Search

Aims: Both fasting (FPG) and postprandial plasma glucose (PPG) contribute to HbA1c levels. We investigated the relationship between achievement of American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) recommended FPG and/or PPG targets and glycaemic efficacy outcomes in two trials. Methods: In this post hoc analysis, data from participants with Type 2 diabetes in the phase 3 LixiLan‐O (NCT 02058147) and LixiLan‐L (NCT 02058160) trials were evaluated to compare the relationship between achievement of society‐recommended FPG and/or PPG targets and efficacy (HbA1c change, HbA1c goal attainment, weight change) and safety outcomes in the treatment groups. Results: Across treatment arms, iGlarLixi achieved the highest proportion of participants meeting both ADA‐ and AACE‐recommended FPG and PPG targets at study end in both trials. A higher proportion of participants in the iGlarLixi (fixed‐ratio combination of insulin glargine and lixisenatide) vs. insulin glargine alone or lixisenatide alone treatment arms achieved HbA1c goals (P < 0.001 for overall comparisons), irrespective of ADA‐ or AACE‐defined targets. Hypoglycaemia rates [any, documented symptomatic (plasma glucose ≤ 3.9 mmol/l), and clinically important (plasma glucose < 3.0 mmol/l)] were low across all groups. Participants treated with iGlarLixi tended to show weight loss or less weight gain compared with participants receiving insulin glargine alone. No differences were observed in average daily basal insulin dose at week 30 between the two treatment arms or across the different FPG and PPG target groups. Conclusion: Insulin glargine and lixisenatide as a fixed‐ratio combination resulted in more participants reaching both FPG and PPG targets, leading to better HbA1c target attainment. What's new?: Achievement of both fasting (FPG) and postprandial plasma glucose (PPG) targets is important for optimal glycaemic control in Type 2 diabetes.This post hoc analysis of the LixiLan‐O and LixiLan‐L trials shows that targeting both FPG and PPG results in improved glycaemic control, with weight neutrality and a low risk of hypoglycaemia.It is clinically desirable to achieve control of FPG and PPG. More people treated with iGlarLixi achieved control, and those who did so reached an HbA1c target of < 53 mmol/mol (< 7.0%), had a greater drop in HbA1c, and did not gain weight compared with insulin glargine or lixisenatide alone. [ABSTRACT FROM AUTHOR]

Summary: Sarcopenia, described as the loss of muscle mass and/or strength, is gaining importance as it can be increasingly related to many chronic diseases. It is also associated with chronic liver disease, and recently it has been more frequently linked to non‐alcoholic fatty liver disease (NAFLD) in particular. Both sarcopenia and NAFLD are subject to complex and intermingled pathophysiological processes, of which some are in common. Furthermore, it is presently unclear if sarcopenia directly contributes to NAFLD or vice versa. The mechanisms that are involved may include obesity, insulin resistance, vitamin D deficiency, aging, physical inactivity and certain cytokines. Current clinical evidence is subject to an important heterogeneity in methods and definitions, with additionally also a relative overrepresentation of evidence in Asian ethnicities. Nonetheless, all studies so far point towards the same association between sarcopenia and NAFLD, including an association with NAFLD‐severity and NAFLD‐related fibrosis. Since the field is in its infancy, clear definitions and further research are needed to aid to improve understanding of the association between NAFLD and sarcopenia. This can eventually lead to additional potential therapeutic interventions. This review attempts to give an overview of the current published literature that links sarcopenia to NAFLD, followed by a discussion of the presumably involved pathophysiological factors, and ends by discussing current unmet needs. [ABSTRACT FROM AUTHOR]

Summary: Background: The composite histological endpoint comprising nonalcoholic steatohepatitis (NASH) and NAFLD activity score ≥4 and advanced fibrosis (F ≥ 2) (“fibrotic NASH”) is becoming an important diagnostic target in NAFLD: it is currently used to select patients for inclusion in phase III therapeutic trials and will ultimately be used to indicate treatment in clinical practice once the new drugs are approved. Aim: To develop a new blood test specifically dedicated for this new diagnostic target of interest. Methods: Eight Hundred and forty‐six biopsy‐proven NAFLD patients from three centres (Angers, Nice, Antwerp) were randomised into derivation and validation sets. Results: The blood fibrosis tests BARD, NFS and FIB4 had poor accuracy for fibrotic NASH with respective AUROC: 0.566 ± 0.023, 0.654 ± 0.023, 0.732 ± 0.021. In the derivation set, fibrotic NASH was independently predicted by AST, HOMA and CK18; all three were combined in the new blood test MACK‐3 (hoMa, Ast, CK18) for which 90% sensitivity and 95% specificity cut‐offs were calculated. In the validation set, MACK‐3 had a significantly higher AUROC (0.847 ± 0.030, P ≤ 0.002) than blood fibrosis tests. Using liver biopsy in the grey zone between the two cut‐offs (36.0% of the patients), MACK‐3 provided excellent accuracy for the diagnosis of fibrotic NASH with 93.3% well‐classified patients, sensitivity: 90.0%, specificity: 94.2%, positive predictive value: 81.8% and negative predictive value: 97.0%. Conclusion: The new blood test MACK‐3 accurately diagnoses fibrotic NASH. This new test will facilitate patient screening and inclusion in NAFLD therapeutic trials and will enable the identification of patients who will benefit from the treatments once approved. [ABSTRACT FROM AUTHOR]

Objective Ectopic fat depostion in youth with obesity is associated with an increased cardiovascular disease risk. The aim of this meta-analysis was to summarize the evidence for the use of diet and/or exercise on ectopic adiposity in this population. Methods A systematic literature search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. Clinical trials that assessed ectopic fat deposition and included study arms with diet and/or exercise were searched in PubMed, PEDro and the Cochrane database. Results Hepatic fat content and intramyocellular lipid content were described in nine studies and three studies, respectively. Most studies included teenagers, and study duration ranged between 3 and 12 months without follow-up. Using random-effects weights, the standardized mean difference of the change in hepatic adiposity (totalling 320 subjects) was −0.54 Hedges' g (95% confidence interval: −0.69 to −0.38 with p < 0.0001). By re-expressing this effect size, it is seen that diet and/or exercise results in an absolute reduction of intrahepatic lipid with 2%, which accords with a relative reduction up to 70%. Although there were significant ameliorations of insulin sensitivity, no significant changes in intramyocellular lipid were observed. Conclusions This meta-analysis showed that diet and/or exercise is effective to reduce hepatic adiposity in youth with obesity. [ABSTRACT FROM AUTHOR]

The prevalence of non-cigarette tobacco use in electronic cigarettes, also called vaping, is rapidly increasing, especially in adolescents and young adults, due to attractive marketing techniques promoting them as healthier alternatives to conventional tobacco cigarettes. Although smoking is associated with weight loss, it increases insulin resistance and attributes to other features of the metabolic syndrome, increasing the cardiometabolic risk profile. Whether vaping has the same deleterious effects on metabolic parameters as regular cigarette smoke has not yet been studied thoroughly in humans. However, animal model experiments attribute comparable effects of e-cigarette smoking, even without nicotine exposure, on weight and metabolic parameters as compared to smoking cigarettes. In this review paper, we want to give an overview of published data on the effects on weight and cardiometabolic parameters of e-cigarette use and formulate some mechanistic hypotheses. [ABSTRACT FROM AUTHOR]

This post hoc analysis assessed the evidence behind common reimbursement practices by evaluating the relationship of body mass index ( BMI) ranges (<30, 30-35 and >35 kg/m2) with treatment effects of exenatide twice daily among patients with type 2 diabetes. Patients received exenatide twice daily added to insulin glargine in two 30-week studies (exenatide twice daily vs insulin lispro, n = 627; exenatide twice daily vs placebo, n = 259). No association of baseline BMI with changes in efficacy variables was observed. Glycated haemoglobin ( HbA1c) reductions were significant (p < 0.0001) and similar across BMI range groups in the lispro-comparator study and greater for exenatide versus placebo in the placebo-controlled study. Significant weight loss occurred with exenatide across BMI range groups (p < 0.0001), while weight increased with both comparators. Achievement of HbA1c <7.0% (<53 mmol/mol) without weight gain was greater for exenatide versus comparators. Systolic blood pressure decreased across BMI range groups with exenatide in the lispro-comparator study (p < 0.0001); changes in lipids were not clinically meaningful. Minor hypoglycaemia was less frequent for exenatide versus insulin lispro. These findings suggest that BMI alone should not limit clinical decision-making or patient access to medication. [ABSTRACT FROM AUTHOR]

What is already known about this subject BDNF is involved in the regulation of food intake and body weight., BDNF deficient animal models are obese., Chromosomal abnormalities cause obesity in humans., What this study adds Evaluation of point mutations in BDNF., Identification of BDNF mutations in obese children., Point mutations in BDNF are not a common cause of childhood obesity., Introduction There is ample evidence that BDNF has a role in the regulation of food intake and body weight. Study of various mouse models gave a clear indication that BDNF deficiency leads to the development of obesity. Functional loss of one copy of the BDNF gene, due to chromosomal rearrangements or microdeletions, can cause an obesity phenotype in humans. Therefore, we wanted to investigate whether point mutations in the gene also result in a comparable phenotype. Methods We screened 554 severely overweight and obese children and adolescents and 565 lean adults for mutations in the coding region of BDNF. Mutation screening was performed by high-resolution melting curve analysis and direct sequencing. Results Screening of obese patients led to the identification of two synonymous variations ( V37V and H65H) and two non-synonymous coding mutations ( T2I and V46M) in the BDNF gene. When we subsequently screened our control population, we found T2I with comparable frequency and confirmed that this is a rare and non-pathogenic variant. In addition, we found another non-synonymous mutation ( N187S) in the control population. Conclusions In silico analysis of the V46M variant did not support a clear disease-causing effect and no family data were available in order to determine whether the mutation segregates with obesity. However, we cannot rule out a possible pathogenic effect for this variant. In general, we tend to conclude that mutations in the coding region of BDNF are uncommon in obese patients and are therefore not likely to play an essential role in the pathogenesis of childhood obesity. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim Visceral adipose tissue ( VAT) and liver fat ( LF) are strongly associated with type 2 diabetes. It is not known, however, how diabetes treatment and/or risk factor management modulates the association between VAT, LF and diabetes. The aim was to determine the level of VAT and LF in patients with type 2 diabetes according to their treatment status and achievement of the American Diabetes Association's ( ADA) diabetes management goals. Methods We performed a cross-sectional analysis of the baseline data of the International Study of the Prediction of Intra-Abdominal Adiposity and its Relationship with Cardiometabolic risk/Intra-Abdominal Adiposity ( INSPIRE ME IAA), a 3-year prospective cardiometabolic imaging study conducted in 29 countries. Patients (n = 3991) were divided into four groups: (i) those without type 2 diabetes ( noT2D n = 1003 men, n = 1027 women); (ii) those with type 2 diabetes but not treated with diabetes medications ( T2Dnomeds n = 248 men, n = 198 women); (iii) those with type 2 diabetes and treated with diabetes medications but not yet using insulin ( T2Dmeds-ins n = 591 men, n = 484 women) and (iv) those with type 2 diabetes and treated with insulin ( T2Dmeds+ins n = 233 men, n = 207 women). Abdominal and liver adiposity were measured by computed tomography. Results Fewer patients with high VAT or LF achieved the ADA's goals for high-density lipoprotein cholesterol ( HDL-C) or triglycerides compared to patients with low VAT or LF. Visceral adiposity (p = 0.02 men, p = 0.003 women) and LF (p = 0.0002 men, p = 0.0004 women) increased among patients who met fewer of the ADA treatment criteria, regardless of type 2 diabetes treatment. Conclusion Residual cardiometabolic risk exists among patients with type 2 diabetes characterized by elevated VAT and LF. [ABSTRACT FROM AUTHOR]

Aim: The Sibutramine Cardiovascular OUTcomes trial showed that sibutramine produced greater mean weight loss than placebo but increased cardiovascular morbidity but not mortality. The relationship between 12-month weight loss and subsequent cardiovascular outcomes is explored. Methods: Overweight/obese subjects (N = 10 744), ≥55 years with cardiovascular disease and/or type 2 diabetes mellitus, received sibutramine plus weight management during a 6-week Lead-in Period before randomization to continue sibutramine (N = 4906) or to receive placebo (N = 4898). The primary endpoint was the time from randomization to first occurrence of a primary outcome event (non-fatal myocardial infarction, non-fatal stroke, resuscitated cardiac arrest or cardiovascular death). Results: For the total population, mean weight change during Lead-in Period (sibutramine) was −2.54 kg. Post-randomization, mean total weight change to Month 12 was −4.18 kg (sibutramine) or −1.87 kg (placebo). Degree of weight loss during Lead-in Period or through Month 12 was associated with a progressive reduction in risk for the total population in primary outcome events and cardiovascular mortality over the 5-year assessment. Although more events occurred in the randomized sibutramine group, on an average, a modest weight loss of approximately 3 kg achieved in the Lead-in Period appeared to offset this increased event rate. Moderate weight loss (3-10 kg) reduced cardiovascular deaths in those with severe, moderate or mild cardiovascular disease. Conclusions: Modest weight loss over short-term (6 weeks) and longer-term (6-12 months) periods is associated with reduction in subsequent cardiovascular mortality for the following 4-5 years even in those with pre-existing cardiovascular disease. While the sibutramine group experienced more primary outcome events than the placebo group, greater weight loss reduced overall risk of these occurring in both groups. [ABSTRACT FROM AUTHOR]

Objective: To assess treatment responses to sibutramine and weight management in diabetic patients during the lead-in period of the Sibutramine Cardiovascular OUTcomes (SCOUT) trial. Methods: SCOUT is an ongoing, prospective, randomized, double-blind, placebo-controlled outcome trial in cardiovascular high-risk overweight/obese patients. A total of 10 742 patients received single-blind sibutramine and individualized weight management during the 6-week lead-in period; 84% had a history of type 2 diabetes mellitus and additional co-morbidities. Post-hoc analyses assessed anthropomorphic and vital sign responses between patients with and without diabetes. Results: Concomitant antidiabetic medication use was reported by 86% of the diabetic patients (approximately 30% required insulin–alone or in combination). Body weight and waist circumference decreased in diabetic patients: median 2.1 kg; 2.0 cm (both men and women); for those on insulin: 1.9 kg; 1.5/2.0 cm (men/women); without insulin: 2.3 kg; 2.0 cm (both men and women); blood pressure (BP) was also reduced (median systolic/diastolic 3.5/1.0 mmHg) with larger reductions in diabetic patients who were hypertensive and/or lost the most weight (>5%). In diabetic patients who entered with BP at target (<130/<85 mmHg) but did not lose weight (N = 245), increases of 3.5/2.0 mmHg were observed. Non-diabetic patients had greater weight losses (2.5 kg) but smaller reductions in BP (systolic/diastolic −2.5/−0.5 mmHg). Pulse rate increases were less in diabetic vs. non-diabetic patients (1.5 vs. 2.0 bpm). Conclusion: In these high-risk diabetic patients, sibutramine and lifestyle modifications for 6 weeks resulted in small, but clinically relevant, median reductions in body weight, waist circumference and BP. A small median increase in pulse rate was recorded. [ABSTRACT FROM AUTHOR]

Objective: To explore vital sign changes among patient subgroups during the 6-week lead-in period of the sibutramine cardiovascular outcomes (SCOUT) trial. Methods: SCOUT is an ongoing, double-blind, randomized, placebo-controlled outcome trial in overweight/obese patients at high risk of a cardiovascular event. During the 6-week lead-in period, 10 742 patients received sibutramine and weight management. Vital sign changes were assessed post hoc by initial blood pressure (mmHg) categorized as normal (<130/<85), high-normal (130 to <140/85 to <90) or hypertensive (≥140/≥90); weight change categories (weight gain/no weight change, >0 to 2.5% weight loss, >2.5 to 5% weight loss and >5% weight loss) and current antihypertensive medication class use (none, one, or two or more). To assess the impact of sibutramine on blood pressure and pulse rate, only patients (N = 10 025) who reported no change in the class of antihypertensive medication used and who did not report an increase in antihypertensive medication use were analysed. Results: At entry, approximately 50% of patients were hypertensive and 26% were high-normal. In hypertensive patients, blood pressure changes (mmHg) decreased by median [5th, 95th percentile] of −6.5 systolic [−27.0, 8.0] and −2.0 diastolic [−15.0, 8.0] (p < 0.001). Hypertensive patients with no weight loss or with weight gain had median decreases of −3.5 systolic [−26.0, 10.0] and −1.5 diastolic [−16.0, 9.0] (p < 0.001). Normotensive patients had median increases of 1.5 systolic [−15.0, 19.5] and 1.0 diastolic [−10.5, 13.0] (p < 0.001) attenuated with increasing weight loss. Approximately 43% of patients initially categorized as hypertensive had a lower blood pressure category at end-point. Concomitant antihypertensive medication classes did not affect blood pressure reductions. Pulse rates were uniformly elevated (median 1–4 bpm, p < 0.001) across blood pressure and weight change categories. Conclusions: In hypertensive patients (≥140/≥90), blood pressure decreases were observed during 6-week treatment with sibutramine even when body weight was unchanged. In patients with normal blood pressure (<130/<85), weight loss of >5% induced decreases in systolic blood pressure; otherwise, small increases were observed. Small pulse rate increases were observed regardless of blood pressure or weight change status. [ABSTRACT FROM AUTHOR]

Objective. To assess if the severity of sleep-disordered breathing (SDB) and mainly intermittent hypoxia is associated with increased peripheral leukocytes in overweight children and adolescents, controlling for adiposity and obesity-related metabolic abnormalities. Methods.Consecutive subjects were recruited at a pediatric obesity clinic. All subjects underwent polysomnography and a fasting blood sample. Results. In total, 95 subjects were included (=11.1±2.6, 43 boys, body mass index, =2.3±0.5, 29 subjects were overweight and 66 obese). Total white blood cell count increased significantly by worsening of intermittent hypoxia. Total white blood cell count was correlated with the maximal degree of desaturation, independent of puberty, HOMA and HDL-cholesterol. Neutrophil levels were associated with the degree of desaturation, while controlling for puberty and HOMA. Conclusion.This study supports the hypothesis of an independent interaction between intermittent hypoxia and nocturnal desaturation during sleep, and increased white blood cell and neutrophil levels in overweight and obese children and adolescents. This finding may contribute to the mechanisms linking SDB with increased cardiovascular morbidity. [ABSTRACT FROM AUTHOR]

Background The age at clinical onset of type 1 diabetes is decreasing. Preliminary Belgian data suggested that this anticipation occurred preferentially in boys. We investigated whether this gender-specific anticipation could be confirmed over a 15-year observation period. Methods In Antwerp, we studied incidence trends between 1989 and 2003 in 746 type 1 diabetic patients under age 40. For 2928 antibody-positive patients diagnosed nationwide during the same period, age at diagnosis was analysed according to gender and calendar year. Results In Antwerp, the incidence of type 1 diabetes under age 15 increased significantly with time from 10.9/100 000/year in 1989-1993 to 15.8/100 000/year in 1999-2003 ( p = 0.008). The rising incidence in children was largely restricted to boys under age 10 where the incidence more than doubled during the 15-year period (6.8/100 000/year in 1989-1993 vs 17.2/100 000/year in 1999-2003; p < 0.001). Such an increase was not found in girls under age 10 ( p = 0.54). This selective trend toward younger age at diagnosis in boys was confirmed in the larger group of Belgian patients where the median age at diagnosis decreased in boys-but not in girls-from 20 years in 1989-1993 to 15 years in 1999-2003 ( p < 0.001). Conclusions Over a 15-year observation period, a selective anticipation of clinical onset of type 1 diabetes was found in boys but not in girls. This suggests that an environmental factor may preferentially accelerate the sub-clinical disease process in young boys. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aim: To determine the effect of two different levels of energy deficit on weight loss in obese patients treated with orlistat. Methods: Patients (n = 430) were randomized in a 1-year, multicentre, open-label, parallel group study conducted at 23 hospital centres and university medical departments worldwide. Obese outpatients (body mass index 30–43 kg/m2) aged 18–70 years with a body weight of ≥90 kg and a waist circumference of ≥88 cm (women) or ≥102 cm (men) were treated with orlistat 120 mg three times daily plus a diet that provided an energy deficit of either 500 or 1000 kcal/day for 1 year. Orlistat treatment was discontinued in patients who did not achieve ≥5% weight loss after assessment at 3 and 6 months. The primary outcome measure was change in body weight from baseline at week 52. Results: Reported mean difference in energy intake between the two groups (500–1000 kcal/day deficit) at weeks 24 and 52 was actually 111 and 95 kcal/day respectively. Of the 430 patients involved in the study, 295 achieved ≥5% weight loss at both 3 and 6 months. In this population, at week 52, weight loss from baseline was similar for patients randomized to either the 500 or the 1000 kcal/day deficit diet (−11.4 kg vs. −11.8 kg, respectively; p = 0.778). After 12 months of treatment with orlistat, 84% (n = 118/141) and 85% (n = 131/154) of patients in the 500 and 1000 kcal/day deficit groups, respectively, achieved ≥5% weight loss, and 50% (n = 70/141) and 53% (n = 82/154) of patients, respectively, achieved ≥10% weight loss. Patients in both the diet treatment groups showed similar significant improvements in blood pressure, lipid levels and waist circumference at week 52. Conclusions: Treatment with orlistat was associated with a clinically beneficial weight loss, irrespective of the prescribed dietary energy restriction (−500 or −1000 kcal/day). Patients who achieved ≥5% weight loss at 3 months achieved long-term, clinically beneficial weight loss with orlistat plus either diet. Therefore, identifying patients who lose at least 5% weight after 3 months and who maintain this weight loss up to 6 months is a valuable treatment algorithm to select patients who will benefit most from orlistat treatment in combination with diet. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the interventions by general practitioners on cardiovascular risk factors among persons without a history of cardiovascular disease attending for a cardiovascular check-up. All inhabitants of three Belgian towns aged between 45 and 64 years were invited for a cardiovascular check-up and blood test. Of all the attending persons without a history of cardiovascular disease (n = 898), 51% received at least one prescription, diet or health advice: 28% for hyperlipidaemia, 23% for physical activity, 22% for caloric intake, 9% for blood sugar, 5% for blood pressure and 4% for smoking. Interventions on lipoproteins, blood sugar and smoking habits were significantly more often proposed to persons with a medium or high cardiovascular risk compared to those at low cardiovascular risk. For persons at low cardiovascular risk, therapeutic lifestyle changes are often not advised, and isolated risk factors often remain untreated. [ABSTRACT FROM AUTHOR]

Aim: These analyses were undertaken to evaluate the efficacy of the insulin sensitizer rosiglitazone (RSG) when added to the therapy of obese type 2 diabetes mellitus patients (T2DM) taking near-maximal doses (2.5 g/day) of metformin (MET). In obese, insulin-resistant patients with T2DM who are inadequately controlled on MET, the addition of an agent that reduces insulin resistance may be a more rational and innovative approach than the addition of an insulin secretagogue. Methods: Data were pooled from two double-blind studies of RSG added to 2.5 g/day MET, involving a total of 550 T2DM patients. Patients were categorized as non-overweight, overweight and obese according to their baseline BMI using WHO criteria (<25 kgm-2 , 25–30 kgm-2 , >30 kgm-2 respectively). Results: RSG improved glycaemia (HbA1c) and fasting plasma glucose (FPG) to a clinically significant extent in all three subgroups but the effect was most pronounced in the obese patients. Improvements in HOMA estimates of insulin resistance and beta-cell function were also greatest in the obese patients (4 mg: -16% and +19%; 8 mg: -37% and + 33% respectively), as were reductions in fasting insulin. The profile of adverse events was not demonstrably different in obese patients from the non-obese. Conclusions: In obese type 2 diabetic patients inadequately controlled on MET alone, addition of rosiglitazone improves glycaemic control, insulin sensitivity and beta-cell function to a clinically important extent. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: This study evaluated the addition of nateglinide, a d-phenylalanine derivative that restores early phase insulin release, to metformin in type 2 diabetes patients stabilized on high-dose metformin. Methods: This multicentre, double-blind, parallel group trial included 467 metformin-treated patients with glycosylated haemoglobin (HbA1c ) between 6.8% and 11%. Patients were randomized to add nateglinide 60 mg, 120 mg or placebo before three meals to metformin 1000 mg b.i.d. for 24 weeks. Results: HbA1c was significantly reduced with nateglinide 60 mg and 120 mg plus metformin compared with metformin control (-0.36%, p = 0.003; -0.59%, p < 0.001 respectively). Greater benefits occurred if patients had elevated HbA1c at baseline (-1.38% with nateglinide 120 mg in patients with HbA1c > 9.5%). A modest fasting plasma glucose reduction was observed. Most symptoms suggestive of hypoglycaemia occurred in patients with low HbA1c levels (≤ 8%) at baseline, although no confirmed cases of hypoglycaemia occurred with nateglinide 60 mg in this patient group. Events suggestive of hypoglycaemia were confirmed in 1.1% of cases (plasma glucose ≤ 3.3 mmol/l). Weight gain over 24 weeks was 0.9 kg with nateglinide 120 mg vs. metformin alone, and plasma lipids remained unchanged. Conclusions/interpretation: In patients stabilized on high-dose metformin, the addition of nateglinide improved glycaemic control. The combination of these agents was well tolerated and both doses of nateglinide proved effective. The efficacy of nateglinide 60 mg and the low rate of hypoglycaemia observed at this dose make it suitable for patients close to their therapeutic target on metformin monotherapy. [ABSTRACT FROM AUTHOR]

Background: Fifteen to 20% of type 1 diabetic patients exhibit parietal cell antibodies (PCA), which are associated with autoimmune gastritis, hypochlorhydria, iron deficiency and pernicious anaemia. Aim: To examine whether Helicobacter pylori infection could explain the high prevalence of PCA and autoimmune gastropathy in diabetes. If so, H. pylori eradication could prevent autoimmune gastritis. Methods: In 229 type 1 diabetics (M/F: 135/94; age: 41 ± 12 years) PCA were measured. H. pylori infection was assessed by serology, urea breath test in all and by histology (updated Sydney system) in 88 subjects. Pentagastrin tests were performed in 42 patients. Results: Sixty-nine patients were PCA-positive. H. pylori infection was present in 72 patients and was negatively associated with HLA-DQA1*0103-B1*0603 (OR=0.12, P=0.015) and positively with DQA1*0501-B1*0201 (OR=1.9, P=0.032). PCA-positivity was linked to HLA-DQA1*0501-B1*0301 (OR=3.9, P=0.017). A link between H. pylori and PCA was observed when PCA-positivity was defined as a titre ≥ 1/20 (OR=2.0, P=0.03), but not if ≥ 1/40 was the cut-off point. PCA-positivity, but not H. pylori infection, was associated with iron deficiency anaemia (OR=2.7, P=0.008), pernicious anaemia (OR= 33.5, P < 0.0001), hypochlorhydria (OR=12.1, P=0.0008) and autoimmune gastritis (OR=12.5, P < 0.0001). Conclusions: The HLA-bound susceptibility of H. pylori and PCA differed. PCA-positivity but not ongoing H. pylori infection is associated with autoimmune gastritis. Low titres of PCA might reflect H. pylori infection rather than autoimmune gastropathy. [ABSTRACT FROM AUTHOR]

SUMMARY Aim To investigate the efficacy and safety of miglitol vs. placebo in type 2 diabetic outpatients insufficiently controlled (HbA1c between 7.5 and 10.5%) with diet and metformin. Methods Patients treated with diet and metformin (1500–2250 mg/day) were randomized to receive additional treatment with either miglitol or placebo for 32 weeks. The dosages were force-titrated: 4 weeks at 25 mg miglitol t.i.d., 12 weeks at 50 mg miglitol t.i.d., and 16 weeks at 100 mg miglitol t.i.d. or matching placebo. If the highest dosage could not be tolerated, patients could be down-titrated to 50 mg t.i.d. The primary efficacy criterion was the change in glycated haemoglobin (HbA1c). Secondary efficacy parameters included fasting and 1 h postprandial blood glucose, serum insulin, and fasting and 1 h postprandial triglyceride levels. Safety and tolerability were evaluated by the incidence of adverse events and changes in vital signs or routine biochemical and haematological parameters. Results One hundred and fifty-two patients were valid for the intent-to-treat (ITT) analysis. There was a significant decrease in HbA1c on adding miglitol to metformin compared to adding placebo (miglitol treatment effect, - 0.21%; placebo treatment effect, + 0.22%; p = 0.011). Postprandial blood glucose declined in both the miglitol/metformin and placebo/metformin groups with a statistically significant difference in favour of miglitol/metformin (end of treatment adjusted means 13.8 mmol/l for miglitol vs. 15.8 mmol/l for placebo, p = 0.0007). Adverse events (AEs) were reported by only 8% more patients in the miglitol/metformin group than placebo/metformin. No cases of hypoglycaemia were reported. Conclusions Miglitol can safely and effectively be added to diet and metformin in patients whose type 2 diabetes is insufficiently controlled, and improves glycaemic control by significantly reducing HbA1c and postprandial blood glucose levels. [ABSTRACT FROM AUTHOR]

In the primary care setting providers have more tools available than ever before to impact positively obesity, diabetes, and their complications, such as renal and cardiac diseases. It is important to recognise what is available for treatment taking into account diabetes heterogeneity. For those who develop type 2 diabetes (T2DM), effective treatments are available that for the first time have shown a benefit in reducing mortality and macrovascular complications, in addition to the well-established benefits of glucose control in reducing microvascular complications. Some of the newer medications for treating hyperglycaemia have also a positive impact in reducing heart failure (HF). Technological advances have also contributed to improving the quality of care in patients with diabetes. The use of technology, such as continuous glucose monitoring systems (CGM), has improved significantly glucose and glycated haemoglobin A1c (HbA1c) values, while limiting the frequency of hypoglycaemia. Other technological support derives from the use of predictive algorithms that need to be refined to help predict those subjects who are at great risk of developing the disease and/or its complications, or who may require care by other specialists. In this review we also provide recommendations for the optimal use of the new medications; sodium-glucose co-transporter-2 inhibitors (SGLT2i) and Glucagon-like peptide-receptor agonists 1 (GLP1RA) in the primary care setting considering the relevance of these drugs for the management of T2DM also in its early stage., (© 2023 John Wiley & Sons Ltd.)

Objective: To evaluate the glucose and insulin profiles during an oral glucose tolerance test (OGTT) after Roux-en-Y gastric bypass (RYGB) in symptomatic and asymptomatic patients., Research Design and Methods: This retrospective study consisted of two groups that had undergone RYGB. The symptomatic (S) group (n = 27) had an OGTT at presentation, whereas the asymptomatic (A) group (n = 99) had an OGTT 1 year after RYGB. Each group was subdivided into two groups, namely, those with glycaemia <54 mg/dL (S1/A1) and those with glycaemia >54 mg/dL (S2/A2) during OGTT. Most of the patients underwent OGTT preoperatively., Results: Preoperatively, the glucose and insulin levels, as well as the speed of increase and decrease, were similar in all groups. Postoperatively, the minimum glucose levels during the OGTT did not differ between the symptomatic and asymptomatic groups (55 ± 19 vs. 54 ± 17 mg/dL) or between the S1 and A1 subgroups (39 ± 7 vs. 43 ± 8 mg/dL). The peak glucose values were higher in the symptomatic versus the asymptomatic group (236 ± 52 vs. 189 ± 43 mg/dL; P <0.05) and in the S1 and S2 versus the A1 and A2 subgroups. The speed of glucose increase and decline was significantly higher in the symptomatic group versus the asymptomatic group, with the speed of glucose decline being the highest in the S1 subgroup., Conclusion: Assessing hypoglycaemia after a gastric bypass remains challenging. Our study suggests that the main difference in glucose dynamics between symptomatic and asymptomatic patients might be the speed of glucose and insulin increase and decline during OGTT rather than the absolute values obtained., (© 2020 John Wiley & Sons Ltd.)

Background: The development of accurate, non-invasive markers to diagnose and stage non-alcoholic fatty liver disease (NAFLD) is critical to reduce the need for an invasive liver biopsy and to identify patients who are at the highest risk of hepatic and cardio-metabolic complications. Disruption of steroid hormone metabolic pathways has been described in patients with NAFLD., Aim(s): To assess the hypothesis that assessment of the urinary steroid metabolome may provide a novel, non-invasive biomarker strategy to stage NAFLD., Methods: We analysed the urinary steroid metabolome in 275 subjects (121 with biopsy-proven NAFLD, 48 with alcohol-related cirrhosis and 106 controls), using gas chromatography-mass spectrometry (GC-MS) coupled with machine learning-based Generalised Matrix Learning Vector Quantisation (GMLVQ) analysis., Results: Generalised Matrix Learning Vector Quantisation analysis achieved excellent separation of early (F0-F2) from advanced (F3-F4) fibrosis (AUC receiver operating characteristics [ROC]: 0.92 [0.91-0.94]). Furthermore, there was near perfect separation of controls from patients with advanced fibrotic NAFLD (AUC ROC = 0.99 [0.98-0.99]) and from those with NAFLD cirrhosis (AUC ROC = 1.0 [1.0-1.0]). This approach was also able to distinguish patients with NAFLD cirrhosis from those with alcohol-related cirrhosis (AUC ROC = 0.83 [0.81-0.85])., Conclusions: Unbiased GMLVQ analysis of the urinary steroid metabolome offers excellent potential as a non-invasive biomarker approach to stage NAFLD fibrosis as well as to screen for NAFLD. A highly sensitive and specific urinary biomarker is likely to have clinical utility both in secondary care and in the broader general population within primary care and could significantly decrease the need for liver biopsy., (© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Aims: Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce several cardiovascular risk factors, including plasma glucose, blood pressure, albuminuria and body weight. Long-term treatment lowers risks of cardiovascular and renal events. The objective of this post hoc analysis was to determine the effects of canagliflozin treatment versus placebo on clinical outcomes in relation to body mass index (BMI)., Materials and Methods: The CANVAS Program randomized 10 142 participants with type 2 diabetes to canagliflozin or placebo. These analyses tested the consistency of canagliflozin treatment effects across BMI levels for cardiovascular, renal, safety and body weight outcomes in three groups defined by baseline BMI: <25, 25-<30 and ≥30 kg/m 2 ., Results: In total, 10 128 participants with baseline BMI measurements were included. There were 966 participants with BMI <25 kg/m 2 , 3153 with BMI 25-<30 kg/m 2 and 6009 with BMI ≥30 kg/m 2 . Mean percent body weight reduction with canagliflozin compared with placebo was greater at 12 months [-2.77%  (95% confidence interval (CI): -2.95, -2.59)] than at 3 months [-1.72%  (95% CI: -1.83, -1.62)]. The hazard ratios (HRs) for canagliflozin compared with placebo control for the composite outcome of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke were 1.03 (95% CI: 0.66, 1.59) in participants with BMI <25 kg/m 2 , 0.97 (0.76, 1.23) with BMI 25-<30 kg/m 2 and 0.79 (0.67, 0.93) with BMI ≥30 kg/m 2 (P for heterogeneity = 0.55). The effects of canagliflozin on each component of the composite were also similar across BMI subgroups, as were effects on heart failure and renal outcomes (P for heterogeneity ≥0.19). The effects on safety outcomes were also broadly similar., Conclusions: Canagliflozin improved cardiovascular and renal outcomes consistently across patients with a broad range of BMI levels., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Obesity and type 2 diabetes are drivers of non-alcoholic fatty liver disease (NAFLD). Glucagon-like peptide-1 analogues effectively treat obesity and type 2 diabetes and may offer potential for NAFLD treatment., Aim: To evaluate the effect of the glucagon-like peptide-1 analogue, semaglutide, on alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) in subjects at risk of NAFLD., Methods: Data from a 104-week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52-week weight management trial (semaglutide 0.05-0.4 mg/day) were analysed. Treatment ratios vs placebo were estimated for ALT (both trials) and hsCRP (weight management trial only) using a mixed model for repeated measurements, with or without adjustment for change in body weight., Results: Elevated baseline ALT (men >30 IU/L; women >19 IU/L) was present in 52% (499/957) of weight management trial subjects. In this group with elevated ALT, end-of-treatment ALT reductions were 6%-21% (P<0.05 for doses≥0.2 mg/day) and hsCRP reductions 25%-43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day). Normalisation of elevated baseline ALT occurred in 25%-46% of weight management trial subjects, vs 18% on placebo. Elevated baseline ALT was present in 41% (1325/3268) of cardiovascular outcomes trial subjects. In this group with elevated ALT, no significant ALT reduction was noted at end-of-treatment for 0.5 mg/week, while a 9% reduction vs placebo was seen for 1.0 mg/week (P = 0.0024). Treatment ratios for changes in ALT and hsCRP were not statistically significant after adjustment for weight change., Conclusions: Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes., (© 2019 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Aims: In addition to increased risk of cardiovascular disease, the prevalence of diabetic cardiomyopathy is increasingly recognized in patients with type 1 diabetes mellitus (T1DM). We aimed to identify the occurrence of subclinical markers of cardiovascular risk and cardiac dysfunction and assess their relation to clinical parameters in asymptomatic patients with T1DM., Methods and Results: A total of 102 patients (mean age 46 years [20-73], 62% male) with a history of T1DM ranging from 5 to 47 years underwent standard 2D and pulse-wave tissue Doppler echocardiography (Philips iE33) and computerized tomography for assessment of coronary calcium score (CACS) and visceral fat. Global peak longitudinal strain (GPLSS, speckle tracking) was calculated by offline analysis (Qlab 9.0). Whereas systolic function was preserved in all patients (LVEF > 50%), subclinical dysfunction (defined as global longitudinal peak systolic strain [GLPSS] of >-20%) was present in 39% and 66% had diastolic dysfunction. Fifty patients had a CACS above the 50th percentile according to age and gender. These patients were older, more obese, had higher levels of visceral fat, higher SBP and increased levels of LDL cholesterol. Higher CACS meant increased risk of diastolic and subclinical systolic dysfunction. However, decreased GLPSS was also detected in 30% of patients with CACS of <50th percentile. Stepwise linear regression analysis indicated visceral fat as a strong predictor of abnormal GPLSS and CACS., Conclusion: Subclinical left ventricular dysfunction and atherosclerosis were highly prevalent in asymptomatic T1DM. Abnormal GPLSS was noted with or without associated increase in CACS. Visceral fat was a strong predictor of increased CACS as well as abnormal GLPSS., (© 2019 Wiley Periodicals, Inc.)

Aim: To assess the prevalence of metabolic syndrome (MetS) among students attending vocational secondary school (VSE). VSE provides practice-oriented education in which young people learn a specific occupation. Previously we reported VSE to be the type of education with the highest prevalence of overweight and obesity., Methods: All data were collected in a cross-sectional school-based survey. Subjects were recruited from a community sample of 869 adolescents in 14 secondary schools. In this total sample all components of the metabolic syndrome were assessed in a subgroup of 506 students. MetS was defined analogous to National Cholesterol Education Program: Adult Treatment Panel III criteria, with modifications for students under 19 years of age., Results: In the subsample (n=506) 4.1% of the students had metabolic syndrome. There was a significant difference in the prevalence of metabolic syndrome among BMI categories (p<0.001). The prevalence of metabolic syndrome was higher in obese students (39.1%) than in overweight students (2.8%) and normal weight students (0.3%)., Conclusion: Being overweight or obese substantially increases the risk for metabolic syndrome, even in an adolescent school population.

Background: Diabetes is an inflammatory condition associated with iron abnormalities and increased oxidative damage. We aimed to investigate how diabetes affects the interrelationships between these pathogenic mechanisms., Methods: Glycaemic control, serum iron, proteins involved in iron homeostasis, global antioxidant capacity and levels of antioxidants and peroxidation products were measured in 39 type 1 and 67 type 2 diabetic patients and 100 control subjects., Results: Although serum iron was lower in diabetes, serum ferritin was elevated in type 2 diabetes (p = 0.02). This increase was not related to inflammation (C-reactive protein) but inversely correlated with soluble transferrin receptors (r = - 0.38, p = 0.002). Haptoglobin was higher in both type 1 and type 2 diabetes (p < 0.001) and haemopexin was higher in type 2 diabetes (p < 0.001). The relation between C-reactive protein and haemopexin was lost in type 2 diabetes (r = 0.15, p = 0.27 vs r = 0.63, p < 0.001 in type 1 diabetes and r = 0.36, p = 0.001 in controls). Haemopexin levels were independently determined by triacylglycerol (R(2) = 0.43) and the diabetic state (R(2) = 0.13). Regarding oxidative stress status, lower antioxidant concentrations were found for retinol and uric acid in type 1 diabetes, alpha-tocopherol and ascorbate in type 2 diabetes and protein thiols in both types. These decreases were partially explained by metabolic-, inflammatory- and iron alterations. An additional independent effect of the diabetic state on the oxidative stress status could be identified (R(2) = 0.5-0.14)., Conclusions: Circulating proteins, body iron stores, inflammation, oxidative stress and their interrelationships are abnormal in patients with diabetes and differ between type 1 and type 2 diabetes., (Copyright (c) 2006 John Wiley & Sons, Ltd.)

Background: Pre-prandial glucose gives insufficient information on glycemic excursions throughout the day. We aimed to test a continuous subcutaneous glucose-monitoring device (GlucoDay) to describe postprandial glucose changes., Methods: In 23 T1DM patients, 24-h GlucoDay registrations were started about 14 h before receiving a standard breakfast B and 3 h later lunch L., Results: The 3-min glucose values were computed into parameters describing the postprandial changes after B and L. Two-hour glucose was higher after B (243 +/- 69 vs 180 +/- 79 mg/dL after L, p < 0.0001). Maximum glycemia (313 +/- 105 mg/dL after B and 304 +/- 119 after L, p < 0.0001) was higher and was reached after 78 and 57 min respectively. Three-hour AUC was higher but 30-min AUC was lower after B (5725 +/- 2414 vs 7488 +/- 2208 min mg/dL after L, p = 0.004). Glucose spikes (maximum peak minus fasting plasma glucose) were similar after B and L but the difference between maximum and minimum values was smaller after B (165 +/- 110 vs 219 +/- 115 mg/dL after L, p = 0.020). Duration of hyperglycemic periods >200, 140 or 126 mg/dL were not different after B or L, but time spent at glucose <100 mg/dL was longer after L (p < 0.0001)., Conclusions: These results illustrate the use of subcutaneous glucose registration to characterize postprandial glycemia patterns in T1DM. Application of such methods to evaluate this and other clinical situations in DM can lead to therapeutic and dietary adjustments and ultimately improve glycemic control., (Copyright 2004 John Wiley & Sons, Ltd.)

This supplement focuses on the benefits of targeting insulin resistance through therapy with a new class of oral antidiabetic agents, the thiazolidinediones (TZDs) or 'glitazones'. There are important differences between the three TZD class members that warrant discussion to enable physicians to make rational and informed therapeutic choices between the agents. Overall the TZDs appear to be similar in their effects on blood glucose, as all class members have demonstrated effective glycaemic control, both as monotherapy and in combination with sulphonylureas, metformin or exogenous insulin. The safety profiles of the three agents are more diverse, with what appear to be 'TZD class effects', (probably mediated via activation of peroxisome proliferator-activated receptor gamma [PPAR gamma]) and 'TZD-specific effects', which are unique to each agent and may be a consequence of differing chemical structures. While rosiglitazone and pioglitazone share some class effects with troglitazone, they have several characteristics that define them as unique agents. By tackling the control of type 2 diabetes through direct effects on insulin resistance, the TZDs represent an important new therapeutic tool for healthcare professionals.