochemistry to observe the distribution of FAS protein. Human hepatocellular liver carcinoma cell of the line HepG2 were cultured with TO (10 micromol/L) or DMSO for 24 hours. Another HepG2 cells were transfected with mouse FAS promoter-luciferase reporter recombinants with or without pcDNA3.1, LXR expression vector, or an active sterol regulatory element binding protein-1c (SREBP-1c) expression vector for 12 hours. Real-time PCR and Western blotting were used to detect the levels of mRNA and protein of FAS and SREBP-1c respectively. Luciferase reporter assay was utilized to examine the activity of mouse FAS promoter. RESULTS: FAS was abundantly expressed in the mouse livers, especially in the cytoplasm of liver cells. The FAS mRNA levels of the livers of the db/db mice was about 5.5 times as high as that of the db/m mice (P < 0.01). The FAS protein levels in the livers of db/db and db/m mice treated with TO were 1.7 and 3.5 times higher than those of the control mice (both P < 0.05). The SREBP-1 mRNA levels in the liver of the db/m and db/db mice treated with TO were 2.4 and 2.1 times higher compared with the control mice (P < 0.05, P < 0.01). Luciferase test showed that the FAS promoter activity of the HepG2 cells treated with TO was 1.5 times that of the control cells (P < 0.01). The FAS promoter activities of the HepG2 cells transfected with LXR and SREBP-1c were 1.9 and 1.6 times those of the control cells (botn P < 0.01). CONCLUSION: LXRE directly or indirect (via SREBP-lc) upregulates the expression of FAS gene in the diabetic liver. LXR may mediate the lipid accumulation in liver of diabetes.