Modulation of gene expression by traditional Asian antidiabetic nutraceuticals: A review of potential effects.

Dear Editor-in-Chief I read with interest the published article in the esteemed journal by Heshmat et al., entitled “effect of vitamin D on insulin resistance and anthropometric parameters in type 2 diabetes; a randomized double-blind clinical trial” [1]. The study has focused to investigate the effect of injection of vitamin D on insulin resistance and anthropometric parameters in type 2 diabetes mellitus (T2DM) [1]. Heshmat et al. studied 42 diabetic patients with similar baseline characteristics in two groups; intervention group with single intramuscular injection of 300,000 IU of vitamin D3 and the placebo group. They found that, 3 months after vitamin D injection, HbA1c, anthropometric factors and homeostasis model assessment (HOMA) index in intervention group stayed constant, however, serum 25- OHD3 was significantly increased. They suggested that, single injection of vitamin D was not accompanied by better diabetes control and improvement of insulin resistance [1]. Similar to this study, we conducted a double blind randomized clinical trial on 60 T2DM patients who were divided into 2 groups with 30 patients in each [2]. Group 1 were treated with oral Vitamin D, and group 2 were treated with placebo drug. After 3 months of treatment intervention, no significant difference of serum HbA1c and lipids between two groups was found. We concluded that, weekly vitamin D supplementation for 12 weeks had not significant decremented effect on HbA1c and lipid profiles [2]. Studies concerning the beneficial effects of vitamin D supplementation on improvement of diabetes or improvement of insulin sensitivity are limited and revealed different results. To find, whether receiving vitamin D3 (4000 IU/d) is associated with improved markers of insulin sensitivity and resistance, and also reduced inflammation in obese adolescents, Belenchia et al. studied participants who have supplemented with vitamin D3 for 6 months. They found a significant increase in serum 25-hydroxyvitamin D concentrations after this period. However, there were no significant differences in body mass index, serum inflammatory markers or plasma glucose concentrations in comparison to control group. Moreover, inflammatory markers remained unchanged [3]. Meanwhile, in the study conducted by Lim et al., on 1080 non-diabetic Korean subjects, it was found that 25(OH)D baseline is associated with the incidence of T2DM in high-risk subjects for up to 5 years of follow-up, independently of obesity, baseline insulin resistance, and β cell function [4]. Furthermore, to test the association of low plasma 25-hydroxyvitamin D with increased risk of T2DM in the general population, Afzal et al. measured 25-hydroxyvitamin D level in 9841 participants from the general population, of whom 810 developed type 2 diabetes during 29 years of follow-up. They found the association of low plasma 25-hydroxyvitamin D with increased risk of T2DM [5]. Prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide [6-11] and based on increasing evidence from animal and human studies, vitamin D deficiency is now regarded as a potential T2DM risk factor [12-18]. Hence, the present data is not convincing and further studies with large sample sizes are needed to show the definite effect of vitamin D supplementation on control of diabetes and its risk.

To clarify the expression of N6-methyladenosine (m6 A) modulators involved in the pathogenesis of type 2 diabetes mellitus (T2DM). We further explored the association of serum insulin-like growth factor 2 mRNA-binding proteins 3 (IGF2BP3) levels and odds of T2DM in a high-risk population. The gene expression data set GSE25724 was obtained from the Gene Expression Omnibus, and a cluster heatmap was generated by using the R package ComplexHeatmap. Differential expression analysis for 13 m6 A RNA methylation regulators between nondiabetic controls and T2DM subjects was performed using an unpaired t test. A cross-sectional design, including 393 subjects (131 patients with newly diagnosed T2DM, 131 age- and sex-matched subjects with prediabetes, and 131 healthy controls), was carried out. The associations between serum IGF2BP3 concentrations and T2DM were modeled by restricted cubic spline and logistic regression models. Two upregulated (IGF2BP2 and IGF2BP3) and 5 downregulated (methyltransferase-like 3 [METTL3], alkylation repair homolog protein 1 [ALKBH1], YTH domain family 2 [YTHDF2], YTHDF3, and heterogeneous nuclear ribonucleoprotein [HNRNPC]) m6 A-related genes were found in islet samples of T2DM patients. A U-shaped association existed between serum IGF2BP3 levels and odds of T2DM according to cubic natural spline analysis models, after adjustment for body mass index, waist circumference, diastolic blood pressure, total cholesterol, and triglyeride. Multivariate logistic regression showed that progressively higher odds of T2DM were observed when serum IGF2BP3 levels were below 0.62 ng/mL (odds ratio 3.03 [95% confidence interval 1.23-7.47]) in model 4. Seven significantly altered m6 A RNA methylation genes were identified in T2DM. There was a U-shaped association between serum IGF2BP3 levels and odds of T2DM in the general Chinese adult population. This study provides important evidence for further examination of the role of m6 A RNA methylation, especially serum IGF2BP3 in T2DM risk assessment.

Selective Insulin and Leptin Resistance in Metabolic Disorders

The Effect of Vitamin D Supplementation on Glycemic Control and Body Mass Index in the Obese, Vitamin D Deficient Adult with Type 2 Diabetes Mellitus: A Systematic Review Protocol

Arlen L. Rosenblooma, Janet H. Silversteinb, Shin Amemiyac, Phil Zeitlerd and Georgeanna J Klingensmithe abDivision of Endocrinology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; cDivision of Endocrinology, Department of Pediatrics, Saitama Medical University, Saitama, Japan; dDivision of Endocrinology, Department of Pediatrics, The Children’s Hospital, University of Colorado Denver, Aurora, CO, USA; eDepartment of Pediatrics, The Children’s Hospital and Barbara Davis Center, University of Colorado Denver, Aurora, CO, USA. Corresponding author: Professor Emeritus Arlen L Rosenbloom Division of Endocrinology Department of Pediatrics, University of Florida College of Medicine, 1701 SW 16th Avenue Gainesville, FL 32608 USA. e-mail: rosenal@peds.ufl.edu

Comment on: Hormone changes and diabetes resolution following biliopancreatic diversion and laparoscopic sleeve gastrectomy. A comparative prospective study

Short-term intensive insulin therapy could be the preferred option for new onset Type 2 diabetes mellitus patients with HbA1c > 9.

Background Globally, 422 million adults have type 2 diabetes mellitus (T2DM), causing 1.5 million deaths per year. Kuwait has one of the highest T2DM prevalence in the world and determining the proportion of patients and relatives who have pre-diabetes (PDM), insulin resistance (IR) and T2DM is crucial to inform preventive activities and curative services. Study objectives: The study describes the prevalence and risk factors of PDM, IR and T2DM, in adult patients attending a primary health care facility in Kuwait and the prevalence and risk factors of the same conditions among the patients’ first-degree relatives. The study also describes the degree of glycaemic control achieved by patients with T2DM and risk factors for poor glycaemic control. Finally, we assessed the agreement of a point of care (POC) device to measure glycated haemoglobin (HbA1c) to monitor T2DM control. Methods We conducted cross-sectional surveys of patients and first-degree relatives attending Nuzha health care facility in Kuwait and case-control studies of participants attending Nuzha’s diabetic clinic. Diabetic participants were consecutively tested by the Quo-test (POC) device to compare its agreement with a reference test. Results The prevalence of T2DM, IR and PDM among patients attending the clinics were 29.6% (95% CI: 25.1%-34.1%), 34.6% (95% CI: 29.1%-40.2%) and 26.0% (95% CI: 21.6%-30.4%), respectively. The proportion of patients with T2DM increased with age (AOR=5.4), with the highest prevalence occurring at 60-69 years of age. T2DM was associated with hypertension (AOR=1.95) and being a widow (AOR=6.11). IR was associated with low HDL (AOR=1.96), overweight (OR=8.25), obesity (OR=18.33) and increased waist circumference (OR= 5.5). Sugar-sweetened beverages were associated with IR. The prevalence of T2DM, IR and PDM among first-degree relatives of T2DM patients were 29.1% (95%CI: 23.7%-34.5%), 32.8% (95%CI: 26.2%-39.4%), 20.4% (95%CI: 15.6%-25.2%). The risk factors for T2DM were similar among patients and first-degree relatives, but IR was associated with manual labour occupations (AOR=3.6). Only 30% of T2DM patients achieved good glycaemic. Poor control was associated with high triglycerides (AOR=2.2), smoking (AOR=4.1) and the number of years since diagnosis (AOR=4). The Quo-Test had comparable performance to the reference test, with a Coefficient of Variation of 2.1% (r2 = 935, Kappa 90% and 87% at HbA1c cut-offs of 7.0 and 9.0% respectively). The POC and the reference tests performed poorly in patients with haemoglobinopathies. Conclusion This study demonstrates that a high proportion of patients and first-degree relatives attending one of the main primary health care centres in Kuwait have T2DM. Many patients and relatives were unaware of their condition. There was also a very high prevalence of IR and PDM suggesting the burden of T2DM will increase further in the future. Major efforts are needed to upscale detection, and preventive programmes for IR, PDM and T2DM and the quality of T2DM management needs to improve. The POC device tested could provide timely information for the management of T2DM.

Role of Obesity and Lipotoxicity in the Development of Nonalcoholic Steatohepatitis: Pathophysiology and Clinical Implications

Introduction: Diabetes mellitus (DM) resulting from chronic pancreatitis(CP) and pancreatic ductal adenocarcinoma (PDAC) is classified by the American Diabetes Association as a form of pancreatogenic DM, which has also been referred to as type 3c DM.However, there are no data on the comparison of insulin resistance(IR) and β-cell function(BCF) among patients with Type 3c versus Type 2 DM(T2DM). Also,new-onset DM (< 2 yrs from diagnosis) resulting from PDAC(PDAC-NOD) may have a distinct pathophysiology from CP-DM.The Homeostatic Model Assessment (HOMA) estimates IR and BCF using fasting serum glucose and insulin values. Using HOMA,we aimed to distinguish:a) Type 3c DM from T2DM,b) Among CP-DM,PDAC-DM and T2DM, and c)between PDAC-NOD and new-onset T2DM(Type2NOD). Methods: A total of 265 patients with PDAC,112 with CP and 118 controls seen at our center between 1996 and 2011 had fasting levels of glucose,insulin and c-peptide measured as part of other studies. Patients with unknown glycemic status, impaired fasting glucose,no DM and those on insulin were excluded. Overall, 90 patients with PDAC-DM, 24 with CP-DM and 46 with T2DM were included in the final analysis. IR and BCF were measured using standard formulae for HOMA. Results: Mean age of CP patients(53.35 years) was lower than that of PDAC(66.22 years) and T2DM (66.10 years) respectively (P<0.0001*).Patients with T2DM had higher BMI(29.24 kg/m2) vs CP(24.52 kg/m2) and PDAC (26.28 kg/m2) respectively; P<0.0001*. Among patients with Type3c and T2DM, while there was no difference in age- and BMI-adjusted mean HOMA-IR(4.00 vs 6.21 respectively, P=0.5051), HOMA-BCF was lower in patients with Type3cDM(45.09% vs 73.90% respectively, P=0.0356*).No differences were observed in age and BMI- adjusted HOMA-IR and HOMA-BCF between PDAC-DM,CP-DM and T2DM(Table 1).Notably,patients with PDAC-NOD(n=41) had lower age- and BMI-adjusted HOMA-BCF as compared to those with Type 2 NOD(n=39)(43.89% vs 74.61%; P=0.0163*),with similar HOMA-IR (3.86 vs 6.34; P=0.1388).Table: Table. Comparison of Mean Glucose, C-peptide, Insulin, HOMA-IR and HOMA-BCF values between patients with PDAC-DM, CP-DM and Type 2 DMConclusion: IR and BCF are similar in CP-DM,PDAC-DM and T2DM.However,lower HOMA-BCF in patients with Type 3c DM and PDAC-NOD might suggest a significant role of β-cell dysfunction in their pathogenesis, as opposed to T2DM which is driven primarily by insulin resistance, with β-cell dysfunction at later stages.Identification of biomarkers responsible for these differences might allow for earlier detection of PDAC by distinguishing PDAC-NOD from Type 2NOD and other forms of Type 3c DM.

Diabetes mellitus, defined as a fasting plasma glucose of ≥126 mg/dL or a glycosylated hemoglobin A1c level (HbA1c) of ≥6.5%, afflicts ≈12.9% of adults in the United States and nearly 285 million adults worldwide.1,2 Diabetes mellitus is a major risk factor for the development of cardiovascular disease, independently conferring a 2-fold excess risk of coronary heart disease and stroke.3 Macrovascular events in diabetes mellitus remain the leading cause of mortality, and the burden of cardiovascular disease attributable to diabetes mellitus has increased over the past decade.4 An increase in the prevalence of obesity has contributed to the rise in diabetes mellitus. Additionally, obesity independently increases the risk of cardiovascular disease in patients with diabetes mellitus.5 Although strict glycemic control unequivocally reduces the microvascular complications of diabetes mellitus, the macrovascular benefits of intensive therapy have been difficult to establish, with conflicting results from large clinical trials.6–9 Multifactorial strategies are recommended to reduce cardiovascular risk in diabetes mellitus through enhanced glycemic control, blood pressure reduction, lipid management, weight loss, and physical activity.10 Unfortunately, despite aggressive interventions for hyperglycemia, <50% of patients achieve standard HbA1c targets with conventional therapy.11 Polypharmacy is required to achieve glycemic control in the majority of patients within 3 years of diagnosis.12 Although combinations of drug classes can synergistically target multiple pathophysiological defects, novel therapies are required to manage diabetes mellitus and mitigate cardiovascular risks. Dipeptidyl-peptidase IV (DPP-IV) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist incretin therapies were developed to complement conventional treatment options for diabetes mellitus. Despite promising initial reports of cardioprotective effects, DPP-IV inhibitors have failed to demonstrate improved cardiovascular outcomes in large clinical trials.13–15 Randomized studies to evaluate cardiovascular outcomes associated with GLP-1 receptor agonists are currently underway. This review presents …

Diabetes, which is one of the metabolic diseases, is a complex and chronic illness to keep maintaining medical and diet care against abnormal glycemic symptoms such as high blood glucose level and insulin resistance. This diabetes, which is inextricably bound up with obesity, can cause decrease of life expectancy, increase of healthcare cost, and weakening of quality of life by risk of acute or long-term complication. In particular, type 2 diabetes mellitus (T2DM) rate of all diabetes reported about over 90%. Also, prevailing population and increasing healthcare budget of diabetes are conservatively estimated to be as much as 366 million people and be as much as 396 billion international dollars in 2030. Even if many clinical doctors and researchers have developed medical care and found therapeutic agent for T2DM, it is difficult to avoid side effects such as hypoglycemia, hyperinsulinemia, diarrhea, and heart failure. Here, this special issue suggested how we accessed alternative treatment or safe therapy for T2DM patients by introducing several research papers using herbal medicines. Traditional medicine has a history of more than 3000 years in clinical trials including China and Korea. The major use of herbal medicines is for health promotion about diverse disease including T2DM and therapy for chronic, as opposed to life-threatening, conditions. It is the most important reason for which herbal medicines are widely perceived as natural and safe without side effects. The historical factors that the herbal medicine has been prescribed in T2DM patients and evaluated safety against side effects for a long time let our group experimentally test whether hyperglycemia effects by taking herbal medicines are related to glucagon-like peptide-1 (GLP-1) stimulation via taste receptor signaling on enteroendocrine L cells or not. Firstly, our group tested whether prescribed extracts of herbal medicines, Citrus aurantium, Anemarrhena asphodeloides, and Bupleurum falcatum, were responsible for GLP-1 secretion and taste receptor signaling or not in enteroendocrine L cells using GLP-1 assay and microarray. GLP-1 is one of the incretin hormones and is secreted from intestinal enteroendocrine L cells, which existed mainly in the proximal ileum and colon, and GLP-1 is induced through nutrient sensing taste receptor that responds to sweet, bitter, umami, and fatty acids. These herbal medicines stimulated GLP-1 secretion and upregulated the mRNA of taste receptor genes in L cells. Additionally, we tested whether GLP-1 secretion practically affected hyperglycemia effects on diabetic mice model or not. Diabetic mice exhibited more ameliorated hyperglycemia than control group. However, this GLP-1 secretion by herbal medicines lacks biochemical evidence. It is unknown which components on herbal medicines stimulate GLP-1 and which specific taste receptor signaling among sweet, bitter, umami, and fatty acids was activated by herbal medicines. To overcome these limitations, the study supplemented systemic inhibition study and component analysis on herbal medicine, Gentiana scabra extracts. In aspect of systemic inhibition study, pharmacologic inhibitors associated with taste receptor signaling on GLP-1 and calcium imaging study and knockout mice of α-gustducin applied to mechanism definition of taste receptor signaling of Gentiana scabra extracts on in vivo study of plasma GLP-1 and insulin measurements. Furthermore, to confirm components in Gentiana scabra extracts and to evaluate active compound of GLP-1 secretion, the components of Gentiana scabra extractswere analyzed by HPLC-MS and active compound of GLP-1 secretion in L cells was selected by GLP-1 assay. This issue tried to explain safe application for T2DM patients by regulating hyperglycemia via taste receptor signaling. We provide previous study of therapeutic application via taste receptor signaling for T2DM patients and challenging limitation such as structural assessments. To accurately define specific taste receptor of binding difference according to chemical characters or structure, the components derived from herbal medicines of structural assessment binding taste receptor should be reinforced to cooperate with structural biology areas. Also, for GLP-1 secretagogue of discovery of evidence-based complementary and alternative medicine via taste receptor signaling, development of agonistic component with taste receptor from each herbal medicine, structural assessment of specific taste receptor on discovery agonistic component, and its GLP-1 secretagogue of clinical evaluation need to be supported by future researches. Hyeung-Jin Jang Jae-Young Um Hanseok Ko Won-Seok Chung

ObjectivesTo compare the level of insulin resistance and β-cell function between lean and overweight/obese Filipino patients with newly diagnosed type 2 diabetes mellitus (T2DM).MethodologyThis was a cross-sectional analytical study including newly diagnosed T2DM Filipino patients from St. Luke’s Medical Center - Quezon City. The patients were classified as either lean or overweight/obese. Age, sex, smoking history, anthropometric measures and blood pressure were obtained. Insulin resistance and β-cell function were determined using the homeostasis model assessment (HOMA). The original model (HOMA1) and the updated model (HOMA2) were used.ResultsA total of 80 subjects were included. There were 40 subjects in each group. The overweight/obese subjects had significantly higher mean insulin resistance (HOMA1-IR 9.8±11.7, HOMA2-IR 3.0±2.0) compared to the lean group (HOMA1-IR 2.9±1.5, HOMA2-IR 1.3±0.5). This was consistent in both HOMA1 and HOMA2 (p-values=0.001 and <0.001, respectively). The mean β-cell function of the overweight/obese patients was significantly higher than the lean subjects when using HOMA1 (lean=57.8±35.5, overweight/obese=93.6±66.4, p-value=0.003), but not in HOMA2 (lean=57.6±30.5, overweight/obese=74.8±45.7, p-value=0.051). Overweight/obesity increased HOMA1-IR by 4.0 and HOMA1-B by 46.1 (p-values= 0.002 and <0.001, respectively). Through the use of HOMA2, overweight/obesity increased HOMA2-IR by 1.4 and HOMA2-B by 29.1 (p-values<0.001). Being overweight/obese was also associated with significantly higher odds for developing greater insulin resistance (HOMA1-IR adjOR = 5.6, 95%CI= 1.7-19.2, p-value=0.005; HOMA2-IR adjOR=10.9, 95%CI=3.4-34.9, p-value<0.001) and lower odds for a decreased β-cell function (HOMA1-B adjOR = 0.2, 95%CI = 0.05-0.9, p-value=0.033; HOMA2-B adjOR=0.2, 95%CI=0.04-0.9, p-value=0.043) compared to being lean.ConclusionNewly diagnosed overweight/obese T2DM had higher mean insulin resistance and β-cell function compared to lean T2DM. Overweight/obesity was also associated with higher odds of developing insulin resistance and lower odds for a decreased β-cell function compared to being lean. The overweight/obese T2DM group also had worse metabolic profile manifested by higher FPG, HbA1c, SGPT and blood pressures compared to the lean T2DM group.

Objective To study change of insulin resistance and beta-cell function of the patients in hyper-tension with normal glucose tolerance(NGT) to phthogonesis of type 2 diabetes mellitus(T2DM). Methods 84 pa-tients with hypertension were divided into NGT group,and groups of impaired glucose tolerance(IGT) with groups of T2DM. The blood pressure, height, weight, waist circumference, hip circumference, high-density lipoproteins (HDL-C)and total cholesterol(TC) ,fasting plasma glucose(FPG) and fasting plasma insulin(FINS) were measured to deter-mine the body mass index(BMI) ,waist/hip ratio(WHR) ,insulin secretion function[ including Homa β-cell function index(HBCI) and fasting β-cell function index(FBCI)] and insulin resistance level [ including Homa model insulin resistance index(IR) and insulin action index(IAI)] ,statistic comparison were measured between the groups of dif-ferent glucose tolerances. Results The BMI, WHR, diastolic blood pressure ( DBP), TC in IGT group and T2DM group were bigger or higher than those in NGT group ( P<0.05, P<0.01 ), the IAI, HOMA-IS and FBCI in T2DM group were lower than those in NGT group with these in NGT group were lower than those in NGT group( P<0.05 ,P<0.01 ). The HOMA-IR in IGT group and T2DM group were higher than those in NGT group with these in T2DM group were higher than those in NGT group. Conclusion T2DM group and IGT group had more insulin resistance level,sensitivity of insulin and islet β-cell function decrease than those in IGT group,the IGT group and T2DM group are analogous at the body weight is heavier, with waist/hips ratio, triglyceride level and DBP are higher than those in the NGT group in clinic. Key words: Insulin resistance; Islets of langerhuns; Hypertension; Impaired glucose tolerance

The association between Insulin resistance, a global health issue, and endocrine disruptors (EDCs), chemicals interfering with the endocrine system, has sparked concern in the scientific community. This article provides a comprehensive review of the existing literature regarding the intricate relationship between EDCs and insulin resistance. Phthalates, commonly found in consumer products, are well-established EDCs with documented effects on insulin-signaling pathways and metabolic processes. Epidemiological studies have connected phthalate exposure to an increased risk of type 2 diabetes mellitus (T2DM). Perfluoroalkyl substances (PFAS), persistent synthetic compounds, have shown inconsistent associations with T2DM in epidemiological research. However, studies suggest that PFAS may influence insulin resistance and overall metabolic health, with varying effects depending on specific PFAS molecules and study populations. Bisphenol A (BPA), found in plastics and resins, has emerged as a concern for glucose regulation and insulin resistance. Research has linked BPA exposure to T2DM, altered insulin release, obesity, and changes in the mass and function of insulin-secreting β-cells. Triclosan, an antibacterial agent in personal care products, exhibits gender-specific associations with T2DM risk. It may impact gut microbiota, thyroid hormones, obesity, and inflammation, raising concerns about its effects on metabolic health. Furthermore, environmental EDCs like polycyclic aromatic hydrocarbons, pesticides, and heavy metals have demonstrated associations with T2DM, insulin resistance, hypertension, and obesity. Occupational exposure to specific pesticides and heavy metals has been linked to metabolic abnormalities.