Rates of obesity and diabetes have increased significantly over the past decades and the prevalence is expected to continue to rise further in the coming years. Many observations suggest that obesity and diabetes are associated with an increased risk of developing several types of cancers, including liver, pancreatic, endometrial, colorectal, and post-menopausal breast cancer. The path towards developing obesity and diabetes is affected by multiple factors, including adipokines, inflammatory cytokines, growth hormones, insulin resistance, and hyperlipidemia. The metabolic abnormalities associated with changes in the levels of these factors in obesity and diabetes have the potential to significantly contribute to the development and progression of cancer through the regulation of distinct signaling pathways. Here, we highlight the cellular and molecular pathways that constitute the links between obesity, diabetes, cancer risk and mortality. This includes a description of the existing evidence supporting the obesity-driven morphological and functional alternations of cancer cells and adipocytes through complex interactions within the tumor microenvironment.
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Background Type 2 diabetes mellitus (T2DM) is characterized by elevated fasting glucagon and impaired suppression of postprandial glucagon secretion, which may participate in diabetic complications. Therefore, we investigated the associations of plasma glucagon with estimated glomerular filtration rate (eGFR), albuminuria and diabetic kidney disease (DKD) in T2DM patients.
Methods Fasting glucagon and postchallenge glucagon (assessed by area under the glucagon curve [AUCgla]) levels were determined during oral glucose tolerance tests. Patients with an eGFR <60 mL/min/1.73 m2 and/or a urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g who presented with diabetic retinopathy were identified as having DKD.
Results Of the 2,436 recruited patients, fasting glucagon was correlated with eGFR and UACR (r=–0.112 and r=0.157, respectively; P<0.001), and AUCgla was also correlated with eGFR and UACR (r=–0.267 and r=0.234, respectively; P<0.001). Moreover, 31.7% (n=771) presented with DKD; the prevalence of DKD was 27.3%, 27.6%, 32.5%, and 39.2% in the first (Q1), second (Q2), third (Q3), and fourth quartile (Q4) of fasting glucagon, respectively; and the corresponding prevalence for AUCgla was 25.9%, 22.7%, 33.7%, and 44.4%, respectively. Furthermore, after adjusting for other clinical covariates, the adjusted odds ratios (ORs; 95% confidence intervals) for DKD in Q2, Q3, and Q4 versus Q1 of fasting glucagon were 0.946 (0.697 to 1.284), 1.209 (0.895 to 1.634), and 1.521 (1.129 to 2.049), respectively; the corresponding ORs of AUCgla were 0.825 (0.611 to 1.114), 1.323 (0.989 to 1.769), and 2.066 (1.546 to 2.760), respectively. Additionally, when we restricted our analysis in patients with glycosylated hemoglobin <7.0% (n=471), we found fasting glucagon and AUCgla were still independently associated with DKD.
Conclusion Both increased fasting and postchallenge glucagon levels were independently associated with DKD in T2DM patients.
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Background There is a lack of recent research on the changes in risk factors for metabolic syndrome (MetS) in the Asian pediatric population. We aimed to determine the 12-year trends in the prevalence of MetS and relevant lifestyle factors such as smoking, exercise, and calorie intake among Korean adolescents.
Methods We investigated trends in MetS and lifestyle factors among 6,308 adolescents aged 12 to 18 years from the Korea National Health and Nutrition Examination Survey, 2007 to 2018.
Results The prevalence of MetS was stable from 2007 to 2018 (1.7% to 2.2%). There were significant increases in the prevalence of central obesity (from 8.1% to 11.2%, P=0.012) and hyperglycemia (from 5.3% to 10.4%, P<0.001) and decreases in hypo-high-density lipoprotein (HDL)-cholesterolemia (from 22.4% to 14.8%, P<0.001). Total calorie intake and calorie intake from fat significantly increased (P<0.001), whereas calorie intake from carbohydrates significantly decreased (P<0.001) during the study period. The proportions of tobacco smokers and regular walkers significantly decreased from 2007 to 2018. After controlling for all covariates, total calorie intake was positively correlated with waist circumference (P<0.05). HDL-cholesterol was negatively associated with carbohydrate consumption (P<0.01) and positively associated with fat consumption (P<0.001). Regular walking and regular strength training were associated with lower waist circumference (P<0.05). Smoking was associated with lower fasting glucose levels (P<0.01).
Conclusion Although the prevalence rate of MetS is stable among Korean adolescents, the prevalence of central obesity and hyperglycemia has increased greatly in the recent decade. Public education on proper dietary intake and lifestyle modification is required.
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Background Fatty liver and/or increased liver enzyme values have been reported to be associated with incident diabetes. We sought to determine whether increased visit-to-visit liver enzyme variability is associated with incident diabetes.
Methods Study participants were recruited from the Korean Genome and Epidemiologic Study (KoGES). A total of 4,151 people aged 40 to 69 years was recruited and tested every 2 years for up to 12 years. Visit-to-visit aspartate aminotransferase (AST) and alanine aminotransferase (ALT) variability was evaluated in first the 6-year period through the use of various variability measurements: standard deviation (SD), average successive variability, coefficient of variation (CV), and variation independent of mean (VIM). Oral glucose tolerance test was performed at every visit.
Results During the 6-year follow‐up appointments, 13.0% (538/4,151) of people developed incident diabetes. Visit-to-visit AST variability was associated with an increased risk of diabetes independent of conventional risk factors for diabetes (hazard ratio per 1-SD increment [95% confidence interval]: 1.06 [1.00 to 1.11], 1.12 [1.04 to 1.21], and 1.13 [1.04 to 1.22] for SD, CV, and VIM, respectively; all P<0.05); however, no such associations were observed in the visit-to-visit ALT variability. According to alcohol consumption status, both AST and ALT variability were independent predictors for incident diabetes in subjects with heavy alcohol consumption; however, neither AST nor ALT variability was associated with diabetes risk in subjects who did not drink alcohol heavily.
Conclusion Visit-to-visit liver enzyme variability is an independent predictor of incident diabetes. Such association was more evident in those who consumed significant amounts of alcohol.
Background Tyrosine kinase 2 (TYK2) is a candidate gene for type 1 diabetes mellitus (T1DM) since it plays an important role in regulating apoptotic and pro-inflammatory pathways in pancreatic β-cells through modulation of the type I interferon signaling pathway. The rs2304256 single nucleotide polymorphism (SNP) in TYK2 gene has been associated with protection for different autoimmune diseases. However, to date, only two studies have evaluated the association between this SNP and T1DM, with discordant results. This study thus aimed to investigate the association between the TYK2 rs2304256 SNP and T1DM in a Southern Brazilian population.
Methods This case-control study comprised 478 patients with T1DM and 518 non-diabetic subjects. The rs2304256 (C/A) SNP was genotyped by real-time polymerase chain reaction technique using TaqMan minor groove binder (MGB) probes.
Results Genotype and allele frequencies of the rs2304256 SNP differed between T1DM patients and non-diabetic subjects (P<0.0001 and P=0.001, respectively). Furthermore, the A allele was associated with protection against T1DM under recessive (odds ratio [OR], 0.482; 95% confidence interval [CI], 0.288 to 0.806) and additive (OR, 0.470; 95% CI, 0.278 to 0.794) inheritance models, adjusting for human leukocyte antigen (HLA) DR/DQ genotypes, gender, and ethnicity.
Conclusion The A/A genotype of TYK2 rs2304256 SNP is associated with protection against T1DM in a Southern Brazilian population.
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Background The dietary agent sulforaphane (SFN) has been reported to reduce diabetes-induced renal fibrosis, as well as inhibit histone deacetylase (HDAC) activity. Bone morphologic protein 7 (BMP-7) has been shown to reduce renal fibrosis induced by transforming growth factor-beta1. The aim of this study was to investigate the epigenetic effect of SFN on BMP-7 expression in diabetes-induced renal fibrosis.
Methods Streptozotocin (STZ)-induced diabetic mice and age-matched controls were subcutaneously injected with SFN or vehicle for 4 months to measure the in vivo effects of SFN on the kidneys. The human renal proximal tubular (HK11) cell line was used to mimic diabetic conditions in vitro. HK11 cells were transfected to over-express HDAC2 and treated with high glucose/palmitate (HG/Pal) to explore the epigenetic modulation of BMP-7 in SFN-mediated protection against HG/Pal-induced renal fibrosis.
Results SFN significantly attenuated diabetes-induced renal fibrosis in vivo. Among all of the HDACs we detected, HDAC2 activity was markedly elevated in the STZ-induced diabetic kidneys and HG/Pal-treated HK11 cells. SFN inhibited the diabetes-induced increase in HDAC2 activity which was associated with histone acetylation and transcriptional activation of the BMP-7 promoter. HDAC2 over-expression reduced BMP-7 expression and abolished the SFN-mediated protection against HG/Pal-induced fibrosis in vitro.
Conclusion Our study demonstrates that the HDAC inhibitor SFN protects against diabetes-induced renal fibrosis through epigenetic up-regulation of BMP-7.
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Background Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that exhibit multiple extraglycemic effects. However, there are conflicting results regarding the effects of SGLT2 inhibition on energy expenditure and thermogenesis. Therefore, we investigated the effect of ipragliflozin (a selective SGLT2 inhibitor) on energy metabolism.
Methods Six-week-old male 129S6/Sv mice with a high propensity for adipose tissue browning were randomly assigned to three groups: normal chow control, 60% high-fat diet (HFD)-fed control, and 60% HFD-fed ipragliflozin-treated groups. The administration of diet and medication was continued for 16 weeks.
Results The HFD-fed mice became obese and developed hepatic steatosis and adipose tissue hypertrophy, but their random glucose levels were within the normal ranges; these features are similar to the metabolic features of a prediabetic condition. Ipragliflozin treatment markedly attenuated HFD-induced hepatic steatosis and reduced the size of hypertrophied adipocytes to that of smaller adipocytes. In the ipragliflozin treatment group, uncoupling protein 1 (Ucp1) and other thermogenesis-related genes were significantly upregulated in the visceral and subcutaneous adipose tissue, and fatty acid oxidation was increased in the brown adipose tissue. These effects were associated with a significant reduction in the insulin-to-glucagon ratio and the activation of the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway in the liver and adipose tissue.
Conclusion SGLT2 inhibition by ipragliflozin showed beneficial metabolic effects in 129S6/Sv mice with HFD-induced obesity that mimics prediabetic conditions. Our data suggest that SGLT2 inhibitors, through their upregulation of energy expenditure, may have therapeutic potential in prediabetic obesity.
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Background Carnitine orotate complex (Godex) has been shown to decrease glycated hemoglobin levels and improve steatosis in patients with type 2 diabetes mellitus with non-alcoholic fatty liver disease. However, the mechanisms of Godex in glucose metabolism remain unclear.
Methods Male C57BL/6J mice were divided into four groups: normal-fat diet, high-fat diet, a high-fat diet supplemented with intraperitoneal injection of (500 mg or 2,000 mg/kg/day) Godex for 8 weeks. Computed tomography, indirect calorimetry, and histological analyses including electron microscopy of the liver were performed, and biochemical profiles and oral glucose tolerance test and insulin tolerance test were undertaken. Expressions of genes in the lipid and glucose metabolism, activities of oxidative phosphorylation enzymes, carnitine acetyltransferase, pyruvate dehydrogenase, and acetyl-coenzyme A (CoA)/CoA ratio were evaluated.
Results Godex improved insulin sensitivity and significantly decreased fasting plasma glucose, homeostatic model assessment for insulin resistance, steatosis, and gluconeogenesis, with a marked increase in fatty acid oxidation as well as better use of glucose in high-fat diet-fed mice. It preserved mitochondrial function and ultrastructure, restored oxidative phosphorylation enzyme activities, decreased acetyl-CoA/CoA ratio, and increased carnitine acetyltransferase content and pyruvate dehydrogenase activity. Carnitine acetyltransferase knockdown partially reversed the effects of Godex in liver and in vitro.
Conclusion Godex improved insulin resistance and steatosis by regulating carnitine acetyltransferase in liver in high-fat diet-fed mice.
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The aims of this study were to determine the short-term effectiveness of an internet-based lifestyle modification (LSM) program in preventing the onset of type 2 diabetes mellitus (T2DM) in prediabetes patients in community settings. A total of 415 subjects who were diagnosed with prediabetes were randomly assigned to the LSM and standard management (SM) groups. After the 6-month intervention, the LSM group had a statistically significant reduction in body weight, body mass index compared to the SM group participants. In the LSM group, blood glucose levels were significantly decreased after intervention and the clinical improvement effect was evident in the group that achieved the target weight loss of 5% or more of the initial weight for 6 months. Internet-based 6-month-intensive LSM programs conducted by public health center personnel are an effective way to provide lifestyle intervention programs and encourage maintenance of healthy behaviors in subjects with a high risk of T2DM in community settings.
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