The Role of Oestrogen Receptor Beta (ERß) in the Aetiology and Treatment of Type 2 Diabetes Mellitus.

INTRODUCTION: Challenges facing the treatment of type 2 diabetes necessitate the search for agents which act via alternative pathways to provide better therapeutic outcomes. Recently, an increasing body of evidence implicates the activation of oestrogen receptors (ERα and ERß) in the development and treatment of underlying conditions in type 2 diabetes. This article summarizes available evidence for the involvement of oestrogen receptors in insulin secretion, insulin resistance as well as glucose uptake and highlights the potential of ERß as a therapeutic target. BACKGROUND: Recent studies indicate an association between the activation of each of the isoforms of ER and recent findings indicate that ERß shows promise as a potential target for antidiabetic drugs. In vitro and in vivo studies in receptor knockout mice indicate beneficial actions of selective agonists of ERß receptor and underscore its therapeutic potential. CONCLUSION: Studies are needed to further elucidate the exact mechanism underlying the role of ERß activation as a therapeutic approach in the management of type 2 diabetes.

Possible association between ABCC8 C49620T polymorphism and type 2 diabetes in a Nigerian population.

BACKGROUND: The association between ABCC8 gene C49620T polymorphism and type 2 diabetes (T2D) in populations of diverse ethnic backgrounds has been reported. However, such occurrence in an African population is yet to be established. This case-control study involving 73 T2D and 75 non-diabetic (ND) patients investigated the occurrence of this polymorphism among T2D patients in Nigeria and assessed its relationship with body lipids of patients. METHODS: Demographic and clinical characteristics of patients were collected and lipid profile indices including total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and high density lipoprotein (HDL) were assayed. Restriction fragment length polymorphism-PCR (RFLP-PCR) was employed to genotype the ABCC8-C49620T polymorphism using PstI restriction enzyme. RESULTS: This study revealed significantly (p < 0.05) higher prevalence of the T allele of the ABCC8 gene in T2D patients (33.1%) compared to ND patients (28.0%). The mutant TT genotype was also higher than the CC and CT genotypes in T2D patients compared to ND patients but did not show any significant risk (p>0.05) of T2D for the unadjusted codominant, dominant and recessive models. Following age adjustment, the mutant genotypes (CT and TT) showed significant (p<0.05) risk of T2D for all the models with the recessive model presenting the greatest risk of T2D (OR: 2.39, 95% CI: 1.16-4.91, p<0.018). The TT genotype significantly (p<0.05) associated with high level of HDL and reduced levels of TC, TG and LDL in non-diabetic patients but was not associated with any of the demographic and clinical characteristics among T2D patients. CONCLUSIONS: ABCC8 C49620T polymorphism showed possible association with T2D marked by predominance of the mutant TT genotype in T2D patients. However, the relationship between TT genotype and lipid abnormalities for possible beneficial effect on people suffering from T2D is unclear.

Assessment of the Pro12Ala Polymorphism in the PPAR-γ2 Gene among Type 2 Diabetes Patients in a Nigerian Population.

The association between the Pro12Ala polymorphism of the PPARγ2 gene, type 2 diabetes (T2D), and obesity in certain ethnic populations has been reported. However, this relationship has not yet been described among diabetes patients in Nigeria. This study investigated the relationship between the Pro12Ala polymorphism in the PPARγ2 gene, obesity, and lipid abnormalities characterizing T2D among patients in Nigeria. This case-control study recruited 73 T2D and 75 non-diabetic (ND) patients. Demographic and clinical data were collected and blood glucose levels together with serum lipid profile for patients were measured. Pro12Ala polymorphism in the PPARγ2 gene was genotyped by restriction fragment length-Polymerase Chain Reaction (RFLP-PCR). The PPAR-γ2 gene (amplicon size = 270 base pair) was successfully amplified for all samples. Following restriction enzyme digestion and analysis by agarose gel electrophoresis, amplicons from samples showed a band of size 270 bp and were of the wild homozygous Pro/Pro genotype. Ala12 variant was totally absent from the study population. Obesity, estimated using Body Mass Index (BMI) and waist circumference (WC), was significantly higher (p < 0.05) in T2D patients compared to the non-diabetic patients. More so, the prevalence of lipid abnormalities; hypercholesterolaemia (TC > 200 mg/dL), hypertriglyceridaemia (TG > 150 mg/dL), high HDL (>100 mg/dL), and low HDL (<50 mg/dL) was significantly greater (p < 0.001) in T2D patients compared to non-diabetic patients. Results obtained further indicated lack of significant association between PPAR-γ2 gene polymorphism, T2D, and obesity. However, obesity and dyslipidaemia were strongly associated in T2D patients.

Magainin-related peptides stimulate insulin-release and improve glucose tolerance in high fat fed mice.

Earlier peptidomic analysis of the skin secretion of Xenopus amieti led to the identification of orthologs of magainins and other peptides. This study investigated the degradation, in vitro insulin-releasing and acute metabolic effects of magainin-AM1 (GIKEFAHSLGKFG KAFVGGILNQ) and magainin-AM2 (GVSKILHSAGKFGKAFLGEIMKS). Plasma degradation was investigated using reversed-phase HPLC and MALDI-TOF mass spectroscopy. Insulin-releasing effects were determined using BRIN-BD11 clonal beta cells and mouse islets. Effects of magainin peptides on cytosolic enzyme lactate dehydrogenase release, membrane potential and intracellular Ca(2+) concentration were assessed using BRIN-BD11 cells while their in vivo effects on glucose tolerance and insulin release were assessed in obese, insulin-resistant Swiss National Institute of Health (NIH) mice. Both peptides were resistant to degradation by plasma enzymes in vitro for up to 8 h. Though magainin-AM1 elicited non-toxic, concentration-dependent stimulation of insulin-release from clonal BRINBD11 cells at concentrations ≥ 100nM, magainin-AM2 produced a higher stimulation of insulin-release from BRIN-BD11 cells and isolated mouse islets. Membrane depolarization and intracellular [Ca(2+)]i in BRIN-BD11 cells were significantly (P<0.05) induced by both peptides and chelation of extracellular Ca(2+), addition of diazoxide or verapamil significantly (P<0.01) reduced the insulinotropic actions of the peptides. Administration of magainin-AM2 (75 nmol/kg body weight) to high-fat fed mice significantly enhanced insulin-release (P<0.01) and improved glucose tolerance (P<0.05). These data indicate magainin-AM2 peptides have potential for development into agents for treatment of type 2 diabetes.