Robert A. Ngala

Male mice that lack the G-protein-coupled receptor GPR41 have low energy expenditure and increased body fat content

SCFA are produced in the gut by bacterial fermentation of undigested carbohydrates. Activation of the Gαi-protein-coupled receptor GPR41 by SCFA in β-cells and sympathetic ganglia inhibits insulin secretion and increases sympathetic outflow, respectively. A possible role in stimulating leptin secretion by adipocytes is disputed. In the present study, we investigated energy balance and glucose homoeostasis in GPR41 knockout mice fed on a standard low-fat or a high-fat diet. When fed on the low-fat diet, body fat mass was raised and glucose tolerance was impaired in male but not female knockout mice compared to wild-type mice. Soleus muscle and heart weights were reduced in the male mice, but total body lean mass was unchanged. When fed on the high-fat diet, body fat mass was raised in male but not female GPR41 knockout mice, but by no more in the males than when they were fed on the low-fat diet. Body lean mass and energy expenditure were reduced in male mice but not in female knockout mice. These results suggest that the absence of GPR41 increases body fat content in male mice. Gut-derived SCFA may raise energy expenditure and help to protect against obesity by activating GPR41.

Metabolic responses to BRL37344 and clenbuterol in soleus muscle and C2C12 cells via different atypical pharmacologies and β2‐adrenoceptor mechanisms

Picomolar concentrations of the β3‐adrenoceptor agonist BRL37344 stimulate 2‐deoxyglucose uptake in soleus muscle via undefined receptors. Higher concentrations alter uptake, apparently via β2‐adrenoceptors. Effects of BRL37344 and β2‐adrenoceptor agonists are compared.

Antiproliferative Activity of Aqueous Leaf Extract of Annona muricata L. on the Prostate, BPH-1 Cells, and Some Target Genes

Background. Annona muricata L. has been reported to possess antitumor and antiproliferative properties. Not much work has been done on its effect on BPH-1 cell lines, and no in vivo studies targeting the prostate organ exist. The study determined the effect of A muricata on human BPH-1 cells and prostate organ. Methods. The MTT assay was performed on BPH-1 cells using the aqueous leaf extract of A muricata. Cells (1 × 105 per well) were challenged with 0.5, 1.0, and 1.5 mg/mL extract for 24, 48, and 72 hours. Cell proliferation and morphology were examined microscopically. BPH-1 cells (1 × 104 per well) were seeded into 6-well plates and incubated for 48 hours with 0.5, 1.0, and 1.5 mg/mL A muricata extract. Reverse transcriptase polymerase chain reaction was performed using mRNA extracted from the cells. Possible target genes, Bax and Bcl-2, were examined. Twenty F344 male rats (≈200 g) were gavaged 30 mg/mL (10 rats) and 300 mg/mL (10 rats) and fed ad libitum alongside 10 control rats. Rats were sacrificed after 60 days. The prostate, seminal vesicles, and testes were harvested for histological examination. Results. Annona muricata demonstrated antiproliferative effects with an IC50 of 1.36 mg/mL. Best results were obtained after 48 hours, with near cell extinction at 72 hours. Bax gene was upregulated, while Bcl-2 was downregulated. Normal histological architecture was observed for all testes. Seminal vesicle was significantly reduced in test groups (P < .05) and demonstrated marked atrophy with increased cellularity and the acinii, empty of secretion. Prostate of test groups were reduced with epithelial lining showing pyknotic nucleus, condensation, and marginalization of the nuclear material, characteristic of apoptosis of the glandular epithelium. Furthermore, scanty prostatic secretion with flattening of acinar epithelial lining occurred. Conclusion. Annona muricata has antiproliferative effects on BPH-1 cells and reduces prostate size, possibly through apoptosis.

Effect of hormonal contraceptives on lipid profile and the risk indices for cardiovascular disease in a Ghanaian community

Background Hormonal contraceptives (HCs) have been shown to alter lipid profile among various population groups with different patterns of dyslipidemia and cardiovascular (CV) risk. The study aimed at determining the lipid profile pattern and CV risk in a Ghanaian cohort. Methods Purposive random sampling was done. Forty-seven and 19 cases were on oral contraceptives (OCs) and injectable contraceptives (ICs), respectively; five were on subdermal implant. Twenty-four non-users served as controls. Biodemographic and lipid profiles were determined. Total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), and very-low-density lipid lipoprotein cholesterol (VLDLC), were determined. Castelli index I and II were calculated. Results The mean age difference between the HC and control groups was insignificant. However, diastolic blood pressure (BP) differences were significant (P=0.006). The body mass index (BMI) of the OC and IC groups were significantly different from the control group (P=0.003 and P=0.008, respectively). TC levels for the control and case groups were 3.35±0.62 mmol/L and 4.07±0.91 mmol/L, respectively (P=0.002). LDLC levels for the control and case groups were 1.74±0.57 mmol/L and 2.38±0.84 mmol/L, respectively (P=0.003). Castelli index I (TC/HDLC) and II (LDLC/HDLC) were significantly different between the control and OC groups (P=0.026 and P=0.014, respectively). Spearman’s rho correlation showed significant influence of HC use on TG (P=0.026), TC (P=0.000), LDLC (P=0.004), and VLDLC (P=0.026) over time. Conclusion HC use is associated with significant increases in BMI, diastolic BP, TC, LDLC, and Castelli index I and II. These changes carry a potential risk in the development of CV disease.

β2-Adrenoceptors and non-β-adrenoceptors mediate effects of BRL37344 and clenbuterol on glucose uptake in soleus muscle: studies using knockout mice

Background and purpose:  In previous work, 10 pM BRL37344 and 10 pM clenbuterol stimulated glucose uptake in mouse soleus muscle. Ten nM BRL37344 also stimulated uptake but 100 nM clenbuterol inhibited uptake. Antagonist studies suggested that the opposite effects of 10 nM BRL37344 and 100 nM clenbuterol are mediated by the β2‐adrenoceptor. BRL37344 and clenbuterol have been studied in muscles that lack β3‐, β2‐ or all three β‐adrenoceptors. Effects of β‐adrenoceptor antagonists on responses to the agonists have been studied further using muscles from wild‐type mice.

Stimulation of glucose uptake in murine soleus muscle and adipocytes by 5-(4-phenoxybutoxy)psoralen (PAP-1) may be mediated by Kv1.5 rather than Kv1.3

Kv1 channels are shaker-related potassium channels that influence insulin sensitivity. Kv1.3−/− mice are protected from diet-induced insulin resistance and some studies suggest that Kv1.3 inhibitors provide similar protection. However, it is unclear whether blockade of Kv1.3 in adipocytes or skeletal muscle increases glucose uptake. There is no evidence that the related channel Kv1.5 has any influence on insulin sensitivity and its expression in adipose tissue has not been reported. PAP-1 is a selective inhibitor of Kv1.3, with 23-fold, 32-fold and 125-fold lower potencies as an inhibitor of Kv1.5, Kv1.1 and Kv1.2 respectively. Soleus muscles from wild-type and genetically obese ob/ob mice were incubated with 2-deoxy[1-14C]-glucose for 45 min and formation of 2-deoxy[1-14C]-glucose-6-phosphate was measured. White adipocytes were incubated with D-[U-14C]-glucose for 1 h. TNFα and Il-6 secretion from white adipose tissue pieces were measured by enzyme-linked-immunoassay. In the absence of insulin, a high concentration (3 µM) of PAP-1 stimulated 2-deoxy[1-14C]-glucose uptake in soleus muscle of wild-type and obese mice by 30% and 40% respectively, and in adipocytes by 20% and 50% respectively. PAP-1 also stimulated glucose uptake by adipocytes at the lower concentration of 1 µM, but at 300 nM, which is still 150-fold higher than its EC50 value for inhibition of the Kv1.3 channel, it had no effect. In the presence of insulin, PAP-1 (3 µM) had a significant effect only in adipocytes from obese mice. PAP-1 (3 µM) reduced the secretion of TNFα by adipose tissue but had no effect on the secretion of IL-6. Expression of Kv1.1, Kv1.2, Kv1.3 and Kv1.5 was determined by RT-PCR. Kv1.3 and Kv1.5 mRNA were detected in liver, gastrocnemius muscle, soleus muscle and white adipose tissue from wild-type and ob/ob mice, except that Kv1.3 could not be detected in gastrocnemius muscle, nor Kv1.5 in liver, of wild-type mice. Expression of both genes was generally higher in liver and muscle of ob/ob mice compared to wild-type mice. Kv1.5 appeared to be expressed more highly than Kv1.3 in soleus muscle, adipose tissue and adipocytes of wild-type mice. Expression of Kv1.2 appeared to be similar to that of Kv1.3 in soleus muscle and adipose tissue, but Kv1.2 was undetectable in adipocytes. Kv1.1 could not be detected in soleus muscle, adipose tissue or adipocytes. We conclude that inhibition of Kv1 channels by PAP-1 stimulates glucose uptake by adipocytes and soleus muscle of wild-type and ob/ob mice, and reduces the secretion of TNFα by adipose tissue. However, these effects are more likely due to inhibition of Kv1.5 than to inhibition of Kv1.3 channels.

The effects of plasma chromium on lipid profile, glucose metabolism and cardiovascular risk in type 2 diabetes mellitus. A case - control study

Background The study was aimed at determining the effect of plasma chromium concentration on the metabolism of glucose, and lipids and their subsequent cardiovascular risk in patients with type 2 diabetes in the Bolgatanga district of Ghana. Material and methods Fasting blood glucose and lipids profile were determined by enzymatic assay using the BT 5000® Random Access Chemistry Analyzer. Fasting serum insulin and High sensitive C-reactive protein were determined by ELISA, a solid phase direct sandwich immunoassay method. HOMA-IR, which is based on fasting blood sample for insulin and glucose concentrations measured in a single blood sample, was used to calculate insulin resistance. Plasma chromium was measured using an atomic Absorption Spectrometer. Results Patientswith diabeteshad significantly (p<0.0001) increased LDL, TC, TG, VLDL, insulin, CRP and HOMAIR and a significantly reduced plasma chromium (p<0.0001) (0.53± 0.02μg/l and 0.11±0.01μg/l control and case respectively). Low Cr (p ≤0.001) was associated with high blood pressure, obesity and lipid dysregulation. Plasma Cr significantly correlated negatively with blood pressure and LDL. Conclusion Lower plasma Cr level was associated with hyperglycaemia, hyperinsulinemia, hypertension, insulin resistance and high inflammation marker HsCRP.

Placental peptides metabolism and maternal factors as predictors of risk of gestational diabetes in pregnant women. A case-control study

Background Gestational diabetes is a risk factor for perinatal complications; include shoulder dystocia, birth injuries such as bone fractures and nerve palsies. It is associated with later development of type 2 diabetes, the risk of macrosomia and other long-term health effects of infants born to diabetic mothers. The study assesses placental peptides and maternal factors as potential predictors of gestational diabetes among pregnant women. Material and methods A total of 200 pregnant women were recruited for the study, 150 pregnant women without pre gestational diabetes including 50 women with low risk factors of diabetes as controls and 50 other pregnant women with pregestational diabetes as control. Fasting blood glucose and the lipid profile were determined by enzymatic methods using Envoy® 500 reagents (Vital Diagnostics, USA). Glycated haemoglobin was assessed using the Cation Exchange resin method. Leptin and the Human Placenta Lactogen were assayed using the Sandwich-ELISA technique. Beta chorionic gonadotrophin, insulin, progesterone and estradiol were determined using chemilumiscence imunoassay technique on MAGLUMI 600 analyzer. Anthropometry, including BMI and blood pressure were also measured. Results Fasting plasma glucose (FBG), insulin, insulin resistance, glycated haemoglobin and Human Placenta Lactogen(HPL)were significantly (p<0.0001) increased in the pregestational diabetic women whereas progesterone and estradiol were significantly decreased. In the second trimester however, there was no significant difference (p>0.05) in estradiol, insulin, insulin resistance and HPL between the pregnant women who developed gestational diabetes and those who did not. Leptin, progesterone and FBG were significantly increased in those who developed GDM. The risk of developing gestational diabetes increased with overweight (OR = 1.76, P = 0.370) and family history of diabetes (OR = 2.18, P = 0.282). Conclusion Leptin, progesterone, estradiol estimated in this study were increased in the gestational diabetes mellitus women and fairly predicted gestational diabetes in the non-diabetics pregnant women. Obesity, aging and family history of diabetes were strongly predictive of gestational diabetes.