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  1. Lokman EF, Gu HF, Wan Mohamud WN, Östenson CG
    PMID: 26199630 DOI: 10.1155/2015/120572
    Aims. To evaluate the antidiabetic effects of Gynostemma pentaphyllum (GP) in Goto-Kakizaki (GK) rat, an animal model of type 2 diabetes, and to investigate the mechanisms of insulin release. Methods. Oral glucose tolerance test was performed and plasma insulin levels were measured. Results. An oral treatment with GP (0.3 g/kg of body weight daily) for two weeks in GK rats improved glucose tolerance versus placebo group (P < 0.01). Plasma insulin levels were significantly increased in the GP-treated group. The insulin release from GP-treated GK rats was 1.9-fold higher as compared to the control group (P < 0.001). GP stimulated insulin release in isolated GK rat islets at high glucose. Opening of ATP-sensitive potassium (K-ATP) channels by diazoxide and inhibition of calcium channels by nifedipine significantly decreased insulin response to GP. Furthermore, the protein kinase A (PKA) inhibitor H89 decreased the insulin response to GP (P < 0.05). In addition, GP-induced insulin secretion was decreased after preincubation of GK islets with pertussis toxin to inhibit exocytotic Ge proteins (P < 0.05). Conclusion. The antidiabetic effect of GP is associated with the stimulation of insulin release from the islets. GP-induced insulin release is partly mediated via K-ATP and L-type Ca(2+) channels, the PKA system and also dependent on pertussis toxin sensitive Ge-protein.
  2. Abu Seman N, Witasp A, Wan Mohamud WN, Anderstam B, Brismar K, Stenvinkel P, et al.
    J Diabetes Res, 2013;2013:298019.
    PMID: 24350299 DOI: 10.1155/2013/298019
    Recent reports have demonstrated that elevated plasma long pentraxin 3 (PTX3) levels are associated with cardiovascular and chronic kidney diseases. In the current study, we investigated the plasma PTX3 levels in 296 Malay subjects including the subjects with normal glucose tolerance (NGT) and type 2 diabetes (T2DM) patients with or without DN by using an enzyme-linked immune-sorbent assay. Results showed that in males, plasma PTX3 levels in T2DM patients without DN were lower than that in the subjects with NGT (2.78 versus 3.98 ng/mL; P = 0.021). Plasma PTX3 levels in T2DM patients with DN were decreased compared to the patients without DN (1.63 versus 2.78 ng/mL; P = 0.013). In females, however, no significant alteration of plasma PTX3 levels among NGT subjects and T2DM patients with and without DN was detected. Furthermore, an inverse correlation between PTX3 and body mass index was found in male subjects with NGT (P = 0.012; r = -0.390), but not in male T2DM patients, neither in all females. The current study provided the first evidence that decreased plasma PTX3 levels are associated with T2DM and DN in Malay men and also suggested that PTX3 may have different effects in DN and chronic kidney diseases.
  3. Mansor F, Gu HF, Ostenson CG, Mannerås-Holm L, Stener-Victorin E, Wan Mohamud WN
    Adv Pharmacol Sci, 2013;2013:808914.
    PMID: 23935612 DOI: 10.1155/2013/808914
    Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor that regulates lipid and glucose metabolism. We investigated the effects of Labisia pumila (LP) standardized water extract on PPARgamma transcriptional activity in adipocytes in vitro and in vivo. We used a rat model of dihydrotestosterone- (DHT-) induced polycystic ovary syndrome (PCOS), a condition characterized by insulin resistance. At 9 weeks of age, the PCOS rats were randomly subdivided into two groups: PCOS-LP (50 mg/kg/day of LP) and PCOS-control (1 mL of deionised water) for 4-5 weeks on the same schedule. Real-time RT-PCR was performed to determine the PPARgamma mRNA levels. LP upregulated PPARgamma mRNA level by 40% in the PCOS rats. Western blot analysis further demonstrated the increased PPARgamma protein levels in parallel with upregulation in mRNA. These observations were further proven by adipocytes culture. Differentiated 3T3-L1 adipocytes were treated with final concentration of 100  μ g/mL LP and compared to untreated control and 10  μ M of rosiglitazone (in type of thiazolidinediones). LP increased PPARgamma expressions at both mRNA and protein levels and enhanced the effect of glucose uptake in the insulin-resistant cells. The data suggest that LP may ameliorate insulin resistance in adipocytes via the upregulation of PPARgamma pathway.
  4. Yeow TP, Lim SL, Hor CP, Khir AS, Wan Mohamud WN, Pacini G
    PLoS One, 2015;10(6):e0129017.
    PMID: 26057782 DOI: 10.1371/journal.pone.0129017
    Gestational Diabetes Mellitus (GDM) and vitamin D deficiency are related to insulin resistance and impaired beta cell function, with heightened risk for future development of diabetes. We evaluated the impact of vitamin D supplementation on markers of glucose metabolism and cardio metabolic risk in Asian women with former GDM and hypovitaminosis D. In this double blind, randomized controlled trial, 26 participants were randomized to receive either daily 4000 IU vitamin D3 or placebo capsules. 75 g Oral Glucose Tolerance Test (OGTT) and biochemistry profiles were performed at baseline and 6 month visits. Mathematical models, using serial glucose, insulin and C peptide measurements from OGTT, were employed to calculate insulin sensitivity and beta cell function. Thirty three (76%) women with former GDM screened had vitamin D level of <50 nmol/L at baseline. Supplementation, when compared with placebo, resulted in increased vitamin D level (+51.1 nmol/L vs 0.2 nmol/L, p<0.001) and increased fasting insulin (+20% vs 18%, p = 0.034). The vitamin D group also demonstrated a 30% improvement in disposition index and an absolute 0.2% (2 mmol/mol) reduction in HbA1c. There was no clear change in insulin sensitivity or markers of cardio metabolic risk. This study highlighted high prevalence of vitamin D deficiency among Asian women with former GDM. Six months supplementation with 4000 IU of vitamin D3 safely restored the vitamin D level, improved basal pancreatic beta-cell function and ameliorated the metabolic state. There was no effect on markers of cardio metabolic risk. Further mechanistic studies exploring the role of vitamin D supplementation on glucose homeostasis among different ethnicities may be needed to better inform future recommendations for these women with former GDM at high risk of both hypovitaminosis D and future diabetes.
  5. Robert SA, Rohana AG, Shah SA, Chinna K, Wan Mohamud WN, Kamaruddin NA
    Obes Res Clin Pract, 2015 May-Jun;9(3):301-4.
    PMID: 25870084 DOI: 10.1016/j.orcp.2015.03.005
    We examined the effects of liraglutide, a glucagon-like peptide-1 analogue on appetite and plasma ghrelin in non-diabetic obese participants with subclinical binge eating (BE). Forty-four obese BE participants (mean age: 34±9 years, BMI: 35.9±4.2kg/m(2)) were randomly assigned to intervention or control groups for 12 weeks. All participants received standard advice for diet and exercise. Binge eating score, ghrelin levels and other anthropometric variables were evaluated at baseline and at the end of the study. Participants who received liraglutide showed significant improvement in binge eating, accompanied by reduction in body weight, BMI, waist circumference, systolic blood pressure, fasting glucose and total cholesterol. Ghrelin levels were significantly increased which may potentially diminish the weight loss effects of liraglutide beyond the intervention.
  6. Abu Seman N, Anderstam B, Wan Mohamud WN, Östenson CG, Brismar K, Gu HF
    J Diabetes Complications, 2015 Nov-Dec;29(8):1234-9.
    PMID: 26255081 DOI: 10.1016/j.jdiacomp.2015.07.004
    Recent research has implicated that the inflammation may be a key pathophysiological mechanism in diabetic nephropathy (DN). Intercellular adhesion molecule 1 (ICAM-1) is an acute phase marker of inflammation. In the present study, we carried out genetic, epigenetic and protein analyses of ICAM-1 in a Malaysian population, including normal glucose tolerance (NGT) subjects and type 2 diabetes (T2D) patients with or without DN in order to evaluate its role in DN.
  7. Wan Mohd Zin RM, Ahmad Kamil ZI, Tuan Soh TR, Embong M, Wan Mohamud WN
    BMC Res Notes, 2013 Dec 18;6:540.
    PMID: 24344903 DOI: 10.1186/1756-0500-6-540
    BACKGROUND: Measurement of HbA1c has been widely used for long-term monitoring and management of diabetes control. There is increasing use of point-of-care (POC) devices for measuring HbA1c where quicker results would allow immediate clinical management decisions to be made. Therefore, it is important to evaluate and compare the performance of such devices to the reference laboratory method.

    FINDINGS: A total of 274 venous blood was collected from normal healthy adults during the community screening programmes. The performance of POC devices, Afinion and Quo-test were compared to central laboratory HPLC method; Adams A1c HA 8160. Both POC devices showed good correlation to HA 8160 with r = 0.94 (p < 0.001) and r = 0.95 (p < 0.001) for Afinion and Quo-test respectively. The means difference were statistically higher between POC and HA 8160 with 0.23% (95% CI 0.19-0.26, p < 0.001) and 0.29% (95% CI 0.24-0.34, p < 0.001) for Afinion and Quo-test respectively.

    CONCLUSIONS: Both POC devices could be considered in health clinics for diabetes management but not to be used for the diagnostic purposes.

  8. Lokman FE, Gu HF, Wan Mohamud WN, Yusoff MM, Chia KL, Ostenson CG
    PMID: 24319481 DOI: 10.1155/2013/727602
    Aims. To evaluate the antidiabetic properties of borapetol B known as compound 1 (C1) isolated from Tinospora crispa in normoglycemic control Wistar (W) and spontaneously type 2 diabetic Goto-Kakizaki (GK) rats. Methods. The effect of C1 on blood glucose and plasma insulin was assessed by an oral glucose tolerance test. The effect of C1 on insulin secretion was assessed by batch incubation and perifusion experiments using isolated pancreatic islets. Results. An acute oral administration of C1 improved blood glucose levels in treated versus placebo groups with areas under glucose curves 0-120 min being 72 ± 17 versus 344 ± 10 mmol/L (P < 0.001) and 492 ± 63 versus 862 ± 55 mmol/L (P < 0.01) in W and GK rats, respectively. Plasma insulin levels were increased by 2-fold in treated W and GK rats versus placebo group at 30 min (P < 0.05). C1 dose-dependently increased insulin secretion from W and GK isolated islets at 3.3 mM and 16.7 mM glucose. The perifusions of isolated islets indicated that C1 did not cause leakage of insulin by damaging islet beta cells (P < 0.001). Conclusion. This study provides evidence that borapetol B (C1) has antidiabetic properties mainly due to its stimulation of insulin release.
  9. Ghani RA, Bin Yaakob I, Wahab NA, Zainudin S, Mustafa N, Sukor N, et al.
    J Clin Lipidol, 2013 Sep-Oct;7(5):446-53.
    PMID: 24079286 DOI: 10.1016/j.jacl.2013.04.004
    BACKGROUND: Type 2 diabetes is associated with early development of endothelial dysfunction. Patients present with typical dyslipidemia (predominantly high levels of triglycerides [TG] and low levels of high-density lipoprotein cholesterol [HDL-C]) or mixed hypercholesterolemia (high levels of low-density lipoprotein cholesterol [LDL-C] and TG with low HDL-C). Normal levels include LDL-C < 100 mg/dL, TG < 135 mg/dL, and HDL-C > 40 mg/dL for men and >50 mg/dL for women.
    OBJECTIVE: To determine the effects of 8 weeks' administration of fenofibrate on inflammatory markers, metabolic parameters, and endothelial dysfunction.
    METHODS: We administered micronized fenofibrate (Laboratories Fourneir S.A Dijon, France) daily for 8 weeks to 40 dyslipidemic, type 2 diabetes patients with equal numbers in each arm of the typical or mixed dyslipidemia groups. Noninvasive endothelial function assessments were performed and serum inflammatory markers obtained before and after treatment.
    RESULTS: The typical group demonstrated significantly greater TG reduction and HDL-C increment, ie, 56% vs, 21.3% (P < .005) and 21% vs. 7.6% (P = .001), respectively, compared with the mixed group. There was greater LDL-C reduction within the mixed group compared with the typical group 21.0% vs. 2.2% (P < .05). Endothelial dysfunction was present in both groups at baseline. After treatment, the typical group demonstrated significant improvement in resting brachial diameter (3.9 mm [interquartile range {IQR} 3.3-4.7] to 4.2 mm [IQR 3.4-4.8], P = .001) compared with no change within the mixed group (3.6 mm [IQR 3.1-5.4] to 3.7 mm [IQR 3.1-5.3], P = .26). Flow-mediated diameter improved significantly in both groups. The mixed group had significantly greater levels of hs-CRP at baseline but no changes throughout the study. The mixed group demonstrated an increase in vascular adhesion molecule-1 from 706 ng/mL (IQR 566-1195) to 845 ng/mL (637-1653; P = .01), a reduction of tumor necrosis factor-α from 7.0 pg/mL (IQR 1.0-43.5) to 2.5 pg/mL (IQR 1.5-13.5; P = .04) throughout the study.
    CONCLUSIONS: We effectively compared 8 weeks of fenofibrate therapy in type 2 diabetics with contrasting lipid abnormalities. The typical dyslipidemia group showed significantly greater lipid improvements compared with the mixed dyslipidemia group. Both groups had improvements in endothelial functions that were independent of the lipid levels. We concluded that fibrate therapy in type 2 diabetics is beneficial, especially those with typical dyslipidemia and extends beyond its lipid lowering properties.
    KEYWORDS: Endothelial dysfunction; Fenofibrate; High-density lipoprotein cholesterol; Low density lipoprotein; Noninvasive endothelial function assessments; Triglyceride; Vascular cell adhesion molecule-1; hsCRP
  10. Lokman FE, Seman NA, Ismail AA, Yaacob NA, Mustafa N, Khir AS, et al.
    J Nephrol, 2011;24(6):778-89.
    PMID: 21360476 DOI: 10.5301/JN.2011.6382
    BACKGROUND: Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD) among type 2 diabetes mellitus patients (DM) in Malaysia. This study used microarray analysis to determine the gene expression profiling in ethnic Malay patients with type 2 DM.
    METHODS: A total of 312 patients were recruited; 25 were on dialysis due to ESRD, 128 were classified as normoalbuminuric, 93 as microalbuminuric and 66 as macroalbuminuric, based on urine albumin to creatinine ratio of <3.5, between 3.5 and 35 and =35 mg/mmol, respectively.
    RESULTS: Microalbuminuria was associated with up- and down-regulation of 2,694 and 2,538 genes, respectively, while macroalbuminuria was associated with up-regulation of 2,520 genes and down-regulation of 2,920 genes. There was significant up-regulation of 1,135 genes and down-regulation of 908 genes in the ESRD samples. Thirty-seven significantly up-regulated genes and 40 down-regulated genes were commonly expressed in all 3 groups of patients with worsening of renal functions. Up-regulated genes included major histocompatibility complex (HLA-C), complement component 3a receptor 1 (C3AR1), solute carrier family 16, member 3 (SLC16A3) and solute carrier family 9 (sodium/hydrogen exchanger) (SLC9A8). Consistently down-regulated genes included were bone morphogenetic phosphatase kinase (BMP2K), solute carrier family 12, member 1 (SLC12A1), solute carrier family 7 (SLC7A2), paternally expressed 10 (PEG10) and protein phosphatase 1 regulatory (inhibitor unit) (PPP1R1C).
    CONCLUSION: This study has identified several genes of interest, such as HLA-C, SLC16A3, SLC9A8, SLC12A1 and SLC7A2, that require verification of their roles as susceptibility genes for diabetic nephropathy in ethnic Malays with type 2 DM.
  11. Mustafa N, Kamarudin NA, Ismail AA, Khir AS, Ismail IS, Musa KI, et al.
    Diabetes Care, 2011 Jun;34(6):1362-4.
    PMID: 21498788 DOI: 10.2337/dc11-0005
    OBJECTIVE:
    To determine the prevalence of prediabetes and diabetes among rural and urban Malaysians.
    RESEARCH DESIGN AND METHODS:
    This cross-sectional survey was conducted among 3,879 Malaysian adults (1,335 men and 2,544 women). All subjects underwent the 75-g oral glucose tolerance test (OGTT).
    RESULTS:
    The overall prevalence of prediabetes was 22.1% (30.2% in men and 69.8% in women). Isolated impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) were found in 3.4 and 16.1% of the study population, respectively, whereas 2.6% of the subjects had both IFG and IGT. Based on an OGTT, the prevalence of newly diagnosed type 2 diabetes was 12.6% (31.0% in men and 69.0% in women). The prediabetic subjects also had an increased prevalence of cardiovascular disease risk factors.
    CONCLUSIONS:
    The large proportion of undiagnosed cases of prediabetes and diabetes reflects the lack of public awareness of the disease.
  12. Yeow TP, Pacini G, Tura A, Hor CP, Lim SL, Tan FH, et al.
    BMJ Open Diabetes Res Care, 2017;5(1):e000352.
    PMID: 28321312 DOI: 10.1136/bmjdrc-2016-000352
    OBJECTIVE: Youth onset type 2 diabetes mellitus (YT2DM) is a globally rising phenomenon with substantial Asians representation. The understanding of its pathophysiology is derived largely from studies in the obese African-American and Caucasian populations, while studies on incretin effect are scarce. We examined the insulin resistance, β-cell function (BC), glucagon-like peptide (GLP)-1 hormone and incretin effect in Asian YT2DM.

    RESEARCH DESIGN AND METHODS: This case-control study recruited 25 Asian YT2DM and 15 healthy controls, matched for gender, ethnicity and body mass index. Serum glucose, insulin, C peptide and GLP-1 were sampled during 2-hour oral glucose tolerance tests (OGTTs) and 1-hour intravenous glucose tolerance tests (IVGTTs). Insulin sensitivity was derived from the Quantitative Insulin Sensitivity Check Index (QUICKI), Oral Glucose Insulin Sensitivity Index (OGIS) in OGTT and surrogate index of SI from the minimal model (calculated SI, CSI). Acute insulin response (AIR) was obtained from IVGTT. Total BC was computed as incremental area under the curve of insulin/incremental area under the curve of glucose, during OGTT (BCOG) and IVGTT (BCIV), respectively. Disposition index (DI) was calculated using the product of insulin sensitivity and insulin secretion. GLP-1 response to oral glucose was calculated as incremental area under the curve of GLP-1 (ΔAUCGLP-1). Per cent incretin effect was estimated as 100×(BCOG-BCIV)/BCOG).

    RESULTS: The YT2DM had marked impairment in BC (>80% reduction in AIR and BCOG, p<0.001) and lower QUICKI (p<0.001), OGIS (p<0.001) and CSI (p=0.015) compared with controls. There was no difference in GLP-1 at all time points and ΔAUCGLP-1 but the per cent incretin effect was reduced in the YT2DM compared with controls (12.1±8.93 vs 70.0±4.03, p<0.001).

    CONCLUSIONS: Asian YT2DM showed similar GLP-1 response to oral glucose as controls but reduced incretin effect, BC and insulin sensitivity. The lack of compensatory mechanisms, as shown by the DI may be partly ascribed to the impaired incretin effect, similar to that of adult T2DM.

    TRIAL REGISTRATION NUMBER: NMRR-12-1042-13254.
  13. Nur Zati Iwani AK, Jalaludin MY, Wan Mohd Zin RM, Fuziah MZ, Hong JYH, Abqariyah Y, et al.
    Int J Endocrinol, 2019;2019:8586167.
    PMID: 31885562 DOI: 10.1155/2019/8586167
    Metabolic syndrome (MetS) is an important predictor of cardiovascular diseases in adulthood. This study aims to examine the clinical utility of triglyceride to high-density lipoprotein ratio (TG : HDL-C) in identifying cardiometabolic risk and insulin resistance (IR) among children with obesity, in comparison with MetS as defined by the International Diabetes Federation (IDF). Data of 232 children with obesity aged 10-16 years were obtained from our study, MyBFF@school study, conducted between January and December 2014. Children were divided into tertiles of TG : HDL-C ratio. The minimum value of the highest tertile was 1.11. Thus, elevated TG : HDL-C ratio was defined as TG : HDL-C ≥1.11. Children with MetS were categorized based on the definition established by the IDF. Out of 232 children, 23 (9.9%) had MetS, out of which 5.6% were boys. Almost twofold of boys and girls had elevated TG : HDL-C ratio compared to MetS: 13.8% vs. 5.6% and 13.8% vs. 4.3%, respectively. Children with elevated TG : HDL-C ratio had lower fasting glucose compared to children with MetS (boys = 5.15 ± 0.4 vs. 6.34 ± 2.85 mmol/l, p=0.02; girls = 5.17 ± 0.28 vs. 6.8 ± 4.3 mmol/l, p=0.03). Additionally, boys with elevated TG : HDL-C ratio had a higher HDL-C level compared to those with MetS (1.08 ± 0.18 vs. 0.96 ± 0.1 mmol/l, p=0.03). There was no significant difference across other MetS-associated risk factors. Overall, TG : HDL-C ratio demonstrated higher sensitivity (42.7% vs. 12.9%) but lower specificity (74.8% vs. 93.2%) than MetS in identifying IR, either in HOMA-IR ≥2.6 for prepubertal children or HOMA-IR ≥4 for pubertal children. TG : HDL-C ratio in children with obesity is thus as useful as the diagnosis of MetS. It should be considered an additional component to MetS, especially as a surrogate marker for IR.
  14. Abdul Kadir A, Nik Hussain NH, Wan Bebakar WM, Mohd DM, Wan Mohammad WM, Hassan II, et al.
    PMID: 22701504 DOI: 10.1155/2012/216525
    This is a randomized, double-blind, placebo-controlled study comparing the effects of a water extract of Labisia pumila var. alata at 280 mg/day with placebo, given for 6 months in postmenopausal Malay women. There were 29 patients treated with Labisia pumila and 34 patients in the placebo group. Menopausal symptoms were assessed at baseline and at 6 months. The blood pressure, body mass index, waist circumference, fasting blood sugar, lipid profile, and hormonal profile (follicle stimulating hormone/luteinizing hormone/estradiol) were measured during visits every two months. ANCOVA model analysis showed significantly lower triglycerides levels in LP subjects at 6 months after treatment as compared to placebo (1.4 versus 1.9 mmol/L; adj. mean difference 0.5, 95% CI: 0.02, 0.89 after adjusted for the baseline values, age, BMI, and duration of menopause placebo). Other parameters in both groups did not differ significantly. In conclusion, daily intake of Labisia pumila at 280 mg/day for six months was found to provide benefit in reducing the triglyceride (TG) values.
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