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Minocycline attenuates the development of diabetic neuropathic pain: possible anti-inflammatory and anti-oxidant mechanisms

Pabreja K, Dua K, Sharma S, Padi SS, Kulkarni SK

Eur J Pharmacol, 2011 Jul 1;661(1-3):15-21.
PMID: 21536024 DOI: 10.1016/j.ejphar.2011.04.014

Painful neuropathy, a common complication of diabetes mellitus is characterized by allodynia and hyperalgesia. Recent studies emphasized on the role of non-neuronal cells, particularly microglia in the development of neuronal hypersensitivity. The purpose of the present study is to evaluate the effect of minocyline, a selective inhibitor of microglial activation to define the role of neuroimmune activation in experimental diabetic neuropathy. Cold allodynia and thermal and chemical hyperalgesia were assessed and the markers of inflammation and oxidative and nitrosative stress were estimated in streptozotocin-induced diabetic rats. Chronic administration of minocycline (40 and 80 mg/kg, i.p.) for 2 weeks started 2 weeks after diabetes induction attenuated the development of diabetic neuropathy as compared to diabetic control animals. In addition, minocyline treatment reduced the levels of interleukin-1β and tumor necrosis factor-α, lipid peroxidation, nitrite and also improved antioxidant defense in spinal cords of diabetic rats as compared to diabetic control animals. In contrast, minocycline (80 mg/kg, per se) had no effect on any of these behavioral and biochemical parameters assessed in age-matched control animals. The results of the present study strongly suggest that activated microglia are involved in the development of experimental diabetic neuropathy and minocycline exerted its effect probably by inhibition of neuroimmune activation of microglia. In addition, the beneficial effects of minocycline are partly mediated by its anti-inflammatory effect by reducing the levels of proinflammatory cytokines and in part by modulating oxidative and nitrosative stress in the spinal cord that might be involved in attenuating the development of behavioral hypersensitivity in diabetic rats.

Matched MeSH terms: Blood Glucose/metabolism
Nicotinamide supplementation protects gestational diabetic rats by reducing oxidative stress and enhancing immune responses

John CM, Ramasamy R, Al Naqeeb G, Al-Nuaimi AH, Adam A

Curr Med Chem, 2012;19(30):5181-6.
PMID: 23237188

Gestational diabetes (GD) is a common complication during pregnancy. Metabolic changes in GD affect fetal development and fetal glucose homeostasis. The present study utilized a rat model of GD to evaluate the effects of nicotinamide on diabetic parameters; antioxidant gene expression viz, superoxide dismutase (SOD) and catalase (CAT); reactive oxygen species (ROS) production by neutrophils and enhancement of lymphocyte mediated immune response. Nicotinamide (50, 100 and 200 mg/kg) was orally supplemented to gestational diabetic rats from days 6 through 20 of gestation. After GD induction, the control group had elevated glucose and reduced insulin while nicotinamide (100 & 200 mg/kg) supplementation reversed these changes. The same doses of nicotinamide upregulated mRNA expressions of SOD and CAT genes in liver but reduced the oxidative burst activity of neutrophils in response to phorbol myristate acetate (PMA), N-formyl-methionyl-leucyl-phenylalanine (FMLP) or E. coli activation. Nicotinamide (100 & 200 mg/kg) supplementation also increased expression of activated T helper (CD4+CD25+) cells and induced proliferation of splenocytes. These findings provide evidence for utilizing nicotinamide as supplement or adjunct to support existing therapeutic agents for gestational diabetes and in pregnant individuals with weakened immune systems.

Matched MeSH terms: Blood Glucose/analysis
Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells

Soo JS, Ng CH, Tan SH, Malik RA, Teh YC, Tan BS, et al.

Apoptosis, 2015 Oct;20(10):1373-87.
PMID: 26276035 DOI: 10.1007/s10495-015-1158-5

Metformin, an AMPK activator, has been reported to improve pathological response to chemotherapy in diabetic breast cancer patients. To date, its mechanism of action in cancer, especially in cancer stem cells (CSCs) have not been fully elucidated. In this study, we demonstrated that metformin, but not other AMPK activators (e.g. AICAR and A-769662), synergizes 5-fluouracil, epirubicin, and cyclophosphamide (FEC) combination chemotherapy in non-stem breast cancer cells and breast cancer stem cells. We show that this occurs through an AMPK-dependent mechanism in parental breast cancer cell lines. In contrast, the synergistic effects of metformin and FEC occurred in an AMPK-independent mechanism in breast CSCs. Further analyses revealed that metformin accelerated glucose consumption and lactate production more severely in the breast CSCs but the production of intracellular ATP was severely hampered, leading to a severe energy crisis and impairs the ability of CSCs to repair FEC-induced DNA damage. Indeed, addition of extracellular ATP completely abrogated the synergistic effects of metformin on FEC sensitivity in breast CSCs. In conclusion, our results suggest that metformin synergizes FEC sensitivity through distinct mechanism in parental breast cancer cell lines and CSCs, thus providing further evidence for the clinical relevance of metformin for the treatment of cancers.

Matched MeSH terms: Glucose/metabolism
Fulltext Pharmacoinformatics and UPLC-QTOF/ESI-MS-Based Phytochemical Screening of Combretum indicum against Oxidative Stress and Alloxan-Induced Diabetes in Long-Evans Rats

Forid MS, Rahman MA, Aluwi MFFM, Uddin MN, Roy TG, Mohanta MC, et al.

Molecules, 2021 Jul 30;26(15).
PMID: 34361788 DOI: 10.3390/molecules26154634

This research investigated a UPLC-QTOF/ESI-MS-based phytochemical profiling of Combretum indicum leaf extract (CILEx), and explored its in vitro antioxidant and in vivo antidiabetic effects in a Long-Evans rat model. After a one-week intervention, the animals' blood glucose, lipid profile, and pancreatic architectures were evaluated. UPLC-QTOF/ESI-MS fragmentation of CILEx and its eight docking-guided compounds were further dissected to evaluate their roles using bioinformatics-based network pharmacological tools. Results showed a very promising antioxidative effect of CILEx. Both doses of CILEx were found to significantly (p < 0.05) reduce blood glucose, low-density lipoprotein (LDL), and total cholesterol (TC), and increase high-density lipoprotein (HDL). Pancreatic tissue architectures were much improved compared to the diabetic control group. A computational approach revealed that schizonepetoside E, melianol, leucodelphinidin, and arbutin were highly suitable for further therapeutic assessment. Arbutin, in a Gene Ontology and PPI network study, evolved as the most prospective constituent for 203 target proteins of 48 KEGG pathways regulating immune modulation and insulin secretion to control diabetes. The fragmentation mechanisms of the compounds are consistent with the obtained effects for CILEx. Results show that the natural compounds from CILEx could exert potential antidiabetic effects through in vivo and computational study.

Matched MeSH terms: Blood Glucose/drug effects
Fulltext Reduction of oxidative-nitrosative stress underlies anticataract effect of topically applied tocotrienol in streptozotocin-induced diabetic rats

Abdul Nasir NA, Agarwal R, Sheikh Abdul Kadir SH, Vasudevan S, Tripathy M, Iezhitsa I, et al.

PLoS One, 2017;12(3):e0174542.
PMID: 28350848 DOI: 10.1371/journal.pone.0174542

Cataract, a leading cause of blindness, is of special concern in diabetics as it occurs at earlier onset. Polyol accumulation and increased oxidative-nitrosative stress in cataractogenesis are associated with NFκB activation, iNOS expression, ATP depletion, loss of ATPase functions, calpain activation and proteolysis of soluble to insoluble proteins. Tocotrienol was previously shown to reduce lens oxidative stress and inhibit cataractogenesis in galactose-fed rats. In current study, we investigated anticataract effects of topical tocotrienol and possible mechanisms involved in streptozotocin-induced diabetic rats. Diabetes was induced in Sprague Dawley rats by intraperitoneal injection of streptozotocin. Diabetic rats were treated with vehicle (DV) or tocotrienol (DT). A third group consists of normal, non-diabetic rats were treated with vehicle (NV). All treatments were given topically, bilaterally, twice daily for 8 weeks with weekly slit lamp monitoring. Subsequently, rats were euthanized and lenses were subjected to estimation of polyol accumulation, oxidative-nitrosative stress, NFκB activation, iNOS expression, ATP levels, ATPase activities, calpain activity and total protein levels. Cataract progression was delayed from the fifth week onwards in DT with lower mean of cataract stages compared to DV group (p<0.01) despite persistent hyperglycemia. Reduced cataractogenesis in DT group was accompanied with lower aldose reductase activity and sorbitol level compared to DV group (p<0.01). DT group also showed reduced NFκB activation, lower iNOS expression and reduced oxidative-nitrosative stress compared to DV group. Lenticular ATP and ATPase and calpain 2 activities in DT group were restored to normal. Consequently, soluble to insoluble protein ratio in DT group was higher compared to DV (p<0.05). In conclusion, preventive effect of topical tocotrienol on development of cataract in STZ-induced diabetic rats could be attributed to reduced lens aldose reductase activity, polyol levels and oxidative-nitrosative stress. These effects of tocotrienol invlove reduced NFκB activation, lower iNOS expression, restoration of ATP level, ATPase activities, calpain activity and lens protein levels.

Matched MeSH terms: Blood Glucose/metabolism
Cortisol affects metabolic and ionoregulatory responses to a different extent depending on feeding ration in common carp, Cyprinus carpio

Liew HJ, Fazio A, Faggio C, Blust R, De Boeck G

Comp Biochem Physiol A Mol Integr Physiol, 2015 Nov;189:45-57.
PMID: 26219478 DOI: 10.1016/j.cbpa.2015.07.011

Interacting effects of feeding and stress on corticoid responses in fish were investigated in common carp fed 3.0% or 0.5% body mass (BM) which received no implant, a sham or a cortisol implant (250 mg/kg BM) throughout a 168 hour post-implant period (168 h-PI). At 12h-PI, cortisol implants elevated plasma cortisol, glucose and lactate. Plasma osmolality and ions remained stable, but cortisol increased gill and kidney Na(+)/K(+) ATPase (NKA) and H(+) ATPase activities. Gill NKA activities were higher at 3%-BM, whereas kidney H(+) ATPase activity was greater at 0.5%-BM. Cortisol induced liver protein mobilization and repartitioned liver and muscle glycogen. At 3%-BM, this did not increase plasma ammonia, reflecting improved excretion efficiency concomitant with upregulation of Rhesus glycoprotein Rhcg-1 in gill. Responses in glucocorticoid receptors (GR1/GR2) and mineralocorticoid receptor (MR) to cortisol elevation were most prominent in kidney with increased expression of all receptors at 24 h-PI at 0.5%-BM, but only GR2 and MR at 0.5%-BM. In the liver, upregulation of all receptors occurred at 24 h-PI at 3%-BM, whilst only GR2 and MR were upregulated at 0.5%-BM. In the gill, there was a limited upregulation: GR2 and MR at 72 h-PI and GR1 at 168 h-PI at 3%-BM but only GR2 at 72 h-PI at 0.5%-BM. Thus cortisol elevation led to similar expression patterns of cortisol receptors in both feeding regimes, while feeding affected the type of receptor that was induced. Induction of corticoid receptors occurred simultaneously with increases in Rhcg-1 mRNA expression (gill) but well after NKA and H(+) ATPase activities increased (gill/kidney).

Matched MeSH terms: Blood Glucose/metabolism
Fulltext Why do some people with type 2 diabetes who are using insulin have poor glycaemic control? A qualitative study

Tong WT, Vethakkan SR, Ng CJ

BMJ Open, 2015 Jan 29;5(1):e006407.
PMID: 25633285 DOI: 10.1136/bmjopen-2014-006407

OBJECTIVE: To explore factors influencing poor glycaemic control in people with type 2 diabetes using insulin.
RESEARCH DESIGN: A qualitative method comprising in-depth individual interviews. A semistructured interview guide was used. The interviews were audiorecorded, transcribed verbatim and analysed using a thematic approach.
PARTICIPANTS: Seventeen people with type 2 diabetes using insulin with glycated haemoglobin (HbA1c) ≥9% for >1 year.
SETTING: The Primary Care Clinic and Diabetes Clinic in the University of Malaya Medical Centre (UMMC), Malaysia.
RESULTS: Data analysis uncovered four themes: lifestyle challenges in adhering to medical recommendations; psychosocial and emotional hurdles; treatment-related factors; lack of knowledge about and self-efficacy in diabetes self-care.
CONCLUSIONS: Factors that explain the poor glycaemic control in people with type 2 diabetes using insulin were identified. Healthcare providers could use these findings to address patients' concerns during consultations and help to improve glycaemic control.
Study site: Primary Care Clinic and Diabetes Clinic, University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia

Matched MeSH terms: Blood Glucose Self-Monitoring
Fulltext Effects of red pitaya juice supplementation on cardiovascular and hepatic changes in high-carbohydrate, high-fat diet-induced metabolic syndrome rats

Ramli NS, Brown L, Ismail P, Rahmat A

BMC Complement Altern Med, 2014;14:189.
PMID: 24919841 DOI: 10.1186/1472-6882-14-189

The fruit of Hylocereus polyrhizus, also known as red pitaya, and buah naga in Malay, is one of the tropical fruits of the cactus family, Cactaceae. Red pitaya has been shown to protect aorta from oxidative damage and improve lipid profiles in hypercholesterolemic rats probably due to phytochemicals content including phenolics and flavonoids. The aim of this study was to investigate the changes in cardiac stiffness, hepatic and renal function in high-carbohydrate, high-fat diet-induced obese rats following supplementation of red pitaya juice.

Matched MeSH terms: Glucose Tolerance Test
Fulltext Poor glycemic control in younger women attending Malaysian public primary care clinics: findings from adults diabetes control and management registry

Cheong AT, Lee PY, Sazlina SG, Mohamad Adam B, Chew BH, Mastura I, et al.

BMC Fam Pract, 2013;14:188.
PMID: 24325794 DOI: 10.1186/1471-2296-14-188

BACKGROUND: Women of reproductive age are a group of particular concern as diabetes may affect their pregnancy outcome as well as long-term morbidity and mortality. This study aimed to compare the clinical profiles and glycemic control of reproductive and non-reproductive age women with type 2 diabetes (T2D) in primary care settings, and to determine the associated factors of poor glycemic control in the reproductive age group women.
METHODS: This was a cross-sectional study using cases reported by public primary care clinics to the Adult Diabetes Control and Management registry from 1st January to 31st December 2009. All Malaysian women aged 18 years old and above and diagnosed with T2D for at least 1 year were included in the analysis. The target for glycemic control (HbA1c < 6.5%) is in accordance to the recommended national guidelines. Both univariate and multivariate approaches of logistic regression were applied to determine whether reproductive age women have an association with poor glycemic control.
RESULTS: Data from a total of 30,427 women were analyzed and 21.8% (6,622) were of reproductive age. There were 12.5% of reproductive age women and 18.0% of non-reproductive age women that achieved glycemic control. Reproductive age group women were associated with poorer glycemic control (OR = 1.5, 95% CI = 1.2-1.8). The risk factors associated with poor glycemic control in the reproductive age women were being of Malay and Indian race, longer duration of diabetes, patients on anti-diabetic agents, and those who had not achieved the target total cholesterol and triglycerides.
CONCLUSION: Women with T2D have poor glycemic control, but being of reproductive age was associated with even poorer control. Health care providers need to pay more attention to this group of patients especially for those with risk factors. More aggressive therapeutic strategies to improve their cardiometabolic control and pregnancy outcome are warranted.

Matched MeSH terms: Blood Glucose
Cost-effectiveness of insulin detemir versus insulin glargine for Thai type 2 diabetes from a payer's perspective

Permsuwan U, Thavorn K, Dilokthornsakul P, Saokaew S, Chaiyakunapruk N

J Med Econ, 2017 Sep;20(9):991-999.
PMID: 28649943 DOI: 10.1080/13696998.2017.1347792

AIMS: An economic evidence is a vital tool that can inform the decision to use costly insulin analogs. This study aimed to evaluate long-term cost-effectiveness of insulin detemir (IDet) compared with insulin glargine (IGlar) in type 2 diabetes (T2DM) from the Thai payer's perspective.
METHODS: Long-term costs and outcomes were projected using a validated IMS CORE Diabetes Model, version 8.5. Cohort characteristics, baseline risk factors, and costs of diabetes complications were derived from Thai data sources. Relative risk was derived from a systematic review and meta-analysis study. Costs and outcomes were discounted at 3% per annum. Incremental cost-effectiveness ratio (ICER) was presented in 2015 US Dollars (USD). A series of one-way and probabilistic sensitivity analyses were performed.
RESULTS: IDet yielded slightly greater quality-adjusted life years (QALYs) (8.921 vs 8.908), but incurred higher costs than IGlar (90,417.63 USD vs 66,674.03 USD), resulting in an ICER of ∼1.7 million USD per QALY. The findings were very sensitive to the cost of IDet. With a 34% reduction in the IDet cost, treatment with IDet would become cost-effective according to the Thai threshold of 4,434.59 USD per QALY.
CONCLUSIONS: Treatment with IDet in patients with T2DM who had uncontrolled blood glucose with oral anti-diabetic agents was not a cost-effective strategy compared with IGlar treatment in the Thai context. These findings could be generalized to other countries with a similar socioeconomics level and healthcare systems.

Matched MeSH terms: Blood Glucose
Reduced mitochondrial DNA content in lymphocytes is associated with insulin resistance and inflammation in patients with impaired fasting glucose

Abu Bakar MH, Hairunisa N, Zaman Huri H

Clin Exp Med, 2018 Aug;18(3):373-382.
PMID: 29550985 DOI: 10.1007/s10238-018-0495-4

Altered mitochondrial DNA (mtDNA) is the most common denominator to numerous metabolic diseases. The present study sought to investigate the correlation between mtDNA content in lymphocytes and associated clinical risk factors for impaired fasting glucose (IFG). We included 23 healthy control and 42 IFG participants in this cross-sectional study. The measurements of mtDNA content in lymphocytes and pro-inflammatory markers derived from both normal and diseased individuals were quantified. Spearman partial correlation and multivariate statistical analyses were employed to evaluate the association between mtDNA content and other metabolic covariates in IFG. Reduced mtDNA content was observed in the IFG group with microvascular complications than those without complications. The IFG patients with lowest median of mtDNA content had considerably elevated hyperglycemia, insulin resistance and inflammation. The adjusted partial correlation analysis showed that mtDNA content was positively correlated with HDL-cholesterol and IL-10 (P

Matched MeSH terms: Glucose Tolerance Test

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