HOMA-β) And Insulin Resistance Research Articles

Early Predictors in the Onset of Type 2 Diabetes at Different Fasting Blood Glucose Levels.

PurposeThis study investigates the possible roles and potential prediction ability of metabolic parameters in the early development of T2D by detecting their serum levels at different fasting blood glucose (FBG) levels.MethodsThe subjects were included and divided into normal glucose tolerance (NGT), prediabetes (PD), and T2Dsubgroups. Apart from detecting the levels of routine biochemical parameters, fasting serum insulin (FINS), 25(OH)D, thioredoxin-interacting protein (TXNIP), thioredoxin (TRX), and NOD-like receptor family, pyrin domain-containing 3 (NLRP3) were detected. β-cell dysfunction (HOMA-β) and insulin resistance (HOMA-IR) were assessed by homeostasis model assessment. Both univariate and multivariate logistic regression analyses were used to estimate the risk of metabolic parameters, and their optimal cut-off values were obtained in the receiver operating characteristic (ROC) curve analysis and the Youden index.ResultsAmong the 207 subjects, aged from 20 to 60 years (44.62+12.92) contain 118 males and 89 females. There was a significantly lower trend of TRX, HOMA-β, and 25(OH)D following the higher FBG level among these three subgroups, while a significantly higher trend of all the other metabolic parameters. The multivariate analysis showed that subjects with higher values of TRX, HOMA-β, and 25(OH)D had a significantly lower risk for patients to be diagnosed as PD (aOR: 0.945, 0.961, and 0.543) and T2D (aOR: 0.912, 0.947, 0.434). Under the reliable 95% CI, TXNIP with a cut-off value of 119.27 showed the highest AUC value, sensitivity, and specificity (AUC: 0.981, 95% CI: 0.8524–0.9839, 91.49%, and 83.33%) to diagnose PD. FINS with a cut-off value of 28.1 also showed the highest ones (AUC=0.9872, 95% CI: 0.9753–0.9992, 100%, and 92.91%) to diagnose T2D.ConclusionEarly prediction of T2D is vital for timely intervention. Based on the FBG ≥100.8 mg/dl, the results provide evidence that 25(OH)D might be the protective factor in the early development of T2D. Besides, TXNIP and FINS might be the predictor for PD and T2D, respectively.

Morus alba leaves ethanol extract protects pancreatic islet cells against dysfunction and death by inducing autophagy in type 2 diabetes

Protection of pancreatic islet cells against dysfunction or death by regulating autophagy is considered to be an effective method for treatment of type 2 diabetes mellitus (T2DM). Morus alba leaves (mulberry leaves), a popular herbal medicine, have been used for prevention of T2DM since ancient times. This study aimed to clarify whether Morus alba leaves ethanol extract (MLE) could protect islet cells in vivo and in vitro by regulating autophagy in T2DM, and explore the possible mechanism of action. The main chemical constituents in MLE were analyzed by HPLC. The T2DM rat model was induced via high-fat diet combined with peritoneal injection of low-dose streptozotocin, and MLE was administered by oral gavage. Fasting blood glucose (FBG) and plasma insulin were measured, and homeostatic model assessment of β cell function (HOMA-β) and insulin resistance (HOMA-IR) were determined. The histomorphology of pancreas islets was evaluated by haematoxylin and eosin staining. In palmitic acid (PA)-stressed INS-1 rat insulinoma cells, cell viability was assayed by an MTT method. Expression of the autophagy-related proteins LC3 I/II, p62, p-AMPK and p-mTOR in islet tissues and INS-1 cells was evaluated by western blotting or immunohistochemistry analysis. The four main chemical constituents in MLE were identified as chlorogenic acid, rutin, isoquercitrin and quercitrin. MLE ameliorated hyperglycemia, insulin resistance and dyslipidemia of T2DM rats with prominent therapeutic effect. Further study indicated that MLE observably improved islet function, alleviated islet injury of T2DM rats, and inhibited PA-induced INS-1 cell death. On the other hand, MLE significantly induced autophagy in islet cells both in vivo and in vitro, and autophagy inhibitors abolished its therapeutic effect on T2DM rats and protective effect on islet cells. Apart from this, MLE markedly activated the AMPK/mTOR pathway in INS-1 cells, and the AMPK inhibitor prevented the autophagy induction ability of MLE. Together, MLE could protect islet cells against dysfunction and death by inducing AMPK/mTOR-mediated autophagy in T2DM, and these findings provide a new perspective for understanding the treatment mechanism of Morus alba leaves against T2DM.

The effects of incretin-based therapies on β-cell function and insulin resistance in type 2 diabetes: A systematic review and network meta-analysis combining 360 trials.

To evaluate the comparative effects of incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is), on β-cell function and insulin resistance in patients with type 2 diabetes mellitus (T2DM). Medline, Embase, the Cochrane Library and www.clinicaltrials.gov were searched for randomized controlled trials (RCTs) with a duration of at least 4 weeks. Network meta-analysis was performed, followed by subgroup analysis and meta-regression. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the quality of evidence. Outcomes of interest include homeostasis model assessment for β cell function (HOMA-β) and insulin resistance (HOMA-IR), fasting C-peptide and fasting plasma glucose (FPG). Weighted mean difference (WMD) with 95% confidence interval (CI) was calculated as the measure of effect size. A total of 360 RCTs (74% at least double-blinded) with 157 696 patients were included. Incretin-based therapies were compared with six other classes of glucose-lowering drugs or with placebo. Compared with placebo, a significant increase in HOMA-β and fasting C-peptide was detected for GLP-1RAs (WMD = 20.31 [95% CI, 16.34-24.39] with low quality; WMD = 0.16 ng/mL [95% CI, 0.03-0.29] with low quality) and for DPP-4Is (WMD = 9.90 [95% CI, 8.27-11.61] with moderate quality; WMD = 0.09 ng/mL [95% CI, 0.04-0.14] with moderate quality) separately, while a significant reduction in HOMA-IR and FPG were found in favour of GLP-1RAs (WMD = -0.67 [95% CI, -1.08 to -0.27] with low quality; WMD = -1.04 mmol/L [95% CI, -1.26 to -0.83] with moderate quality) and DPP-4Is (WMD = -0.23 [95% CI, -0.38 to -0.08] with low quality; WMD = -0.77 mmol/L [95% CI, -0.98 to -0.57] with moderate quality), respectively. Incretin-based therapies not only show an increase in HOMA-β and fasting C-peptide level, but also achieve a reduction in HOMA-IR and FPG in comparison with placebo. Although GRADE scores indicate low to moderate for most comparisons, incretin-based therapies seem to be an advisable option for long-term treatment to preserve β-cell function.

Bisphenol A is not associated with a 5-year incidence of type 2 diabetes: a prospective nested case-control study.

The relationship between bisphenol A (BPA) and diabetes remains controversial. This study aims to investigate whether serum BPA level could predict the 5-year incidence of type 2 diabetes (T2D). A nested case-control study was performed among Chinese who participated in the environment, inflammation and metabolic diseases study (2008-2013). Of the 3510 subjects who were free of diabetes, 232 subjects developed diabetes during the 5-year follow-up. Cases and controls were matched for age and gender by a ratio of 1:1. Homoeostasis model assessment was used to estimate basal β-cell function (HOMA-β) and insulin resistance (HOMA-IR). Participants were stratified into tertiles based on low, median and high baseline serum BPA levels. Regression models were used to analyze the relationship between serum BPA concentration and the incidence of T2D. At baseline, no significant difference in serum BPA concentration was observed between patients with T2D and controls [1.3 (0.3, 3.7) vs. 1.6 (0.4, 3.9)μmol/L, P=0.199]; serum BPA concentration was positively associated with fasting plasma glucose (r=0.27, P<0.001); however, neither HOMA-β nor HOMA-IR correlated with serum BPA concentration. During the follow-up, baseline BPA levels could not predict the 5-year T2D incidence, whether or not adjusted for the potential confounders such as body mass index and blood pressure. [Low BPA tertile was the reference, OR 0.66 (95% CI 0.30, 1.44) for median, OR 0.93 (95% CI 0.41, 2.13) for high.] CONCLUSION: BPA is not associated with a 5-year T2D incidence. These data do not support previous cross-sectional study that BPA exerted a detrimental effect on glucose metabolism.

Association of maternal and fetal LEPR common variants with maternal glycemic traits during pregnancy

Recent studies suggested that maternal and placental leptin receptor (LEPR) may be involved in maternal glucose metabolism in pregnancy. To identify maternal and fetal LEPR common variants influencing gestational glycemic traits, we performed association study of 24-28-week maternal fasting glucose, glucose 1 hour after the consumption of a 50-g oral glucose load, fasting insulin and indices of beta-cell function (HOMA-β) and insulin resistance (HOMA-IR) in 1,112 unrelated women and their children. Follow-up of 36 LEPR loci identified 3 maternal loci (rs10889567, rs1137101 and rs3762274) associated with fasting glucose, these 3 fetal loci associated with fasting insulin and HOMA1-IR, as well as these 3 maternal-fetal loci combinations associated with HOMA2-β. We also demonstrated association of maternal locus rs7554485 with HOMA2-β and HOMA2-IR, maternal locus rs10749754 with fasting glucose, fetal locus rs10749754 with HOMA2-IR. However, these associations were no longer statistically significant after Bonferroni correction. In conclusion, our results first revealed multiple associations between maternal and fetal LEPR common variants and gestational glycemic traits. These associations did not survive Bonferroni correction. These corrections are overly conservative for association studies. We therefore believe the influence of these nominally significant variants on gestational glycometabolism will be confirmed by additional studies.

Sitagliptin down-regulates retinol-binding protein 4 and reduces insulin resistance in gestational diabetes mellitus: a randomized and double-blind trial.

Gestational diabetes mellitus (GDM) is a condition that affects increasing number of pregnant women worldwide. Sitagliptin was reported to alleviate symptoms of type 2 diabetes mellitus by reducing serum levels of retinol-binding protein 4 (RBP-4). We investigated the effectiveness of sitagliptin on insulin sensitivity parameters in GDM patients. Pregnant GDM women in the 2nd trimester were recruited for this study. Participants were then assigned randomly to sitagliptin treatment group or placebo treatment group, and administered sitagliptin or placebo daily for 16weeks. Glucose and insulin profiles, as well as serum RBP-4 level, were measured at both baseline and end of the study. After 16weeks of treatment, participants in the STL group exhibited significantly improved levels of fasting plasma glucose and serum insulin, homeostasis model of assessment of β cell function (HOMA-β) and insulin resistance (HOMA-IR), compared with those in the placebo group. Serum levels of RBP-4 were also markedly decreased in the sitagliptin treatment group, and more importantly it was positively correlated with improved insulin resistance parameters. Our study supports a potentially promising role of sitagliptin in improving insulin resistance by decreasing RBP-4 in GDM-affected women.

Biochemical Profile of Some Nutritionally Stunted Egyptian Children

Childhood nutritional stunting, an indicator of chronic malnutrition, has been suggested as one factor that can contribute to high incidences of obesity, and impaired lipid and glucose metabolism in developing countries. This study aimed to determine health risks of developing hyperlipidemia, obesity, and diabetes as non-communicable diseases (NCDs) among nutritionally stunted Egyptian children. A total of 90 children were enrolled; 60 nutritional stunted children and 30 non- stunted of matched age and sex. Clinical, demographic characteristics were determined for the studied children. Lipid profile levels, fasting plasma levels of glucose, and insulin were measured in these subjects. Pancreatic beta cells’ function (HOMA-β) and insulin resistance (HOMA-IR) were calculated by homeostasis model assessment (HOMA). Stunted children exhibited significantly lower values for weight, weight-for-age Z score (WAZ), height, and height-for-age Z score (HAZ) as compared to normal ones. Significant elevation in total cholesterol (TC), and low density lipoprotein cholesterol (LDL-c), significant decrease in high density lipoprotein cholesterol (HDL-c) and HDL/LDL ratio were detected compared to that of the healthy control subjects. There were no significant differences in the levels of fasting glucose, fasting insulin, homeostasis model assessment of beta-cell function (HOMA-β), and homeostasis model assessment of insulin resistance (HOMA-IR) between the two compared groups. Conclusion: Alterations in lipid pattern among nutritionally stunted Egyptian children may predict the future of NCDs later in life.

Relationship between serum osteocalcin levels and glucolipid metabolism in elderly type 2 diabetic patients with non-alcoholic fatty liver disease

Objective To explore the relationship between serum osteocalcin levels and glucolipid metabolism in elderly type 2 diabetic patients with non-alcoholic fatty liver disease(NAFLD). Methods Data collected from 97 patients with type 2 diabetes mellitus(T2DM)admitted to the Department of Geriatric Endocrinology of the First Affiliated Hospital of Zhengzhou University from June 2014 to April 2015 were retrospectively analyzed.Patients were divided into the T2DM group(type 2 diabetic patients without NAFLD, n=47)and the NAFLD group(T2DM patients with NAFLD, N=50). Healthy elderly subjects(n=30)from the same period served as the control group.Body mass index(BMI), osteocalcin, fasting blood glucose, fasting insulin, homeostasis model assessment for insulin secretion index(HOMA-β)and insulin resistance(HOMA-IR), glycosylated hemoglobin(HbA1c), total cholesterol, triglyceride, high-density lipoprotein cholesterol(HDL-C)and low-density lipoprotein cholesterol(LDL-C)were compared between the 3 groups. Results Levels of fasting blood glucose, fasting insulin, HbA1c, total cholesterol, triglyceride, LDL-C and HOMA-IR were higher, while levels of HDL-C, HOMA-β and osteocalcin were lower in the T2DM and NAFLD groups than in the control group(all P<0.05). Levels of BMI, fasting glucose, fasting insulin, HbA1c, total cholesterol, triglyceride, LDL-C and HOMA-IR were higher and levels of osteocalcin were lower in the T2DM group than in the NAFLD group(all P<0.05). Pearson correlation analysis showed that the osteocalcin level was negatively correlated with fasting blood glucose, HbA1C, HOMA-IR and BMI(r=-0.701, -0.442, -0.337 and -0.543, P<0.05 or P<0.01), and positively correlated with HOMA-β(r=0.341, P<0.05)in the NAFLD group. With serum osteocalcin as the dependent variable, multiple linear regression results showed that fasting blood glucose was an independent influencing factor for serum osteocalcin(β=-1.57, P<0.05)in the fatty liver group. Conclusions Serum osteocalcin levels significantly decrease in elderly T2DM patients with NAFLD, are closely correlated with glucolipid metabolism, and may have some important clinical significance in the prevention and treatment of NAFLD in elderly patients with type 2 diabetes. Key words: Osteocalcin; Diabetes Mellitus, Type 2; Fatty Liver

Relationship of Hemoglobin A1c with β Cell Function and Insulin Resistance in Newly Diagnosed and Drug Naive Type 2 Diabetes Patients.

Objective. To investigate changes in the glycated hemoglobin A1c (A1c) level and those in β cell function and insulin resistance in newly diagnosed and drug naive type 2 diabetes patients and to evaluate the relationship between them. Design and Methods. A total of 818 newly diagnosed diabetic individuals who were ≥40 years of age were recruited. The subjects were grouped by A1c values (<6.5%, 6.5–7%, 7-8%, 8-9%, and ≥9%). The homeostasis model assessment (HOMA) was used to evaluate pancreatic β cell function (HOMA-β) and insulin resistance (HOMA-IR). ANOVA, t-tests, and binary logistic regression analysis were used for data analysis. Results. Compared with subjects with A1c values <6.5%, individuals with an A1c of 6.5–7% exhibited an increased HOMA-β index. However, the HOMA-β index was significantly decreased at A1c values ≥7% and further decreased by 9.3% and by 23.7%, respectively, at A1c values of 7-8% and 8-9%. As A1c increased to ≥9%, a 62% reduction in β cell function was observed, independently of age, gender, body mass index (BMI), blood pressure (BP), blood lipids, and hepatic enzyme levels. Meanwhile, insulin resistance was significantly increased with an increase in A1c values. Conclusions. Elevated A1c values (≥7%) were associated with substantial reductions in β cell function.

Adipokines and β-cell dysfunction in normoglycemic women with previous gestational diabetes mellitus.

An increased risk of developing type 2 diabetes in women with a history of gestational diabetes mellitus(gestational diabetes mellitus - GDM) may be associated with increased insulin resistance and subclinical inflammation. However, approximately half of women with previous GDM (pGDM) do not develop diabetes. These women were the population of focus in the present study. The aim of the study was to assess β-cell function, insulin resistance, and the levels of pro- and anti inflammatory adipokines in normoglycemic women with pGDM. A study group included 199 women with pGDM; the mean time after delivery was 7.4 years. A control group included 50 women without pGDM. All patients underwent an oral glucose tolerance test (OGTT) with the assessment of glycemia and insulinemia, β-cell function (HOMA-%β), and insulin resistance (HOMA-IR), as well as the levels of soluble tumor necrosis factor α receptor (sTNF-α-R2), interleukin 6 (IL-6), adiponectin, and visfatin. Normal glucose tolerance was found in 113 women with pGDM (56.8%; the NGT-GDM[+] group) and in 44 control subjects (88.0%). In comparison with controls, the NGT-GDM[+] group had significantly higher glycemia in the OGTT and significantly lower HOMA-%β values, with comparable HOMA-IR and body mass index values. The NGT-GDM(+) group was shown to have significantly higher levels of sTNF-α-R2 and IL-6, with similar adiponectin and visfatin levels. Normoglycemic women with a history of GDM are characterized by concomitant disturbances in insulin secretion and subclinical inflammation, with normal body weight and insulin sensitivity. It is not known whether these disturbances were present before a GDM-complicated pregnancy or whether they were induced by pregnancy.

The role of dipeptidyl peptidase 4 inhibitors in fat metabolism in patients with type 2 diabetes and obesity

Objective. To evaluate the influence of combined therapy of sitagliptin and metformin on fat metabolism in patients with type 2 diabetes mellitus.Methods. The study included 82 patients (age, 55.3±9.1 years) with obesity and lipid metabolism disorders. None of the patients had reached their target glycated haemoglobin levels after metformin and diet therapy. Patients in group 1 (n=42) received 1.5–2-g metformin daily before the study and were switched to a formulation of 100-mg sitagliptin and 2-g metformin once a day. Patients in group 2 (n=40) were on a diet therapy before inclusion and were started on 2-g metformin/day. The following were evaluated at baseline and after 6 months of therapy: fasting glucose levels, postprandial glucose levels, glycated haemoglobin, weight, body mass index, waist circumference and lipid profile; insulin, proinsulin, leptin and adiponectin levels; insulin resistance using the homeostatic model assessment (HOMA) of β-cell function (HOMA-β) and insulin resistance (HOMA-IR). In addition, magnetic resonance imaging was performed to assess the amount of visceral fat for the total cohort.Results. After 6 months, glycated haemoglobin decreased by 18.52% (p 0.001) in group 1 and by 8.17% (p 0.001) in group 2. Fasting plasma glucose and postprandial glucose levels in group 1 were reduced by 21% (p 0.001) and 26.35% (p 0.001), respectively; the corresponding reductions in group 2 were 1.45% (p 0.05) and 5.31% (p 0.05), respectively. HOMA-β increased by 33% in group 1 (p 0.001) and by 11% in group 2 (p 0.05). Adiponectin levels increased by 27.06% (p 0.001) in group 1 and by 7.16% in group 2 (p 0.001). Leptin levels were reduced by 30.47% (p 0.001) in group 1 and by 5.41% in group 2 (p 0.001). Magnetic resonance imaging showed a 7.52% reduction in visceral fat for group 1 (p 0.001) and a 1.76% reduction for group 2 (p 0.01). The comparison of subcutaneous fat dynamics did not show statistically significant differences between the groups.Conclusion. Compared with metformin monotherapy, sitagliptin and metformin combination therapy had a prominent effect on non-glycaemic parameters, with more marked decreases in visceral fat and leptin and increases in adiponectin levels.

Serum Acylated Ghrelin Is Negatively Correlated with the Insulin Resistance In the CODING study

ObjectiveGhrelin is a 28-amino acid orexigenic peptide synthesized mainly in the stomach. Acute administration of ghrelin has been found to decrease insulin secretion. However, little data is available regarding whether ghrelin contributes to the long-term regulation of insulin resistance at the population level. The aim of this study is to investigate the association between circulating ghrelin and insulin resistance in a large population based study.DesignA total of 2082 CODING study (Complex Diseases in the Newfoundland population: Environment and Genetics) subjects were assessed. Subjects were of at least third generation Newfoundland descent, between the ages of 20 and 79 years, and had no serious metabolic, cardiovascular, or endocrine diseases. Ghrelin was measured with an Enzyme Immunoassay method. Insulin and fasting glucose were measured by Immulite 2500 autoanalyzer and Lx20 clinical chemistry analyzer, respectively. Homeostatic Model Assessment of β cell function (HOMA-β) and Insulin Resistance (HOMA-IR) and Quantitative Insulin-sensitivity Check Index (QUICKI) were used for measurement of insulin resistance.ResultsPartial correlation analyses showed a significant negative correlation between circulating ghrelin and insulin level and insulin resistance in the entire cohort and also in men and women separately. The aforementioned correlation was independent of age, percentage of trunk fat and HDL-cholesterol. According to menopausal status, only pre-menopausal women revealed negative correlations.ConclusionOur results suggest that except for postmenopausal women, high circulating ghrelin level is associated with lower insulin resistance in the general population.

Adult glucose metabolism in extremely birthweight-discordant monozygotic twins

Low birthweight (BW) is associated with increased risk of type 2 diabetes. We compared glucose metabolism in adult BW-discordant monozygotic (MZ) twins, thereby controlling for genetic factors and rearing environment. Among 77,885 twins in the Danish Twin Registry, 155 of the most BW-discordant MZ twin pairs (median BW difference 0.5kg) were assessed using a 2h oral glucose tolerance test with sampling of plasma (p-)glucose, insulin, C-peptide, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. HOMA for beta cell function (HOMA-β) and insulin resistance (HOMA-IR), and also insulin sensitivity index (BIGTT-SI) and acute insulin response (BIGTT-AIR), were calculated. Subgroup analyses were performed in those with: (1) double verification of BW difference; (2) difference in BW >0.5kg; and (3) no overt metabolic disease (type 2 diabetes, hyperlipidaemia or thyroid disease). No intra-pair differences in p-glucose, insulin, C-peptide, incretin hormones, HOMA-β, HOMA-IR or BIGTT-SI were identified. p-Glucose at 120min was higher in the twins with the highest BW without metabolic disease, and BIGTT-AIR was higher in those with the highest BW although not in pairs with a BW difference of >0.5kg. BW-discordant MZ twins provide no evidence for a detrimental effect of low BW on glucose metabolism in adulthood once genetic factors and rearing environment are controlled for.

Pancreatic β-cell function relates positively to HDL functionality in well-controlled Type 2 diabetes mellitus

BackgroundHigh density lipoproteins (HDLs) have been implicated in glucose homeostasis. Among subjects with normal fasting glucose (NFG), impaired fasting glucose (IFG) and Type 2 diabetes mellitus (T2DM) we tested whether pancreatic β-cell function relates to HDL functionality, as determined by HDL anti-oxidative capacity and cellular cholesterol efflux to plasma. Subjects and methodsHDL anti-oxidative capacity (inhibition of LDL oxidation in vitro), cellular cholesterol efflux (the ability of plasma to stimulate cholesterol efflux out of cultured fibroblasts obtained from a single human donor), glucose and insulin were determined in fasting plasma samples from 37 subjects with NFG, 36 with IFG and 22 with T2DM (no glucose lowering drug or insulin treatment; HbA1c 6.0±1.0%). Homeostasis model assessment was used to estimate pancreatic β-cell function (HOMA-β) and insulin resistance (HOMAir). ResultsHOMA-β was lowest, whereas HOMAir was highest in T2DM (P<0.01 and P<0.001 vs. NFG). HDL anti-oxidative capacity and cellular cholesterol efflux did not differ significantly according to glucose tolerance category. In univariate analysis and after controlling for HOMAir both HDL anti-oxidative capacity (P<0.05) and cellular cholesterol efflux (P<0.01) were positively correlated with HOMA-β in T2DM, but not in NFG and IFG. In age-, sex- and HOMAir-adjusted analyses, T2DM status interacted positively with HDL anti-oxidative capacity (P=0.001) and cellular cholesterol efflux (P=0.042) on HOMA-β. HbA1c interacted similarly with HDL functionality measures on HOMA-β. ConclusionsPancreatic β-cell function relates to pathophysiologically relevant measures of HDL function in T2DM, but not in NFG and IFG. Better HDL functionality may contribute to maintenance of β-cell function in subjects with well-controlled T2DM.

Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes

To compare the efficacy and safety of monotherapy with sitagliptin and metformin in treatment-naïve patients with type 2 diabetes. In a double-blind study, 1050 treatment-naïve patients (i.e. not taking an antihyperglycaemic agent for > or =16 weeks prior to study entry) with type 2 diabetes and an HbA(1c) 6.5-9% were randomized (1:1) to treatment with once-daily sitagliptin 100 mg (N = 528) or twice-daily metformin 1000 mg (N = 522) for 24 weeks. Metformin was up-titrated from 500 to 2000 mg per day (or maximum tolerated daily dose > or =1000 mg) over a period of 5 weeks. The primary analysis used a per-protocol (PP) approach to assess whether sitagliptin was non-inferior to metformin based on HbA(1c) change from baseline at week 24. Non-inferiority was to be declared if the upper boundary of the 95% confidence interval (CI) for the between-group difference in this endpoint was <0.40%. From a mean baseline HbA(1c) of 7.2% in the PP population, HbA(1c) change from baseline was -0.43% with sitagliptin (n = 455) and -0.57% with metformin (n = 439). The between-group difference (95% CI) was 0.14% (0.06, 0.21), thus confirming non-inferiority. Baseline HbA(1c) influenced treatment response, with larger reductions in HbA(1c) observed in patients with baseline HbA(1c)> or =8% in the sitagliptin (-1.13%; n = 74) and metformin (-1.24%; n = 73) groups. The proportions of patients at week 24 with HbA(1c) values at the goals of <7 or <6.5% were 69 and 34% with sitagliptin and 76 and 39% with metformin, respectively. Fasting plasma glucose changes from baseline were -11.5 mg/dL (-0.6 mmol/l) and -19.4 mg/dl (-1.1 mmol/l) with sitagliptin and metformin, respectively (difference in LS mean change from baseline [95% CI] = 8.0 mg /dl [4.5,11.4]). Both treatments led to similar improvements from baseline in measures of homeostasis model assessment-beta cell function (HOMA-beta) and insulin resistance (HOMA-IR). The incidence of hypoglycaemia was 1.7% with sitagliptin and 3.3% with metformin (p = 0.116). The incidence of gastrointestinal-related adverse experiences was substantially lower with sitagliptin (11.6%) compared with metformin (20.7%) (difference in incidence [95% CI] = -9.1% [-13.6,-4.7]), primarily because of significantly decreased incidences of diarrhoea (3.6 vs. 10.9%; p < 0.001) and nausea (1.1 vs. 3.1%; p = 0.032). Body weight was reduced from baseline with both sitagliptin (LS mean change [95% CI] = -0.6 kg [-0.9,-0.4]) and metformin (-1.9 kg [-2.2, -1.7]) (p < 0.001 for sitagliptin vs. metformin). In this 24-week monotherapy study, sitagliptin was non-inferior to metformin in improving HbA(1c) in treatment-naïve patients with type 2 diabetes. Although both treatments were generally well tolerated, a lower incidence of gastrointestinal-related adverse experiences was observed with sitagliptin.