Paraoxonase 1 phenotype distribution and activity differs in subjects with newly diagnosed Type 2 diabetes (the CODAM Study)

Aims Paraoxonase 1 (PON1) is an antioxidant high‐density lipoprotein‐bound enzyme, which was recently found to be expressed in the islets of Langerhans. A substitution (Q/R) at position 192 results in enzymes with different activity. Oxidation has been implicated in the onset of diabetes, and it can be hypothesized that PON1 may have a protective effect on diabetes. Our aim was to compare PON1 activities and PON1 Q/R phenotypes in subjects with different degrees of glucose intolerance. Methods We examined 566 members of the Cohort study of Diabetes and Atherosclerosis Maastricht (CoDAM), including subjects with normal glucose tolerance (NGT, n = 298), impaired glucose regulation (IGR, n = 128), newly diagnosed Type 2 diabetes (nDM, n = 78) and treated, that is to say known, Type 2 diabetes (kDM, n = 64). PON1 activity was measured in serum using paraoxon and diazoxon as substrates. The PON1 phenotype was determined using two‐dimensional enzyme analysis. Results The RR‐phenotype was significantly more frequent in nDM compared with NGT subjects (14.1 vs. 6.0%, P = 0.05). Adjusted for the PON1 phenotype, subjects with nDM had significant lower PON1 activity towards paraoxon and diazoxon than subjects with NGT. Adjusted odds ratios comparing the RR‐variant with the QQ‐variant were 2.17 [95% confidence interval (CI): 0.90–5.24] for impaired glucose tolerance, 2.84 (95% CI: 1.03–7.83) for nDM, 2.13 (95% CI; 0.61–7.42) for kDM and 2.65 (95% CI: 1.10–6.40) for total diabetes mellitus. Conclusions An aberrant PON1 phenotype distribution and PON1 activity were observed in early diabetes. In addition, the higher state of oxidative stress may affect the future development of complications.     

The locus of control in patients with Type 1 and Type 2 diabetes managed by individual and group care

Aims The locus of control theory distinguishes people (internals) who attribute events in life to their own control, and those (externals) who attribute events to external circumstances. It is used to assess self‐management behaviour in chronic illnesses. Group care is a model of systemic group education that improves lifestyle behaviour and quality of life in patients with Type 1 and Type 2 diabetes. This study investigated the locus of control in Type 1 and Type 2 diabetes and the possible differences between patients managed by group care and control subjects followed by traditional one‐to‐one care. Methods Cross‐sectional administration of two questionnaires (one specific for diabetes and one generic for chronic diseases) to 83 patients followed for at least 5 years by group care (27 Type 1 and 56 Type 2) and 79 control subjects (28 Type 1 and 51 Type 2) of similar sex, age and diabetes duration. Both tools explore internal control of disease, the role of chance in changing it and reliance upon others (family, friends and health professionals). Results Patients with Type 1 diabetes had lower internal control, greater fatalistic attitudes and less trust in others. Patients with either type of diabetes receiving group care had higher internal control and lower fatalism; the higher trust in others in those with Type 1 diabetes was not statistically significant. The differences associated with group care were independent of sex, age and diabetes duration. Conclusions Patients with Type 1 diabetes may have lower internal control, fatalism and reliance upon others than those with Type 2 diabetes. Receiving group care is associated with higher internal control, reduced fatalism and, in Type 1 diabetes, increased trust in others.     

Ketoacidosis occurs in both Type 1 and Type 2 diabetes— a population‐based study from Northern Sweden

Aims To determine the occurrence of diabetic ketoacidosis (DKA) in adult Type 2 and Type 1 diabetic patients in Northern Sweden and to determine whether DKA presents with a different clinical picture in Type 2 compared with Type 1 diabetic subjects. Methods All adult patients from a hospital catchment area in Northern Sweden with diagnosed DKA episodes during 1997–2000 were included in a retrospective study. Medical records and laboratory reports were analysed. Results During the years 1997 to 2000, the average annual incidence rate for DKA was 5.9 per 100 000 adult inhabitants. Twenty‐five patients developed DKA, eight (32%) had Type 2 diabetes, while 17 (68%) had Type 1 diabetes. Type 2 diabetic patients with DKA were older and had higher levels of C‐peptide than Type 1 diabetic patients. On admission because of DKA, a similar degree of hyperglycaemia was present in Type 1 and Type 2 patients. Metabolic acidosis was more severe in Type 1 compared with Type 2 diabetic patients. In 50% of the Type 2 diabetic patients, diabetes was diagnosed at the episode of DKA. Conclusions DKA occurs in Caucasian Type 2 diabetic patients within a Swedish population. Although the frequency of DKA is much higher in Type 1 diabetic patients, Type 2 diabetes may account for as much as one‐third of the overall DKA cases.     

An association between Type 2 diabetes and α1‐antitrypsin deficiency

Aims α₁‐Antitrypsin (AAT) is a serine protease inhibitor which recently has been shown to prevent Type 1 diabetes development, to prolong islet allograft survival and to inhibit pancreatic B‐cell apoptosis in vivo. It has also been reported that Type 1 diabetic patients have significantly lower plasma concentrations of AAT, suggesting the potential role of AAT in the pathogenesis of Type 1 diabetes. We have investigated whether plasma AAT levels are altered in Type 2 diabetes. Methods The study included patients with Type 2 diabetes (n = 163) and non‐diabetic control subjects matched for age, sex and smoking habits (n = 158) derived from the population‐based Malmö Diet and Cancer study. Plasma samples were analysed for AAT concentration and phenotype and serum glucose, insulin, C‐reactive protein and lipid levels were measured. Glycated haemoglobin was also measured. Results In the diabetic group, the women had higher mean plasma AAT levels than men (P < 0.05). The mean plasma AAT levels did not differ between diabetic and control subjects. However, the number of individuals with low AAT levels (< 1.0 mg/ml) was 50% higher in the diabetic group (P < 0.05) and the frequency of AAT deficiency genotypes was 50% higher (NS) in diabetic compared with control subjects. In the group of diabetic patients with AAT < 1 mg/ml, AAT directly correlated with systolic blood pressure (P = 0.048) and inversely correlated with waist–hip ratio (P = 0.031). Conclusions Our results provide evidence that deficiency of AAT may be associated with an increased risk of developing Type 2 diabetes.     

Childhood body mass index (BMI), breastfeeding and risk of Type 1 diabetes: findings from a longitudinal national birth cohort

Aims To perform a longitudinal analysis of the association between childhood body mass index (BMI) and later risk of Type 1 diabetes, controlling for socio‐economic status, birthweight, height in early and late childhood, breastfeeding history and pubertal status. Methods Analysis of the 1970 British Birth Cohort, followed up at age 5, 10 and 30 years (n = 11 261). Data were available on birthweight, breastfeeding; height, weight, pubertal status, socio‐economic status at age 10 years; self‐report data on history of diabetes (type, age at onset) at age 30 years. Cox proportional hazards models were used to examine relations of childhood growth, socio‐economic status and breastfeeding history to the incidence of Type 1 diabetes between 10 and 30 years of age. Results Sixty‐one subjects (0.5%) reported Type 1 diabetes at 30 years of age; 47 (77%) reported onset ≥ age 10 years. Higher BMI z‐score at 10 years predicted higher risk of subsequent Type 1 diabetes (hazard ratio 1.8, 95% confidence interval 1.2 to 2.8, P = 0.01) when adjusted for birthweight, pubertal status, breastfeeding history and socio‐economic status. Repeating the model for childhood obesity, the hazard ratio was 3.1 (1.0, 9.3; P = 0.05). Birthweight, breastfeeding, height growth and pubertal timing were not associated with incidence of Type 1 diabetes. Conclusions Higher BMI in childhood independently increased the risk of later Type 1 diabetes, supporting suggestions that obesity may provide a link between Type 1 and Type 2 diabetes. This supports observations of a rise in Type 1 diabetes prevalence. Reduction in childhood obesity may reduce the incidence of Type 1 as well as Type 2 diabetes.     

Postprandial C‐peptide to glucose ratio as a predictor of β‐cell function and its usefulness for staged management of type 2 diabetes

Aims/Introduction

Type 2 diabetes is characterized by progressive deterioration of β‐cell function. Recently, it was suggested that the C‐peptide‐to‐glucose ratio after oral glucose ingestion is a better predictor of β‐cell mass than that during fasting. We investigated whether postprandial C‐peptide‐to‐glucose ratio (PCGR) reflects β‐cell function, and its clinical application for management of type 2 diabetes.

Materials and Methods

We carried out a two‐step retrospective study of 919 Korean participants with type 2 diabetes. In the first step, we evaluated the correlation of PCGR level with various markers for β‐cell function in newly diagnosed and drug‐naïve patients after a mixed meal test. In the second step, participants with well‐controlled diabetes (glycated hemoglobin <7%) were divided into four groups according to treatment modality (group I: insulin, group II: sulfonylurea and/or dipeptityl peptidase IV inhibitor, group III: metformin and/or thiazolidinedione and group IV: diet and exercise group).

Results

In the first step, PCGR was significantly correlated with various insulin secretory indices. Furthermore, PCGR showed better correlation with glycemic indices than homeostatic model assessment of β‐cell function (HOMA‐β). In the second step, the PCGR value significantly increased according to the following order: group I, II, III, and IV after adjusting for age, sex, body mass index and duration of diabetes. The cut‐off values of PCGR for separating each group were 1.457, 2.870 and 3.790, respectively (P < 0.001).

Conclusions

We suggest that PCGR might be a useful marker for β‐cell function and an ancillary parameter in the choice of antidiabetic medication in type 2 diabetes.     

Safety and efficacy of inhaled insulin (AERx® iDMS1) compared with subcutaneous insulin therapy in patients with Type 1 diabetes: 1‐year data from a randomized,parallel group trial

Aims Assessment of the long‐term safety and efficacy of liquid inhaled insulin via AERx^® insulin Diabetes Management System (iDMS) in a basal/bolus treatment regimen of adults with Type 1 diabetes. Methods Patients were randomized 2 : 1 to prandial inhaled (n = 205) or subcutaneous (s.c.) (n = 99) insulin, plus one/two daily injections of neutral protamine Hagedorn (NPH) insulin for 12 months. The primary endpoints were pulmonary function tests (PFT) and baseline changes in chest X‐rays at 12 months. Safety and efficacy assessments were measured at regular intervals. Results PFTs after 12 months were comparable between the groups, except for reduced per cent of predicted carbon monoxide lung diffusing capacity with inhaled insulin (difference: –2.03%, P = 0.04) occurring after the first 3 months and then stabilizing. There were no apparent treatment differences in chest X‐rays. Overall risk of hypoglycaemia [risk ratio (RR) 1.02, P = 0.83] and adverse events were comparable between groups. Risk of nocturnal hypoglycaemia was higher in the inhaled group (RR 1.58, P = 0.001). Cough [10% (inhaled); 3% (s.c.)] tended to be mild in nature. Inhaled insulin was non‐inferior to s.c. insulin for change in glycated haemoglobin (HbA_1c) after 12 months [difference 0.18% (CI 95%–0.04; 0.39)]. At trial end, mean laboratory measured fasting plasma glucose was lower in the inhaled group (inhaled 9.2 mmol/l; s.c. 11.7 mmol/l; difference: –2.53 mmol/l, P < 0.001). Conclusions The safety and efficacy results in this trial were similar to those reported with other inhaled insulins; however, inhaled insulin using AERx^® iDMS requires further optimization to reduce nocturnal hypoglycaemia before it has comparable safety and efficacy to s.c. insulin aspart.     

Quality of life in children with Type 1 diabetes: a comparison of general and diabetes‐specific measures and support for a unitary diabetes quality‐of‐life construct

Aims To assess the factor structure of the Pediatric Quality of Life Inventory (PedsQL) Diabetes Module and to compare the PedsQL general and diabetes‐specific quality of life (QOL) measures regarding psychometric properties and relations to relevant outcomes. Methods The instruments were completed by 447 children age 9 to 15.5 years with Type 1 diabetes > 1 year from four US paediatric diabetes clinics; parents completed the parallel parent‐proxy measures. Principal components factor analysis was used to examine the factor structure of the PedsQL diabetes module. Analyses of the generic and diabetes QOL measures included psychometric properties, parent–child correlations and correlations with depression, adherence and glycated haemoglobin (HbA_1c). Results The factor structure of the PedsQL diabetes module did not support the original five subscales. Both one‐ and two‐factor models were supported; however, parallel parent and child subscales did not emerge. While the generic and diabetes‐specific measures of QOL were moderately to highly correlated with each other, the constructs were differentially associated with relevant diabetes outcomes. Generic QOL was more highly associated with depression than diabetes QOL. Conversely, diabetes QOL was more highly associated with adherence and HbA_1c, although this was seen to a greater extent for parent‐proxy report than for child report. Conclusions Factor analysis of the PedsQL diabetes module supports the use of a total diabetes QOL score. Findings regarding the associations of the generic and diabetes modules with diabetes outcomes underscore the unique contribution provided by both generic and diabetes QOL.     

Relationship between soluble CD40 ligand and γ‐glutamyltransferase concentrations in non‐drinking,young Type 1 diabetic individuals

Aims To assess the association between circulating levels of soluble CD40 ligand (sCD40L), an emerging cardiovascular risk factor, and γ‐glutamyltransferase (GGT) activity concentrations in Type 1 diabetic subjects. Methods Plasma concentrations of sCD40L and GGT activity, a marker of liver dysfunction, were measured in 54 non‐smoking, non‐drinking, young Type 1 diabetic patients, who were free of diagnosed cardiovascular disease. Results When participants were grouped according to tertiles of GGT, plasma sCD40L concentrations steadily increased across GGT tertiles (P = 0.007 for trend). Similarly, plasma sCD40L concentrations were positively correlated with plasma GGT levels in the whole group of participants (r = 0.532; P < 0.0001). In multivariate linear regression analysis, plasma GGT activity levels were positively associated with sCD40L (standardized beta coefficient = 0.342; P = 0.027) independently of age, gender, diabetes duration, glycated haemoglobin, total cholesterol and systolic blood pressure. Further adjustment for the presence of diabetic retinopathy and microalbuminuria did not appreciably attenuate this association. Conclusions Our findings suggest that there is a strong, graded, relationship between plasma GGT activity and sCD40L concentrations in non‐smoking, non‐drinking, young Type 1 diabetic individuals. This association appears to be independent of numerous confounding factors. Further studies are required to confirm the reproducibility of these results.     

Serum chemokine levels are associated with the outcome of pegylated interferon and ribavirin therapy in patients with chronic hepatitis C

Aim: Serum chemokine levels and amino acid substitutions in the interferon‐sensitivity determining region (ISDR) and core region have been associated with treatment outcome of pegylated interferon and ribavirin therapy in genotype 1 hepatitis C virus (HCV)‐infected patients. The present study was conducted to clarify the association between serum chemokines and treatment outcome in patients with chronic HCV‐1 infection in a Japanese cohort. Methods: A total of six serum chemokines were quantified before, during and after pegylated interferon and ribavirin treatment in 79 genotype 1 chronic HCV patients using a multiple bead array system. Viral ISDR and core region variants were determined by direct sequencing. Results: The baseline serum levels of eotaxin, IP‐10 and RANTES were significantly higher in chronic HCV patients than in controls. High levels of eotaxin and macrophage inflammatory protein (MIP)‐1β before therapy and more than two mutations in the ISDR were associated with a sustained virological response, and patients with more than two mutations in the ISDR also had significantly higher MIP‐1β levels. Receiver–operator curve analysis showed a 77% sensitivity and 73% specificity for predicting an SVR using MIP‐1β values. Conclusion: Serum MIP‐1β levels may predict the response to HCV treatment with pegylated interferon and ribavirin and are associated with amino acid substitutions in the ISDR.     

Initiating therapy in patients newly diagnosed with type 2 diabetes: Combination therapy vs a stepwise approach

There is clear evidence that achieving glycaemic targets reduces the risk of developing complications as a result of type 2 diabetes (T2D). Many patients, however, continue to have suboptimal glycaemic control because of issues that include unclear advice on how to achieve these targets as well as clinical inertia. The two management approaches recommended for patients newly diagnosed with T2D are stepwise and combination therapy, each of which has advantages and disadvantages. Stepwise therapy may result in good patient adherence and allow greater individualization of therapy, and minimization of side effects and cost, and so may be appropriate for patients who are closer to goal. Stepwise therapy, however, may also lead to frequent delays in achieving glycaemic goals and longer exposure to hyperglycaemia. Combination therapy, which is now emerging as an important therapy option, has a number of potential advantages over stepwise therapy, including reduction in clinical inertia and earlier and more frequent achievement of glycated haemoglobin goals by targeting multiple pathogenic mechanisms simultaneously, which may more effectively delay disease progression. Compared with stepwise therapy, the disadvantages of combination therapy include reduced patient adherence resulting from complex, multi‐drug regimens, difficulty determining the cause of poor efficacy and/or side effects, patient refusal to accept disease, and higher cost. Fixed‐dose and fixed‐ratio combinations are novel therapeutic approaches which may help address several issues of treatment complexity and patient burden associated with combination therapy comprising individual drugs. The choice of which drugs to administer and the decision to use stepwise vs combination therapy, however, should always be made on an individualized basis.     

Secretory units of islets in transplantation index is a useful predictor of insulin requirement in Japanese type 2 diabetic patients

Aims/Introduction

The objective of the present study was to clarify the validity of β‐cell function‐related parameters for predicting the insulin requirement of Japanese type 2 diabetic patients.

Materials and Methods

In 188 patients with type 2 diabetes who had been admitted to the University of Toyama Hospital (Toyama, Japan) without receiving insulin therapy, we carried out a cross‐sectional study examining the relationship between the homeostasis model assessment of β‐cell function (HOMA‐β) and C‐peptide‐based indices, and also carried out a retrospective study to examine the utility for predicting insulin requirement of several β ‐cell function‐related indices using a receiver operating characteristic (ROC) curve analysis.

Results

The secretory units of islets in transplantation index (SUIT) had the strongest correlation with HOMA‐β, followed by the fasting serum C‐peptide immunoreactivity index (CPI); the fasting serum C‐peptide immunoreactivity itself (F‐CPR) had the least correlation. The CPI, HOMA‐β and SUIT were significantly lower in the insulin‐requiring group than in the non‐insulin‐requiring group, even after adjustments for confounding factors (P < 0.01). The areas under the ROC curve for insulin requirement were 0.622, 0.774, 0.808, and 0.759 for F‐CPR, CPI, SUIT, and HOMA‐β, respectively. The cut‐off values of SUIT, CPI, and HOMA‐β for an over 80% specificity for the prediction of insulin therapy were 23.5, 1.00, and 14.9, respectively.

Conclusions

The present study shows that SUIT is the best predictor of insulin requirement among these β‐cell function‐related markers.     

Prevalence of GORD (gastro‐oesophageal reflux disease) in Type 2 diabetes and a comparison of clinical profiles between diabetic patients with and without GORD

Aims To examine the incidence of gastro‐oesophageal reflux disease (GORD) and its associated factors in patients with Type 2 diabetes mellitus (Type 2 DM). Methods In 859 Type 2 DM outpatients, we conducted a QUEST inquiry and considered those showing a QUEST score of 4 or higher as having GORD. We surveyed clinical variables {physical findings, gender, age, duration of disease, glycated haemoglobin (HbA_1c), type of oral glucose‐lowering agent, presence or absence of insulin therapy, complications, and presence or absence of agents that may be associated with GORD [Ca channel blocker (CCB) anti‐platelet agents]} to investigate their association with the onset of GORD. Results We analysed 813 subjects, of whom 56.6% were male. The mean age was 63.7 ± 11.3 years and HbA_1c 7.2 ± 1.2%. The incidence of GORD was 29.0% (n = 221). GORD was positively correlated with body weight, body mass index (BMI) and HbA_1c. It was negatively correlated with age, serum creatinine and proportion of patients treated with pioglitazone or CCB. In addition, GORD was more common in females. The incidence of GORD was significantly higher in younger patients. Conclusions Previous studies have suggested a relationship of GORD with pioglitazone/CCB. However, the results of this study do not support this; these agents may not induce GORD.     

Insulin and glucose profiles during continuous subcutaneous insulin infusion compared with injection of a long-acting insulin in Type 2 diabetes1

Aims To compare insulin and glucose profiles during basal continuous subcutaneous infusion of a rapid-acting insulin analogue and once daily subcutaneous injection of a long-acting insulin analogue in Type 2 diabetes. Methods Twenty-one patients with Type 2 diabetes treated with oral glucose-lowering agents were randomized in this two-period crossover study to an equivalent 24-h dose of continuous subcutaneous infusion of insulin aspart and subsequently once-daily bedtime subcutaneous injection of insulin glargine, or vice versa, for eight consecutive days. Plasma profiles of insulin and glucose were recorded. Results On the last day of each treatment period, the area under the curve (AUC) for glucose was 10% lower on the continuous subcutaneous infusion regimen compared with the insulin injection regimen (P = 0.002). This was accomplished by a flat exogenous insulin infusion profile compared with a peaking profile with injected insulin (AUC was 74% higher after injection compared with pre-injection levels (P = 0.001)). During the last 6 days in each treatment period, the intra-subject variability of exogenous fasting insulin levels in the mornings was 41% lower during insulin infusion compared with insulin injection (P = 0.012). The corresponding intra-subject variability for fasting glucose only showed a tendency to be lower during infusion as compared to the injection regimen (28%; P = 0.104). Thirteen symptomatic-only or minor hypoglycaemic episodes were recorded during the entire infusion period compared with three episodes during the injection period. Conclusions Basal continuous subcutaneous infusion of a rapid-acting insulin analogue improved plasma insulin (more flat insulin profile with a lower variability) and glucose (lower AUC) profiles compared with once-daily subcutaneous injection of a long-acting insulin analogue in Type 2 diabetes.