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Effects of metformin on the cerebral metabolic changes in type 2 diabetic patients.

ABSTRACT: Metformin, a widely used antidiabetic drug, has numerous effects on human metabolism. Based on emerging cellular, animal, and epidemiological studies, we hypothesized that metformin leads to cerebral metabolic changes in diabetic patients. To explore metabolism-influenced foci of brain, we used 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) positron emission tomography for type 2 diabetic patients taking metformin (MET, n = 18), withdrawing from metformin (wdMET, n = 13), and not taking metformin (noMET, n = 9). Compared with the noMET group, statistical parametric mapping showed that the MET group had clusters with significantly higher metabolism in right temporal, right frontal, and left occipital lobe white matter and lower metabolism in the left parahippocampal gyrus, left fusiform gyrus, and ventromedial prefrontal cortex. In volume of interest (VOI-) based group comparisons, the normalized FDG uptake values of both hypermetabolic and hypometabolic clusters were significantly different between groups. The VOI-based correlation analysis across the MET and wdMET groups showed a significant negative correlation between normalized FDG uptake values of hypermetabolic clusters and metformin withdrawal durations and a positive but nonsignificant correlation in the turn of hypometabolic clusters. Conclusively, metformin affects cerebral metabolism in some white matter and semantic memory related sites in patients with type 2 diabetes.

SUBMITTER: Huang YC

PROVIDER: S-EPMC3982461 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Effects of metformin on the cerebral metabolic changes in type 2 diabetic patients.

Huang Yung-Cheng YC Hsu Chien-Chin CC Lin Wei-Che WC Yin Tang-Kai TK Huang Chi-Wei CW Wang Pei-Wen PW Chang Han-Hsuan HH Chiu Nan-Tsing NT

TheScientificWorldJournal 20140324

Metformin, a widely used antidiabetic drug, has numerous effects on human metabolism. Based on emerging cellular, animal, and epidemiological studies, we hypothesized that metformin leads to cerebral metabolic changes in diabetic patients. To explore metabolism-influenced foci of brain, we used 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) positron emission tomography for type 2 diabetic patients taking metformin (MET, n = 18), withdrawing from metformin (wdMET, n = 13), and not taking metformin (noME ...[more]

PMID: 24782665

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Project description:BackgroundThe association between prolong metformin usage and B12 deficiency has been documented. However, the prevalence estimates of metformin-induced vitamin B12 deficiency showed substantial disparity among studies due to varied study definitions of vitamin B12 deficiency. Metformin blocks the calcium dependent absorption of the vitamin B12-Intrinsic Factor complex at the terminal ileum. Lack of intrinsic factor due to the presence of auto-antibodies to parietal cells (IFA) could lead to vitamin B12 deficiency and subsequently cause peripheral neuropathy. We investigated the prevalence of vitamin B12 deficiency using more sensitive, combined markers of vitamin B12 status (4cB12) and the immuno-biochemical mediators of vitamin B12 deficiency.MethodsIn this observational study, 200 consecutive consenting metformin-treated T2DM patients, aged 35 and above, attending the diabetic clinic at KATH were recruited. Vitamin B12 deficiency was classified based on the Fedosov age-normalized wellness quotient. Anthropometric measurement was taken as well as blood samples for immunological and biochemical mediators. Peripheral neuropathy was assessed using the Michigan Neuropathy Screening Instrument (MNSI). Statistical analysis was performed using the R Language for Statistical Computing.ResultsUsing the combined indicator (4cB12), the prevalence of metformin induced vitamin B12 deficiency was 40.5% whilst the prevalence of MNSI-Q and MNSI-PE diabetic neuropathy was 32.5% and 6.5% respectively. Participants with vitamin B12 deficiency had significantly higher levels of IFA, GPA, TNF-α, TC, LDL and albumin compared to those with normal vitamin B12 levels (p < 0.05). Correlation analysis revealed a statistically significant negative association between 4cB12 and the immunological markers [IFA (rs = -0.301, p<0.0001), GPA (rs = -0.244, p = 0.001), TNF-α (rs = -0.242, p = 0.001) and IL-6 (rs = -0.145, p = 0.041)]. Likewise, 4cB12 was negatively associated with TC (rs = -0.203, p = 0.004) and LDL (rs = -0.222, p = 0.002) but positively correlated with HDL (rs = 0.196, p = 0.005).ConclusionVitamin B12 deficiency and diabetic neuropathy are very high among metformin-treated T2DM patients and it is associated with increased GPA, IFA, TNF-α and cardiometabolic risk factors (higher LDL and TC and lower HDL). Upon verification of these findings in a prospective case-control study, it may be beneficial to include periodic measurement of Vitamin B12 using the more sensitive combined indicators (4cB 12) in the management of patients with T2DM treated with metformin in Ghana.

Project description:BACKGROUND:Metformin might reduce insulin requirement and improve glycaemia in patients with type 1 diabetes, but whether it has cardiovascular benefits is unknown. We aimed to investigate whether metformin treatment (added to titrated insulin therapy) reduced atherosclerosis, as measured by progression of common carotid artery intima-media thickness (cIMT), in adults with type 1 diabetes at increased risk for cardiovascular disease. METHODS:REMOVAL was a double-blind, placebo-controlled trial undertaken at 23 hospital diabetes clinics in five countries (Australia, Canada, Denmark, the Netherlands, and the UK). Adults aged 40 years and older with type 1 diabetes of at least 5 years' duration and at least three of ten specific cardiovascular risk factors were randomly assigned (via an interactive voice response system) to oral metformin 1000 mg twice daily or placebo. Participants and site staff were masked to treatment allocation. The primary outcome was averaged mean far-wall cIMT, quantified annually for 3 years, analysed in a modified intention-to-treat population (all randomly assigned participants with post-randomisation data available for the outcome of interest at any given timepoint, irrespective of subsequent adherence or study participation), using repeated measures regression. Secondary outcomes were HbA1c, LDL cholesterol, estimated glomerular filtration rate (eGFR), incident microalbuminuria (not reported), incident retinopathy, bodyweight, insulin dose, and endothelial function, also analysed in all participants with post-randomisation data available for the outcome of interest at any given timepoint. This trial is registered with ClinicalTrials.gov, number NCT01483560. FINDINGS:Between Dec 14, 2011, and June 24, 2014, 493 participants entered a 3 month run-in to optimise risk factor and glycaemic control (single-blind placebo in the final month). Of 428 randomly assigned patients, 219 were allocated to metformin and 209 to placebo. Progression of mean cIMT was not significantly reduced with metformin (-0·005 mm per year, 95% CI -0·012 to 0·002; p=0·1664), although maximal cIMT (a prespecified tertiary outcome) was significantly reduced (-0·013 mm per year, -0·024 to -0·003; p=0·0093). HbA1c (mean 8·1% [SD 0·9] for metformin and 8·0% [0·8] for placebo at baseline) was reduced on average over 3 years by metformin (-0·13%, 95% CI -0·22 to -0·037; p=0·0060), but this was accounted for by a reduction at the 3-month timepoint (-0·24%, -0·34 to -0·13; p<0·0001) that was not sustained thereafter (p=0·0163 for visit-by-treatment interaction). Bodyweight (-1·17 kg, 95% CI -1·66 to -0·69; p<0·0001) and LDL cholesterol (-0·13 mmol/L, -0·24 to -0·03; p=0·0117) were reduced with metformin over 3 years of treatment, and eGFR was increased (4·0 mL/min per 1·73m2, 2·19 to 5·82; p<0·0001). Insulin requirement was not reduced on average over 3 years (-0·005 units per kg, 95% CI -0·022 to 0·012; p=0·545), but there was a significant visit-by-treatment interaction (p=0·0018). There was no effect on endothelial function as measured by reactive hyperaemia index, or on retinopathy. Discontinuation of treatment in 59 (27%) participants on metformin versus 26 (12%) on placebo (p=0·0002) was mainly due to an excess of gastrointestinal adverse effects, and there was no increase in hypoglycaemia with metformin. Five deaths occurred among patients allocated to metformin and two occurred among those allocated to placebo; none were judged by site principal investigators to be related to study medication. INTERPRETATION:These data do not support use of metformin to improve glycaemic control in adults with long-standing type 1 diabetes as suggested by current guidelines, but suggest that it might have a wider role in cardiovascular risk management. FUNDING:JDRF.

Project description:Objective: The Food and Drug Administration recently updated metformin prescribing recommendations for patients with diabetes and renal disease. The American Diabetes Association as well as the American Association of Clinical Endocrinologists and American Clinical Endocrinologists also recommend periodic monitoring of vitamin B12 levels for patients using metformin. A review of the literature was conducted to assess data to evaluate the recent updates to metformin usage and provide rationales for these recommendations. Data Sources: PubMed MESH terms “Diabetes Mellitus, Type 2” and “Renal Insufficiency, Chronic” and “Metformin” were searched with an English limitation from 1990 to May 2017. A MEDLINE search was conducted using the terms “metformin” and “renal disease” from 1990 to May 2017. A PubMed search was conducted using the MESH terms “vitamin b12 deficiency” and “metformin” from 1970 to May 2017. A MEDLINE search was conducted using terms “metformin” and “vitamin B12 deficiency” with an English limitation from 1970 to May 2017. Study Selection and Data Extraction: Retrospective and prospective clinical trials, meta-analyses, and systematic reviews were considered for inclusion. Citations from identified articles were also reviewed for inclusion. Data Synthesis: The incidence of metformin-associated lactic acidosis is minimal. Data indicate metformin-treated patients with an estimated glomerular filtration rate above 30 mL/min/1.73 m2 have a reduction in mortality. Additionally, data suggest metformin may lead to vitamin B12 deficiency. Conclusion: Data support recommendations for metformin use in patients with diabetes and renal insufficiency with an estimated glomerular filtration rate above 30 mL/min/1.73 m2. Data also suggest that baseline and periodic testing of vitamin B12 levels are warranted and supported by clinical guidelines due to the risk of vitamin B12 deficiency in metformin-treated patients.

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Effects of metformin on the cerebral metabolic changes in type 2 diabetic patients.

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Effects of metformin on the cerebral metabolic changes in type 2 diabetic patients.

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