Diabetes predicts severity of COVID-19 infection in a retrospective cohort: A mediatory role of the inflammatory biomarker C-reactive protein.

Diabetes is a risk factor for developing severe COVID-19, but the pathogenesis remains unclear. We investigated if the association of diabetes and COVID-19 severity may be mediated by inflammation. We also hypothesized that this increased risk may extend to prediabetes. Hospitalized patients in Singapore with COVID-19 were subdivided into three groups in a retrospective cohort: normoglycemia (HbA1c: ≤5.6%), prediabetes (HbA1c: 5.7%-6.4%) and diabetes (HbA1c: ≥6.5%). The primary outcome of severe COVID-19 was defined by respiratory rate ≥30, SpO2 ≤93% or intensive care unit admission. The association between clinical factors on severe COVID-19 outcome was analyzed by cox regression. Adjusted mediation analysis of C-reactive protein (CRP) on the relationship between diabetes and severe COVID-19 was performed. Of 1042 hospitalized patients, mean age 39 ± 11 years, 13% had diabetes, 9% prediabetes and 78% normoglycemia. Severe COVID-19 occurred in 4.9% of subjects. Compared to normoglycemia, diabetes was significantly associated with severe COVID-19 on both univariate (hazard ratio [HR]: 9.94; 95% confidence interval [CI]: 5.54-17.84; p < .001) and multivariate analysis (HR: 3.99; 95% CI: 1.92-8.31; p < .001), while prediabetes was not a risk factor (HR: 0.94; 95% CI: 0.22-4.03; p = .929). CRP, a biomarker of inflammation, mediated 32.7% of the total association between diabetes and severe COVID-19 outcome. In conclusion, CRP is a partial mediator of the association between diabetes and severe COVID-19 infection, confirming that inflammation is important in the pathogenesis of severe COVID-19 in diabetes.

Correlation of Telomere Length in Adipose Tissue and Leukocytes and its Association with Postsurgical Weight Loss.

OBJECTIVE: The aim of this study was to determine the relationship between telomere length (TL) in subcutaneous adipose tissue (SAT), visceral adipose tissues (VAT), and leukocytes, as well as to examine the associations of TL in these tissues with postsurgical weight loss in Asians with severe obesity. METHODS: Presurgery TL was measured in leukocytes, SAT, and VAT of 91 patients who underwent weight loss surgery. Correlation between TL in multiple tissues was assessed using Pearson correlation. The association of presurgery TL and postsurgical weight loss at 6 or 12 months, expressed as a percentage of weight loss, was determined using linear regression in 70 patients. RESULTS: Telomeres were longer in VAT compared with those in leukocytes and SAT (P < 0.001) but were highly correlated between tissues. The strongest correlation was observed between TL in VAT and leukocytes (r = 0.739, P = 6.22 × 10-17 ). Compared with individuals in the highest tertile, those in the lowest tertile of VAT TL showed greater weight loss (ß = 6.23, SE = 3.10, P = 0.044) independent of age, sex, ethnicity, types of surgery, diabetes condition, preoperative BMI, and follow-up period. CONCLUSIONS: Among patients with severe obesity, TL in leukocytes and adipose tissue was highly correlated. However, there was variability in the association of TL in these tissues with weight loss after surgery.

Plasma osteoprotegerin as a biomarker of poor glycaemic control that predicts progression of albuminuria in type 2 diabetes mellitus: A 3-year longitudinal cohort study.

AIMS: Poor glycaemic control elevates the risk for vascular complications. Biomarkers for predicting susceptibility to glycaemic worsening are lacking. This 3-year prospective analysis assessed the utility of several circulating diabetes-related biomarkers for predicting loss of glycaemic control, and their contribution to albuminuria progression in type 2 diabetes mellitus (T2DM). METHODS: T2DM subjects with adequately-controlled diabetes (HbA1c < 8%) at initial recruitment were analysed (N = 859). Baseline plasma levels of osteoprotegerin (OPG), C-reactive protein (CRP), adiponectin, intercellular-cell adhesion molecule-1, and vascular-cell adhesion molecule-1 were quantified using immunoassay. Definitions for development of uncontrolled diabetes and albuminuria progression were HbA1c ≥ 8.0% and increase in albuminuria category at follow-up, respectively. RESULTS: At follow-up, 185 subjects developed uncontrolled diabetes. Higher baseline CRP and OPG levels were observed in the high-risk individuals, and predicted increased risk for developing uncontrolled diabetes. OPG, but not CRP, was associated with albuminuria progression after multivariable adjustment. The relationship was attenuated following adjustment for development of uncontrolled diabetes, which emerged as a significant associate. Mediation analysis revealed that loss of glycaemic control explained 64.5% of the relationship between OPG and albuminuria progression. CONCLUSIONS: OPG outperformed other diabetes-related biomarkers to be a potentially useful biomarker for predicting loss of glycaemic control and its associated albuminuria deterioration.

Association between gain in adiposity and diabetic kidney disease worsening in type 2 diabetes is mediated by deteriorating glycaemic control: A 3-year follow-up analysis.

AIMS: Increased adiposity confers elevated risk for diabetic kidney disease (DKD) progression in type 2 diabetes mellitus (T2DM). This 3-year prospective study examined whether worsening of metabolic control e.g. development of uncontrolled diabetes mediated the relationship between increased adiposity and DKD deterioration. METHODS: T2DM subjects who had adequately controlled diabetes (HbA1c < 8%) at initial recruitment were analysed (N = 853). HbA1c ≥ 8% at follow-up was classified as development of uncontrolled T2DM. Absolute changes in body weight (ΔWeight), body mass index (ΔBMI), and body fat mass (ΔBFM) were calculated by subtracting baseline from follow-up values. DKD deterioration (outcome) was defined as an increase in the composite ranking of relative risk by glomerular filtration rate and albuminuria levels (Kidney Disease: Improving Global Outcomes 2009). RESULTS: Subjects with deteriorated DKD displayed lower reduction in body composition at follow-up than those who remained stable or/improved (all P < 0.05). In separate regression models, ΔWeight (risk ratio (RR):1.04, 95% CI:1.01-1.06), ΔBMI (RR:1.07, 95% CI:1.01-1.13), and ΔBFM (RR:1.03, 95% CI:1.01-1.06) were independently associated with worsened DKD. The associations were attenuated after accounting for the loss of glycaemic control. Binary mediation analysis revealed that the development of uncontrolled diabetes explained 41.7%, 45.4% and 39.7%, respectively, of the effects of ΔWeight, ΔBMI and ΔBFM on the outcome. CONCLUSIONS: Among T2DM individuals who had adequately-controlled T2DM at initial recruitment, the relationship between gain in adiposity and DKD deterioration is mediated by the development of poor glycaemic control over time. Therefore, preventing worsening adiposity and hyperglycaemia is pivotal to impede DKD progression.

Association of circulating proinflammatory marker, leucine-rich-α2-glycoprotein (LRG1), following metabolic/bariatric surgery.

BACKGROUND: Obesity confers substantial excess risk for morbidity and mortality, especially for type 2 diabetes (T2D). Leucine-rich-α2-glycoprotein 1 (LRG1), a novel proinflammatory factor, was recently reported to be higher in patients with T2D with complications of peripheral arterial disease. Association of LRG1, obesity, and weight loss is unknown. We examined whether plasma LRG1 is associated with obesity in health screening participants and if it predicts future weight loss in morbidly obese patients after metabolic/bariatric surgery. METHODS: Cohort 1 was a cross-sectional study from a Health Screening program (n = 616) in a tertiary hospital. Cohort 2 was a prospective study of morbidly obese patients (n = 231) who underwent metabolic/bariatric surgery with follow-up weight measurements. Anthropometric data, baseline fasting glucose, plasma adiponectin, high sensitivity C-reactive protein (HsCRP), and LRG1 were measured. Postsurgery blood, after metabolic/bariatric surgery, were available for LRG1and HsCRP measurements in 57 patients. RESULTS: In the group with highest tertile of LRG1, body mass index (BMI), waist circumference, and HsCRP were significantly higher, while total cholesterol, high-density lipoprotein, low-density lipoprotein, and adiponectin were lower than tertiles 1 and 2. Generalized linear model analysis showed that female gender (P < .0001), non-Chinese ethnicity (P < .019), and higher HsCRP (P < .0001) levels were independent and significant determinants of higher plasma LRG1 levels. After adjustment for age, gender, ethnicity, and baseline BMI, female gender (P = .020), higher presurgery BMI (P = .001), and lower presurgery LRG1 (P = .002) remained statistically significant predictors for greater weight loss. Plasma LRG1 increased significantly [from 28.2 (21.9-36.8) to 34.9 (22.6-49.5)] µg/mL (P = .003) within 1.5 months, after metabolic/bariatric surgery. CONCLUSIONS: Our study demonstrates that LRG1 level is positively associated with obesity and a lower level of plasma LRG1 predicts weight loss in metabolic/bariatric surgery. Our novel findings suggest LRG1, itself or in combination with other known factors, is a potential biomarker of inflammation and obesity.

Obesity is a determinant of arterial stiffness independent of traditional risk factors in Asians with young-onset type 2 diabetes.

OBJECTIVE: Type 2 diabetes (T2DM) among the young population has become a serious concern globally, presumably due to the rising trend of obesity. Compared to other forms of diabetes, young-onset T2DM experiences more cardiovascular events and other vascular complications although the underlying mechanisms remain largely unknown. Increased arterial stiffness is a hallmark of vasculopathy. We aim to study the clinical and metabolic determinants of arterial stiffness in a cohort of multi-ethnic Asians with young-onset T2DM. METHODS: 179 subjects with T2DM onset age below 30 years old were selected in this cross sectional study. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV). RESULTS: PWV was correlated with age, duration of diabetes, systolic blood pressure, alanine aminotransferase, urinary albumin-to-creatinine ratio (ACR) and eGFR in bivariate correlation analysis. However, PWV was only significantly correlated with body mass index (BMI), waist circumference, urinary ACR and eGFR after adjustment for age. Overweight individuals with young-onset T2DM had significantly higher PWV levels compared to their lean counterparts (7.3 ± 2.4 m/s vs 6.4 ± 2.3 m/s, p = 0.072 and p < 0.0001 without and with adjustment for age, respectively). Multivariable regression models revealed that age, BMI, eGFR and usage of insulin were independently associated with PWV. These 4 variables explained 35.5% variance in PWV levels. CONCLUSION: Age, BMI, renal function and insulin usage are the main determinants of PWV levels in Asians with young-onset T2DM. Notably, obesity is a modifiable determinant of arterial stiffness independent of high blood pressure, dyslipidemia and hyperglycemia in this population.