PPARG2 Pro12Ala and ADAMTS9 rs4607103 as “insulin resistance loci” and “insulin secretion loci” in Italian individuals. The GENFIEV study and the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 4

We investigated cross-sectionally whether the type 2 diabetes (T2DM) risk alleles of rs1801282 (PPARG2) and rs4607103 (ADAMTS9) were associated with T2DM and/or insulin sensitivity (IS) and beta cell function (βF) in Italians without and with newly diagnosed T2DM. In 676 nondiabetic subjects (336 NGR and 340 IGR) from the GENFIEV study and in 597 patients from the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS), we (1) genotyped rs1801282 and rs4607103, (2) assessed βF by C-peptide/glucose modeling after OGTT, and (3) assessed IS by HOMA-IR in both studies and by euglycemic insulin clamp in VNDS only. Logistic, linear, and two-stage least squares regression analyses were used to test (a) genetic associations with T2DM and with pathophysiological phenotypes, (b) causal relationships of the latter ones with T2DM by a Mendelian randomization design. Both SNPs were associated with T2DM. The rs4607103 risk allele was associated to impaired βF (p < 0.01) in the GENFIEV study and in both cohorts combined. The rs1801282 genotype was associated with IS both in the GENFIEV study (p < 0.03) and in the VNDS (p < 0.03), whereas rs4607103 did so in the VNDS only (p = 0.01). In a Mendelian randomization design, both HOMA-IR (instrumental variables: rs1801282, rs4607103) and βF (instrumental variable: rs4607103) were related to T2DM (p < 0.03–0.01 and p < 0.03, respectively). PPARG2 and ADAMTS9 variants are both associated with T2DM and with insulin resistance, whereas only ADAMTS9 may be related to βF. Thus, at least in Italians, they may be considered bona fide “insulin resistance genes”.     

New Injectable Agents for the Treatment of Type 2 Diabetes Part 2—Glucagon-Like Peptide-1 (GLP-1) Agonists

The US Food and Drug Administration has recently approved several new glucagon-like peptide-1 (GLP-1) agonists alone and in combination with various insulin products. The second of 2 articles in a series, this review will describe the potential advantages and disadvantages of the GLP-1 agonist class of products.     

Declining incidence of severe retinopathy and persisting decrease of nephropathy in an unselected population of Type 1 diabetes—the Linköping Diabetes Complications Study

Aims/hypothesis In a previous study conducted over the last decades we found a decreased incidence of nephropathy but unchanged incidence of severe retinopathy among patients with Type 1 diabetes diagnosed in childhood and with 20 years duration of diabetes. The aim of our current study was to investigate the incidence 5 to10 years later in the same population.Methods We studied all 269 patients in whom Type 1 diabetes was diagnosed in childhood between 1961 and 1985 in a district in southeastern Sweden. Ninety-one percent were monitored for retinopathy until at least 1997 and 95% were monitored for nephropathy. Severe retinopathy was defined as laser-treated retinopathy and nephropathy as persistent proteinuria. Survival analysis was used and the patients divided into five cohorts according to the time of onset of diabetes.Results The cumulative proportion of severe retinopathy had declined (p=0.006). After 25 years it was 47% (95% CI 34–61), 28% (15–40) and 24% (12–36) in the cohorts 1961 to 1965, 1966 to 1970 and 1971 to 1975 respectively. After 30 years it was 53% (40–66) and 44% (28–59) in the oldest cohorts. The cumulative proportion of nephropathy after 25 years duration was 30% (18–42), 8% (1–16) and 13% (4–23) in the cohorts 1961 to 1965, 1966 to 1970 and 1971 to 1975 respectively. After 30 years, it was 32% (20–44) and 11% (2–20) for the oldest cohorts (p<0.0001).Conclusions/interpretation In an unselected population with Type 1 diabetes diagnosed in childhood, modern diabetes care markedly reduced the incidence of severe retinopathy and nephropathy.Abbreviations SMR standardised mortality ratio     

Outcome of bowel function following anterior resection for rectal cancer—an analysis using the low anterior resection syndrome (LARS) score

Purpose

Severity of anorectal dysfunction after low anterior resection is associated with various patient- and treatment-related factors. We aimed to quantify anorectal dysfunction after treatment for rectal cancer using the low anterior resection syndrome (LARS) score.

Methods

We retrieved from a prospective database 331 eligible patients on whom anterior resection for rectal cancer had been performed from 2000 to 2014. All patients were sent a LARS score accompanied by a supplementary questionnaire. Response rate was 78.8% (261 patients). The main outcome measure was the relation of the LARS score to potentially associated patient and treatment factors. Secondary endpoints were further measures that reflect anorectal dysfunction, e.g., Vaizey score.

Results

Overall, 144 (55.2%) patients exhibited scores >?20 reflecting minor (n?=?51 (19.5%)) or major (n?=?93 (35.6%)) LARS. A significant difference for scores >?20 was found for intersphincteric resection (IR, 73.2% affected patients) compared to total mesorectal excision (TME, 58.4%) and partial mesorectal excision (PME, 38.0%, p?=?0.001). Radio(chemo)therapy resulted in LARS scores >?20 in 64.6% of patients compared to 43.1% in patients without irradiation (p?=?0.001). Type of procedure (TME and IR as compared to PME), radio(chemo)therapy, and younger age were independently associated with LARS in logistic regression analysis. However, younger age remained the only independent factor for higher scores after exclusion of PME.

Conclusions

The LARS score identified a substantial proportion of patients after surgery for rectal cancer with anorectal dysfunction. The extent of surgical procedure is independently associated with the severity of symptoms whereas the role of radiotherapy needs further assessment.

     

Differences in function and recovery profiles between patterns of multimorbidity among older medical patients the first year after an acute admission—An exploratory latent class analysis

IntroductionMultimorbidity is common among older people and may contribute to adverse health effects, such as functional limitations. It may help stratify rehabilitation of older medical patients, if we can identify differences in function under and after an acute medical admission, among patient with different patterns of multimorbidity.AimTo investigate differences in function and recovery profiles among older medical patients with different patterns of multimorbidity the first year after an acute admission.MethodsLongitudinal prospective cohort study of 369 medical patients (77.9 years, 62% women) acutely admitted to the Emergency Department. During the first 24 h after admission, one month and one year after discharge we assessed mobility level using the de Morton Mobility Index. At baseline and one-year we assessed handgrip strength, gait speed, Barthel20, and the New Mobility Score. Information about chronic conditions was collected by national registers. We used Latent Class Analysis to determine differences among patterns of multimorbidity based on 22 chronic conditions.ResultsFour distinct patterns of multimorbidity were identified (Minimal chronic disease; Degenerative, lifestyle, and mental disorders; Neurological, functional and sensory disorders; and Metabolic, pulmonary and cardiovascular disorders). The “Neurological, functional and sensory disorders”-pattern showed significant lower function than the “Minimal chronic disease”-pattern in all outcome measures. There were no differences in recovery profile between patients in the four patterns.ConclusionThe results support that patients with different patterns of multimorbidity among acutely hospitalized older medical patients differ in function, which suggests a differentiated approach towards treatment and rehabilitation warrants further studies.     

Associations of measures of lung function with insulin resistance and Type 2 diabetes: findings from the British Women’s Heart and Health Study

Aims/hypothesis The aim of this study was to assess the associations of lung function with insulin resistance and Type 2 diabetes.Methods We did a cross-sectional study of 3911 women who were 60 to 79 years old from 23 British towns, assessing the association of measures of lung function with insulin resistance (based on fasting insulin and glucose concentrations) and Type 2 diabetes (World Health Organisation diagnostic criteria).Results Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were inversely associated with insulin resistance and prevalence of Type 2 diabetes. In age-adjusted analyses, the homeostasis model assessment (HOMA) score (insulin resistance) decreased by 5% (95% CI: 2–7%) for a one standard deviation increase in log FEV1 and by 8% (95% CI: 6–10%) for a one standard deviation increase in log FVC. With additional adjustment for height, smoking, BMI, waist-to-hip ratio, physical activity, white cell count, adult social class, childhood social class and respiratory medication, these associations attenuated to 3% (95% CI: 1 to 5%) and 5% (95% CI: 3 to 8%). The fully adjusted odds ratio for diabetes prevalence was 0.85 (95% CI: 0.74–0.98) for a one standard deviation increase in log FEV1 and 0.80 (95% CI: 0.70–0.92) for a one standard deviation increase in log FVC. Forced expiratory flow in the central period of FVC was not associated with insulin resistance or diabetes.Conclusions/interpretation Lung function measures which predominantly reflect lung volume are inversely associated with insulin resistance and Type 2 diabetes. These associations could reflect childhood exposures which affect lung growth and also programme insulin resistance.Abbreviations FEV1 Forced expiratory volume in 1 second - FVC forced vital capacity - FEF25–75 forced expiratory flow in the central period of forced vital capacity - HOMA Homeostasis model assessment - WHO World Health Organization     

Can the Glycemic Index (GI) be used as a tool in the prevention and management of Type 2 diabetes?

The large increase in type 2 diabetes (T2DM), the considerable lifetime risk of diabetes and the loss of lifetime call for concerted action to prevent T2DM and its complications. Since diabetes is characterized by abnormal glucose metabolism, the question arises of whether a high intake of carbohydrates that are rapidly absorbed as glucose may increase the risk and worsen the course of T2DM. To quantify the impact of carbohydrates on blood glucose the glycemic index (GI) and the glycemic load (GL) have been applied. The GI of a food is a method of ranking carbohydrate rich foods according to their glycemic responses. GI is defined as the incremental area under the blood glucose curve of 50g carbohydrate of a test food expressed as a percentage of the area of the response to an equivalent amount of a reference food (glucose or white bread). In relation to GI/GL and prevention of T2DM there is insufficient information from observational studies to determine whether a positive association exists or not. Only randomized controlled clinical intervention studies will be able to provide the final answer. From meta-analyses of randomised controlled clinical trials comparing low and high GI diets in the treatment of diabetes it has been found that low GI diets improve the glycemic control. Labeling of foods with GI would be helpful for persons with diabetes, but the usefulness for healthy subjects remains to be clarified. At present it seems premature to introduce GI labeling for the entire population.     

Towards the improvement in stability of an anti-Aβ single-chain variable fragment,scFv-h3D6, as a way to enhance its therapeutic potential

ScFv-h3D6 is a single-chain variable fragment derived from the monoclonal antibody bapineuzumab that prevents Aβ-induced cytotoxicity by capturing Aβ oligomers. The benefits of scFv-h3D6 treatment in Alzheimer’s disease are known at the behavioural, cellular and molecular levels in the 3xTg-AD mouse model. Antibody-based therapeutics are only stable in a limited temperature range, so their benefit in vivo depends on their capability for maintaining the proper fold. Here, we have stabilized the scFv-h3D6 folding by introducing the mutation V_H-K64R and combining it with the previously described elongation of the V_L domain (C3). The stabilities of the different scFv-h3D6 constructs were calculated from urea and thermal denaturation followed by Trp-fluorescence, CD and DSC and resulted in the order C3?>?K64R/C3?>?V_H-K64R?≥?scFv-h3D6; showing that the combination of both mutations was not additive, instead they partially cancelled each other. The three mutants assayed showed a decreased aggregation tendency but maintained their capability to aggregate in the form of worm-like fibrils, basis of the protective effect of scFv-h3D6. Cytotoxicity assays showed that all the mutants recovered cell viability of Aβ-treated neuroblastoma cell cultures in a dose-dependent manner and with efficiencies that correlated with stability, therefore improving the therapeutic ability of this antibody.     

REFLECT—a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset

Journal of Gastroenterology - A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with...     

UKPDS Outcomes Model 2: a new version of a model to simulate lifetime health outcomes of patients with type 2 diabetes mellitus using data from the 30 year United Kingdom Prospective Diabetes Study: UKPDS 82

Aims/hypothesis

The aim of this project was to build a new version of the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS-OM1), a patient-level simulation tool for predicting lifetime health outcomes of people with type 2 diabetes mellitus.

Methods

Data from 5,102 UKPDS patients from the 20 year trial and the 4,031 survivors entering the 10 year post-trial monitoring period were used to derive parametric proportional hazards models predicting absolute risk of diabetes complications and death. We re-estimated the seven original event equations and estimated new equations for diabetic ulcer and some second events. The additional data permitted inclusion of new risk factor predictors such as estimated GFR. We also developed four new equations for all-cause mortality. Internal validation of model predictions of cumulative incidence of all events and death was carried out and a contemporary patient-level dataset was used to compare 10 year predictions from the original and the new models.

Results

Model equations were based on a median 17.6 years of follow-up and up to 89,760 patient-years of data, providing double the number of events, greater precision and a larger number of significant covariates. The new model, UKPDS-OM2, is internally valid over 25 years and predicts event rates for complications, which are lower than those from the existing model.

Conclusions/interpretation

The new UKPDS-OM2 has significant advantages over the existing model, as it captures more outcomes, is based on longer follow-up data, and more comprehensively captures the progression of diabetes. Its use will permit detailed and reliable lifetime simulations of key health outcomes in people with type 2 diabetes mellitus.     

Development of a new scoring system for predicting the 5?year incidence of type 2 diabetes in Japan: the Toranomon Hospital Health Management Center Study 6 (TOPICS 6)

Aims/hypothesis

The aims of this study were to assess the clinical significance of introducing HbA_1c into a risk score for diabetes and to develop a scoring system to predict the 5?year incidence of diabetes in Japanese individuals.

Methods

The study included 7,654 non-diabetic individuals aged 40–75?years. Incident diabetes was defined as fasting plasma glucose (FPG) ≥7.0?mmol/l, HbA_1c ≥6.5% (48?mmol/mol) or self-reported clinician-diagnosed diabetes. We constructed a risk score using non-laboratory assessments (NLA) and evaluated improvements in risk prediction by adding elevated FPG, elevated HbA_1c or both to NLA.

Results

The discriminative ability of the NLA score (age, sex, family history of diabetes, current smoking and BMI) was 0.708. The difference in discrimination between the NLA + FPG and NLA + HbA_1c scores was non-significant (0.836 vs 0.837; p?=?0.898). A risk score including family history of diabetes, smoking, obesity and both FPG and HbA_1c had the highest discrimination (0.887, 95% CI 0.871, 0.903). At an optimal cut-off point, sensitivity and specificity were high at 83.7% and 79.0%, respectively. After initial screening using NLA scores, subsequent information on either FPG or HbA_1c resulted in a net reclassification improvement of 42.7% or 52.3%, respectively (p?<?0.0001). When both were available, net reclassification improvement and integrated discrimination improvement were further improved at 56.7% (95% CI 47.3%, 66.1%) and 10.9% (9.7%, 12.1%), respectively.

Conclusions/interpretation

Information on HbA_1c or FPG levels after initial screening by NLA can precisely refine diabetes risk reclassification.     

Prognostic implications of glucose-lowering treatment in patients with acute myocardial infarction and diabetes: experiences from an extended follow-up of the Diabetes Mellitus Insulin–Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 Study

Aims/hypothesis  

This post hoc analysis from the Diabetes Mellitus Insulin–Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 trial reports on extended long-term outcome in relation to glucose-lowering agents in patients with myocardial infarction and type 2 diabetes.     

The effectiveness of structured personal care of type 2 diabetes on recurrent outcomes: a 19 year follow-up of the study Diabetes Care in General Practice (DCGP)

Aims/hypothesis

The estimation of effect size in clinical trials commonly disregards recurrent outcomes. We investigated the effectiveness of a complex intervention on recurrent outcomes in patients with type 2 diabetes.

Methods

In the Diabetes Care in General Practice (DCGP) randomised controlled trial, 1,381 patients newly diagnosed with type 2 diabetes were randomised to 6 years of structured personal care or routine care (ClinicalTrials.gov NCT01074762). The trial had 19 years of registry-based follow-up and was analysed with Cox regression models. Repeated occurrences in the same patient of outcomes (any diabetes-related endpoint, myocardial infarction [MI], stroke, peripheral vascular disease and microvascular disease) were accounted for with the Wei, Lin and Weissfeld method.

Results

As previously shown, the intervention reduced the rates of first occurrence of both MI and any diabetes-related endpoint. However, for all outcomes, the HR for a second event showed a statistically non-significant tendency to be increased. We estimated a combined HR for all marginal failure times, regardless of whether they were first, second or later events. This showed that the intervention had no effect on the rate of any of the outcomes, including MI (HR 0.89, 95% CI 0.76, 1.05) and any diabetes-related endpoint (HR 0.98, 95% CI 0.87, 1.09).

Conclusions/interpretation

In the DCGP study, a smaller proportion of patients who received structured care experienced a first occurrence of MI or any diabetes-related endpoint compared with patients who received routine care. However, the patients who received structured care tended to experience more recurrent outcomes, so the total outcome rate was not affected by the intervention.