Intermittent fasting has become an increasingly popular strategy in losing weight and associated reduction in obesity-related medical complications. Overwhelming studies support metabolic improvements from intermittent fasting in blood glucose levels, cardiac and brain function, and other health benefits, in addition to weight loss. However, concerns have also been raised on side effects including muscle loss, ketosis, and electrolyte imbalance. Of particular concern, the effect of intermittent fasting on hormonal circadian rhythms has received little attention. Given the known importance of circadian hormonal changes to normal physiology, potential detrimental effects by dysregulation of hormonal changes deserve careful discussions. In this review, we describe the changes in circadian rhythms of hormones caused by intermittent fasting. We covered major hormones commonly pathophysiologically involved in clinical endocrinology, including insulin, thyroid hormones, and glucocorticoids. Given that intermittent fasting could alter both the level and frequency of hormone secretion, decisions on practicing intermittent fasting should take more considerations on potential detrimental consequences versus beneficial effects pertaining to individual health conditions.
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The prevalence of obesity is rapidly increasing worldwide. Obesity should not be understood only as the accumulation of fat in the body, but instead as a phenomenon that exerts different effects on our health according to the place of fat deposition and its stability. Obesity is the starting point of most metabolic diseases, such as diabetes, hypertension, metabolic syndrome, sleep apnea, and eventually cardiovascular disease. There are different kinds of obesity, ranging from simple obesity to sarcopenic obesity. The main purpose of intervening to address obesity is to decrease the ultimate consequence of obesity—namely, cardiovascular disease. The main mechanism through which obesity, especially abdominal obesity, increases cardiovascular risk is the obesity-induced derangement of metabolic health, leading to the development of metabolic diseases such as diabetes, non-alcoholic fatty liver disease, and metabolic syndrome, which are the main initiators of vascular damage. In this review, I discuss the influence of various types of obesity on the risk of metabolic diseases, and how these diseases increase cardiovascular disease risk.
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Background Type 1 diabetes mellitus induced by immune-checkpoint inhibitors (ICI-T1DM) is a rare critical entity. However, the etiology of ICI-T1DM remains unclear.
Methods In order to elucidate risk factors for ICI-T1DM, we evaluated the clinical course and immunological status of patients with ICI-T1DM who had been diagnosed during 2016 to 2021.
Results Seven of 871 (0.8%, six men and one woman) patients developed ICI-T1DM. We revealed that the allele frequencies of human leukocyte antigen (HLA)-DPA1*02:02 and DPB1*05:01 were significantly higher in the patients with ICI-T1DM In comparison to the controls who received ICI (11/14 vs. 10/26, P=0.022; 11/14 vs. 7/26, P=0.0027, respectively). HLA-DRB1*04:05, which has been found to be a T1DM susceptibility allele in Asians, was also observed as a high-risk allele for ICI-T1DM. The significance of the HLA-DPB1*05:01 and DRB1*04:05 alleles was confirmed by an analysis of four additional patients. The absolute/relative neutrophil count, neutrophils-lymphocyte ratio, and neutrophil-eosinophil ratio increased, and the absolute lymphocyte count and absolute/relative eosinophil count decreased at the onset as compared with 6 weeks before. In two patients, alterations in cytokines and chemokines were found at the onset.
Conclusion Novel high-risk HLA alleles and haplotypes were identified in ICI-T1DM, and peripheral blood factors may be utilized as biomarkers.
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The coronavirus disease 2019 (COVID-19) pandemic remains an unbeaten enemy. Unfortunately, no targeted treatment option is available. Patients with type 2 diabetes mellitus (T2DM) have increased odds for severe or fatal disease, as demonstrated in recent observational studies. There is an ongoing discussion regarding the impact of different antidiabetic drug classes on outcomes of interest among affected subjects. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been placed at the epicenter, since the DPP-4 enzyme seems to be implicated in the disease pathogenesis. Herein we present an updated meta-analysis of observational studies addressing the risk of COVID-19 death among patients with T2DM on prior DPP-4 inhibitor treatment. We pooled data from 10 observational studies, showing that DPP-4 inhibitors produce a non-significant decrease in the risk for COVID-19-related death. However, when administered in the inpatient setting, DPP-4 inhibitors decrease the risk for COVID-19-related death by 50%. Ongoing randomized controlled trials will shed further light.
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Original Article
Diabetes, Obesity and Metabolism Big Data Articles (National Health Insurance Service Database)
Background To investigate the clinical characteristics of gestational diabetes mellitus (GDM) in Korea, using a nationwide database.
Methods We analyzed 417,139 women who gave birth between 2011 and 2015 using the Korean National Health Information Database. They underwent the Korean National Health Screening Program within one year before pregnancy and were not prescribed drugs for diabetes nor diagnosed with diabetes mellitus before 280 days antepartum. Patients with GDM were defined as those who visited the outpatient clinic more than twice with GDM codes.
Results The prevalence of GDM was 12.70% and increased with increasing maternal age, prepregnancy body mass index (BMI), waist circumference (WC), and fasting plasma glucose (FPG) (P for trend <0.05). As compared with those aged <25 years, the odds ratio for women with GDM aged ≥40 years were 4.804 (95% confidence interval [CI], 4.436 to 5.203) after adjustment for covariates. Women with prepregnancy BMI ≥30 kg/m2 were at 1.898 times (95% CI, 1.736 to 2.075) greater risk for GDM than those with prepregnancy BMI <18.5 kg/m2. Women with WC of ≥95 cm were at 1.158 times (95% CI, 1.029 to 1.191) greater risk for GDM than women with WC of less than 65 cm. High FPG, high income, smoking, and drinking were associated with an elevated risk of GDM.
Conclusion The prevalence of GDM in Korean women increased up to 12.70% during 2011 to 2015. These data suggest the importance of GDM screening and prevention in high-risk groups in Korea.
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Background Obesity is a chronic disease associated with metabolic diseases such as diabetes and cardiovascular disease. Since the U.S. Food and Drug Administration approved liraglutide as an anti-obesity drug for nondiabetic patients in 2014, it has been widely used for weight control in overweight and obese people. This study aimed to systematically analyze the effects of liraglutide on body weight and other cardiometabolic parameters.
Methods We investigated articles from PubMed, EMBASE, and the Cochrane Library to search randomized clinical trials that examined body weight changes with liraglutide treatment.
Results We included 31 studies with 8,060 participants for this meta-analysis. The mean difference (MD) between the liraglutide group and the placebo group was −4.19 kg (95% confidence interval [CI], −4.84 to −3.55), with a −4.16% change from the baseline (95% CI, −4.90 to −3.43). Liraglutide treatment correlated with a significantly reduced body mass index (MD: −1.55; 95% CI, −1.76 to −1.34) and waist circumference (MD: −3.11 cm; 95% CI, −3.59 to −2.62) and significantly decreased blood pressure (systolic blood pressure, MD: −2.85 mm Hg; 95% CI, −3.36 to −2.35; diastolic blood pressure, MD: −0.66 mm Hg; 95% CI, −1.02 to −0.30), glycated hemoglobin (MD: −0.40%; 95% CI, −0.49 to −0.31), and low-density lipoprotein cholesterol (MD: –2.91 mg/dL; 95% CI, −5.28 to −0.53; MD: −0.87% change from baseline; 95% CI, −1.17 to −0.56).
Conclusion Liraglutide is effective for weight control and can be a promising drug for cardiovascular protection in overweight and obese people.
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Background This study investigated the effect of short-chain fatty acids (SCFAs) on diabetes in a mouse model.
Methods Autophagy in Akita mice and streptozocin (STZ)-induced diabetic C57BL/6 mice was determined by Western blots and immunohistochemistry (IHC). Western blots, IHC, hematoxylin and eosin staining, Masson staining, periodic acid-Schiff staining, and picrosirius red staining were conducted to detect whether autophagy and renal function improved in Akita mice and STZ-induced diabetic C57BL/6 mice after treatment of SCFAs. Western blots, IHC, and chromatin immunoprecipitation were performed to determine whether SCFAs affected diabetic mice via the histone deacetylase (HDAC2)/unc-51 like autophagy activating kinase 1 (ULK1) axis. Diabetic mice with kidney-specific knockout of HDAC2 were constructed, and IHC, Masson staining, and Western blots were carried out to detect whether the deletion of endogenous HDAC2 contributed to the improvement of autophagy and renal fibrosis in diabetic mice.
Results Reduced autophagy and severe fibrosis were observed in Akita mice and STZ-induced diabetic C57BL/6 mice. Increased autophagy and reduced renal cell fibrosis were found in SCFA-treated Akita diabetic mice and STZ-induced diabetic C57BL/6 mice. Diabetic mice treated with SCFAs had lower HDAC2 expression and more enriched binding of ULK1 promoter sequences to H3K27Ac. Endogenous knockout of HDAC2 caused enhanced autophagy and decreased renal fibrosis in diabetic mice treated with SCFAs.
Conclusion SCFAs enhanced autophagy of renal tubular cells and attenuated renal fibrosis in diabetic mice through the HDAC2/ULK1 axis.
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Background Farnesoid X receptor (FXR), a bile acid–activated nuclear receptor, is a potent regulator of glucose and lipid metabolism as well as of bile acid metabolism. Previous studies have demonstrated that FXR deficiency is associated with metabolic derangements, including atherosclerosis and nonalcoholic fatty liver disease (NAFLD), but its mechanism remains unclear. In this study, we investigated the role of FXR in atherosclerosis and NAFLD and the effect of peroxisome proliferator-activated receptor (PPAR) agonists in mouse models with FXR deficiency.
Methods En face lipid accumulation analysis, liver histology, serum levels of glucose and lipids, and mRNA expression of genes related to lipid metabolism were compared between apolipoprotein E (ApoE)−/− and ApoE−/−FXR−/− mice. The effects of PPARα and PPARγ agonists were also compared in both groups of mice.
Results Compared with ApoE−/− mice, ApoE−/−FXR−/− mice showed more severe atherosclerosis, hepatic steatosis, and higher levels of serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, accompanied by increased mRNA expression of FAS, ApoC2, TNFα, IL-6 (liver), ATGL, TGH, HSL, and MGL (adipocytes), and decreased mRNA expressions of CPT2 (liver) and Tfam (skeletal muscle). Treatment with a PPARα agonist, but not with a PPARγ agonist, partly reversed atherosclerosis and hepatic steatosis, and decreased plasma triglyceride levels in the ApoE−/−FXR−/− mice, in association with increased mRNA expression of CD36 and FATP and decreased expression of ApoC2 and ApoC3 (liver).
Conclusion Loss of FXR is associated with aggravation of atherosclerosis and hepatic steatosis in ApoE-deficient mice, which could be reversed by a PPARα agonist through induction of fatty acid uptake, β-oxidation, and triglyceride hydrolysis.
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Evidence for involvement of the central nervous system (CNS) in the regulation of glucose metabolism dates back to the 19th century, although the majority of the research on glucose metabolism has focused on the peripheral metabolic organs. Due to recent advances in neuroscience, it has now become clear that the CNS is indeed vital for maintaining glucose homeostasis. To achieve normoglycemia, specific populations of neurons and glia in the hypothalamus sense changes in the blood concentrations of glucose and of glucoregulatory hormones such as insulin, leptin, glucagon-like peptide 1, and glucagon. This information is integrated and transmitted to other areas of the brain where it eventually modulates various processes in glucose metabolism (i.e., hepatic glucose production, glucose uptake in the brown adipose tissue and skeletal muscle, pancreatic insulin and glucagon secretion, renal glucose reabsorption, etc.). Errors in these processes lead to hyper- or hypoglycemia. We here review the current understanding of the brain regulation of glucose metabolism.
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Background While the triglyceride-glucose (TyG) index is a measure of insulin resistance, its association with cardiovascular disease (CVD) has not been well elucidated. We evaluated the TyG index for prediction of CVDs in a prospective large communitybased cohort.
Methods Individuals 40 to 70 years old were prospectively followed for a median 15.6 years. The TyG index was calculated as the Ln [fasting triglycerides (mg/dL)×fasting glucose (mg/dL)/2]. CVDs included any acute myocardial infarction, coronary artery disease or cerebrovascular disease. We used a Cox proportional hazards model to estimate CVD risks according to quartiles of the TyG index and plotted the receiver operating characteristics curve for the incident CVD.
Results Among 8,511 subjects (age 51.9±8.8 years; 47.5% males), 931 (10.9%) had incident CVDs during the follow-up. After adjustment for age, sex, body mass index, diabetes mellitus, hypertension, total cholesterol, smoking, alcohol, exercise, and C-reactive protein, subjects in the highest TyG quartile had 36% increased risk of incident CVD compared with the lowest TyG quartile (hazard ratio, 1.36; 95% confidence interval, 1.10 to 1.68). Carotid plaque, assessed by ultrasonography was more frequent in subjects in the higher quartile of TyG index (P for trend=0.049 in men and P for trend <0.001 in women). The TyG index had a higher predictive power for CVDs than the homeostasis model assessment of insulin resistance (HOMA-IR) (area under the curve, 0.578 for TyG and 0.543 for HOMA-IR). Adding TyG index on diabetes or hypertension alone gave sounder predictability for CVDs.
Conclusion The TyG index is independently associated with future CVDs in 16 years of follow-up in large, prospective Korean cohort.
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Background We aimed to investigate the association of hepatic steatosis with liver fibrosis and to assess the interactive effects of hepatic steatosis and insulin resistance on liver fibrosis in a nationally representative sample of United States adults.
Methods We conducted a cross-sectional analysis using data from National Health and Nutrition Examination Survey 2017 to 2018, which for the first time included transient elastography to assess liver stiffness and hepatic steatosis. We evaluated the association between hepatic steatosis (using controlled attenuation parameter [CAP]) and clinically significant liver fibrosis (defined as liver stiffness ≥7.5 kPa) using logistic regression with an interaction term for hepatic steatosis and insulin resistance (defined as homeostatic model assessment of insulin resistance ≥3.0).
Results Among adults undergoing transient elastography (n=2,023), 45.9% had moderate or greater hepatic steatosis and 11.3% had clinically significant liver fibrosis. After adjustment for demographic and metabolic factors, the odds of significant liver fibrosis increased as CAP score rose (odds ratio, 1.35 per standard deviation increment; 95% confidence interval, 1.11 to 1.64). We detected a significant interaction effect between CAP score and insulin resistance on the probability of significant liver fibrosis (P=0.016 for interaction). The probability of significant liver fibrosis increased in the presence of insulin resistance with increasing CAP score, while those without insulin resistance had low probability of significant liver fibrosis, even with high CAP scores.
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