Fasting Hyperglycemia Research Articles

Maternal early overfeeding negatively impacts cardiac progenitor cells differentiation and cardiomyocyte maturation in the neonatal offspring.

Maternal obesity has been positively correlated with an increased cardiometabolic risk in the offspring throughout life, implying intergenerational transmission. However, little is known about the early life cardiac cell modifications that imply the onset of heart diseases later in life. This study analyzed cardiac progenitor cells and cardiomyocyte differentiation on day of birth in the offspring born to obese dams. The litter size reduction model was used to induce obesity in female Swiss mice. Both maternal groups, the Small Litter Dams (SLD-F1), which were overfed during lactation, and the Normal Litter Dams (NLD-F1), control group, were mated to healthy male mice. Their first generation offspring (SLD-F2 and NLD-F2, n=6 by group) were euthanized on birth. Mothers from SLD had increased body mass, Lee Index, fat deposits, hyperglycemia, and glucose intolerance, confirming the obese phenotype. The offspring born from SLD-F1 had also increased body mass, Lee Index, and fasting hyperglycemia. The heart of SLD-F2 showed decreased cardiac mass/body mass ratio, increased cardiac collagen deposits, and a greater number of undifferentiated cardiac c-kit+ and Sca-1+ progenitor cells, and increased NKX2.5+ cardiomyoblasts compared to control. In addition, SLD-F2 demonstrated immature cardiomyocytes. Obese dams negatively impact its offspring, leading to altered biometric and metabolic parameters, along with an immature heart already at birth, with extracellular matrix adverse remodeling, delayed cardiac progenitor cells differentiation and restrained cardiomyocyte maturation, which can be related with the development of cardiometabolic disease in the adulthood.

Korean Red Ginseng Extract Powder Mitigates Fasting And Postprandial Hyperglycemia in Type 2 Diabetic Mice.

Type 2 diabetes mellitus (T2DM) involves insulin resistance and elevated blood sugar levels, causing complications. Red ginseng extract powder (RGEP) from Panax ginseng Meyer shows promise for diabetes treatment. However, its efficacy in managing T2DM remains unclear. Therefore, this study aims to evaluate the effectiveness of RGEP in a mouse model of T2DM. The efficacy of RGEP in treating T2DM was assessed in db/db mice. Mice were divided into seven groups: control, db/db, metformin, and RGEP at 50, 100, 200, and 400 mg/kg. Administered orally for 9 weeks, RGEP effects on glucose regulation and insulin sensitivity were assessed through various metabolic parameters. In addition, mRNA expression levels of genes associated with hepatic gluconeogenesis and insulin sensitivity were examined. Fasting blood sugar showed a significant decrease in all RGEP concentration groups, but OGTT and insulin tolerance test showed a significant decrease at the RGEP concentration of 400 mg/kg, indicating enhanced glycemic control. Moreover, RGEP dose-dependently decreased serum glucose, HbA1c levels, and homeostatic model assessment of insulin resistance values, suggesting its effectiveness in reducing insulin resistance in db/db mice. Furthermore, RGEP downregulated mRNA expression of key components in the gluconeogenesis pathway (G6Pase, FOXO1, GLUT4, and PEPCK), insulin sensitivity (leptin, insulin1, PTP1B, GLP-1, and DPP-4), and mitochondria energy metabolism (PGC1) in either the liver or pancreas, while simultaneously upregulating GLP-1 expression. In conclusion, these findings highlight the potential of RGEP as a complementary therapy for T2DM, indicating therapeutic efficacy in managing diabetic complications through improved metabolic parameters.

Inhibition of ketohexokinase prevents fructose-induced insulin resistance and endothelial dysfunction in high fat and sucrose-fed mice via enhancing energy expenditure

Abstract Introduction Cardiovascular disease linked to fatty liver poses a significant threat to health. Consumption of high-fat diets (HFD) is known to trigger a cascade of health issues including obesity, diabetes and non-alcoholic fatty liver disease (NAFLD). These conditions are exacerbated, with the addition of dietary sugar to high-fat diets (HFSD), resulting in non-alcoholic steatohepatitis (NASH). Studies have shown that fructokinase (ketohexokinase or KHK) knockdown protects mice from HFSD-induced NASH. Purpose This study focused on examining the temporal changes of metabolic perturbations, triggered by sugar consumption, particularly in the transition from fatty liver to cardiovascular disease. Methods C57/BL6 wild type (WT) and KHK-knockout mice were fed with HFD or HFSD for different durations between 6 to 20 weeks, to induce NAFLD and NASH. Western blotting and quantitative-PCR were carried out on tissues and isolated endothelial cells for protein and mRNA expressions, respectively. Glucose and insulin tolerance tests and whole-body energy measurements were performed at different time-points. Combined Laboratory Animal Monitoring System was used to monitor various parameters of energy expenditure. Functional interactions between endothelial cells and adipose tissues were carried out using an in-house Organ-On-a-chip technology. Endothelial function was studied by measuring isometric tensions in organ bath. Results KHK-deficient mice had significantly lower weight compared to WT littermates. Wild-type mice fed HFD and HFSD exhibited significant glucose intolerance, insulin resistance, and endothelial dysfunction compared to KHK-knockout mice. However, HFSD led to more severe outcomes compared to HFD, demonstrating differing temporal effects on glucose intolerance and insulin resistance. Interestingly, KHK-knockout mice were significantly protected from the effects induced by HFSD, as well as, such as increased body weight, fasting hyperglycemia, hyperinsulinemia and endothelial function. KHK-knockout mice exhibited significant increase in oxygen consumption and energy expenditure, both in HFD and HFSD-fed conditions. These data suggest that high energy-expenditure is one of the primary mechanisms, in reducing adiposity and body weight in HFSD-fed knockout mice. Notably, KHK-deficient mice were protected against sugar-induced fat accumulation, random hyperinsulinemia and significant impairment of endothelial function. Conclusions A novel finding in this study is that KHK ablation protects not only against HFSD-induced, but also HFD-induced pathologies via significantly enhancing energy expenditure. The results suggest that targeting KHK could potentially mitigate the development of fatty liver and cardiovascular diseases, induced by high calorie diets.

Heterogeneity of gestational diabetes and risk for adverse pregnancy outcome: a cohort study.

Diabetes has increasingly been recognized as a heterogeneous disease, with clinical characteristics and outcomes risk varying across different phenotypes. Evidence on heterogeneity of gestational diabetes (GDM) is yet to be provided. To investigate the insulin physiology and pregnancy outcomes of GDM phenotypes characterized by fasting hyperglycemia or postload hyperglycemia. A total of 2050 women who underwent a 75-g oral glucose tolerance test were prospectively recruited and followed up until delivery. Women were categorized into normoglycemia (NGT, n = 936), isolated impaired fasting glucose (gestational-IFG, n = 378), and isolated impaired postload glucose tolerance (gestational-IGT, n = 736) groups. Fasting blood sample at mid-pregnancy were collected to measure C-peptide and insulin concentrations. Homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) were used to evaluate insulin physiology. Maternal and neonatal outcomes were recorded. Gestational-IFG had greater insulin resistance (HOMA-IR 3.11 vs. 2.25, QUICKI-CP 0.94 vs. 1.03, both P < 0.01), and gestational-IGT had worse β-cell function (C-peptide 2.00 vs. 2.26 ng/ml, P < 0.05) when compared to one another. Gestational-IFG was more strongly associated with excessive gestational weight gain (RR 1.62, 95% CI 1.18-2.23) and large-for-gestational-age infants (RR 1.45, 95% CI 1.03-2.03) than gestational-IGT. The risk for neonatal brain injury was increased in gestational-IGT (RR 2.03, 95% CI 1.04-4.09), but not in gestational-IFG (P = 0.439). Gestational-IGT showed a stronger association with the risk of preterm birth compared to gestational-IFG (RR 1.80, 95% CI 1.02-3.36). GDM exhibits distinct insulin physiology profiles. Pregnancy outcome varies between each phenotype. These findings provide evidence on risk stratification and diverse strategies for the treatment of GDM.

8599 Development of an androgen receptor transgenic mouse that displays the complete attributes of Metabolic Syndrome

Abstract Disclosure: C. Alvarado: None. L.K. Beitel: None. M. Paliouras: None. M.A. Trifiro: None. The mouse androgen receptor (AR) shares over 90% homology with the human ortholog, but it lacks the CAG encoded poly-Q tract; instead, it contains a mixed glutamine/histidine tract. To study AR functionality in a more structured fashion, we created a knock-in mouse model that has only the equivalent of human poly-Q tract while maintaining the remaining mouse receptor sequence intact. Our humanized androgen receptor mouse (AR-19Q) displays a phenotype that is best described as Metabolic Syndrome (MetS). The mice gain excess weight, have hypertension, hyperglycemia, pancreatic islet cell abnormalities, and progressive non-alcoholic fatty liver disease (NAFLD). Features of MetS begin at approximately 4 months and progress till 12-14 months. Obesity: AR-19Q mice are significantly heavier, with a 35% gain of weight vs C57BL/6 mice. However, these mice are not hyperphagic at any time and eat identical quantities of chow. To assess obesity status, and found AR-19Q mice to have a significantly higher depositions of total white adipose visceral, lingual and subcutaneous vs age-matched controls. NAFLD: The progression of NAFLD is observed in AR-19Q mice. AR-19Q Histological analysis and immunohistochemistry reveal microvesicular steatosis, superseded by macrovesicular steatosis with hepatocyte balloon degeneration, scattered lobular inflammation (macrophages and lymphocytes) (6-9 months) and further superseded by perisinusoidal fibrosis (12 months). Biochemical blood analysis confirms. that there is a significant increase in alanine aminotransferase (ALT) levels, indicative of liver damage. With time classical NASH hepatitis and subsequent NASH fibrosis ensues; with several mice developing hepatocellular carcinoma (overall 20% of mice). Gene expression profiling AR-19Q mice for fatty liver genes, we observe an upregulation of inflammation genes Il-6, Il-10 and Tnf. In addition, increased Lpl (lipoprotein lipase) is indicative of increased blood triglyceride levels. On the other hand, down-regulation of G6pc (glucose-6-phosphatase) could be linked to glycogen storage disease. Down-regulation of Slc2a2 and Slc2a4, that encode GLUT2 and GLUT4, should have an influence on glucose levels, glucose homeostasis and insulin sensitivity, as insulin promotes glucose uptake through GLUT4. Type 2 Diabetes: Glucose intolerance is observed by 3-4 months followed by fasting hyperglycemia. Pancreases show advanced islet hyperplasia, concurrent with insulin resistance and type 2 diabetes. Pancreases of middle-age AR-19Q mice present with a significant islet hyperplasia, suggesting peripheral insulin resistance. We propose the use of the AR-19Q mice as a model to study the metabolic dysfunction/ deficiency leading to the MetS. The model will allow us to a better understanding into the mechanisms responsible for T2D and NAFLD-related disorders. Presentation: 6/2/2024

9285 Development of an androgen receptor transgenic mouse that displays the complete attributes of Metabolic Syndrome

Abstract Disclosure: C. Alvarado: None. L.K. Beitel: None. M. Paliouras: None. M.A. Trifiro: None. The mouse androgen receptor (AR) shares over 90% homology with the human ortholog, but it lacks the CAG encoded poly-Q tract; instead, it contains a mixed glutamine/histidine tract. To study AR functionality in a more structured fashion, we created a knock-in mouse model that has only the equivalent of human poly-Q tract while maintaining the remaining mouse receptor sequence intact. Our humanized androgen receptor mouse (AR-19Q) displays a phenotype that is best described as Metabolic Syndrome (MetS). The mice gain excess weight, have hypertension, hyperglycemia, pancreatic islet cell abnormalities, and progressive non-alcoholic fatty liver disease (NAFLD). Features of MetS begin at approximately 4 months and progress till 12-14 months. Obesity: AR-19Q mice are significantly heavier, with a 35% gain of weight vs C57BL/6 mice. However, these mice are not hyperphagic at any time and eat identical quantities of chow. To assess obesity status, and found AR-19Q mice to have a significantly higher depositions of total white adipose visceral, lingual and subcutaneous vs age-matched controls. NAFLD: The progression of NAFLD is observed in AR-19Q mice. AR-19Q Histological analysis and immunohistochemistry reveal microvesicular steatosis, superseded by macrovesicular steatosis with hepatocyte balloon degeneration, scattered lobular inflammation (macrophages and lymphocytes) (6-9 months) and further superseded by perisinusoidal fibrosis (12 months). Biochemical blood analysis confirms. that there is a significant increase in alanine aminotransferase (ALT) levels, indicative of liver damage. With time classical NASH hepatitis and subsequent NASH fibrosis ensues; with several mice developing hepatocellular carcinoma (overall 20% of mice). Gene expression profiling AR-19Q mice for fatty liver genes, we observe an upregulation of inflammation genes Il-6, Il-10 and Tnf. In addition, increased Lpl (lipoprotein lipase) is indicative of increased blood triglyceride levels. On the other hand, down-regulation of G6pc (glucose-6-phosphatase) could be linked to glycogen storage disease. Down-regulation of Slc2a2 and Slc2a4, that encode GLUT2 and GLUT4, should have an influence on glucose levels, glucose homeostasis and insulin sensitivity, as insulin promotes glucose uptake through GLUT4. Type 2 Diabetes: Glucose intolerance is observed by 3-4 months followed by fasting hyperglycemia. Pancreases show advanced islet hyperplasia, concurrent with insulin resistance and type 2 diabetes. Pancreases of middle-age AR-19Q mice present with a significant islet hyperplasia, suggesting peripheral insulin resistance. We propose the use of the AR-19Q mice as a model to study the metabolic dysfunction/ deficiency leading to the MetS. The model will allow us to a better understanding into the mechanisms responsible for T2D and NAFLD-related disorders. Presentation: 6/2/2024

9366 The Rnf20 Histone Modifier Is A Crucial Mediator Of Pancreatic Beta Cell Identity And Function

Abstract Disclosure: T.H. Pierre: None. Y. Liu: None. M.M. Bethea: None. K. Coutinho: None. C. Hunter: None. Diabetes is characterized by the loss of pancreatic β-cell mass. As diabetes incidence continues to elevate, it is critical that we develop a better understanding of the factors that define functional β-cells in order to improve current therapeutics. One approach is through the study of transcription factors (TFs), which are essential for β-cell development and function. Prior work from our lab and others has examined Islet-1 (Isl1) a LIM-homeodomain TF that is required for the maturation of the endocrine pancreas and adult β-cell function. We have also extensively characterized several Isl1-interacting co-regulators (e.g., Ldb1 and SSBP3) that facilitate its roles in maintaining glucose homeostasis. Most recently, we have identified that Isl1 interacts with the ubiquitin ligases Ring Finger 20 (Rnf20) and Rnf40, whose histone H2B monoubiquitation (H2Bub1) activity support the gene regulatory functions of Isl1. With in vitro experiments, we demonstrated that Rnf20 and Rnf40 are important for glucose stimulated insulin secretion (GSIS) and mediate the expression of β-cell identity genes. Based on these findings, we hypothesize that Isl1-Rnf complexes modify histones to regulate β-cell gene expression and function. To address this hypothesis in vivo, we developed an adult inducible β-cell knockout of Rnf20 (Rnf20Δβ-cell). Rnf20Δβ-cell mice display fasting hyperglycemia and severe glucose intolerance that is driven by impaired GSIS, reduced insulin content, and the dysregulation of critical β-cell genes including Ins1, Ucn3, and Slc2a2. Additionally, loss of Rnf20 perturbs insulin processing and overall β-cell maturation as observed by measurement of proinsulin:insulin ratios, C-peptide levels, and whole islet RNA-seq. Phenotypes exhibited by Rnf20Δβ-cell mice are similar to those observed in Isl1 β-cell knockout mice, and comparative transcriptomics revealed an overlap of 570 genes involved in metabolism, zinc homeostasis, and islet proliferation including Slc30a8 and Matn2, both of which we found are occupied by Isl1 and Rnf20. Collectively, our findings demonstrate the importance of the Rnf20 histone modifier in regulating β-cell function and expand our understanding of the Isl1 regulatory network. Presentation: 6/2/2024

6985 Intravenous Immunoglobulin induced Type 1 diabetes remission

Abstract Disclosure: N. Shahid: None. D. Newbern: None. Introduction: Intravenous immunoglobulin [IVIG] is an immunomodulatory agent used for treatment of autoimmune and inflammatory conditions. However, it is not indicated in patients with type 1 diabetes [T1D] as its efficacy has not been established. Clinical Case: A 9-year-old previously healthy boy presented to the Emergency Department with several days of unexplained bruising and mucosal bleeding with no prior history of trauma, bleeding disorders or other systemic symptoms. Physical examination showed generalized petechiae, ecchymosis and purpura. Vitals were normal including weight and BMI. Initial labs confirmed Immune thrombocytopenic purpura [ITP] as his platelets were less than 1K/µL with otherwise normal peripheral blood cell counts and smear. Concomitantly, labs showed significant hyperglycemia [260mg/dL] with glycosuria and trace ketonuria. Glycated hemoglobin [Hba1c] was elevated at 10.5% and ultimately Pancreatic autoantibodies [GAD65, Zinc transporter-8 and islet cell antibody] came back positive confirming T1D. Other autoimmune disorders such as adrenal insufficiency, thyroiditis, and celiac disease were ruled out. For the treatment of ITP, he the patient received 1 dose of IVIG 1g/kg and responded well with a rise in platelets to 6K/µL. The morning following the infusion, due to fasting hyperglycemia, the patient was started on basal-bolus insulin regimen. By 2nd day post IVIG, he had hypoglycemia, so insulin was discontinued with normalization of blood sugars. He is now 7 months post IVIG with no recurrent episodes of thrombocytopenia. He also remains off insulin with Hba1c in the 5.9-6.5% range. He eats a regular diet with avoidance of simple carbohydrates. He wears onwears a a continuous glucose monitor, which shows that blood sugars are in range 93% of the time He remains euglycemic overnight with transient self-resolving mild post-prandial hyperglycemia. Pancreatic autoantibodies have been reassessed and remain positive Conclusions: This case demonstrates that IVIG used for the treatment of ITP has induced a state of remission in our patient with newly diagnosed with T1D. IVIG is not a standard of treatment for T1D, however, when given for other autoantibody- or T-cell-mediated autoimmune conditions, it may reduce the insulin need in patients with known diabetes or induce remission in patients with newly diagnosed diabetes.

5180 Atypical Presentation of Type 2 Diabetes Mellitus in a 72Year Old Caucasian Male with Hemoglobin J-Baltimore Variant: A Case Report

Abstract Disclosure: C. Muojieje: None. M. Luzuriaga: None. Objective: This case report discusses the unusual manifestation of Type 2 Diabetes Mellitus (T2DM) in a 72-year-old Caucasian male possessing a rare Hemoglobin variant, Hemoglobin J-Baltimore. It emphasizes the importance of recognizing how hemoglobin variants can impact HbA1c measurements. Alternative markers, such as fructosamine and HbA1c measurement using turbidimetric inhibition immunoassay (TINIA), are discussed as potential tools for a more precise assessment of glycemic control. Furthermore, it accentuates the effectiveness of tailored treatment strategies in such cases. Methods: A 72-year-old Caucasian male with a history of T2DM was referred to an endocrinology clinic due to substantial discordance between the blood glucose (BG) values when self-monitoring and HbA1c. The patient was diagnosed with T2DM a decade ago due to fasting hyperglycemia. His HbA1c levels had remained within normal range. He exhibited signs of diabetic nephropathy with moderately increased albuminuria. He was never prescribed an oral hypoglycemic agent. He reported polyuria, weight loss, and fatigue, prompting him to monitor his BG at home twice daily, revealing readings &amp;gt; 200 mg/dl. HbA1c measurement using high-performance liquid chromatography (HPLC) was 4.8%. His fasting plasma glucose was 190 mg/dl, and fructosamine levels were 292 umol/L (205 - 285 umol/L). An HbA1c level via TINIA was 6.4%. Hemoglobin electrophoresis unveiled the presence of Hemoglobin J-Baltimore. We started metformin, resulting in an improvement in HbA1c from 6.4% to 5.8%. Fructosamine levels improved from 292 umol/L to 210 umol/L. Fasting blood glucose remained &amp;gt; 150 mg/dl. Dulaglutide was introduced. Follow-up analysis showed an improvement in FBS to &amp;lt; 120 mg/dl. HbA1c remained unchanged at 5.9%. Conclusion: The significance of hemoglobin variants, exemplified by Hemoglobin J-Baltimore, cannot be overstated in the context of patients with T2DM, especially within populations where these variants are uncommon. This case underscores the need for a nuanced approach to glycemic control assessment in such individuals. The utilization of alternative markers, such as HbA1c values obtained through TINIA, emerges as a valuable strategy. The role of continuous glucose monitoring (CGM) is crucial, providing real-time and comprehensive data, which enhances the quality of care and contributes to more tailored and effective treatment strategies. Presentation: 6/1/2024

Non-Pharmacological Management of Gestational Diabetes Mellitus with a High Fasting Glycemic Parameter: A Hospital-Based Study in Vietnam

Background/Objectives: The prevalence of gestational diabetes mellitus (GDM) is increasing at an alarming rate worldwide. Delayed management can lead to adverse composite outcomes for both mother and her offspring. To our knowledge, the clinical association between glycemic parameters and the results of the non-pharmacological GDM approach remains limited; thus, this study aimed to address this important clinical issue in the literature. Methods: This was a retrospective cross-sectional study of 174 Vietnamese pregnant women with the positive oral glucose tolerance test (OGTT) for a high fasting glycemic parameter at Hung Vuong Hospital from 04/2022 to 07/2022. This study aimed to evaluate the success rate of GDM with an elevated index of fasting glycemic concentration which was managed after 2 weeks of a dietary regimen combined with adequate physical activities and to reveal its related factors. Results: Out of 174 singleton pregnancies that met the inclusion criteria, 103 GDM pregnant women were successfully managed after 2 weeks of monitoring (59.2%; 95% confidence intervals (CI): 51.9–66.5). The study revealed a fair correlation between the corresponding test of blood glucose at OGTT and after 2 weeks of GDM management (r = 0.270–0.290, p &lt; 0.0001). The GDM pregnant women with an elevated fasting glycemic parameter and with any of elevated 1 h or 2 h blood glucose levels and in cases of three elevated glycemic parameters (fasting, 1 h, and 2 h blood glucose at the initial results of OGTT) reduced the success rate of glycemic control to 56.5%, 49.2%, respectively, compared to the group with solely a high fasting index of blood glucose (69.6%). The pregnant women who participated in high-intensity sports activities related to a two-fold increase in success rate compared with the group engaging in light and moderate-intensity physical activity. Conclusions: The success rate of glycemic control in GDM women was highest in the group with solitary fasting hyperglycemia and lower in the contributory groups with two and three high parameters. The application of diet therapy plus physical activities among GDM pregnant women is potentially necessary to improve the effectiveness of treatment, minimize adverse pregnancy outcomes, and reduce substantially the hospitalization rate.

Male Gender Aggravates Insomnia-Associated Disturbances in IPGTT, Insulin Level and Insulin Resistance, with Less Improvement on Retrieval of Normal Sleep Compared to Aged Females

Abstract Background and Aim Prevalence of type 2 diabetes is growing worldwide in the last decades. Recent studies showed that sleeping hours had decreased in the last decades amongst both young and aged population. This study was conducted to investigate the effects of chronic insomnia and its relief on the intraperitoneal glucose tolerance test (IPGTT),insulin level and insulin resistance in aged male and female rats with insight in the underlying mechanisms. Methods The study was carried out on 66 local strain aged rats of both sexes. Range of male and female rat weights was 350-400 and 250-350 gm, respectively. Range of ages of male and female rats were 23-25 and 24-26 months, respectively. Rats were allocated into two study groups, males (n°= 32) and females (n°= 34). The male group was further subdivided into the following 4 subgroups: Male one month control group (MC1, n°=7); Male sleep -deprived group for one month (MSD, n°=10); Male two -month control group (MC2, n°=7); Male sleep deprived group for one month followed by one month reversion to regular sleep (MSDR, n°=8). The female group was further subdivided into 4 subgroups; Female one month control group (FC1, n°=9); Female sleep deprived group for one month (FSD, n°=7); Female two -month control group (FC2, n°=9); Female sleep deprived group for one month followed by one month reversion to regular sleep (FSDR, n°=9). The experimental method of sleep restriction was the modified multiple platform method (MMPM) which deprives the animal from rapid eye movement (REM) sleep, while the non-REM sleep unaffected without the need for monitoring the EEG. The study duration was 2 months, Rats were assessed for IPGTT, fasting serum insulin (FSI) and homeostasis model assessment of insulin resistance (HOMA-IR) as well as serum levels of corticosterone (Cs) and melatonin (Mt). Results After one month of insomnia, male rats (MSD) became prediabetic with fasting hyperglycemia (FBG 107 mg/dl) and significantly elevated blood glucose values in the IPGTT and area under the curve (AUC), FSI and HOMA-IR as well as Cs and significant decrease of Mt. compared to their matched controls (MC1). Reversion to normal sleep normalized the FBG of MSDR group and blood glucose levels at 30, 90, 120 minutes and area under the curve (AUC), with significant decrease of FSI and HOMA-IR, although not yet normalized compared to MC2 rat group. Similarly, Cs and Mt. levels showed partial improvement compared to MSD group, but not fully normalized compared to MC2 group. On the other hand, FSD rat group had no significant change in their FBG compared to FC1 group but had significant increase in their blood glucose levels at 60, 90, 120 min., AUC of IPGTT as well as FSI and HOMA-IR, Cs and significant decrease of Mt. compared to FC1 group. Reversion to normal sleep normalized IPGTT value of FSDR rats, although FSI and HOMA-IR, remained significantly high compared to FC2 rat group. Similarly, Cs and Mt. levels showed partial improvement compared to FSD group, but not fully normalized compared to FC2 group. When MSD and FSD rat groups were compared, MSD rats showed significantly high FBG and IPGTT values compared to FSD rat group with no significant difference in insulin and insulin resistance values, with significantly higher values of Cs in MSD compared to FSD rat groups, with no significant difference in Mt. levels. Reversion to normal sleep in MSDR and FSDR rats caused more improvement in all values of IPGTT as well as AUC, insulin level and insulin resistance in females (FSDR) compared to males (MSDR) with significantly higher values of Mt in FSDR compared to MSDR rat groups, although Cs. Conclusion chronic insomnia has deleterious effects on glucose utilization and insulin resistance in aged male compared to aged female rats with lack of full recovery with reversion to normal sleep in IPGTT parameters, insulin levels and insulin resistance in aged males compared to aged females. These changes can be attributed to the hormonal changes of Cs. and Mt. who showed significant changes in both insomniac male and female rats with better improvement in Mt. in recovered female rat group compared male recovered group. Assessment of sleep history in prediabetic aged males should be recommended as well as assessment of IPGTT and insulin resistance in insomniac aged patients particularly males.

Thyroid Dysfunction In Metabolic Syndrome In Patients: An Observational Study

Objective: To assess the clinico-demographic profile thyroid dysfunction (TD in patients with metabolic syndrome (MetS). Methods: Research was done at the Medical Department. We included 200 MetS patients in this investigation. Demographics, anthropometric measurements, significant medical (including FPG, serum TG, and HDL-C values from patients' medical records) and surgical history, family history, lifestyle parameters, history of obesogenic medicine use, vital signs, and physical examination details were collected in case report forms at the screening visit. Results: We included 200 MetS patients in this investigation. The baseline demographics of these patients are presented. Of the recruited patients, 60 (30%) had TD, with women being more likely than males. Overt hypothyroidism was detected in 36 of 200 MetS patients and hyperthyroidism in 4. High waist circumference, lowered HDL-C, elevated HOMA-IR, systolic and diastolic blood pressure, fasting hyperglycemia, and TG were seen in TD patients in this research. More women than men had waist circumferences exceeding 80 cm. Conclusion: Metabolic syndrome complications include thyroid problems. High frequency of TD in MetS patients suggests a thyroid-MetS interaction. This investigation will help link TD and MetS in Indian patients. Early identification of TD in MetS may help change disease course with lifestyle modifications.

Dissociation between liver fat content and fasting metabolic markers of selective hepatic insulin resistance in humans.

Fasting hyperglycemia and hypertriglyceridemia are characteristic of insulin resistance (IR) and rodent work has suggested this may be due to selective hepatic IR, defined by increased hepatic gluconeogenesis and de novo lipogenesis (DNL), but this has not been shown in humans. Cross-sectional study in men and women across a range of adiposity. Medication-free participants (n = 177) were classified as normoinsulinemic (NI) or hyperinsulinemic (HI) and as having low (LF) or high (HF) liver fat content measured by magnetic resonance spectroscopy. Fractional gluconeogenesis (frGNG) and hepatic DNL were measured using stable isotope tracer methodology following an overnight fast. Although HI and HF groups had higher fasting plasma glucose and triglyceride concentrations when compared to NI and LF groups respectively, there was no difference in frGNG. However, HF participants tended to have lower frGNG than LF participants. HI participants had higher DNL compared to NI participants but there was no difference observed between liver fat groups. Taken together, we found no metabolic signature of selective hepatic IR in fasting humans. DNL may contribute to hypertriglyceridemia in individuals with HI but not those with HF. Glycogenolysis and systemic glucose clearance may have a larger contribution to fasting hyperglycemia than gluconeogenesis, especially in those with HF, and these pathways should be considered for therapeutic targeting.

New Application of an Old Drug: Anti-Diabetic Properties of Phloroglucinol.

Phloroglucinol (PHG), an analgesic and spasmolytic drug, shows promise in preventing high-fat-diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and insulin resistance. In Wistar rats, 10 weeks of PHG treatment did not prevent HFD-induced weight gain but significantly mitigated fasting hyperglycemia, impaired insulin responses, and liver steatosis. This protective effect was not linked to hepatic lipogenesis or AMP-activated protein kinase (AMPK) activation. Instead, PHG improved mitochondrial function by reducing oxidative stress, enhancing ATP production, and increasing anti-oxidant enzyme activity. PHG also relaxed gastric smooth muscles via potassium channel activation and nitric oxide (NO) signaling, potentially delaying gastric emptying. A pilot intervention in pre-diabetic men confirmed PHG's efficacy in improving postprandial glycemic control and altering lipid metabolism. These findings suggest PHG as a potential therapeutic for NAFLD and insulin resistance, acting through mechanisms involving mitochondrial protection, anti-oxidant activity, and gastric motility modulation. Further clinical evaluation is warranted to explore PHG's full therapeutic potential.

Prevalence of metabolic syndrome and its components among the teaching faculty of Allama Iqbal Medical College and Jinnah Hospital Lahore

BACKGROUND &amp; OBJECTIVES: Metabolic syndrome and its components are established risk factors for type-2 diabetes mellitus and cardiovascular diseases. The Objectives of the current study were to assess the mean values of cardiometabolic risk factors and anthropometric parameters among the teaching faculty of Allama Iqbal Medical College and Jinnah Hospital Lahore (AIMC/JHL). To investigate the prevalence of metabolic syndrome and its components. METHODOLOGY: This cross-sectional study was conducted from December 2022 to July 2023 at AIMC/JHL. Faculty members (n=115), aged 30-60, were recruited by convenience sampling from basic and clinical departments. Metabolic syndrome was defined by ATP-III criteria. Means of quantitative variables were compared by student t-test. Chi-square was used to determine associations between nominal variables. RESULTS: Mean values of arterial blood pressure were significantly higher in males than females. Fasting hyperglycemia was present in 38.3% of participants. Decreased HDL, hypertriglyceridemia, hypertension, and central obesity were found in 65.2%, 24.3%, 34.8%, and 74.8% of participants, respectively. The prevalence of low HDL and central obesity was significantly higher among females; however, hypertriglyceridemia and hypertension were more prevalent among males. A significant correlation (r=0.241) was observed (p=0.009) between age and waist circumference. Pre-metabolic syndrome and metabolic syndrome were present in 38.3% and 43.5% of participants, respectively. CONCLUSION: An alarmingly high prevalence of metabolic syndrome and its components was observed among healthcare professionals who endeavor to treat similar diseases. This irony underscores the need for increased awareness and routine screening of metabolic syndrome among healthcare professionals

The Other Side of the Perfect Cup: Coffee-Derived Non-Polyphenols and Their Roles in Mitigating Factors Affecting the Pathogenesis of Type 2 Diabetes.

The global prevalence of type 2 diabetes (T2D) is 10.5% among adults in the age range of 20-79 years. The primary marker of T2D is persistent fasting hyperglycemia, resulting from insulin resistance and β-cell dysfunction. Multiple factors can promote the development of T2D, including obesity, inflammation, and oxidative stress. In contrast, dietary choices have been shown to prevent the onset of T2D. Oatmeal, lean proteins, fruits, and non-starchy vegetables have all been reported to decrease the likelihood of T2D onset. One of the most widely consumed beverages in the world, coffee, has also demonstrated an impressive ability to reduce T2D risk. Coffee contains a diverse array of bioactive molecules. The antidiabetic effects of coffee-derived polyphenols have been thoroughly described and recently reviewed; however, several non-polyphenolic molecules are less prominent but still elicit potent physiological actions. This review summarizes the effects of select coffee-derived non-polyphenols on various aspects of T2D pathogenesis.

Safety and effectiveness of tofogliflozin in Japanese people with type 2 diabetes: A multicenter prospective observational study in routine clinical practice.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors effectively and safely reduce fasting and postprandial hyperglycemia while promoting weight loss. However, their unique mechanism of action contributes to concerns regarding their safety. We therefore carried out a large-scale, non-commercial, investigator-initiated study on the safety and effectiveness of the SGLT2 inhibitor tofogliflozin. This multicenter, open-label, uncontrolled, prospective observational study was carried out at hospitals and clinics across Japan in participants aged ≥20 years who were SGLT2 inhibitor-naïve and had an established diagnosis of type 2 diabetes. The primary endpoint was adverse drug reactions (ADRs) of special interest. Secondary endpoints included all other ADRs and adverse events, glycated hemoglobin (HbA1c), and weight loss. The study, carried out from June 2014 through February 2020, enrolled 11,480 participants from 1,103 medical institutions; 6,967 participants completed the 104-week follow up. The most common ADRs of special interest were urinary and genital tract infections (1.53%), followed by volume depletion (1.25%). Hypoglycemia occurred in 27 participants (0.24%), adverse events in 1,054 (9.18%) and ADRs in 645 (5.62%). HbA1c decreased by 0.85% (95% confidence interval 0.82%-0.88%) and bodyweight decreased by 3.05 kg (95% confidence interval 2.94-3.17 kg). The HbA1c target was achieved by 51.70% of participants for target HbA1c <7.0%, 85.3% for <8.0% and 5.4% for <6.0% at week 104. Tofogliflozin was associated with only mild or moderate ADRs characteristic of SGLT2 inhibitors, with no unpredictable, new, serious, or high-incidence adverse events or ADRs. This independent study confirmed the safety and effectiveness of tofogliflozin in adult type 2 diabetes patients.

Lymphocyte Levels and Morbidity and Mortality in Cardiovascular Surgery With Cardiopulmonary Bypass.

A year ago, in a sample of 113 patients, our research group found that a high number of lymphocytes in the immediate postoperative period was correlated to a poor prognosis in cardiovascular surgeries. This study is an expansion of the initial study in order to confirm this finding. We analyzed the data of 338 consecutive patients submitted to cardiovascular surgeries with cardiopulmonary bypass performed at Hospital Universitário Ciências Médicas (Belo Horizonte/Brazil) from 2015 to 2017. We analyzed 39 variables with the outcomes death, hospital stay, and intensive care unit stay. The value of lymphocytes in the immediate postoperative period > 2175.0/mm³ was an indicator of poor prognosis in this sample (P<0.001). The variables female sex, age, high level of European System for Cardiac Operative Risk Evaluation II, increased stay in the intensive care unit and in the ward, elevation of creatinine in the preoperative period and at intensive care unit discharge, elevation of the percentage of immediate postoperative period segmented neutrophils, high immediate postoperative period neutrophil/lymphocyte ratio, fasting hyperglycemia, preoperative critical condition, reintubation, mild or transient acute renal failure, surgical infection, cardiopulmonary bypass, and aortic cross-clamping and mechanical ventilation durations also had an impact on the mortality outcome. The value of lymphocytes in the immediate postoperative period > 2175.0/mm3 was an indicator of poor prognosis in cardiovascular surgery with cardiopulmonary bypass.

Normotensive metabolic syndrome in Transient Receptor Potential Canonical Channel type 1 Trpc1-/- mice.

Metabolic syndrome has become a global epidemic, affecting all developed countries and communities with growing economies. Worldwide, increasing efforts have been directed at curbing this growing problem. Mice deleted of the gene encoding Type 1 Transient Receptor Potential Canonical Channel (Trpc1) were found to weigh heavier than controls. They had fasting hyperglycemia and impaired glucose tolerance compared with wild-type controls. Beyond 1 year of age, plasma triglyceride level in Trpc1-/- mice was elevated. Plasma cholesterol levels tended to be higher than in controls. The livers of Trpc1-/- mice were heavier, richer in triglyceride, and more echogenic than those of controls on ultrasound evaluation. Hematocrit was lower in Trpc1-/- mice of both genders beginning at the second to third months of age in the absence of bleeding or hemolysis. Measured by the indirect tail-cuff method or by the direct arterial cannulation, blood pressures in null mice were lower than controls. We conclude that TRPC1 gene regulates body metabolism and that except for hypertension, phenotypes of mice after deletion of the Trpc1 gene resemble mice with metabolic syndrome, suggesting that this could be a good experimental model for future investigation of the pathogenesis and management of this disorder.

Hyperleptinemia as a Marker of Various Phenotypes of Obesity and Overweight in Women with Rheumatoid Arthritis and Systemic Lupus Erythematosus.

The objective of the study was to identify different phenotypes of overweight in women with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) based on body mass index (BMI) and serum leptin levels, as well as to determine the frequencies of various metabolic disorders, hypertension, and cardiovascular complications (CVCs) in individual phenotypes. The study included 50women with RA and 46 with SLE aged 18 to 65 years without a history of diabetes and fasting hyperglycemia. In all patients, the concentration of leptin was determined by ELISA, the concentration of insulin was determined by electrochemiluminescence analysis, and the HOMA-IR index was calculated. Hyperleptinemia was diagnosed at leptin concentrations > 11.1 ng/mL; insulin resistance (IR), at HOMA-IR values ≥ 2.77. Three main phenotypes ofoverweight were distinguished: "classic" (BMI ≥ 25 kg/m2 + hyperleptinemia), "healthy" (BMI ≥ 25 kg/m2, without hyperleptinemia), "hidden" or "latent" (BMI < 25 kg/m2 + hyperleptinemia), as well as "normal weight" (BMI < 25 kg/m2, without hyperleptinemia). Patients with RA and SLE were similar in age (p = 0.4), disease duration (p = 0.2) andBMI (p = 0.5). Hyperleptinemia was found in 46% of women with RA and in 74% of women with SLE (p = 0.005), and IR was found in 10 and 22% of patients, respectively (p = 0.2). The "classic" phenotype ofoverweight was diagnosed in 30%, "healthy" in 8%, and "hidden" in 16% of cases with RA and in 44%, 0%, and 30% of cases with SLE, respectively. IR was found in 3% and hypertension in 6% of patients with "normal weight." With the "classic" phenotype, IR (29%) andhypertension (66%) were more common than with "normal weight" (p < 0.01 in all cases); with the "hidden" phenotype, significant differences were obtained only in hypertension frequency (45%; p = 0.0012), but not IR (18%). Three out of four women with a history of cardiovascular complications suffered from "classic" overweight, and one patient had a "normal weight." In women with SLE up to 65 years of age, the frequency of hyperleptinemia, but not IR, is higher than in patients with RA. In both diseases, the "classic" overweight phenotype is most common. In RA, a "hidden" phenotype was detected less often than in SLE, at the same time, a "healthy" phenotype is not characteristic of SLE. The frequency of metabolic disorders and hypertension is low with the "normal weight" and "healthy" phenotype, high with the "classic" phenotype, and intermediate with the "hidden" phenotype.