Metformin In Treatment Of Type Research Articles

Impact of the timing of metformin administration on glycaemic and glucagon-like peptide-1 responses to intraduodenal glucose infusion in type 2 diabetes: a double-blind, randomised, placebo-controlled, crossover study

Aims/hypothesisMetformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes.MethodsSixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = −60, −30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0–60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = −60 min and t = 120 min.ResultsThere was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = −60 or −30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = −60 or −30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given.Conclusions/interpretationIn well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control.Trial registrationwww.anzctr.org.au ACTRN12621000878875FundingThe study was not funded by a specific research grant.Graphical

Vitamin B12 Deficiency among Metformin Treated Type 2 Diabetic Mellitus Patients Visiting the Department of Medicine of a Tertiary Care Centre.

About 424.9 million people worldwide are affected by Diabetes mellitus. Prevalence among people 20-79 years old in Nepal was 4% in 2017. It is associated with microvascular and macrovascular complications such as peripheral neuropathy leading to risk of foot ulcers and amputation, and impaired sensation in their feet. The study aimed to find the prevalence of vitamin B12 deficiency among metformin-treated type 2 diabetic patients visiting the Department of Medicine of a tertiary care centre. A descriptive cross-sectional study was conducted in a tertiary care centre between 24 May 2021 to 24 May 2022 after obtaining ethical approval from the Institutional Review Committee. Patients who visited the Department of Medicine and gave informed consent were included in the study. Patients with underlying comorbidities were excluded from the study. A convenience sampling method was used. The point estimate was calculated at a 95% Confidence Interval. Among 330 patients, vitamin B12 deficiency was seen in 33 (10%) (6.76-13.24, 95% Confidence Interval). Among them, 27 (81.82%) were male and 6 (18.18%) were female. The prevalence of vitamin B12 deficiency was found to be higher than other studies done in similar settings. diabetic neuropathy; metformin; type 2 diabetes; vitamin B12.

Gene expression of protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1), solute carrier family 2 member 1 (SLC2A1) and mechanistic target of rapamycin (MTOR) in metformin-treated type 2 diabetes patients with COVID-19: impact on inflammation markers.

The COVID-19 pandemic has resulted in a global health crisis that has severely impacted patients with type 2 diabetes (T2D). T2D patients have a higher risk of experiencing severe COVID-19 symptoms, hospitalization, and mortality compared to patients without diabetes. The dysregulated immune response in T2D patients can exacerbate the severity of COVID-19 symptoms. Insulin therapy, a common treatment for T2D patients, has been linked to increased mortality in COVID-19 patients with T2D. However, metformin, an anti-diabetic medication, has been shown to have anti-inflammatory properties that may mitigate the cytokine storm observed in severe COVID-19 cases. In this study, we investigated how the PRKAA1, SLC2A1, and MTOR genes contribute to inflammation markers in COVID-19 patients with T2D, who were receiving either insulin or metformin therapy. Our findings revealed that metformin treatment was associated with reduced expression of genes involved in Th1/Th17 cell differentiation. These results suggest that metformin could be a potential treatment option for T2D patients with COVID-19 due to its anti-inflammatory properties, which may improve patient outcomes.

Acarbose diminishes postprandial suppression of bone resorption in patients with type 2 diabetes.

The alpha-glucosidase inhibitor acarbose is an antidiabetic drug delaying assimilation of carbohydrates and, thus, increasing the amount of carbohydrates in the distal parts of the intestines, which in turn increases circulating levels of the gut-derived incretin hormone glucagon-like peptide 1 (GLP-1). As GLP-1 may suppress bone resorption, acarbose has been proposed to potentiate meal-induced suppression of bone resorption. We investigated the effect of acarbose treatment on postprandial bone resorption in patients with type 2 diabetes and used the GLP-1 receptor antagonist exendin(9-39)NH2 to disclose contributory effect of acarbose-induced GLP-1 secretion. In a randomised, placebo-controlled, double-blind, crossover study, 15 participants with metformin-treated type 2 diabetes (2 women/13 men, age 71 (57-85years), BMI 29.7 (23.6-34.6kg/m2), HbA1c 48 (40-74mmol/mol)/6.5 (5.8-11.6%) (median and range)) were subjected to two 14-day treatment periods with acarbose and placebo, respectively, separated by a six-week wash-out period. At the end of each period, circulating bone formation and resorption markers were assessed during two randomised 4-h liquid mixed meal tests (MMT) with infusions of exendin(9-39)NH2 and saline, respectively. Glucagon-like peptide 2 (GLP-2) was also assessed. Compared to placebo, acarbose impaired the MMT-induced suppression of CTX as assessed by baseline-subtracted area under curve (P=0.0037) and nadir of CTX (P=0.0128). During acarbose treatment, exendin(9-39)NH2 infusion lowered nadir of CTX compared to saline (P=0.0344). Neither parathyroid hormone or the bone formation marker procollagen 1 intact N-terminal propeptide were affected by acarbose or GLP-1 receptor antagonism. Acarbose treatment induced a greater postprandial GLP-2 response than placebo treatment (P=0.0479) and exendin(9-39)NH2 infusion exacerbated this (P=0.0002). In patients with type 2 diabetes, treatment with acarbose reduced postprandial suppression of bone resorption. Acarbose-induced GLP-1 secretion may contribute to this phenomenon as the impairment was partially reversed by GLP-1 receptor antagonism. Also, acarbose-induced reductions in other factors reducing bone resorption, e.g. glucose-dependent insulinotropic polypeptide, may contribute.

Metformin modulates mitochondrial function and mitophagy in peripheral blood mononuclear cells from type 2 diabetic patients

Type 2 diabetes is a chronic metabolic disease that affects mitochondrial function. In this context, the rescue mechanisms of mitochondrial health, such as mitophagy and mitochondrial biogenesis, are of crucial importance. The gold standard for the treatment of type 2 diabetes is metformin, which has a beneficial impact on the mitochondrial metabolism. In this study, we set out to describe the effect of metformin treatment on mitochondrial function and mitophagy in peripheral blood mononuclear cells (PBMCs) from type 2 diabetic patients. We performed a preliminary cross-sectional observational study complying with CONSORT requirements, for which we recruited 242 subjects, divided into 101 healthy volunteers, 93 metformin-treated type 2 diabetic patients and 48 non-metformin-treated type 2 diabetic patients. Mitochondria from the type 2 diabetic patients not treated with metformin displayed more reactive oxygen species (ROS) than those from healthy or metformin-treated subjects. Protein expression of the electron transport chain (ETC) complexes was lower in PBMCs from type 2 diabetic patients without metformin treatment than in those from the other two groups. Mitophagy was altered in type 2 diabetic patients, evident in a decrease in the protein levels of PINK1 and Parkin in parallel to that of the mitochondrial biogenesis protein PGC1α, both of which effects were reversed by metformin. Analysis of AMPK phosphorylation revealed that its activation was decreased in the PBMCs of type 2 diabetic patients, an effect which was reversed, once again, by metformin. In addition, there was an increase in the serum levels of TNFα and IL-6 in type 2 diabetic patients and this was reversed with metformin treatment. These results demonstrate that metformin improves mitochondrial function, restores the levels of ETC complexes, and enhances AMPK activation and mitophagy, suggesting beneficial clinical implications in the treatment of type 2 diabetes.

Prevalence of vitamin B12 deficiency and its association with metformin-treated type 2 diabetic patients: A cross sectional study

Metformin is the most-used drug in type 2 diabetes mellitus (T2DM) management, but it may lower B 12 status as a use consequence. However, few studies in Saudi Arabia have assessed this risk. This study aimed to estimate the prevalence of vitamin B 12 deficiency in metformin-treated type 2 diabetic patients and its association with drug duration and dose with relation to B 12 dietary intake. A cross sectional study was conducted with 206 patients with type 2 diabetic patients using metformin for 6 months or more and attending the diabetic clinics at Al-Noor Specialist Hospital in Holy Makkah. Serum B 12 levels were estimated, and biochemical B 12 deficiency was defined as serum levels <243 nmol/L. Demographic, medical history, dietary assessment for B 12 intake, and data on metformin use were collected using an online survey. Statistical package for the social sciences (SPSS) version 25 was used for statistical analysis. Vitamin B 12 deficiency occurred in 17.5% of the patients using metformin. Significant differences existed according to diabetes duration ( p = 0.002) between patients showing deficiencies and normal ranges of vitamin B 12 . No significant differences were found according to metformin dose, duration, and vitamin B 12 intake. The prevalence of B 12 deficiency in patients with type 2 diabetic patients using metformin was 17.5%. The risk of this relationship might increase with longer metformin use and is influenced by the occurrence and duration of diabetes .

Comparative Effectiveness of Sodium-Glucose Cotransporter 2 Inhibitors vs Sulfonylureas in Patients With Type 2 Diabetes

In the treatment of type 2 diabetes, evidence of the comparative effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors vs sulfonylureas-the second most widely used antihyperglycemic class after metformin-is lacking. To evaluate the comparative effectiveness of SGLT2 inhibitors and sulfonylureas associated with the risk of all-cause mortality among patients with type 2 diabetes using metformin. A cohort study used data from the US Department of Veterans Affairs compared the use of SGLT2 inhibitors vs sulfonylureas in individuals receiving metformin for treatment of type 2 diabetes. A total of 23 870 individuals with new use of SGLT2 inhibitors and 104 423 individuals with new use of sulfonylureas were enrolled between October 1, 2016, and February 29, 2020, and followed up until January 31, 2021. New use of SGLT2 inhibitors or sulfonylureas. This study examined the outcome of all-cause mortality. Predefined variables and covariates identified by a high-dimensional variable selection algorithm were used to build propensity scores. The overlap weighting method based on the propensity scores was used to estimate the intention-to-treat effect sizes of SGLT2 inhibitor compared with sulfonylurea therapy. The inverse probability of the treatment adherence weighting method was used to estimate the per-protocol effect sizes. Among the 128 293 participants (mean [SD] age, 64.60 [9.84] years; 122 096 [95.17%] men), 23 870 received an SGLT2 inhibitor and 104 423 received a sulfonylurea. Compared with sulfonylureas, SGLT2 inhibitors were associated with reduced risk of all-cause mortality (hazard ratio [HR], 0.81; 95% CI, 0.75-0.87), yielding an event rate difference of -5.15 (95% CI, -7.16 to -3.02) deaths per 1000 person-years. Compared with sulfonylureas, SGLT2 inhibitors were associated with a reduced risk of death, regardless of cardiovascular disease status, in several categories of estimated glomerular filtration rate (including rates from >90 to ≤30 mL/min/1.73 m2) and in participants with no albuminuria (albumin to creatinine ratio [ACR] ≤30 mg/g), microalbuminuria (ACR >30 to ≤300 mg/g), and macroalbuminuria (ACR >300 mg/g). In per-protocol analyses, continued use of SGLT2 inhibitors was associated with a reduced risk of death compared with continued use of sulfonylureas (HR, 0.66; 95% CI, 0.60-0.74; event rate difference, -10.10; 95% CI, -12.97 to -7.24 deaths per 1000 person-years). In additional per-protocol analyses, continued use of SGLT2 inhibitors with metformin was associated with a reduced risk of death compared with SGLT2 inhibitor treatment without metformin (HR, 0.70; 95% CI, 0.50-0.97; event rate difference, -7.62; 95% CI, -17.12 to -0.48 deaths per 1000 person-years). In this comparative effectiveness study analyzing data from the US Department of Veterans Affairs, among patients with type 2 diabetes receiving metformin therapy, SGLT2 inhibitor treatment was associated with a reduced risk of all-cause mortality compared with sulfonylureas. The results provide data from a real-world setting that might help guide the choice of antihyperglycemic therapy.

Profiling immuno-metabolic mediators of vitamin B12 deficiency among metformin-treated type 2 diabetic patients in Ghana.

The 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. In 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. Using 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). Vitamin 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.

The role of GLP-1 in the postprandial effects of acarbose in type 2 diabetes.

The alpha-glucosidase inhibitor acarbose is believed to reduce plasma glucose by delaying hydrolysis of carbohydrates. Acarbose-induced transfer of carbohydrates to the distal parts of the intestine increases circulating glucagon-like peptide 1 (GLP-1). Using the GLP-1 receptor antagonist exendin(9-39)NH2, we investigated the effect of acarbose-induced GLP-1 secretion on postprandial glucose metabolism in patients with type 2 diabetes. In a double-blinded, placebo-controlled, randomized, crossover study, 15 participants with metformin-treated type 2 diabetes (age: 57-85 years, HbA1c: 40-74 mmol/mol) were subjected to two 14-day treatment periods with acarbose or placebo, respectively, separated by a 6-week wash-out period. At the end of each period, two randomized 4-h liquid mixed meal tests with concomitant infusion of exendin(9-39)NH2 and saline, respectively, were performed. Compared to placebo, acarbose increased postprandial GLP-1 concentrations and decreased postprandial glucose. We observed no absolute difference in the exendin(9-39)NH2-induced increase in postprandial glucose excursions between placebo and acarbose periods, but relatively, postprandial glucose was increased by 119 ± 116% (mean ± s.d.) during exendin(9-39)NH2 infusion in the acarbose period vs a 39 ± 27% increase during the placebo period (P = 0.0163). We confirm that acarbose treatment stimulates postprandial GLP-1 secretion in patients with type 2 diabetes. Using exendin(9-39)NH2, we did not see an impact of acarbose-induced GLP-1 secretion on absolute measures of postprandial glucose tolerance, but relatively, the effect of exendin(9-39)NH2 was most pronounced during acarbose treatment.

Incretin mimetics and sodium-glucose co-transporter 2 inhibitors as monotherapy or add-on to metformin for treatment of type 2 diabetes: a systematic review and network meta-analysis.

Although there are many different methods of treating type 2 diabetes (T2D), it is still difficult to draw coincident conclusions concerning the efficacy and safety of different classes of new drugs, and the recommendation level of them has still kept uncertain as second anti-diabetic agents. Therefore, the aim of this study was to summarize evidence on the efficacy and safety of DPP-4is, GLP-1RAs and SGLT-2is as monotherapy or add-on to metformin (Met) for treatment of T2D. We searched PubMed, Embase, Cochrane library and ClinicalTrials.gov for relevant articles in keeping with established methods using terms associated with anti-diabetic agents up to February, 2020, with no start date restriction. Weighted mean difference and risk ratios with 95% confidence intervals were calculated within traditional and network meta-analysis. Primary outcomes were the mean change in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG) change and the frequency of hypoglycemic events from baseline after 12weeks of treatment. In total, 64 eligible studies comprising 37,780 patients and 7 treatment strategies were included. The results of primary outcomes showed that GLP-1RAs were significantly more effective than DPP-4is or SGLT-2is in reducing HbA1c when add-on to Met. For FPG, both GLP-1RAs and SGLT-2is significantly reduced FPG compared with DPP-4is whether add-on to Met or not. For hypoglycemia, monotherapy has a lower risk than combination therapy except for SGLT-2is. Ranking probability analysis indicated that GLP-1RAs and SGLT-2is, respectively, reduced HbA1c and FPG most when add-on to Met. Meanwhile, GLP-1RAs took the lowest risk to induce the hypoglycemia, whereas GLP-1RAs plus Met the highest. Both GLP-1RAs and SGLT-2is have their own advantages in efficacy and safety. Monotherapy is beneficial for reducing the risk of hypoglycemia. The recommendation should be a patient-centered approach when selecting treatment choices.

Effects of Sustained Treatment With Lixisenatide on Gastric Emptying and Postprandial Glucose Metabolism in Type 2 Diabetes: A Randomized Controlled Trial.

Tachyphylaxis for slowing of gastric emptying is seen with continuous exposure to glucagon-like peptide 1 (GLP-1). We therefore aimed to establish whether prolonged use of a "short-acting" GLP-1 receptor agonist, lixisenatide, achieves sustained slowing of gastric emptying and reduction in postprandial glycemia. A total of 30 patients with metformin-treated type 2 diabetes underwent assessment of gastric emptying (scintigraphy) and glucose metabolism (dual tracer technique) after a 75-g glucose drink, before and after 8 weeks' treatment with lixisenatide (20 μg subcutaneously daily) or placebo, in a double-blind randomized parallel design. Gastric retention of the glucose drink was markedly increased after lixisenatide versus placebo (ratio of adjusted geometric means for area under the curve [AUC] over 240 min of 2.19 [95% CI 1.82, 2.64], P < 0.001), associated with substantial reductions in the rate of systemic appearance of oral glucose (P < 0.001) and incremental AUC for blood glucose (P < 0.001). Lixisenatide suppressed both glucagon (P = 0.003) and insulin (P = 0.032), but not endogenous glucose production, over 120 min after oral glucose intake. Postprandial glucose lowering over 240 min was strongly related to the magnitude of slowing of gastric emptying by lixisenatide (r = -0.74, P = 0.002) and to the baseline rate of emptying (r = 0.52, P = 0.048) but unrelated to β-cell function (assessed by β-cell glucose sensitivity). Eight weeks' treatment with lixisenatide is associated with sustained slowing of gastric emptying and marked reductions in postprandial glycemia and appearance of ingested glucose. Short-acting GLP-1 receptor agonists therefore potentially represent an effective long-term therapy for specifically targeting postprandial glucose excursions.

Mucosa-associated microbiota in the jejunum of patients with morbid obesity: alterations in states of insulin resistance and metformin treatment.

Stool samples have been widely used to evaluate gut microbiota; however, little is known about the composition of human small intestinal microbiota and the alterations provoked by insulin resistance. To describe the composition of jejunal microbiota in morbidly obese patients, as well as its link with insulin resistance and metformin treatment. Virgen de la Victoria University Hospital and Regional University Hospital, Málaga, Spain. Jejunal biopsies from 46 morbidly obese patients were analyzed by next-generation sequencing method. Patients were classified in the following 3 groups: low homeostasis model assessment of insulin resistance index (HOMA-IR) value, high HOMA-IR value, and metformin-treated type 2 diabetes patients (T2D-metf). Richness (q = .011) together with Proteobacteria (W = 2), Fusobacteria (W = 2), and Bacteroidetes (W = 1) phyla were significantly higher in high HOMA-IR compared with low HOMA-IR group. At family level, several differences were found between low HOMA-IR and T2D-metf group, being the most important the higher abundance of Halomonadacea in T2D-metf group (W = 22). PICRUSt analysis showed that predicted genes involved in trimethylamine-N-oxide biosynthesis pathway could be increased in jejunal microbiota of T2D-metf group compared with the low HOMA-IR group, while indole biosynthesis pathway could be increased in the low HOMA-IR group compared with the high HOMA-IR group. An increase in richness and an enrichment in Proteobacteria, Fusobacteria, and Bacteroidetes was observed in jejunal from morbidly obese patients with high insulin resistance. Halomonadaceae family was significantly increased in metformin-treated patients. Functional analysis of predicted metagenome suggests that trimethylamine-N-oxide biosynthesis pathway could be increased in the jejunal microbiota of T2D-meft group, while indole biosynthesis pathway could be increased in low HOMA-IR group. These results contribute to the increase in the scarce knowledge about the mucosal microbiota of the hardly accessible small intestine.

An Investigation on Vitamin B12 Serum Levels among Type 2 Diabetic Patients Treated with Metformin Compared to Normal Levels

Background: Given the increasing prevalence of type 2 diabetes in the community and the use of metformin as one of its most common therapies as well as presence of some evidences on a link between the use of this medicine and vitamin B12 levels, we decided to measure and compare serum level of vitamin B12 among the diabetic patients under treatment by metformin and compare with its natural content. Decreased Vitamin B12 levels leads to some clinical problems including anemia, gastrointestinal disorders (diarrhea, constipation, decreased appetite, etc.,), neurological disorders (tingle, numbness, muscle weakness, etc.,) and mental disorders (memory impairment, depression, behavioral problems, etc.,). Therefore, we would determine if the duration of metformin use and dosage may be effective on serum levels of vitamin B12 among metformin-treated diabetic patients.&#x0D; Methods: Serum vitamin B12 level in metformin-treated type 2 diabetic patients referred to Rasoul-e-Akram Hospital and Specialist Clinic of Taban in Tehran in 2016 (306 subjects selected by convenience sampling) was determined and then compared to its normal level.&#x0D; Results: Of the 306 participants in the study, 120 ones were females (39.2%) and 186 ones were males (60.8%). Also, 150 ones (49%) were healthy and 156 ones (51%) were suffering from diabetes Miletus. There was a significant difference between the type 2 diabetes mellitus and healthy individuals with quantitative variables such as age, height, weight, BMI, serum cholesterol (Chol) level, LDL serum level, HDL serum level, triglyceride (TG) level. The mean blood level of Vitamin B12 level was 448.92±156.75pg/mL among all participants. A Vitamin B12 deficiency frequency of above 6% was seen among diabetic patients. In regression analysis, a model was defined based on which age, gender, diabetes and Metformin used had a significant effect on serum levels of vitamin B-12. Also, none of the variables gender, age, duration of treatment, metformin quantity, weight and BMI was associated with a deficiency of vitamin B12.&#x0D; Conclusion: In the diabetic group, the prevalence of Vitamin B12 deficiency was more than6%. It was also seen that age, gender, diabetes mellitus, metformin intake and metformin content had a significant effect on serum B12 levels. Therefore, measurement of serum levels of vitamin B12 in metformin-treated subjects is recommended.

Evaluating the correlation between serum vitamin B12 levels and various haematologic indices among metformin-treated type 2 diabetic patients: A prospective analytical study

Background: Metformin-induced vitamin B12 deficiency state or metformin-induced hypocobalaminemia is gradually becoming an epidemic among diabetic patients on moderate-to-high doses of metformin or those diabetic patients on metformin for a long period of time. The potential effect of chronic metformin pharmacotherapy to cause vitamin B12 deficiency with abnormalities in haematologic indices and central/peripheral neuropathy has been widely reported. Long-term usage of metformin has been reported to be associated with intestinal malabsorption of vitamin B12 culminating in vitamin B12 deficiency with likely associated haematologic abnormalities (including macro-ovalocytic anaemia and immune dysfunctioning due to hypersegmentation of polymorphonuclear leukocytes), central/peripheral neuropathy and manifestation of biochemical derangements such as elevated homocysteine and methyl malonate levels. Aim: This study aimed to determine the correlation between serum vitamin B12 levels and various haematologic indices among metformin-treated type 2 diabetic patients in a clinical practice setting with the rational purpose of alleviating/preventing the associated derangements. Materials and Methods: This was a case-control, prospective, analytical, observational study of 200 adult participants (100 per group) attending the Endocrinology Out-patients Clinic of Irrua Specialist Teaching Hospital, Irrua, Edo State, Nigeria. For each participant, serum vitamin B12 level was determined using a vitamin B12 immunoassay technique, while the corresponding complete blood count was done using PCE-210N autohaematology analyser. Data were presented using tables and figures. Chi-square test was used to compare categorical variables, Student t-test was used in comparing means of continuous variables, while Pearson’s correlation study was done to determine the existence of any statistically significant correlation(s) between the serum vitamin B12 levels and various haematologic indices among the participants. Results: Approximately 41% versus 20% of the metformin-treated and metformin-naive diabetic patients, respectively, had frank vitamin B12 deficiency. There was a statistical difference between the total serum vitamin B12 levels in male and female diabetic patients with p = 0.048. Also, statistically significant differences existed with respect to mean corpuscular volume (MCV), mean corpuscular haemoglobin and total white blood cells count among the metformin-treated and metformin-naive diabetic patients. Furthermore, a statistically significant weak positive correlation existed between pack cell volume (PCV) and serum vitamin B12 level ( r = +0.148, p = 0.037), but a statistically significant weak negative correlation existed between MCV and serum vitamin B12 level ( r = −0.245, p = 0.0001). In addition, the test for associations between the serum vitamin B12 categorization status or metformin exposure status and the peripheral neuropathy components assessment revealed that there were statistically significant associations between the serum vitamin B12 categorization status or metformin exposure status versus pain sense ( p &lt; 0.0001 or &lt;0.001), vibration sense ( p &lt; 0.0001 or &lt;0.001) and light touch sense ( p &lt; 0.0001 or &lt;0.001) among the participants. Conclusion: In this study, statistically significant weak positive and weak negative correlations existed between serum vitamin B12 level versus PCV, and serum vitamin B12 level versus MCV, respectively. The peripheral neuropathy components assessment revealed that there were statistically significant associations between the serum vitamin B12 categorization status or metformin exposure status versus pain sense, vibration sense and light touch sense among the participants.

Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy.

SummaryMetformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies.Video

Variation in the Plasma Membrane Monoamine Transporter (PMAT) (Encoded by SLC29A4) and Organic Cation Transporter 1 (OCT1) (Encoded by SLC22A1) and Gastrointestinal Intolerance to Metformin in Type 2 Diabetes: An IMI DIRECT Study.

Gastrointestinal adverse effects occur in 20-30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5-10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects. The study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in the SLC29A4 and SLC22A1 genes on odds of intolerance. Women (P < 0.001) and older people (P < 0.001) were more likely to develop metformin intolerance. Concomitant use of transporter-inhibiting drugs increased the odds of intolerance (odds ratio [OR] 1.72, P < 0.001). In an adjusted logistic regression model, the G allele at rs3889348 (SLC29A4) was associated with gastrointestinal intolerance (OR 1.34, P = 0.005). rs3889348 is the top cis-expression quantitative trait locus for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with transporter-inhibiting drugs had more than three times higher odds of intolerance compared with carriers of no G allele and not treated with inhibiting drugs (OR 3.23, P < 0.001). Use of a genetic risk score derived from rs3889348 and SLC22A1 variants found that the odds of intolerance were more than twice as high in individuals who carry three or more risk alleles compared with those carrying none (OR 2.15, P = 0.01). These results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin.

Assessment of serum vitamin B12levels and chronic haemato-toxicologic adverse profile induced by metformin pharmacotherapy among type 2 diabetic patients: A prospective analytical study

Background:The potential effect of chronic metformin pharmacotherapy to cause vitamin B12deficiency has been of tremendous concern especially among diabetic patients. Haematological abnormalities following vitamin B12deficiency among diabetic patients contribute immensely to morbidity and mortality in this group of patients.Aim:This study was designed to elucidate the chronic haemato-toxicologic adverse profile for metformin with respect to its potential to induce vitamin B12deficiency via reduction in the gastrointestinal absorption of vitamin B12by performing comparative analyses between the serum vitamin B12levels and haematological indices among metformin-treated and metformin-naive type 2 diabetes mellitus (DM) patients attending the outpatient Endocrinology Clinic of Irrua Specialist Teaching Hospital (ISTH), Irrua, Edo State, Nigeria, with the rational purpose of alleviating the associated morbidity and mortality.Materials and Methods:This was a case–control, prospective, analytical, and observational study of 200 adult participants (100 per group) attending the Endocrinology Outpatients Clinic of ISTH. Serum vitamin B12levels were analysed using an immunoassay technique. Haematological indices were determined using standard methods, and patients examined for clinical features of anaemia. Data were presented using tables and charts. χ2and t-tests were used to compare discrete and continuous data, respectively. The receiver operating characteristic (ROC) curve was plotted graphically to determine the sensitivity and specificity of using serum vitamin B12assay as a screening and diagnostic test for the haematologic abnormality of ovalocytosis among the metformin-treated type 2 DM patients.Results:A total of 200 type 2 diabetic patients comprising 100 metformin-treated and 100 metformin-naive patients with average age of 55.8 ± 9.3 years were studied. The mean serum vitamin B12levels in metformin-treated and metformin-naive participants with frank vitamin B12deficiency (i.e. mean serum vitamin B12level ≤ 199 pg ml−1) were 158.29 ± 29.27 pg ml−1and 173.95 ± 14.21 pg ml−1, respectively ( p = 0.028). This was significantly lower for the metformin-treated group compared to metformin-naive group with respect to the participants with frank vitamin B12deficiency. There were instances of statistically significant differences between the mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and total white blood cell (WBC) count among the metformin-treated compared to the metformin-naive type 2 DM patients. The ROC curve showed that serum vitamin B12assay had moderate sensitivity of 72% with moderate specificity of 66% at detecting the presence and absence of ovalocytosis in the presence and absence of frank vitamin B12deficiency, respectively, among the metformin-treated group (i.e. serum vitamin B12≤ 199 pg ml−1with p = 0.002).Conclusion:The occurrence of vitamin B12deficiency was high among metformin-treated type 2 DM patients. Our study showed remarkable statistically and clinically significant differences in the chronic haemato-toxicology of metformin on mean serum vitamin B12level, ovalocytosis, MCV, MCH and total WBC count between the metformin-treated and metformin-naive participants. We advocate for vitamin B12supplements in this group of patients via the parenteral route of administration, most preferably the intramuscular site injection; in order to prevent the occurrence of vitamin B12deficiency among them. Lastly, we recommend the use of serum vitamin B12assay and complete blood count (CBC) with peripheral blood films (PBFs) as a reliable way to diagnose and screen for vitamin B12deficiency among metformin-treated type 2 DM patients.

Prevalence of vitamin B12 deficiency among metformin-treated type 2 diabetic patients in a tertiary institution, South-South Nigeria.

Background:The risk of chronic metformin pharmacotherapy to cause vitamin B12 deficiency and its associated medical complications has been of immense concern among diabetic patients. Some studies have postulated that vitamin B12 deficiency is highly prevalent among chronic metformin-treated adult diabetic patients.Aim:This study aimed to determine the prevalence of vitamin B12 deficiency among metformin-treated and metformin-naïve type 2 diabetes mellitus patients.Materials and methods:This was a case-control, prospective, analytical, observational study of 200 adult participants (100 per group) attending the Endocrinology, Medical Out-patients Clinic of Irrua Specialist Teaching Hospital, Irrua, Edo State, Nigeria. The participants’ serum vitamin B12 levels were determined using an immunoassay technique. Data were presented using tables and charts. Chi-square test was used to compare non-continuous proportional variables.Results:The prevalence of vitamin B12 deficiency was 41% and 20% among metformin-treated and metformin-naïve type 2 diabetes mellitus groups, respectively (p = 0.001). Borderline vitamin B12 status was present among 59% of metformin-treated group and 80% of metformin-naïve group (p = 0.001). Neither metformin-treated nor metformin-naïve groups had normal serum vitamin B12 levels.Conclusion:The prevalence of vitamin B12 deficiency was significantly high in diabetics, especially the metformin-treated patients. We advocate for vitamin B12 supplementation among this group of patients in order to prevent the occurrence of vitamin B12 deficiency complications such as macro-ovalocytic anemia, impaired immunity with hypersegmented neutrophils, peripheral neuropathy and subacute degeneration of the spinal cord.

Vitamin B12 deficiency and the knowledge and practice of physicians regarding screening for vitamin B12 deficiency among type 2 diabetic patients on metformin in selected hospitals in Riyadh, Saudi Arabia.

Background/Aim:The worldwide prevalence of diabetes is high including Saudi Arabia. One standard first-line treatment for diabetes is metformin, which was reported to increase the risk for vitamin B12 deficiency. We wanted to determine the prevalence of vitamin B12 deficiency in metformin-treated type 2 diabetes mellitus patients.Methods:We conducted a cross-sectional study at the diabetic clinics of four hospitals in Riyadh, Saudi Arabia. Type 2 diabetes mellitus patients who were on metformin for at least 1 year were included in the study. Associations between B12 deficiency and age, duration of type 2 diabetes mellitus (T2DM), duration of use and dosage of metformin, and use of proton pump inhibitors (PPIs) were determined.Results:Of 363 T2DM patients, 206 (56.7%) were males and 157 (43.3%) were females, mean age was 53.72 ± 11.31 years, the mean duration of T2DM was 9.89 ± 7.32 years, and the mean duration of metformin use was 9.84 ± 7.29 years. There were 205 patients 56.5% who had a daily dose of 750 mg of metformin. The most commonly used oral hypoglycemic agent was gliclizide only in 138 (38.4%) of patients. There were 107 patients (29.5%) who were on PPIs. There were 210 patients (57.9%) who were on vitamin B12 supplementation, of which 111 (30.6%) had a daily dose of 200 mcg. The use of vitamin B12 supplement, duration of T2DM and duration of metformin use was significantly higher among females. The use of vitamin B12 supplement was significant among patients who were 46 years old and above. There were only 16 patients (4.4%) who had available serum vitamin B12 levels. Only 44.0% of the physician respondents know the current recommendation of American Diabetes Association on vitamin B12 screening and supplementation among diabetic patients, and 21.0% never prescribe vitamin B12 to their patients.Conclusion:Routine testing for serum vitamin B12 level is not practiced in our institution. A large percentage of physicians are not aware of the current recommendations of the American Diabetic Association (ADA) regarding vitamin B12 supplementation and screening. Thus, there is a need for doctors involved in the management of diabetes to keep abreast with guidelines and current recommendations and routinely monitor vitamin B12 levels particularly those who were on long-term takers of metformin and the elderly patients to optimize management of diabetes and its complications.

Combination GLP-1 and Insulin Treatment Fails to Alter Myocardial Fuel Selection vs. Insulin Alone in Type 2 Diabetes.

It is unclear if effects of glucagon-like peptide-1 (GLP-1) and clinically available GLP-1 agonists on the heart occur at clinical doses in humans, possibly contributing to reduced cardiovascular disease risk. To determine whether liraglutide, at clinical dosing, augments myocardial glucose uptake (MGU) alone or combined with insulin compared with insulin alone in metformin-treated type 2 diabetes mellitus (T2D). In a randomized clinical trial of patients with T2D treated with metformin plus oral agents or basal insulin, myocardial fuel use was compared after 3 months of treatment with insulin detemir, liraglutide, or combination detemir plus liraglutide added to background metformin. Myocardial blood flow (MBF), fuel selection, and rates of fuel use were evaluated using positron emission tomography, powered to demonstrate large effects. MBF was greater in the insulin-treated groups [median (25th, 75th percentile): detemir, 0.64 mL/g/min (0.50, 0.69); liraglutide, 0.52 mL/g/min (0.46, 0.58); detemir plus liraglutide, 0.75 mL/g/min (0.55, 0.77); P = 0.035 comparing three groups, P = 0.01 comparing detemir groups to liraglutide alone]. There were no evident differences among groups in MGU [detemir, 0.040 µmol/g/min (0.013, 0.049); liraglutide, 0.055 µmol/g/min (0.019, 0.105); detemir plus liraglutide, 0.037 µmol/g/min (0.009, 0.046); P = 0.68 comparing three groups]. There were no treatment-group differences in measures of myocardial fatty acid uptake or handling, and no differences in total oxidation rate. These observations argue against large effects of GLP-1 agonists on myocardial fuel metabolism as mediators of beneficial treatment effects on myocardial function and ischemia protection.