Obesity-related Type 2 Diabetes Mellitus Research Articles

Synthesis and Anti-Diabetic Activity of an 8-Purine Derivative as a Novel DPP-4 Inhibitor in Obese Diabetic Zücker Rats.

Type 2 diabetes mellitus (T2DM) is one of the world's principal metabolic diseases characterized by chronic hyperglycemia. The gut incretin hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), which has been proposed as a new treatment for T2DM, are extensively metabolized by Dipeptidyl peptidase 4 (DPP-4). Inhibitors of DPP-4 block the degradation of GLP-1 and GIP and may increase their natural circulating levels, favoring glycemic control in T2DM. A novel and potent selective inhibitor of DPP-4 with an 8-purine derived structure (1) has been developed and tested in vitro and in vivo in Zücker obese diabetic fatty (ZDF) rats, an experimental model of the metabolic syndrome and T2DM to assess the inhibitory activity using vildagliptin as reference standard. ZDF rats were subdivided into three groups (n = 7/group), control (C-ZDF), and those treated with compound 1 (Compound1-ZDF) and with vildagliptin (V-ZDF), both at 10 mg/kg/d rat body weight, in their drinking water for 12 weeks, and a group of lean littermates (ZL) was used. ZDF rats developed DM (fasting hyperglycemia, 425 ± 14.8 mg/dL; chronic hyperglycemia, HbA1c 8.5 ± 0.4%), compared to ZL rats. Compound 1 and vildagliptin reduced sustained HbAl1c (14% and 10.6%, P < 0.05, respectively) and fasting hyperglycemia values (24% and 19%, P < 0.05, respectively) compared to C-ZDF group (P < 0.001). Compound 1 and vildagliptin have shown a potent activity with an IC50 value of 4.92 and 3.21 µM, respectively. These data demonstrate that oral compound 1 administration improves diabetes in ZDF rats by the inhibitory effect on DPP-4, and the potential to be a novel, efficient and tolerable approach for treating diabetes of obesity-related T2DM, in ZDF rats.

Gut Microbiota Targeted Approach by Natural Products in Diabetes Management: An Overview.

This review delves into the complex interplay between obesity-induced gut microbiota dysbiosis and the progression of type 2 diabetes mellitus (T2DM), highlighting the potential of natural products in mitigating these effects. By integrating recent epidemiological data, we aim to provide a nuanced understanding of how obesity exacerbates T2DM through gut flora alterations. Advances in research have underscored the significance of bioactive ingredients in natural foods, capable of restoring gut microbiota balance, thus offering a promising approach to manage diabetes in the context of obesity. These findings build upon the traditional use of medicinal plants in diabetes treatment, suggesting a deeper exploration of their mechanisms of action. This comprehensive manuscript underscores the critical role of targeting gut microbiota dysbiosis in obesity-related T2DM management and by bridging traditional knowledge with current scientific evidence; we highlighted the need for continued research into natural products as a complementary strategy for comprehensive diabetes care.

Ube2L6 Promotes M1 Macrophage Polarization in High-Fat Diet-Fed Obese Mice via ISGylation of STAT1 to Trigger STAT1 Activation

Introduction: In obesity-related type 2 diabetes mellitus (T2DM), M1 macrophages aggravate chronic inflammation and insulin resistance. ISG15-conjugation enzyme E2L6 (Ube2L6) has been demonstrated as a promoter of obesity and insulin resistance. This study investigated the function and mechanism of Ube2L6 in M1 macrophage polarization in obesity. Methods: Obesity was induced in Ube2L6^AKO mice and age-matched Ube2L6^flox/flox control mice by high-fat diet (HFD). Stromal vascular cells were isolated from the epididymal white adipose tissue of mice. Polarization induction was performed in mouse bone marrow-derived macrophages (BMDMs) by exposure to IFN-γ, lipopolysaccharide, or IL-4. F4/80 expression was assessed by immunohistochemistry staining. Expressions of M1/M2 macrophage markers and target molecules were determined by flow cytometry, RT-qPCR, and Western blotting, respectively. Protein interaction was validated by co-immunoprecipitation (Co-IP) assay. The release of TNF-α and IL-10 was detected by ELISA. Results: The polarization of pro-inflammatory M1 macrophages together with an increase in macrophage infiltration was observed in HFD-fed mice, which could be restrained by Ube2L6 knockdown. Additionally, Ube2L6 deficiency triggered the repolarization of BMDMs from M1 to M2 phenotypes. Mechanistically, Ube2L6 promoted the expression and activation of signal transducer and activator of transcription 1 (STAT1) through interferon-stimulated gene 15 (ISG15)-mediated ISGlylation, resulting in M1 macrophage polarization. Conclusion: Ube2L6 exerts as an activator of STAT1 via post-translational modification of STAT1 by ISG15, thereby triggering M1 macrophage polarization in HFD-fed obese mice. Overall, targeting Ube2L6 may represent an effective therapeutic strategy for ameliorating obesity-related T2DM.

Mechanism of immune attack in the progression of obesity-related type 2 diabetes

Obesity and overweight are widespread issues in adults, children, and adolescents globally, and have caused a noticeable rise in obesity-related complications such as type 2 diabetes mellitus (T2DM). Chronic low-grade inflammation is an important promotor of the pathogenesis of obesity-related T2DM. This proinflammatory activation occurs in multiple organs and tissues. Immune cell-mediated systemic attack is considered to contribute strongly to impaired insulin secretion, insulin resistance, and other metabolic disorders. This review focused on highlighting recent advances and underlying mechanisms of immune cell infiltration and inflammatory responses in the gut, islet, and insulin-targeting organs (adipose tissue, liver, skeletal muscle) in obesity-related T2DM. There is current evidence that both the innate and adaptive immune systems contribute to the development of obesity and T2DM.

Comparison of Plasma Exosome Proteomes Between Obese and Non-Obese Patients with Type 2 Diabetes Mellitus.

Obesity is considered a promoter of type 2 diabetes mellitus (T2DM). However, the underlying mechanism remains unclear. This study aimed to identify plasma exosome differentially expressed proteins (DEPs) that are potentially involved in the development of obesity-related T2DM. Exosomes were isolated from the plasma of obese and non-obese T2DM patients (n = 10 for each group). A label-free quantitative mass spectrometry analysis was applied to identify plasma exosome DEPs in obese patients compared with non-obese patients, followed by bioinformatics analysis including GO annotation, KEGG analysis, subcellular localization prediction, transcription factor analysis, and protein-protein interaction (PPI) prediction. We identified 2 significantly upregulated proteins (C9 and PON1) and 5 significantly downregulated proteins (HPX, A1BG, CFHR1, ANG, and CALM) in obese patients compared with those in non-obese patients. KEGG analysis demonstrated that the insulin signaling pathway was one of the pathways that significantly correlated with the DEPs. The DEPs were primarily localized in the extracellular space (5 out of 7). HMG-box and NF-Y beta might regulate the transcription of the DEPs. C9, PON1, HPX, and CFHR1 were present in the PPI network. The plasma exosome DEPs are potentially responsible for the development of obesity-related T2DM possibly through the insulin signaling pathway and the interaction with other proteins. Our study may guide future research direction toward the pathogenesis of obesity-related T2DM.

Increased intestinal-fatty acid binding protein in obesity-associated type 2 diabetes mellitus.

Obesity is a traditional risk factor for type 2 diabetes mellitus (T2DM). However, recent studies reported that metabolically unhealthy obesity (MUO) exerts a higher risk of developing T2DM than metabolically healthy obesity (MHO) because of its higher state of insulin resistance. This may happen due to metabolic endotoxemia through gut dysbiosis and increased intestinal permeability. Our study aimed to know the association of intestinal permeability using intestinal fatty acid-binding protein (I-FABP) with obesity-related T2DM patients in Indonesia. This was a cross-sectional study that recruited 63 participants with obesity defined using body mass index (BMI) classification for the Asia-Pacific population (BMI ≥25 kg/m2). All participants were then grouped into T2DM and non-T2DM based on American Diabetes Association (ADA) diagnostic criteria. The I-FABP levels were measured using the enzyme-linked immunosorbent assay method. The I-FABP level of T2DM group was higher compared to non-T2DM group, namely 2.82 (1.23) ng/mL vs. 1.78 (0.81) ng/mL (p<0.001; mean difference 1.033 with 95% CI 0.51-1.55). This difference was not attenuated even after adjustment for age. The fitted regression model using linear regression was: i-FABP = 1.787+1.034*(DM) (R2 = 18.20%, standardized ß = 0.442, p<0.001). This study underscores the association of intestinal permeability with T2DM in people with obesity and supports the evidence of the potential role of intestinal permeability in the pathogenesis of obesity-related T2DM.

Specific Deletion of CASK in Pancreatic β Cells Affects Glucose Homeostasis and Improves Insulin Sensitivity in Obese Mice by Reducing Hyperinsulinemia Running Title: β Cell CASK Deletion Reduces Hyperinsulinemia.

Calcium/calmodulin-dependent serine protein kinase (CASK) is involved in the secretion of insulin vesicles in pancreatic β-cells. The present study revealed a new in vivo role of CASK in glucose homeostasis during the progression of type 2 diabetes mellitus (T2DM). A Cre-loxP system was used to specifically delete the Cask gene in mouse β-cells (βCASKKO), and the glucose metabolism was evaluated in βCASKKO mice fed a normal chow diet (ND) or a high-fat diet (HFD). ND-fed mice exhibited impaired insulin secretion in response to glucose stimulation. Transmission electron microscopy showed significantly reduced numbers of insulin granules at or near the cell membrane in the islets of βCASKKO mice. By contrast, HFD-fed βCASKKO mice showed reduced blood glucose and a partial relief of hyperinsulinemia and insulin resistance when compared to HFD-fed wildtype mice. The IRS1/PI3K/AKT signaling pathway was upregulated in the adipose tissue of HFD-βCASKKO mice. These results indicated that knockout of the Cask gene in β cells had a diverse effect on glucose homeostasis: reduced insulin secretion in ND-fed mice, but improves insulin sensitivity in HFD-fed mice. Therefore, CASK appears to function in the insulin secretion and contributes to hyperinsulinemia and insulin resistance during the development of obesity-related T2DM.

THE ROLE OF GUT MICROBIOTA IN PATIENTS WITH DIABETES TYPE 2 AND INSULIN RESISTANCE

Diabetes mellitus is one of the most common chronic disease. In a number of developing and industrialized countries, diabetes mellitus has become an epidemic and is one of the leading causes of death. The rapid increase of cases of type 2 diabetes mellitus (T2DM) in the past decades has made it a widespread metabolic disorder. In recent years, an increasing understanding of how our microflora is linked to obesity-related T2DM has provided a new potential target for reducing the risk of T2DM. The aim of our project is to expand our view on the key roles of microflora during the onset and development of T2DM as well as its complications. Our aim was to study 2 groups of people with T2DM and Prediabetes in order to reveal any gastro-intestinal problems. According to questionnaires, it appeared that patients with diabetes type 2 had 3 or more gastrointestinal disorders, 72 % had bloating, 16% constipation and 12% diarrhea. Patients with prediabetes had 3 and more intestinal disorders: 56 % had bloating, 23% constipation and 21 % diarrhea. Despite, multiple studies supporting the importance of gut microbiota in pathophysiology of T2DM, the field is in early stage. Currently, we have reached a point in our understanding that some probiotics and related molecular mechanisms may be involved in glucose metabolism related to T2DM. We should work towards precision/personalized medicine selecting anti-diabetics and probiotics for a given patient to treat patients successfully.

Circulating T Cells Exhibit Different TIM3/Galectin-9 Expression in Patients with Obesity and Obesity-Related Diabetes.

Aims Obesity is highly associated with type 2 diabetes mellitus (T2DM). The TIM3/galectin-9 pathway plays an important role in immune tolerance. Herein, we aimed to investigate the expression of TIM3 and galectin-9 in peripheral blood and to evaluate their clinical significance in patients with obesity and obesity-related T2DM. Methods We performed flow cytometry on peripheral blood samples from healthy donors (HC), patients with simple obesity (OB), and patients with obesity comorbid T2DM (OD). The expression of TIM3 on CD3+, CD4+, and CD8+ T cells was determined. The level of galectin-9 in plasma was detected by ELISA. Results We demonstrated the enhancement of TIM3 on CD3+, CD4+, and CD8+ T cells in the OB group when compared with healthy controls, while it was decreased significantly in the OD group. The TIM3+CD8+ T cells of the OB group were positively correlated with risk factors including BMI, body fat rate, and hipline. The concentration of galectin-9 of the OD group in plasma was significantly higher than that of healthy donors and the OB group. Moreover, the level of galectin-9 of the OD group was positively correlated with fasting insulin and C-peptide, which were two clinical features that represented pancreatic islet function in T2DM. Conclusions Our results suggested that TIM3 and galectin-9 may be potential biomarkers related to the pathogenesis of obesity-related T2DM.

Phocea, Pseudoflavonifractor and Lactobacillus intestinalis: Three Potential Biomarkers of Gut Microbiota That Affect Progression and Complications of Obesity-Induced Type 2 Diabetes Mellitus.

PurposeThe purpose of this study was to explore the difference and association between intestinal microbiota and plasma metabolomics between type 2 diabetes mellitus (T2DM) and normal group and to identify potential microbiota biomarkers that contribute the most to the difference in metabolites.MethodsSix male ZDF model (fa/fa) rats were fed by a Purina #5008 Lab Diet (crude protein 23.5%, crude fat 6.5%) for 3 weeks and their age-matched 6 ZDF control (fa/+) rats were fed by normal rodent diet. Their stool and blood samples were collected at 12 weeks. To analyze the microbial populations in these samples, we used a 16S rRNA gene sequencing approach. Liquid chromatography–mass spectrometry (LC-MS) followed by multivariate statistical analysis was applied to the plasma metabolites profiling. Correlation analysis of them was calculated by Pearson statistical method.ResultsTwelve potential biomarkers of intestinal microbial flora and 357 differential metabolites were found in ZDF fa/fa rats, among which there are three flora that contributed the most to the perturbation of metabolites, including genus Phocea, Pseudoflavonifractor and species Lactobacillus intestinalis.ConclusionOur study demonstrates the alterations of the abundance and diversity of the intestinal microbiota and the perturbation of metabolites in ZDF rats (fa/fa). We found three potential biomarkers of intestinal microbiota that may lead to perturbation in plasma metabolites. This may prompt new pathogenesis of obesity-related T2DM, but we also need to study further about the causal relationship between intestinal microbe and T2DM, so as to find the target of T2DM treatment or preventive measures.

Dynamic changes in insulin and glucagon during disease progression in rhesus monkeys with obesity-related type 2 diabetes mellitus.

To investigate the progression of obesity-related type 2 diabetes mellitus (T2DM) in rhesus monkeys, especially dynamic changes in insulin and glucagon. We followed a cohort of 52 rhesus monkeys for 7 years throughout the progression of obesity-related T2DM. Intravenous glucose tolerance tests were performed every 6 months to evaluate dynamic changes in glucose, insulin and glucagon levels. Obesity in rhesus monkeys increased the overall mortality and T2DM morbidity. During the progression of T2DM, glucagon remained consistently elevated, while insulin initially increased in compensation but then dropped to below normal levels when the monkeys developed overt T2DM. After a glucose challenge, both the first and second phases of insulin secretion increased during the early stage of T2DM; in later stages the first phase was delayed and the second phase was diminished. Our findings showed that, beside the decreased insulin level, hyperglucagonaemia also plays an important role in the development of T2DM.

Intestinal luminal content from high-fat-fed prediabetic mice changes epithelial barrier function in vitro

AimsEvidence suggests that administration of a high-fat diet (HFD) results in changes in the intestinal lumen environment. Gut dysbiosis associated with intestinal barrier disruption may be involved in type 2 diabetes mellitus (T2DM) development through increased intestinal permeability, which would trigger an inflammatory response leading to peripheral insulin resistance state and ultimately T2DM. In this study, we investigated the effect of the intestinal luminal content isolated from control or HFD-fed prediabetic mice upon the tight junction (TJ)-mediated epithelial barrier in Caco-2 and MDCK epithelial cell lines. Methods/key findingsExposure to small intestine luminal content (SI) isolated from HFD-fed prediabetic mice induced a more significant decrease in transepithelial electrical resistance (TEER), associated with higher paracellular flux in Caco-2 and MDCK cells after 6 h and 4 h respectively, as compared to the SI obtained from control mice. Such changes were accompanied by a significant decrease in TJ content of claudins, occludin, and ZO-1, indicative of disruption of the TJ barrier. Meanwhile, large intestine luminal content from control (Ctrl-LI) and prediabetic (HFD-LI) animals did not change TEER significantly, however, paracellular flux was significantly increased after 24 h, accompanied by a decrease in ZO-1 (after HFD-LI exposure) in Caco-2 and significant changes in the junctional distribution of claudins-1, -2, occludin and ZO-1 proteins in MDCK, particularly after HFD-LI exposure. SignificanceLuminal components of intestinal content, altered by HFD exposure, induce impairment of the TJ structure and function in vitro, corroborating the idea of a role of the intestinal paracellular barrier in the obesity-related T2DM pathogenesis.

Serum fetuin-A levels in obese and non-obese subjects with and without type 2 diabetes mellitus

BackgroundHigher fetuin-A expression is linked to both obesity and type 2 diabetes mellitus (T2DM), However, studies in non-obese patients with T2DM are scarce. Methods345 newly diagnosed T2DM patients and 300 subjects with normal glucose tolerance (NGT) were divided into obese and non-obese subgroups, respectively. Serum fetuin-A and adiponectin levels and related parameters were measured. ResultsT2DM patients with obesity had higher fetuin-A levels compared with non-obese patients and obese NGT subjects (p<0.001). Significant correlations were observed between fetuin-A and most metabolic parameters in obese NGT and T2DM subjects, but which was not in non-obese patients with T2DM. The independent associations were found between fetuin-A and free fatty acids, HOMA-IR, C-reactive protein and adiponectin only in obese NGT and T2DM subjects (all p<0.05). The adjusted odds ratios for obesity were increased with increasing quartile of fetuin-A in both T2DM and NGT subjects in logistic regression models (p for trend<0.001), but which was more significant in T2DM patients. ConclusionHigher serum fetuin-A levels in obese T2DM patients compared with non-obese patients and obese NGT subjects supports the hypothesis that fetuin-A may be as a bridge connecting obesity and obesity-related T2DM.

Melatonin improves mitochondrial function in inguinal white adipose tissue of Zücker diabetic fatty rats.

Mitochondrial dysfunction in adipose tissue may contribute to obesity-related metabolic derangements such as type 2 diabetes mellitus (T2DM). Because mitochondria are a target for melatonin action, the goal of this study was to investigate the effects of melatonin on mitochondrial function in white (WAT) and beige inguinal adipose tissue of Zücker diabetic fatty (ZDF) rats, a model of obesity-related T2DM. In this experimental model, melatonin reduces obesity and improves the metabolic profile. At 6wk of age, ZDF rats and lean littermates (ZL) were subdivided into two groups, each composed of four rats: control (C-ZDF and C-ZL) and treated with oral melatonin in the drinking water (10mg/kg/day) for 6wk (M-ZDF and M-ZL). After the treatment period, animals were sacrificed, tissues dissected, and mitochondrial function assessed in isolated organelles. Melatonin increased the respiratory control ratio (RCR) in mitochondria from white fat of both lean (by 26.5%, P<0.01) and obese (by 34.5%, P<0.01) rats mainly through a reduction of proton leaking component of respiration (state 4) (28% decrease in ZL, P<0.01 and 35% in ZDF, P<0.01). However, melatonin treatment lowered the RCR in beige mitochondria of both lean (by 7%, P<0.05) and obese (by 13%, P<0.05) rats by maintaining high rates of uncoupled respiration. Melatonin also lowered mitochondrial oxidative status by reducing nitrite levels and by increasing superoxide dismutase activity. Moreover, melatonin treatment also caused a profound inhibition of Ca-induced opening of mPTP in isolated mitochondria from both types of fat, white and beige, in both lean and obese rats. These results demonstrate that chronic oral melatonin improves mitochondrial respiration and reduces the oxidative status and susceptibility to apoptosis in white and beige adipocytes. These melatonin effects help to prevent mitochondrial dysfunction and thereby to improve obesity-related metabolic disorders such as diabetes and dyslipidemia of ZDF rats.

Teachers Dietary Practices during School Day in Jeddah, Western Saudi Arabia

The schools teachers dietary practices during the school day should reflect a healthy dietary pattern both in quality and quantity of foods consumed particularly in countries that witness an epidemic of obesity related Type-2 diabetes mellitus. The objective of this study was to identify the local dietary practices of the schools teachers in Jeddah, western Saudi Arabia. A Cross-section observational study using a pre-designed questionnaire to identify the local pattern of dietary practices during school day of a representative sample of schools teachers was conducted in Jeddah. The questionnaire was piloted and administered to a sample of 140 teachers working in 15 schools across Jeddah. A total of 140 Saudi teachers participated. The mean age of the sample was 34.9 ± 6.1 years. Two thirds (66.4%) were females. Overall, 40.5% were overweight and 22.4% were obese. During the school day, tea and Arabic coffee were the commonest daily consumed drinks (67.9%, 65.7% respectively). Almost half of the sample consumed dates on a daily basis (51.4%). Breads and cheese sandwiches were always consumed by 45% and 33.6% respectively. Two thirds of females 67.7% and 55.3% of males were used to have breakfast and/or snack with their colleagues at school. Males preferred to purchase ready-made traditional foods from outside while females preferred the schools canteens. The percentages of overweight and obesity were higher among males compared to females (46.5 versus 37%) and (25.6% versus 20.5%) respecttively. It is concluded that the dietary practices of Saudi school teachers during school day vary according to gender. Findings indicate the need for dietary modification programs directed towards schools teachers in populations which report high prevalence rates of diabetes of similar cultural backgrounds.

C-peptide Predicts the Remission of Type 2 Diabetes After Bariatric Surgery

C-peptide is a surrogate of the pancreatic beta cell mass. However, the clinical significance of C-peptide in a diabetic patient after bariatric surgery has not been studied clearly. From February 2005 to January 2009, a total of 205 (124 females and 81 males) consecutive morbidly obese patients with type 2 diabetes mellitus (T2DM) enrolled in a surgically supervised weight loss program with at least 1year follow-up were examined. Among them, 147 patients (71.7%) received gastric bypass procedures, while the other 58 patients (28.3%) received restrictive-type procedures. The mean C-peptide before the surgery was 5.3 ± 3.5ng/ml. One hundred nineteen patients (58.0%) had an elevated C-peptide (>4ng/ml), while 2 patients (1.0%) had a low C-peptide (<1.0ng/ml). Multivariate analysis confirmed that waist circumference, triglycerides, and HbA1c were the independent predictors for the elevation of C-peptide. It was observed that the mean C-peptide levels decreased to 1.7 ± 0.9ng/ml 1year after bariatric surgery with a mean reduction of 64.1%. One year after surgery, 160 patients (78.0%) out of a total of 205 patients had a remission of their T2DM. Patients in the bypass group had a higher diabetes remission rate (91.2%; 134 out of 147) in comparison to patients in the restrictive group (44.8%; 26 out of 58, p < 0.001). The diabetes remission rates for those with preoperative C-peptide <3, 3-6, and > 6ng/ml were 26 out of 47 (55.3%), 87 out of 108 (82.0%), and 47 out of 52 (90.3%), p < 0.001, respectively. Baseline C-peptide is commonly elevated in morbidly obese patients with T2DM. There was a marked reduction in C-peptide after a significant weight reduction 1year after surgery with a T2DM remission rate of 78.0%. Thus, bariatric surgery is recommended for obesity-related T2DM patients with elevated C-peptide.

Melatonin improves glucose homeostasis in young Zucker diabetic fatty rats

The aim of this study was to investigate the effects of melatonin on glucose homeostasis in young male Zucker diabetic fatty (ZDF) rats, an experimental model of metabolic syndrome and type 2 diabetes mellitus (T2DM). ZDF rats (n=30) and lean littermates (ZL) (n=30) were used. At 6wk of age, both lean and fatty animals were subdivided into three groups, each composed of ten rats: naive (N), vehicle treated (V), and melatonin treated (M) (10mg/kg/day) for 6wk. Vehicle and melatonin were added to the drinking water. ZDF rats developed DM (fasting hyperglycemia, 460±39.8mg/dL; HbA(1) c 8.3±0.5%) with both insulin resistance (HOMA-IR 9.28±0.9 versus 1.2±0.1 in ZL) and decreased β-cell function (HOMA1-%B) by 75%, compared with ZL rats. Melatonin reduced fasting hyperglycemia by 18.6% (P<0.05) and HbA(1) c by 11% (P<0.05) in ZDF rats. Also, melatonin lowered insulinemia by 15.9% (P<0.05) and HOMA-IR by 31% (P<0.01) and increased HOMA1-%B by 14.4% (P<0.05). In addition, melatonin decreased hyperleptinemia by 34% (P<0.001) and raised hypoadiponectinemia by 40% (P<0.001) in ZDF rats. Moreover, melatonin reduced serum free fatty acid levels by 13.5% (P<0.05). These data demonstrate that oral melatonin administration ameliorates glucose homeostasis in young ZDF rats by improving both insulin action and β-cell function. These observations have implications on melatonin's possible use as a new pharmacologic therapy for improving glucose homeostasis and of obesity-related T2DM, in young subjects.