MARCH2: Comparative Assessment of Therapeutic Effects of Acarbose and Metformin in Newly Diagnosed Type 2 Diabetes Patients

Background

The data of MARCH (Metformin and AcaRbose in Chinese as the initial Hypoglycaemic treatment) trial demonstrated that acarbose and metformin have similar efficacy as initial therapy for hemoglobin A1c (HbA1c) reduction in Chinese patients with newly diagnosed type 2 diabetes. We investigated whether the therapeutic efficacy was diversified under different body mass index (BMI) status.

Methods

All 784 subjects were divided into normal-weight group (BMI<24 kg/m²), overweight group (BMI 24–28 kg/m²) and obese group (BMI≥28 kg/m²). Patients were assigned to 48 weeks of therapy with acarbose or metformin, respectively. The clinical trial registry number was ChiCTR-TRC-08000231.

Results

The reduction of HbA1c levels and the proportion of patients with HbA1c of 6.5% or less were similar in the three groups after acarbose and metformin treatment. In overweight group, fasting blood glucose (FBG) after metformin treatment showed greater decline compared to acarbose group at 48 weeks [−1.73 (−1.99 to −1.46) vs. −1.37 (−1.61 to −1.12), P<0.05), however the decrease of 2 h post-challenge blood glucose (PBG) after acarbose treatment at 48 weeks was bigger compared to metformin group [−3.34 (−3.83 to−2.84) vs. −2.35 (−2.85 to −1.85), P<0.01 ]. Both acarbose and metformin treatment resulted in a significant decrease in waist circumference, hip circumference, weight and BMI in the three groups (all P<0.05).

Conclusion

Acarbose and metformin decreased HbA1c levels similarly regardless of BMI status of Chinese type 2 diabetic patients. Acarbose and metformin resulted in a significant and modest improvement of anthropometric parametres in different BMI status. Thus, acarbose treatment may contribute a similar effect on plasma glucose control compared to metformin, even in obesity patients.

Trial Registration

ChiCTR.org ChiCTR-TRC-08000231     

Glycosylated Hemoglobin and Albumin-Corrected Fructosamine Are Good Indicators for Glycemic Control in Peritoneal Dialysis Patients

Purpose

Diabetes mellitus (DM) is the most common cause of end-stage renal disease and is an important risk factor for morbidity and mortality after dialysis. However, glycemic control among such patients is difficult to assess. The present study examined glycemic control parameters and observed glucose variation after refilling different kinds of fresh dialysate in peritoneal dialysis (PD) patients.

Methods

A total of 25 DM PD patients were recruited, and continuous glucose monitoring system (CGMS) was applied to measure interstitial fluid (ISF) glucose levels at 5-min intervals for 3 days. Patients filled out diet and PD fluid exchange diaries. The records measured with CGMS were analyzed and correlated with other glycemic control parameters such as fructosamine, albumin-corrected fructosamine (AlbF), glycosylated hemoglobin (HbA1c), and glycated albumin levels.

Results

There were significant correlations between mean ISF glucose and fructosamine (r = 0.45, P<0.05), AlbF (r = 0.54, P<0.01), and HbA1c (r = 0.51, P<0.01). The ISF glucose levels in glucose-containing dialysate increased from approximately 7–8 mg/dL within 1 hour of exchange in contrast to icodextrin dialysate which kept ISF glucose levels unchanged.

Conclusion

HbA1c and AlbF significantly correlated with the mean ISF glucose levels, indicating that they are reliable indices of glycemic control in DM PD patients. Icodextrin dialysate seems to have a favorable glycemic control effect when compared to the other glucose-containing dialysates.     

Identifying Good Responders to Glucose Lowering Therapy in Type 2 Diabetes: Implications for Stratified Medicine

Aims

Defining responders to glucose lowering therapy can be important for both clinical care and for the development of a stratified approach to diabetes management. Response is commonly defined by either HbA1c change after treatment or whether a target HbA1c is achieved. We aimed to determine the extent to which the individuals identified as responders and non-responders to glucose lowering therapy, and their characteristics, depend on the response definition chosen.

Methods

We prospectively studied 230 participants commencing GLP-1 agonist therapy. We assessed participant characteristics at baseline and repeated HbA1c after 3 months treatment. We defined responders (best quartile of response) based on HbA1c change or HbA1c achieved. We assessed the extent to which these methods identified the same individuals and how this affected the baseline characteristics associated with treatment response.

Results

Different definitions of response identified different participants. Only 39% of responders by one definition were also good responders by the other. Characteristics associated with good response depend on the response definition chosen: good response by HbA1c achieved was associated with low baseline HbA1c (p<0.001), high C-peptide (p<0.001) and shorter diabetes duration (p = 0.01) whereas response defined by HbA1c change was associated with high HbA1c (p<0.001) only. We describe a simple novel method of defining treatment response based on a combination of HbA1c change and HbA1c achieved that defines response groups with similar baseline glycaemia.

Conclusions

The outcome of studies aiming to identify predictors of treatment response to glucose lowering therapy may depend on how response is defined. Alternative definitions of response should be considered which minimise influence of baseline glycaemia.     

Efficacy and Safety of Traditional Chinese Medicine for Diabetes: A Double-Blind,Randomised, Controlled Trial

Background

Treatment of diabetes mellitus with Traditional Chinese Medicine has a long history. The aim of this study is to establish the safety and efficacy of traditional Chinese medicine combined with glibenclamide to treat type 2 diabetes mellitus.

Methods

In a controlled, double blind, multicentre non-inferiority trial, 800 patients with unsatisfactory glycemic control (fasting glucose 7–13 mmol/L and HbA1c 7–11%) were randomly assigned to receive Xiaoke Pill, a compound of Chinese herbs combined with glibenclamide, or Glibenclamide in two study groups – drug naive group, and patients previously treated with metformin monotherapy (metformin group). Outcome measures at 48 weeks were the incidence and rate of hypoglycemia, mean difference in HbA1c, and proportion of patients with HbA1c<6.5%.

Findings

In drug naïve group, the total hypoglycemia rate and the mild hypoglycemic episode in the Xiaoke Pill arm were 38% (p = 0.024) and 41% (p = 0.002) less compared to Glibenclamide arm; in Metformin group, the average annual rate of hypoglycemia was 62% lower in Xiaoke Pill arm (p = 0.003). Respective mean changes in HbA1c from baseline were −0.70% and −0.66% for Xiaoke Pill and Glibenclamide, with a between-group difference (95% CI) of −0.04% (−0.20, 0.12) in the drug naïve group, and those in metformin group were −0.45% and −0.59%, 0.14% (−0.12, 0.39) respectively. The respective proportions of patients with a HbA1c level <6.5% were 26.6% and 23.4% in the drug naïve group and 20.1% and 18.9% in the metformin group.

Interpretation

In patients with type 2 diabetes and inadequate glycaemic control, treatment with Xiaoke Pill led to significant reduction in risk of hypoglycemia and similar improvements in glycemic control after 48 weeks compared to Glibenclamide.

Trial Registration

Chinese Clinical Trial Register number, ChiCTR-TRC-08000074     

The True Value of HbA1c as a Predictor of Diabetic Complications: Simulations of HbA1c Variables

Aim

The updated mean HbA1c has been used in risk estimates of diabetic complications, but it does not take into account the temporal relationship between HbA1c and diabetic complications. We studied whether the updated mean HbA1c underestimated the risk of diabetic complications.

Method

Continuous HbA1c curves for 10,000 hypothetical diabetes patients were simulated over an average of 7 years. Simulations were based on HbA1c values encountered in clinical practice. We assumed that each short time interval of the continuous HbA1c curves had a long-lasting effect on diabetic complications, as evidenced by earlier studies. We tested several different HbA1c variables including various profiles, e.g. different duration, of such a long-lasting effect. The predictive power of these variables was compared with that of the updated mean HbA1c.

Results

The predictive power of the constructed HbA1c variables differed considerably compared to that of the updated mean HbA1c. The risk increase per standard deviation could be almost 100% higher for a constructed predictor than the updated mean HbA1c.

Conclusions

The importance of good glycemic control in preventing diabetic complications could have been underestimated in earlier hallmark studies by not taking the time-dependent effect of HbA1c into account.     

The Role of HbA1c Determination in Detecting Unknown Glucose Disturbances in Ischemic Stroke

Objectives

To evaluate the usefulness of hemoglobin A1c (HbA1c) determinations during the acute ischemic stroke (IS) to identify undiagnosed glucose disturbances in a prospective series of patients with first-ever IS.

Methods

Retrospective analysis of a prospective series of first-ever IS patients. Patients with previous diagnosis of diabetes mellitus (DM) were excluded from the study. Patients were classified as non-DM (HbA1c<5.7% and no previous evidence of 2 or more fasting blood glucose> = 126 mg/dL), prediabetes (HbA1c from 5.7% to 6.4%), and new suspected DM (HbA1c> = 6.5% independently of current blood glucose). Medical charts from hospital discharge to July 2014 of all suspected DM patients were reviewed to confirm the DM diagnosis.

Results

The initial cohort included 1283 patients, of which 393 were excluded because of previous DM diagnosis and 136 because HbA1c during acute stroke phase was not available. No demographic differences were observed between patients with and without HbA1c determinations. The final cohort was composed of 754 patients with first-ever IS and unknown DM history. HbA1c determination suggested new DM in 87 cases (11.5%) and detected 273 patients with prediabetes (36.2%). New DM cases were identified in all etiological stroke subtypes. After discharge, DM diagnosis was confirmed in 80.2% of patients with available follow-up.

Conclusions

HbA1c determination detected both undiagnosed DM and prediabetes in IS patients without taking into account the blood glucose values during admission, and independently of etiological stroke subtype. HbA1c determination should be included in the systematic screening of all IS patients.     

Glycemic Effects and Safety of L-Glutamine Supplementation with or without Sitagliptin in Type 2 Diabetes Patients—A Randomized Study

Background and Aims

L-glutamine is an efficacious glucagon-like peptide (GLP)-1 secretagogue in vitro. When administered with a meal, glutamine increases GLP-1 and insulin excursions and reduces postprandial glycaemia in type 2 diabetes patients. The aim of the study was to assess the efficacy and safety of daily glutamine supplementation with or without the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin in well-controlled type 2 diabetes patients.

Methods

Type 2 diabetes patients treated with metformin (n = 13, 9 men) with baseline glycated hemoglobin (HbA1c) 7.1±0.3% (54±4 mmol/mol) received glutamine (15 g bd)+ sitagliptin (100 mg/d) or glutamine (15 g bd) + placebo for 4 weeks in a randomized crossover study.

Results

HbA1c (P = 0.007) and fructosamine (P = 0.02) decreased modestly, without significant time-treatment interactions (both P = 0.4). Blood urea increased (P<0.001) without a significant time-treatment interaction (P = 0.8), but creatinine and estimated glomerular filtration rate (eGFR) were unchanged (P≥0.5). Red blood cells, hemoglobin, hematocrit, and albumin modestly decreased (P≤0.02), without significant time-treatment interactions (P≥0.4). Body weight and plasma electrolytes remained unchanged (P≥0.2).

Conclusions

Daily oral supplementation of glutamine with or without sitagliptin for 4 weeks decreased glycaemia in well-controlled type 2 diabetes patients, but was also associated with mild plasma volume expansion.

Trial Registration

ClincalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00673894","term_id":"NCT00673894"}}NCT00673894     

Diabetic Peripheral Neuropathy in Ambulatory Patients with Type 2 Diabetes in a General Hospital in a Middle Income Country: A Cross-Sectional Study

Aim

We aimed to estimate the morbidity rate and associated factors for diabetic peripheral neuropathy (DPN) in a low-middle income country setting.

Methods

Cross-sectional study, data was gathered at Peru''s Ministry of Health national specialized hospital for endocrinological conditions through standardized interviews, anthropometric measurements and blood tests for glycated haemoglobin (HbA1c). DPN was evaluated using two techniques: the Semmes-Weinstein monofilament test and the diabetic neuropathy symptom score. Overall prevalence and 95% confidence intervals (95% CI) were calculated. Potential factors related to DPN explored included body mass index, years with disease (<10 vs. ≥10 years), glycaemic control (HbA1c <7% vs. ≥7%), microalbuminuria, retinopathy, and current pharmacological treatment. Multivariable analysis was performed using Poisson analysis to calculate prevalence ratios.

Results

DPN was observed in 73/129 (56.6%) patients. In multivariable analysis adjusted by age and sex, the prevalence ratio of neuropathy was 1.4 times higher (95% CI 1.07–1.88) in patients who took insulin plus metformin compared to patients who used one treatment alone, and 1.4 higher (95% CI 1.02–1.93) in patients with ≥10 years of disease compared to those with a shorter duration of disease. Also we found some characteristics in foot evaluation associated to neuropathy such as deformities (p<0.001), onychomycosis (p = 0.012), abnormal Achilles reflex (p<0.001), pain perception (p<0.001) and vibration perception (p<0.001).

Conclusion

DPN is highly frequent among patients with diabetes in a national specialized facility from Peru. Associated factors to DPN included being a diabetic patient for over ten years, and receiving insulin plus metformin     

Diabetes is the main factor accounting for hypomagnesemia in obese subjects

Objective

Type 2 diabetes (T2DM) and obesity are associated with magnesium deficiency. We aimed to determine whether the presence of type 2 diabetes and the degree of metabolic control are related to low serum magnesium levels in obese individuals.

Methods

A) Case-control study: 200 obese subjects [50 with T2DM (cases) and 150 without diabetes (controls)] prospectively recruited. B) Interventional study: the effect of bariatric surgery on serum magnesium levels was examined in a subset of 120 obese subjects (40 with type 2 diabetes and 80 without diabetes).

Results

Type 2 diabetic patients showed lower serum magnesium levels [0.75±0.07 vs. 0.81±0.06 mmol/L; mean difference −0.06 (95% CI −0.09 to −0.04); p<0.001] than non-diabetic patients. Forty-eight percent of diabetic subjects, but only 15% of non-diabetic subjects showed a serum magnesium concentration lower than 0.75 mmol/L. Significant negative correlations between magnesium and fasting plasma glucose, HbA1c, HOMA-IR, and BMI were detected. Multiple linear regression analysis showed that fasting plasma glucose and HbA1c independently predicted serum magnesium. After bariatric surgery serum magnesium increased only in those patients in whom diabetes was resolved, but remain unchanged in those who not, without difference in loss weight between groups. Changes in serum magnesium negatively correlated with changes in fasting plasma glucose and HbA1c. Absolute changes in HbA1c independently predicted magnesium changes in the multiple linear regression analysis.

Conclusions

Our results provide evidence that the presence of diabetes and the degree of metabolic control are essential in accounting for the lower levels of magnesium that exist in obese subjects.     

Hemoglobin A1c for Diagnosis of Postpartum Abnormal Glucose Tolerance among Women with Gestational Diabetes Mellitus: Diagnostic Meta-Analysis

Objective

To evaluate the accuracy of glycosylated hemoglobin A1c (HbA1c) for the diagnosis of postpartum abnormal glucose tolerance among women with gestational diabetes mellitus (GDM).

Methods

After a systematic review of related studies, the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and other measures about the accuracy of HbA1c in the diagnosis of postpartum abnormal glucose tolerance were pooled using random-effects models. The summary receiver operating characteristic (SROC) curve was used to summarize the overall test performance.

Results

Six studies met our inclusion criteria. The pooled results on SEN, SPE, PLR, NLR, and DOR were 0.36 (95% CI 0.23–0.52), 0.85 (95% CI 0.73–0.92), 2.4 (95% CI 1.6–3.6), 0.75 (95% CI 0.63–0.88) and 3 (95% CI 2–5). The area under the summary receiver operating characteristic (SROC) curve was 0.67 with a Q value of 0.63.

Conclusions

Measurement of HbA1c alone is not a sensitive test to detect abnormal glucose tolerance in women with prior GDM.     

Phagocytic activity is impaired in type 2 diabetes mellitus and increases after metabolic improvement

Objective

1) To evaluate whether peripheral blood mononuclear cells (PBMCs) from type 2 diabetic patients present an impairment of phagocytic activity; 2) To determine whether the eventual impairment in phagocytic activity is related to glycemic control and can be reversed by improving blood glucose levels.

Methods

21 type 2 diabetic patients and 21 healthy volunteers were prospectively recruited for a case-control study. In addition, those patients in whom HbA1c was higher than 8% (n = 12) were hospitalized in order to complete a 5-day intensification treatment of blood glucose. Phagocytic activity was assessed by using a modified flow cytometry procedure developed in our laboratory based on DNA/RNA viable staining to discriminate erythrocytes and debris. This method is simple, highly sensitive and reproducible and it takes advantage of classic methods that are widely used in flow cytometry.

Results

Type 2 diabetic patients showed a lower percentage of activated macrophages in comparison with non-diabetic subjects (54.00±18.93 vs 68.53±12.77%; p = 0.006) Significant negative correlations between phagocytic activity and fasting glucose (r = −0.619, p = 0.004) and HbA1c (r = −0.506, p = 0.019) were detected. In addition, multiple linear regression analyses showed that either fasting plasma glucose or HbA1c were independently associated with phagocytic activity. Furthermore, in the subset of patients who underwent metabolic optimization a significant increase in phagocytic activity was observed (p = 0.029).

Conclusions

Glycemic control is related to phagocytic activity in type 2 diabetes. Our results suggest that improvement in phagocytic activity can be added to the beneficial effects of metabolic optimization.     

Effects of age and sex in the diagnosis of type 2 diabetes using glycated haemoglobin in Japan: the Yuport Medical Checkup Centre study

Background

We examined how the prevalence of individuals diagnosed with diabetes differs by age and sex using the diagnostic criteria of fasting plasma glucose (FPG) and/or glycated haemoglobin (HbA1c) in a large Japanese population.

Methods

We conducted a cross-sectional study using a dataset of 33,959 people (16,869 men and 17,090 women) without known diabetes who underwent health checkups from 1998 to 2006. We divided the age range of the participants into six groups of similar numbers. We compared the prevalence of diabetes using the criteria of FPG ≥7.0 mmol/l (126 mg/dl), HbA1c ≥48 mmol/mol (6.5%), or both, in men and women in each age group.

Results

Men had higher prevalence of diabetes than women using the criterion of either FPG or HbA1c (7.5% men vs. 3.4% women, P<0.001), or both (4.3% men vs. 1.8% women, P<0.001). HbA1c increased steadily in women through the six age groups. In the oldest group (≥66 years), the proportion of women among those diagnosed with diabetes was as high as 42.3% (215/508) using the criterion of either FPG or HbA1c, and 41.6% (116/279) using both criteria.

Conclusions

Using either FPG or HbA1c, the prevalence of people diagnosed with diabetes would almost double compared to using the criterion of both scores, and this would include more elderly women than men. The impact of introducing HbA1c for diabetes diagnosis should be considered in terms of age and sex.     

Incremental effects of endocrine and metabolic biomarkers and abdominal obesity on cardiovascular mortality prediction

Background

Biomarkers may help clinicians predict cardiovascular risk. We aimed to determine if the addition of endocrine, metabolic, and obesity-associated biomarkers to conventional risk factors improves the prediction of cardiovascular and all-cause mortality.

Methodology/Principal Findings

In a population-based cohort study (the Study of Health in Pomerania) of 3,967 subjects (age 20–80 years) free of cardiovascular disease with a median follow-up of 10.0 years (38,638 person-years), we assessed the predictive value of conventional cardiovascular risk factors and the biomarkers thyrotropin; testosterone (in men only); insulin-like growth factor-1 (IGF-1); hemoglobin A1c (HbA1c); creatinine; high-sensitive C-reactive protein (hsCRP); fibrinogen; urinary albumin-to-creatinine ratio; and waist-to-height ratio (WHtR) on cardiovascular and all-cause death.During follow-up, we observed 339 all-cause including 103 cardiovascular deaths. In Cox regression models with conventional risk factors, the following biomarkers were retained as significant predictors of cardiovascular death after backward elimination: HbA1c, IGF-1, and hsCRP. IGF-1 and hsCRP were retained as significant predictors of all-cause death.For cardiovascular death, adding these biomarkers to the conventional risk factors changed the C-statistic from 0.898 to 0.910 (p = 0.02). The net reclassification improvement was 10.6%. For all-cause death, the C-statistic changed from 0.849 to 0.853 (P = 0.09).

Conclusions/Significance

HbA1c, IGF-1, and hsCRP predict cardiovascular death independently of conventional cardiovascular risk factors. These easily assessed endocrine and metabolic biomarkers might improve the ability to predict cardiovascular death.     

Do Non-Glycaemic Markers Add Value to Plasma Glucose and Hemoglobin A1c in Predicting Diabetes? Yuport Health Checkup Center Study

Background

Many markers have been indicated as predictors of type 2 diabetes. However, the question of whether or not non-glycaemic (blood) biomarkers and non-blood biomarkers have a predictive additive utility when combined with glycaemic (blood) biomarkers is unknown. The study aim is to assess this additive utility in a large Japanese population.

Methods

We used data from a retrospective cohort study conducted from 1998 to 2002 for the baseline and 2002 to 2006 for follow-up, inclusive of 5,142 men (mean age of 51.9 years) and 4,847 women (54.1 years) at baseline. The cumulative incidence of diabetes [defined either as a fasting plasma glucose (FPG) ≥7.00 mmol/l or as clinically diagnosed diabetes] was measured. In addition to glycaemic biomarkers [FPG and hemoglobin A1c (HbA1c)], we examined the clinical usefulness of adding non-glycaemic biomarkers and non-blood biomarkers, using sensitivity and specificity, and the area under the curve (AUC) of the receiver operating characteristics.

Results

The AUCs to predict diabetes were 0.874 and 0.924 for FPG, 0.793 and 0.822 for HbA1c, in men and women, respectively. Glycaemic biomarkers were the best and second-best for diabetes prediction among the markers. All non-glycaemic markers (except uric acid in men and creatinine in both sexes) predicted diabetes. Among these biomarkers, the highest AUC in the single-marker analysis was 0.656 for alanine aminotransferase (ALT) in men and 0.740 for body mass index in women. The AUC of the combined markers of FPG and HbA1c was 0.895 in men and 0.938 in women, which were marginally increased to 0.904 and 0.940 when adding ALT, respectively.

Conclusions

AUC increments were marginal when adding non-glycaemic biomarkers and non-blood biomarkers to the classic model based on FPG and HbA1c. For the prediction of diabetes, FPG and HbA1c are sufficient and the other markers may not be needed in clinical practice.     

Impact of Metformin on Endothelial Ischemia-Reperfusion Injury in Humans In Vivo: A Prospective Randomized Open,Blinded-Endpoint Study

Introduction

Large prospective studies in patients with type 2 diabetes mellitus have demonstrated that metformin treatment improves cardiovascular prognosis, independent of glycemic control. Administration of metformin potently limits infarct size in murine models of myocardial infarction. This study examined, for the first time in humans, whether metformin limits ischemia-reperfusion (IR) injury in vivo using a well-validated forearm model of endothelial IR-injury.

Methods

Twenty-eight healthy volunteers (age 41±6 years, 10 male/16 female) were randomized between pretreatment with metformin (500 mg three times a day for 3 days) or no treatment in a Prospective Randomized Open Blinded Endpoint study. Brachial artery flow mediated dilation (FMD) was measured before and after 20 minutes of forearm ischemia and 20 minutes of reperfusion. FMD analysis was performed offline by investigators blinded for the treatment arm.

Results

Baseline FMD did not differ between metformin pretreatment and no pretreatment (6.9±3.6% and 6.1±3.5%, respectively, p = 0.27, n = 26). FMD was significantly lower after forearm IR in both treatment arms (4.4±3.3% and 4.3±2.8%, respectively, P<0.001 in both conditions). A linear mixed model analysis revealed that metformin treatment did not prevent the decrease in FMD by IR.

Conclusion

A 3 day treatment with metformin in healthy, middle-aged subjects does not protect against endothelial IR-injury, measured with brachial artery FMD after forearm ischemia. Further studies are needed to clarify what mechanism underlies the cardiovascular benefit of metformin treatment.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01610401","term_id":"NCT01610401"}}NCT01610401     

The Association between HbA1c,Fasting Glucose, 1-Hour Glucose and 2-Hour Glucose during an Oral Glucose Tolerance Test and Cardiovascular Disease in Individuals with Elevated Risk for Diabetes

Objective

To determine the association between HbA1c, fasting plasma glucose (FPG), 1-hour (1 hPG) and 2-hour (2 hPG) glucose after an oral glucose tolerance test (OGTT) and cardiovascular disease in individuals with elevated risk for diabetes.

Design

We studied the relationship between baseline, updated mean and updated (last) value of HbA1c, FPG, 1 hPG and 2 hPG after an oral 75 g glucose tolerance test (OGTT) and acute CVD events in 504 individuals with impaired glucose tolerance (IGT) at baseline enrolled in the Finnish Diabetes Prevention Study.

Setting

Follow-up of clinical trial.

Participants

504 individuals with IGT were followed with yearly evaluations with OGTT, FPG and HbA1c.

Main Outcome Measure

Relative risk of CVD.

Results

Over a median follow-up of 9.0 years 34 (6.7%) participants had a CVD event, which increased to 52 (10.3%) over a median follow-up of 13.0 years when including events that occurred among participants following a diagnosis of diabetes. Updated mean HbA1c, 1 hPG and 2 hPG, HR per 1 unit SD of 1.57 (95% CI 1.16 to 2.11), p = 0.0032, 1.51 (1.03 to 2.23), p = 0.036 and 1.60 (1.10 to 2.34), p = 0.014, respectively, but not FPG (p = 0.11), were related to CVD. In analyses of the last value prior to the CVD event the same three glycaemic measurements were associated with the CVD events, with HRs per 1 unit SD of 1.45 (1.06 to 1.98), p = 0.020, 1.55 (1.04 to 2.29), p = 0.030 and 2.19 (1.51 to 3.18), p<0.0001, respectively but only 2 hPG remained significant in pairwise comparisons. Including the follow-up period after diabetes onset updated 2 hPG (p = 0.003) but not updated mean HbA1c (p = 0.08) was related to CVD.

Conclusions and Relevance

Current 2 hPG level in people with IGT is associated with increased risk of CVD. This supports its use in screening for prediabetes and monitoring glycaemic levels of people with prediabetes.     

Hemoglobin A1c Levels and Aortic Arterial Stiffness: The Cardiometabolic Risk in Chinese (CRC) Study

Objective

The American Diabetes Association (ADA) recently published new clinical guidelines in which hemoglobin A1c (HbA1c) was recommended as a diagnostic test for diabetes. The present study was to investigate the association between HbA1c and cardiovascular risk, and compare the associations with fasting glucose and 2-hour oral glucose tolerance test (2 h OGTT).

Research Design and Methods

The study samples are from a community-based health examination survey in central China. Carotid-to-femoral pulse wave velocity (cfPWV) and HbA1c were measured in 5,098 men and women.

Results

After adjustment for age, sex, and BMI, the levels of HbA1c were significantly associated with an increasing trend of cfPWV in a dose-dependent fashion (P for trend <0.0001). The associations remained significant after further adjustment for blood pressure, heart rate, and lipids (P = 0.004), and the difference in cfPWV between the highest and the lowest quintiles of HbA1c was 0.31 m/s. Fasting glucose and 2 h OGTT were not associated with cfPWV in the multivariate analyses. HbA1c showed additive effects with fasting glucose or 2 h OGTT on cfPWV. In addition, age and blood pressure significantly modified the associations between HbA1c and cfPWV (P for interactions <0.0001 for age; and  = 0.019 for blood pressure). The associations were stronger in subjects who were older (≥60 y; P for trend = 0.004) and had higher blood pressure (≥120 [systolic blood pressure]/80 mmHg [diastolic blood pressure]; P for trend = 0.028) than those who were younger and had lower blood pressure (P for trend >0.05).

Conclusions

HbA1c was related to high cfPWV, independent of conventional cardiovascular risk factors. Senior age and high blood pressure might amplify the adverse effects of HbA1c on cardiovascular risk.     

Diabetes mellitus is associated with shortened activated partial thromboplastin time and increased fibrinogen values

Objective

This study was designed to examine the relationship between shortened activated partial thromboplastin time (APTT) and increased fibrinogen values with diabetes mellitus.

Methods

APTT, prothrombin time (PT), fibrinogen, fasting plasma glucose (FPG) and glycosylated hemoglobin A1c (HbA1c) levels were measured in 1,300 patients. Patients were divided into three groups according to their HbA1c and FPG levels.

Results

When participants were grouped according to their HbA1c levels, we found significantly shorter APTT values (26.9±5.6 s) and increased fibrinogen levels (3.1, 1.9–6.3 g/L) in the diabetes group when compared with the other two groups. When participants were grouped according to their FPG levels, we found significantly shorter APTT values (26.9±6.2 s) and increased fibrinogen levels (3.1, 1.8–6.2 g/L) in the diabetes group when compared with the euglycemic group.

Conclusions

Shorter APTT and increased fibrinogen levels might be useful hemostatic markers in patients with diabetes and in patients at high risk for diabetes.     

Metformin Inhibits Glutaminase Activity and Protects against Hepatic Encephalopathy

Aim

To investigate the influence of metformin use on liver dysfunction and hepatic encephalopathy in a retrospective cohort of diabetic cirrhotic patients. To analyze the impact of metformin on glutaminase activity and ammonia production in vitro.

Methods

Eighty-two cirrhotic patients with type 2 diabetes were included. Forty-one patients were classified as insulin sensitizers experienced (metformin) and 41 as controls (cirrhotic patients with type 2 diabetes mellitus without metformin treatment). Baseline analysis included: insulin, glucose, glucagon, leptin, adiponectin, TNFr2, AST, ALT. HOMA-IR was calculated. Baseline HE risk was calculated according to minimal hepatic encephalopathy, oral glutamine challenge and mutations in glutaminase gene. We performed an experimental study in vitro including an enzymatic activity assay where glutaminase inhibition was measured according to different metformin concentrations. In Caco2 cells, glutaminase activity inhibition was evaluated by ammonia production at 24, 48 and 72 hours after metformina treatment.

Results

Hepatic encephalopathy was diagnosed during follow-up in 23.2% (19/82): 4.9% (2/41) in patients receiving metformin and 41.5% (17/41) in patients without metformin treatment (logRank 9.81; p = 0.002). In multivariate analysis, metformin use [H.R.11.4 (95% CI: 1.2–108.8); p = 0.034], age at diagnosis [H.R.1.12 (95% CI: 1.04–1.2); p = 0.002], female sex [H.R.10.4 (95% CI: 1.5–71.6); p = 0.017] and HE risk [H.R.21.3 (95% CI: 2.8–163.4); p = 0.003] were found independently associated with hepatic encephalopathy. In the enzymatic assay, glutaminase activity inhibition reached 68% with metformin 100 mM. In Caco2 cells, metformin (20 mM) decreased glutaminase activity up to 24% at 72 hours post-treatment (p<0.05).

Conclusions

Metformin was found independently related to overt hepatic encephalopathy in patients with type 2 diabetes mellitus and high risk of hepatic encephalopathy. Metformin inhibits glutaminase activity in vitro. Therefore, metformin use seems to be protective against hepatic encephalopathy in diabetic cirrhotic patients.     

Metformin Protects Rat Hepatocytes against Bile Acid-Induced Apoptosis

Background

Metformin is used in the treatment of Diabetes Mellitus type II and improves liver function in patients with non-alcoholic fatty liver disease (NAFLD). Metformin activates AMP-activated protein kinase (AMPK), the cellular energy sensor that is sensitive to changes in the AMP/ATP-ratio. AMPK is an inhibitor of mammalian target of rapamycin (mTOR). Both AMPK and mTOR are able to modulate cell death.

Aim

To evaluate the effects of metformin on hepatocyte cell death.

Methods

Apoptotic cell death was induced in primary rat hepatocytes using either the bile acid glycochenodeoxycholic acid (GCDCA) or TNFα in combination with actinomycin D (actD). AMPK, mTOR and phosphoinositide-3 kinase (PI3K)/Akt were inhibited using pharmacological inhibitors. Apoptosis and necrosis were quantified by caspase activation, acridine orange staining and Sytox green staining respectively.

Results

Metformin dose-dependently reduces GCDCA-induced apoptosis, even when added 2 hours after GCDCA, without increasing necrotic cell death. Metformin does not protect against TNFα/ActD-induced apoptosis. The protective effect of metformin is dependent on an intact PI3-kinase/Akt pathway, but does not require AMPK/mTOR-signaling. Metformin does not inhibit NF-κB activation.

Conclusion

Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation.