Asperulosidic Acid, a Bioactive Iridoid, Alleviates Placental Oxidative Stress and Inflammatory Responses in Gestational Diabetes Mellitus by Suppressing NF-κB and MAPK Signaling Pathways

<b><i>Background:</i></b> Asperulosidic acid (ASP) is a bioactive iridoid exerting broad pharmacological and medicinal properties. However, it is still unknown if ASP has therapeutical effects on gestational diabetes mellitus (GDM). This study aims to evaluate the effects of ASP on GDM as well as its underlying mechanism. <b><i>Methods:</i></b> A mouse model of GDM was established and orally administrated ASP (10, 20, and 40 mg/kg) on gestation day (GD) 0. The mice were sacrificed on GD 18. <b><i>Results:</i></b> Blood glucose and serum insulin were then determined. The inflammatory cytokines including IL-6 and TNF-α and oxidative stress biomarkers including MDA, SOD, GSH, and GPx were determined by using specific ELISAs. In addition, the expressions of NF-κB and MAPK signaling pathway-related proteins were determined by using Western blotting. Treatment with ASP decreased blood glucose in the mouse model of GDM. Besides, ASP also increased serum insulin and attenuated β-cell function. Treatment with ASP suppressed IL-6 and TNF-α and regulated oxidative stress-related biomarkers. Western blotting analysis showed that treatment with ASP suppressed phosphorylation of NF-κB p65, ERK1/2, and p38 in placental tissues. <b><i>Conclusion:</i></b> ASP alleviates placental oxidative stress and inflammatory responses in GDM by the inhibition of the NF-κB and MAPK signaling pathways.

Development and validation of dietary and lifestyle insulinemic indices among Iranian adult population

Background There is no study regarding developing a valid index to predict insulin-related disorders in the Iranian population based on their dietary habits and lifestyle. In the current study, we aimed to develop and validate insulinemic potential indices of diet and lifestyle in Iranian adults. Methods In this cross-sectional study, we analysed data of 1063 men and women aged ≥ 25 years among participants of the examination three of Tehran lipid and glucose study (TLGS) (2006–2008). Dietary intakes were assessed using a valid semi-quantitative food frequency questionnaire. Dietary and lifestyle indices were developed using stepwise linear regression analysis based on dietary intakes, body mass index, and physical activity data. Fasting serum insulin concentration and homeostatic model assessment for insulin resistance (HOMA-IR) were used as biomarkers of hyperinsulinemia (HI) and insulin resistance (IR). Validation analyses were performed in examination four of TLGS. Results We developed four indices related to insulin homeostasis, including the dietary index for HI (DIH), the dietary index for IR (DIR), the lifestyle index for HI (LIH), and the lifestyle index for IR (LIR). Based on multivariable-adjusted models, the relative values of the biomarker in subjects in the highest quartile of indices were 45% for LIH (95% CI 1.36–1.55, Ptrend < 0.001), 28% for DIR (95% CI 1.13–1.42, Ptrend = 0.019), and 51% for LIR (95% CI 1.41–1.61, Ptrend < 0.001), higher than those in the reference quartile, respectively. Conclusion We designed and validated indices to determine the insulin potential of diet and lifestyle for the Iranian population, according to Iran’s demographic and dietary intake characteristics.

Investigation of the Relationship between the Mid_Thigh Adipose Tissue Distribution Measured by MRI and Serum Osteocalcin—A Sex-Based Approach

Osteocalcin, in its non-carboxylated form, has a positive effect on glucose metabolism. Additionally, osteocalcin levels are related to body composition, especially muscle mass. The relation to the distribution of different adipose tissue types, such as subcutaneous, intermuscular, and visceral adipose tissue, is unclear. This study aimed to investigate associations between serum osteocalcin and the distribution of subcutaneous and intermuscular adipose tissue of the mid-thigh. Furthermore, the influence of different training methods on osteocalcin levels was investigated. We performed adipose tissue quantification of subcutaneous adipose tissue (SAT) and intramuscular adipose tissue (IMAT) using MRI measurements of the mid-thigh in 128 volunteers (63 male/65 female). Laboratory analysis included blood lipid panel, serum insulin, adiponectin, and osteocalcin measurements. The main observation was a significant correlation of total serum osteocalcin (TOC) and the distribution of adipose tissue of the mid-thigh (SAT/(SAT + IMAT)) (cc = −0.29/p-value = 0.002), as well as the cross-sectional muscle area (MA), increasing with the weekly resistance training duration in males. Additionally, TOC (p-value = 0.01) and MA (p-value = 0.03) were negatively related to serum insulin. The significant relationship between TOC and SAT/(SAT + IMAT) is a new finding and confirms the negative influence of IMAT on glucose metabolism in a sex-specific approach. We could substantiate this by the negative relation of TOC with serum insulin.

A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY

Aims/hypothesis Systematic studies on the phenotypic consequences of variants causal of HNF1A-MODY are rare. Our aim was to assess the phenotype of carriers of a single HNF1A variant and genetic and clinical factors affecting the clinical spectrum. Methods We conducted a family-based multigenerational study by comparing heterozygous carriers of the HNF1A p.(Gly292fs) variant with the non-carrier relatives irrespective of diabetes status. During more than two decades, 145 carriers and 131 non-carriers from 12 families participated in the study, and 208 underwent an OGTT at least once. We assessed the polygenic risk score for type 2 diabetes, age at onset of diabetes and measures of body composition, as well as plasma glucose, serum insulin, proinsulin, C-peptide, glucagon and NEFA response during the OGTT. Results Half of the carriers remained free of diabetes at 23 years, one-third at 33 years and 13% even at 50 years. The median age at diagnosis was 21 years (IQR 17–35). We could not identify clinical factors affecting the age at conversion; sex, BMI, insulin sensitivity or parental carrier status had no significant effect. However, for 1 SD unit increase of a polygenic risk score for type 2 diabetes, the predicted age at diagnosis decreased by 3.2 years. During the OGTT, the carriers had higher levels of plasma glucose and lower levels of serum insulin and C-peptide than the non-carriers. The carriers were also leaner than the non-carriers (by 5.0 kg, p=0.012, and by 2.1 kg/m2 units of BMI, p=2.2 × 10−4, using the first adult measurements) and, possibly as a result of insulin deficiency, demonstrated higher lipolytic activity (with medians of NEFA at fasting 621 vs 441 μmol/l, p=0.0039; at 120 min during an OGTT 117 vs 64 μmol/l, p=3.1 × 10−5). Conclusions/interpretation The most common causal variant of HNF1A-MODY, p.(Gly292fs), presents not only with hyperglycaemia and insulin deficiency, but also with increased lipolysis and markedly lower adult BMI. Serum insulin was more discriminative than C-peptide between carriers and non-carriers. A considerable proportion of carriers develop diabetes after young adulthood. Even among individuals with a monogenic form of diabetes, polygenic risk of diabetes modifies the age at onset of diabetes. Graphical abstract

Fructose-Rich Diet Is a Risk Factor for Metabolic Syndrome, Proximal Tubule Injury and Urolithiasis in Rats

Excessive consumption of fructose (FR) leads to obesity, metabolic syndrome (MS) and insulin resistance, which are known risk factors for kidney stones. The epidemiological study has suggested the association between fructose consumption and urolithiasis, but the precise mechanism is still not well understood. Male Wistar rats were assigned for 8 weeks to three groups with different FR content in diet: RD (n = 5)—regular diet with a FR < 3%; F10 (n = 6)—regular diet with an addition of 10% Fr in drinking water; F60 (n = 5)—60% FR as a solid food. Serum concentration of FR, creatinine (Cr), insulin (Ins), triglycerides (Tg), homocysteine (HCS), uric acid (UA), calcium (Ca), phosphate (Pi), magnesium (Mg) and sodium (Na) were measured. Based on 24 h urine collection the following tests were performed: urine pH, proteinuria (PCR), excretion of N-Acetyl-(D)-Glucosaminidase (NAG), monocyte chemoattractant protein (MCP-1), uric acid (uUAEx), phosphate (uPiEx), calcium (uCaEx), magnesium (uMgEx) and sodium (uNaEx). The creatinine clearance (CrCl) was calculated. Calcium deposits in kidney sections were examined using hematoxylin and eosin (HE) and von Kossa stains. The rats on F10 and F60, as compared to the RD diet, showed a tendency for lower CrCl, higher HCS level and some features of MS as higher Ins and TG levels. Interestingly, F10 (fluid) versus F60 (solid) diet led to higher serum Ins levels. F10 and F60 versus RD demonstrated higher urinary excretion of MCP-1 and NAG which were suggestive for inflammatory injury of the proximal tubule. F10 and F60 as compared to RD showed significantly lower uUAEx, although there were no differences in clearance and fractional excretion of UA. F60 versus RD induced severe phosphaturia (>30×) and natriuria (4×) and mild calciuria. F10 versus RD induced calciuria (3×), phosphaturia (2×) and mild natriuria. Calcium phosphate stones within the tubules and interstitium were found only in rats on FR diet, respectively, in two rats from the F10 group and another two in the F60 group. The rats which developed stones were characterized by significantly higher serum insulin concentration and urinary excretion of calcium and magnesium. A fructose-rich diet may promote development of calcium stones due to proximal tubule injury and metabolic syndrome.

Impact of Heavy Metals in Ambient Air on Insulin Resistance of Shipyard Welders in Northern Taiwan

Exposure to metals poses potential health risks, including insulin resistance (IR), to those exposed to them in excess. Limited studies have examined such risks in occupational workers, including welders, and these have yielded inconsistent results. Thus, we examined the associations between exposure to welding metals and IR in welders. We recruited 78 welders and 75 administrative staff from a shipyard located in northern Taiwan. Personal exposure to heavy metals, including chromium (Cr), manganese (Mn), iron (Fe), nickel (Ni), copper (Cu), zinc (Zn), and cadmium (Cd), was monitored through particulate matter with an aerodynamic diameter of less than 2.5 μm (PM2.5) and urine analysis by inductively coupled plasma mass spectrometry (ICP–MS). After each participant fasted overnight, blood samples were collected and analyzed for IR assessment through updated homeostasis model assessment (HOMA2) modeling. Air sampling in the personal breathing zone was performed during a Monday shift prior to the blood and urine sample collection the following morning. The welders’ median personal Cr, Mn, Fe, Ni, Cu, and Zn airborne PM2.5 levels and urinary Cd levels were significantly higher than those of the administrative staff. After adjustment for covariates, logarithmic PM2.5-Mn, PM2.5-Fe, PM2.5-Cu, and PM2.5-Zn levels were positively correlated with logarithmic fasting plasma glucose (P-FGAC) levels (PM2.5-Mn: β = 0.0105, 95% C.I.: 0.0027–0.0183; PM2.5-Fe: β = 0.0127, 95% C.I.: 0.0027–0.0227; PM2.5-Cu: β = 0.0193, 95% C.I.: 0.0032–0.0355; PM2.5-Zn: β = 0.0132, 95% C.I.: 0.0005–0.0260). Logarithmic urinary Zn was positively correlated with logarithmic serum insulin and HOMA2-IR levels and negatively correlated with logarithmic HOMA2-insulin sensitivity (%S; βinsulin = 0.2171, 95% C.I.: 0.0025–0.4318; βIR = 0.2179, 95% C.I.: 0.0027–0.4330; β%S = −0.2180, 95% C.I.: −0.4334 to −0.0026). We observed that glucose homeostasis was disrupted by Mn, Fe, Cu, and Zn exposure through increasing P-FGAC and IR levels in shipyard welders.

Protective Effects and Mechanisms of Polyethylene Glycol Loxenatide Against Hyperglycemia and Liver Injury in db/db diabetic Mice

Background: Type 2 diabetes mellitus (T2DM) is a metabolic disorder with insulin resistance and impaired insulin secretion that can cause complications, including liver injury. Polyethylene glycol loxenatide (PEG-Loxe), a glucagon-like peptide-1 (GLP-1) analog, is widely used to treat T2DM. However, its specific glucose-lowering and hepatoprotective mechanisms of action have not been established yet.METHODS: Using a high glucose-induced hepatocyte injury model and a type 2 diabetic db/db mouse model, we assessed PEG-Loxe’s impact on reducing blood glucose and improving liver injury in T2DM and revealed its mechanism.RESULTS: PEG-Loxe treatment significantly reduced body weight and fasting glucose, increased glucose tolerance, improved serum and liver biochemical parameters (glycated hemoglobin, serum insulin, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, and aspartate aminotransferase), and attenuated hepatic steatosis and liver and pancreatic tissue damages in db/db mice. Additionally, PEG-Loxe considerably inhibited oxidative stress, decreased pro-inflammatory factor (TNF-α, IL-6, and MCP-1) levels, and increased anti-inflammatory factor IL-10 levels. PEG-Loxe possibly inhibits hepatic lipid synthesis, oxidative stress, and inflammatory response by upregulating Sirt1, p-AMPK, and p-ACC expressions in the Sirt1/AMPK/ACC pathway of lipid metabolism, thereby improving T2DM liver injury. PEG-Loxe most likely also promotes GLP-1R expression by inhibiting β-cell apoptosis, which in turn activates the insulin PI3K/AKT pathway to promote insulin synthesis and secretion, thereby exerting hypoglycemic effects. In vitro cellular experiments further confirmed that PEG-Loxe possibly exerts hypoglycemic effects by activating the insulin PI3K/AKT pathway.Conclusion: PEG-Loxe improved liver injury in T2DM probably by activating Sirt1/AMPK/ACC lipid metabolism pathway, and exerted hypoglycemic effects through activation of insulin PI3K/AKT pathway.

Association of Adiponutrin/Patatin Like Phospholipase 3 (PNPLA3) I148M Gene Variant with Chronic Hepatitis C in Egyptian Children

Background: Chronic hepatitis C (CHC) represents a leading cause of liver-related mortality worldwide. The patatin-like phospholipase domain-containing 3 gene (PNPLA3/adiponutrin) rs738409 (I148M) single-nucleotide polymorphism (SNP) has been reported to be linked with the severity and progression of liver fat content and liver fibrosis in CHC among different racial groups. Such reports are lacking in CHC Egyptian children. Aim of Study: To evaluate the possible association of PNPLA3-I148M gene variant with the severity of liver fat content and liver fibrosis in Egyptian children with CHC. Patients and Methods: Fifty normal-weighted children (mean age 10.62±2.59 years) with CHC were subjected to genotyping of PNPLA3-I148M gene variant using the real time PCR TaqMan assay. FibroScan examination for assessment of both liver fibrosis by Fibroscan liver stiffness (LMS) and liver steatosis by the controlled attenuation parameter (CAP) scores and histological examination of liver biopsies for assessment of liver steatosis, and METAVIER scoring for necroinflammatory activity grades and liver fibrosis stages were done for all patients as well as appropriate laboratory investigations. APRI and FIB-4 indices as well as insulin resistance using HOMA-IR were also calculated. Results: 34 cases (68%) had CC genotype (wild CC genotype) ,9 cases (18%) had CG genotype (heterozygous for the risk G allele) and 7 cases (14%) had GG genotype (homozygous for the risk G allele). Significant higher values of LSM and CAP steatosis scores were found in patients with CG and GG genotypes compared to those with CC genotype. CG gene variant and GG gene variant were significant positive predictive factors for histopathological liver steatosis and fibrosis stages and inflammatory activity grades among the studied patients. Significant higher values of many laboratory variables (AST, fasting blood glucose, fasting serum insulin, and HOMA-IR) but lower platelets count was found in patients with G allele (CG+ GG) compared to patients without G allele (CC). In addition, significant positive correlations between PNPLA3-I148M gene variant and indicators of hepatic steatosis and fibrosis and many laboratory parameters (AST, APRI, FIB4, FBS, fasting serum insulin, and HOMA-IR) but a significant negative correlation between PNPLA3-I148M gene variant and platelet cell count were found among the studied patients. Conclusion: Data of this study suggested that polymorphisms in the PNPLA3 I148M gene variant could contribute to the severity of hepatic steatosis and fibrosis of the studied Egyptian children with CHC.

Tumour-Not So Sweet, Tumour-Induced Hypoglycemia: A Rare Case of Refractory Hypoglycemia in a Toddler

Tumour-induced hypoglycaemia is a rare complication/condition mainly seen in adults. It is caused due to increased production of insulin or insulin-like growth factor (IGF) 2 tumour cells. We present a 3-year-old paediatric patient with non-islet cell tumour induced hypoglycaemia (NICTH) secondary to rhabdomyosarcoma. She presented with abdominal mass and refractory hypoglycaemia, requiring high glucose infusion and steroids. Critical sample analysis during hypoglycaemia showed suppression of insulin, IGF-1, C-peptide, growth hormone, and ketones, with a high cortisol level. CT scan of abdomen and pelvis showed a huge retroperitoneal mass, later diagnosed as rhabdomyosarcoma. In a resource-limited setting, where IGF-2 is not possible, low serum insulin and IGF-1 levels during hypoglycaemia aids in diagnosis of NICTH. This is one of the first few reported paediatric cases with NICTH from India, and we believe that reporting this case would add more information to the existing literature. Thus, NICTH should be suspected in all malignancies presenting with intractable hypoglycaemia irrespective of their age.