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Papers by Peter Owira

Journal of Endocrinology and Metabolism, 2017

The use of highly active antiretroviral therapy (HAART) has extremely enhanced the clinical outco... more The use of highly active antiretroviral therapy (HAART) has extremely enhanced the clinical outcome of HIV disease with a decrease in mortality and morbidity. However, the inclusion of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (tNRTIs) has strongly been linked to the development of metabolic abnormalities and lipodystrophy. Lipodystrophy is defined by the loss of peripheral subcutaneous fat and central adiposity, mainly in the abdomen, breast and dorsocervical region. These disorders are reported to be cosmetically distressing and socially stigmatizing to many patients leading to decreased adherence to antiretroviral therapy. Metabolic syndrome precedes lipodystrophy leading to increased risk of diabetes and cardiovascular diseases. With a shifted trajectory of HIV/AIDS morbidity from immunodeficiency and opportunistic infections to metabolic complications, clinical management of these patients has therefore become more complex. Currently there are no evidence-based standard guidelines for the management of HIV-associated lipodystrophy. Several pharmacological interventions such as using anti-diabetic, anti-dyslipidemic drugs or hormone replacement therapy have been tried to effectively improve metabolic syndrome and lipodystrophy but have been hampered by low efficacy, drug interactions, or unwanted side-effects. Non-pharmacological interventions including surgical manipulations, dietary and lifestyle modifications have also been tried with limited success. This review focuses on the proposed mechanisms involved in the development of metabolic syndrome and lipodystrophy, and highlights suggested potential therapeutic interventions to prevent lipodystrophy associated with HAART.

Journal of Chromatography B, Sep 1, 2018

European Journal of Pharmacology, May 1, 2017

Metformin-like antidiabetic, cardio-protective and non-glycemic effects of naringenin: molecular ... more Metformin-like antidiabetic, cardio-protective and non-glycemic effects of naringenin: molecular and pharmacological insights.

Social Science Research Network, 2022

Journal of Functional Foods, 2019

Protective effects of naringin against HIV-1 protease inhibitors (PIs)-induced dyslipidemia and o... more Protective effects of naringin against HIV-1 protease inhibitors (PIs)-induced dyslipidemia and oxidative stress were investigated in vivo. Male Wistar rats were orally treated daily with atazanavir {ATV; 133 mg/kg body weight (BW)}, saquinavir (SQV; 333 mg/kg BW), distilled water (3.0 ml/kg BW) and with or without naringin (NAR; 50 mg/kg BW) for 56 days, respectively. ATV or SQV significantly reduced body weights and plasma HDL cholesterol concentrations but increased total cholesterol, triglycerides, LDL-cholesterol, VLDL-cholesterol concentrations and calculated atherogenic index ratio, respectively. Furthermore, ATV or SQV treatment significantly increased lipid peroxidation and carbonyl proteins concentrations in plasma, liver and pancreas tissues but significantly reduced antioxidant activities in the liver and pancreas compared to the controls, respectively. However, naringin treatment significantly improved weight loss, dyslipidemia and oxidative stress in ATV-or SQV-treated rats, respectively. Naringin prevents HIV PIs-induced dyslipidemia and oxidative stress and may therefore mitigate PI-associated metabolic complications in HIV patients.

Journal of diabetes & metabolism, Oct 7, 2017

Journal of Parenteral and Enteral Nutrition, 2008

Background: Chronic pancreatic exocrine insufficiency results in maldigestion. As a result, incre... more Background: Chronic pancreatic exocrine insufficiency results in maldigestion. As a result, increased amounts of undigested nutrients reach the colon, providing more substrate for bacterial fermentation to produce short‐chain fatty acids, which could therefore provide additional energy supplement. Methods: This study aimed to assess carbohydrate malabsorption in patients with chronic pancreatic exocrine insufficiency after ingestion of a standard diet and to calculate energy salvaged by colonic bacterial metabolism. A 72‐hour stool collection was done on 10 adult patients receiving a 3‐day standard diet containing 100 g fat, 329 g carbohydrate, and 154 g protein, and short‐chain fatty acids, fat, carbohydrate, and nitrogen excretion were assessed. A breath hydrogen test after ingestion of 200 g (dry weight) cooked maize meal (test meal) and 10 g oral inulin (standard), respectively, was subsequently done on the patients and 15 healthy adult controls. Results: Breath hydrogen production after ingestion of maize meal and inulin, respectively, and calculated carbohydrate malabsorption were significantly greater in patients (21.4% ± 17%) than in controls (10.2 ± 1.4%; p < .05). Patients malabsorbed 70.4 g/d (281.6 kcal) carbohydrate in the standard diet. Total carbohydrate loss in stool amounted to 8.1 g/d (2.4%), and 62.3 g/d (19%) was hence salvaged as short‐chain fatty acids for energy provision. Colonic bacterial fermentation therefore converted 88.5% of malabsorbed carbohydrate to short‐chain fatty acids, 92.8% of which was absorbed and 7.2% excreted. This suggests that 10.2% of energy expenditure/requirement in these patients is derived from salvage of malabsorbed carbohydrate. Conclusions: Colonic bacterial metabolism is a significant source of energy salvage in patients with pancreatic enzyme deficiency.

Effect of grapefruit juice on plasma insulin Effect of grapefruit juice on hepatic glucose homeos... more Effect of grapefruit juice on plasma insulin Effect of grapefruit juice on hepatic glucose homeostasis 4.5.1 Hepatic glycogen content 4.5.2 Hepatic glucokinase activity 4.5.3 Hepatic glucose-6-phosphatase activity 4.5.4 Hepatic phosphoenolpyruvate activity 4.5.5 Hepatic adenosine monophosphate-activated protein kinase activity Effect of grapefruit juice on metformin-induced lactic acidosis Effect of grapefruit juice on hepatic metformin uptake Effect of grapefruit juice on hepatic expression of OCT 1 protein CHAPTERS DISCUSSION

Systematic Reviews, Jul 25, 2018

Background: Metformin is one of the most commonly used drugs for type 2 diabetes mellitus (T2DM).... more Background: Metformin is one of the most commonly used drugs for type 2 diabetes mellitus (T2DM). Despite its efficacy and safety, metformin is frequently associated with highly variable glycemic responses, which is hypothesized to be the result of genetic variations in its transport by organic cation transporters (OCTs). This systematic review aims to highlight and summarize the overall effects of OCT1 polymorphisms on therapeutic responses to metformin and to evaluate their potential role in terms of interethnic differences with metformin responses. Methods/design: We will systematically review observational studies reporting on the genetic association between OCT1 polymorphisms and metformin responses in T2DM patients. A comprehensive search strategy formulated with the help of a librarian will be used to search MEDLINE via PubMed, Embase, and CINAHL for relevant studies published between January 1990 and July 2017. Two review authors will independently screen titles and abstracts in duplicate, extract data, and assess the risk of bias with discrepancies resolved by discussion or arbitration of a third review author. Mined data will be grouped according to OCT1 polymorphisms, and their effects on therapeutic responses to metformin will be narratively synthesized. If sufficient numbers of homogeneous studies are scored, meta-analyses will be performed to obtain pooled effect estimates. Funnel plots analysis and Egger's test will be used to assess publication bias. This study will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Discussion: This review will summarize the genetic effects of OCT1 polymorphisms associated with variabilities in glycemic responses to metformin. The findings of this study could help to develop genetic tests that could predict a person's response to metformin treatment and create personalized drugs with greater efficacy and safety.

Methods and Findings in Experimental and Clinical Pharmacology, 2009

Recent clinical studies have indicated that grapefruit juice (GFJ) improves insulin resistance an... more Recent clinical studies have indicated that grapefruit juice (GFJ) improves insulin resistance and reduces weight gain in humans. The effect of GFJ on glucose tolerance and metformin-induced lactic acidosis in normal, non-diabetic in rats is hereby investigated. Three groups (A, B, C) of 20 male Wistar rats each, were treated with stepwise, escalated oral doses of 0, 1.0, 2.0, 3.0 (group A), and 3.0 ml/kg body weight (groups B and C) of GFJ. Group C rats additionally received 250 mg/kg body weight of metformin. All the animals were sacrificed after 14 days of treatment. Fasting blood glucose levels were significantly (P < 0.0001) lower in GFJ-treated test (2.9 +/- 0.4 mmol/L) compared with control (3.7 +/- 0.39 mmol/L) rats, but 1.5-hr plasma insulin levels were similar. GFJ alone or in combination with metformin, significantly (P < 0.05) lowered blood glucose levels compared with control animals. Blood lactic acid levels were similar in GFJ-treated test (2.81 +/- 1.4 mmol/L) and control (2.54 +/- 0.7 mmol/L) rats, respectively, but were significantly increased (P = 0.0079) in rats that were treated with either metformin alone (5.38 +/- 2.53 mmol/L) or in combination with GFJ (8.31 +/- 3.48 mmol/L). Metformin concentration in liver tissue was significantly higher (P < 0.05) in GFJ-treated (397 +/- 19 microg/g) than in control (280 +/- 15 microg/g) rats, respectively. Plasma metformin levels were comparable between the control (95 +/- 8.1 microg/ml) and GFJ-treated test (108 +/- 20 microg/ml) rats, respectively. Liver tissue metformin concentrations and plasma lactic acid levels showed significant correlation in both control (P = 0.0122; r(2) = 0.9080) and GFJ-treated test rats (P = 0.0005; r(2) = 0.9893). Although GFJ may be beneficial to diabetic patients, it may exacerbate lactic acidosis in diabetic patients taking metformin concurrently.

Journal of Functional Foods, Aug 1, 2019

Modulation of metformin transporters could affect its pharmacokinetics/pharmacodynamics. The effe... more Modulation of metformin transporters could affect its pharmacokinetics/pharmacodynamics. The effects of naringenin on the renal tubular Organic Cation Transporter 1 (OCT1) and 2 (OCT2) protein expressions and subsequently the metformin clearance in diabetic rats are hereby investigated. Male Sprague Dawley rats were divided into 7 groups. Animals were daily treated orally with metformin (250 mg/kg) or naringenin (60 mg/kg) alone or both for 56 days. Blood glucose tests were done. Serum, urine, and kidney samples were collected. Naringenin alone or in combination with metformin significantly increased creatinine clearance and lowered plasma metformin concentrations in diabetic rats compared to controls. OCT1 and OCT2 protein expressions in renal tissues were unchanged in diabetic rats treated with either naringenin or metformin, respectively. However, co-administration of metformin and naringenin upregulated OCT2 expression in diabetic rats. Naringenin may stimulate renal uptake/excretion of metformin by increasing OCT2 protein expression which facilitates metformin clearance in diabetic rats.

Basic & Clinical Pharmacology & Toxicology, Apr 3, 2020

Naringenin possesses many pharmacological effects and may modulate metformin disposition. The pur... more Naringenin possesses many pharmacological effects and may modulate metformin disposition. The purpose of this study was to evaluate the role of naringenin on hepatic expression of organic cation transporter 1 (OCT1) protein and its associated effects on metformin‐associated hyperlactataemia in diabetes. Forty‐nine male Sprague Dawley rats randomly assigned to seven groups (n = 7) were orally treated daily with 3.0 mL/kg body‐weight (BW) of distilled water (group 1) or 60 mg/kg BW of naringenin (groups 2 and 5) or 250 mg/kg BW of metformin (groups 3 and 6), respectively, dissolved in distilled water. Similarly, group 7 was given metformin and naringenin. Groups 4, 5, 6 and 7 were administered intraperitoneally with streptozotocin at a single dose of 60 mg/kg BW to induce diabetes. Glucose tolerance tests were performed. The animals were killed after 8 weeks of treatment, blood was collected, and livers excised for further biochemical analysis. Lowered body‐weight, increased polydipsia and reduced hepatic glycogen concentrations were observed in diabetic rats compared to controls. Naringenin only significantly decreased plasma lactate levels, while metformin only or with naringenin significantly increased plasma lactate levels in diabetic compared to non‐treated diabetic animals. Metformin only but not naringenin significantly increased plasma lactate levels in non‐diabetic compared to control rats. Furthermore, naringenin with or without metformin but not metformin only significantly increased hepatic organic cation transporter 1 (OCT1) expression in diabetic compared to non‐treated diabetic rats. Contrastingly, metformin only but not naringenin significantly increased hepatic OCT1 expression in non‐diabetic rats compared to controls. Diabetic rats treated with metformin exhibited significantly increased plasma metformin concentrations compared to non‐diabetic but naringenin significantly dropped this parameter. Conversely, hepatic metformin concentrations were significantly lower in diabetic rats treated with metformin compared to non‐diabetic rats but significantly increased when naringenin was added. These results suggest that naringenin ameliorated hyperglycaemia‐induced reduction in hepatic OCT1 expression leading to metformin accumulation and increased lactic acid production.

PLOS ONE, Nov 9, 2017

Background Insulin resistance, glucose intolerance and overt diabetes are known metabolic complic... more Background Insulin resistance, glucose intolerance and overt diabetes are known metabolic complications associated with chronic use of HIV-Protease Inhibitors. Naringin is a grapefruit-derived flavonoid with anti-diabetic, anti-dyslipidemia, anti-inflammatory and anti-oxidant activities. Objectives The study investigated the protective effects of naringin on glucose intolerance and impaired insulin secretion and signaling in vivo. Methods Male Wistar rats were divided into six groups (n = 6) and were daily orally treated with distilled water {3.0 ml/kg body weight (BW)}, atazanavir (133 mg/kg BW), saquinavir (333 mg/ kg BW) with or without naringin (50 mg/kg BW), respectively for 56 days. Body weights and water consumption were recorded daily. Glucose tolerance tests were carried out on day 55 of the treatment and thereafter, the rats were sacrificed by halothane overdose. Results Atazanavir (ATV)-or saquinavir (SQV)-treated rats exhibited significant weight loss, polydipsia, elevated Fasting blood glucose (FBG), reduced Fasting Plasma Insulin (FPI) and expression of phosphorylated, Insulin Receptor Substrate-1 (IRS-1) and Akt proteins, hepatic and pancreatic glucokinase levels, and also increasing pancreatic caspase-3 and-9 as well as UCP2 protein expressions compared to controls, respectively. These effects were completely reversed by naringin treatment. Conclusion Naringin prevents PI-induced glucose intolerance and impairment of insulin signaling and as nutritional supplement it could therefore alleviate metabolic complications associated with antiretroviral therapy.

PLOS ONE, Apr 13, 2016

Background Hypoglycemic effects of grapefruit juice are well known but the effects of naringin, i... more Background Hypoglycemic effects of grapefruit juice are well known but the effects of naringin, its main flavonoid on glucose intolerance and metabolic complications in type 1 diabetes are not known. Objectives To investigate the effects of naringin on glucose intolerance, oxidative stress and ketonemia in type 1 diabetic rats. Methods Sprague-Dawley rats divided into 5 groups (n = 7) were orally treated daily with 3.0 ml/kg body weight (BW)/day of distilled water (group 1) or 50 mg/kg BW of naringin (groups 2 and 4, respectively). Groups 3, 4 and 5 were given a single intra-peritoneal injection of 60 mg/kg BW of streptozotocin to induce diabetes. Group 3 was further treated with subcutaneous insulin (4.0 IU/kg BW) twice daily, respectively. Results Stretozotocin (STZ) only-treated groups exhibited hyperglycemia, polydipsia, polyuria, weight loss, glucose intolerance, low fasting plasma insulin and reduced hepatic glycogen content compared to the control group. Furthermore they had significantly elevated Malondialdehyde (MDA), acetoacetate, β-hydroxybutyrate, anion gap and significantly reduced blood pH and plasma bicarbonate compared to the control group. Naringin treatment significantly improved Fasting Plasma Insulin (FPI), hepatic glycogen content, malondialdehyde, β-hydroxybutyrate, acetoacetate, bicarbonate, blood pH and anion gap but not Fasting Blood Glucose (FBG) compared to the STZ only-treated group.

Phytotherapy Research, Feb 1, 2009

The traditional uses, therapeutic attributes, phytochemical and pharmacological profiles of 'Afri... more The traditional uses, therapeutic attributes, phytochemical and pharmacological profiles of 'African potato' (Hypoxis hemerocallidea corm) extracts have been reviewed. Available biomedical evidence suggests that 'African potato' is a potential plant-medicine for some modern and 21st century diseases of mankind. Thus far, biomedical evidence has revealed that 'African potato' extracts possess antiinflammatory, antineoplastic, antioxidant, antidiabetic and antiinfective properties in vivo and in vitro. However, more laboratory and clinical studies are required to clarify these observations, and to isolate, purify and characterize the active chemical constituents responsible for the herb's pharmaco-therapeutic effects.

Pharmaceutical medicine, Sep 13, 2022

Cellular senescence, a hallmark of ageing, contributes to tissue or organ dysfunction and the pat... more Cellular senescence, a hallmark of ageing, contributes to tissue or organ dysfunction and the pathophysiology of diverse agerelated diseases (ARD) by various mechanisms. Targeting it by selective elimination of senescent cells (SCs) or blocking senescence-associated secretory phenotypes (SASP) with natural or synthetic compounds has been suggested to improve lifespan. Dietary phytochemicals possess a broad spectrum of biochemical and pharmacological effects that are beneficial to human health. Flavonoids, which are widely consumed in fruits and vegetables worldwide, are emerging as potential therapeutic agents to mitigate senescence. Naringenin, hesperetin, hesperidin, quercetin, fisetin, kaempferol, rutin, apigenin, luteolin, nobiletin, tangeretin, genistein, wogonin, epigallocatechin gallate (EGCG), theaflavin-3-gallate (TF2A), and procyanidin C1 possess potent antisenescence effects. A single biochemical process may not explain their pleiotropic pharmacological impact. Flavonoids directly modulate underlying cellular senescence processes or interact with molecular targets that regulate ageing-related pathways. This review discusses the potential use of flavonoids to mitigate senescence and consequently delay the onset of ageing-related diseases. We also highlight the underlying mechanisms of action of flavonoids as potential senotherapeutics and reflect on future perspectives and possible strategies to optimize and increase the translatability from bench to bedside in senotherapy.

Life Sciences, Mar 1, 2006

Introduction: Ceramide induces programmed cell death and it is thought to contribute to cardiac i... more Introduction: Ceramide induces programmed cell death and it is thought to contribute to cardiac ischemia/reperfusion (I/R) injury. In contrast, we have demonstrated that administration of low doses of ceramide engenders cardiac preconditioning (PC). Ceramide is known to generate reactive oxygen species (ROS) in cells. Since mechanisms triggering the ceramide-induced cardioprotection remain unknown, we investigated the role of ROS in the genesis of this protective mechanism. Methods: Using an isolated Langendorff-perfused rat heart model, four groups (n ! 6 in each group) were considered: Control hearts underwent 30 min index regional ischemia and 120 min of reperfusion. In the ceramide group, hearts were preconditioned with c2-ceramide 1 AM for 7 min followed by 10 min washout prior to the I/R insult. In additional groups, MPG (1 mM), a synthetic antioxidant was given for 15 min alone or bracketing the ceramide perfusion. In each group, infarct size was determined at the end of the reperfusion period and superoxide dismutases (CuZnSOD and MnSOD) and catalase activities were evaluated. Results: Ceramide preconditioning reduced the infarct/area at risk (I/AAR) ratio (8.3 T 1.1% for ceramide vs. 36.4 T 1.2% for control, p < 0.001). Perfusion with MPG abolished the preconditioning effect of ceramide (I/AAR ratio = 36.7 T 4.9%). Ceramide was also associated with a 29% and 38% increase in catalase and CuZnSOD activities, respectively, compared with control group. Conclusion: Production of reactive oxygen species following ceramide preconditioning of the ischemic-reperfused heart appears to play a role in the cardioprotective effect of ceramide.

Journal of Cardiovascular Pharmacology, Feb 1, 2012

Antiatherogenic and hypoglycemic effects of naringin are hereby investigated in type 1 diabetes. ... more Antiatherogenic and hypoglycemic effects of naringin are hereby investigated in type 1 diabetes. Wistar rats (n = 6) were treated daily with 1.0 mL of water (group 1), naringin (50 mg/kg) (groups 2 and 3, respectively), regular insulin (4 U/kg, subcutaneously, twice daily) (group 4), and simvastatin (20 mg/kg) (group 6). Groups 3, 4, 5, and 6 exhibited polydipsia and hyperglycemia after injection with streptozotocin (60 mg/kg body weight). Insulin, but not naringin, significantly lowered fasting blood glucose levels in diabetic rats. Plasma low-density lipoprotein cholesterol concentrations were significantly higher in nontreated diabetic rats (group 5) compared with control (group 1), whereas total and high-density lipoprotein cholesterol were significantly higher in naringin- and simvastatin-treated diabetic rats, respectively. Hepatic total cholesterol and triglycerides were significantly elevated in nontreated diabetic compared with the control, naringin-, insulin-, and simvastatin-treated diabetic rats, respectively. Hepatic 3-hydroxy-3-methyl-glutaryl CoA reductase and Acyl-CoA:cholesterol acyltransferase activities were significantly elevated in nontreated diabetic compared with the control, naringin-, and simvastatin-treated diabetic rats, respectively. However, plasma low-density lipoprotein to high-density lipoprotein ratio was significantly higher in nontreated diabetic compared with the control, whereas naringin and simvastatin significantly reduced the ratio in diabetic rats. Naringin is not hypoglycemic but improves atherogenic index in type 1 diabetes.

Tropical Medicine & International Health, Sep 24, 2013

SummaryThe true incidence of diabetic ketoacidosis (DKA) in sub‐Saharan Africa is unknown but unl... more SummaryThe true incidence of diabetic ketoacidosis (DKA) in sub‐Saharan Africa is unknown but unlike in the Western countries, DKA is also uniquely frequent among type 2 diabetes patients of African origin. Increased hyperglycaemia and hepatic ketogenesis lead to osmotic diuresis, dehydration and tissue hypoxia. Acute complications of DKA include cerebral oedema, which may be compounded by malnutrition, parasitic and microbial infections with rampant tuberculosis and HIV. Overlapping symptoms of these conditions and misdiagnosis of DKA contribute to increased morbidity and mortality. Inability of the patients to afford insulin treatment leads to poor glycemic control as some patients seek alternative treatment from traditional healers or use herbal remedies further complicating the disease process. Standard treatment guidelines for DKA currently used may not be ideal as they are adapted from those of the developed world. Children presenting with suspected DKA should be screened for comorbidities which may complicate fluid and electrolyte replacement therapy protocol. Patient rehabilitation should take into account concurrent treatment for infectious conditions to avoid possible life‐threatening drug interactions. We recommend that health systems in sub‐Saharan Africa leverage the Expanded Immunization Programme or TB/HIV/AIDS programmes, which are fairly well entrenched to support diabetes services.

Digestive Diseases and Sciences, Jun 1, 2005

Although often used as a reference standard in the breath hydrogen test (BHT), lactulose fermenta... more Although often used as a reference standard in the breath hydrogen test (BHT), lactulose fermentation produces more hydrogen, compared to starch, and may therefore not be ideal. This study compares inulin with lactulose as reference standard in the study of carbohydrate malabsorption. Seventeen patients with malabsorption due to chronic pancreatitis and 15 normal controls were studied. Following overnight fasts, BHTs were performed after ingesting 10 g lactulose, 10 g inulin, and 200 g (16 g highly resistant starch) maize meal. Lactulose fermentation produced significantly more hydrogen than inulin in patients with malabsorption (97 ± 20 vs 45 ± 22 ppm • hr; P < 0.05) and controls (43 ± 18 vs 21 ± 10 ppm • hr; P < 0.05). Patients produced more hydrogen than controls with both standards (lactulose, 97 ± 20 vs 43 ± 18 ppm • hr, P < 0.05; inulin 45 ± 22 vs 21 ± 10 ppm • hrs; P < 0.05), suggesting adaptation of the colonic flora. Calculated CHO malabsorption was 2.5 ± 0.8 vs 5.2 ± 3.8 g with lactulose and 5.2 ± 3.1 vs 11.2 ± 9.6 g with inulin as standards in controls and patients, respectively (P < 0.05). Lactulose produces more breath hydrogen than inulin. Calculation of CHO malabsorption using these standards is therefore not comparable.