Michael Røder

Monokine Antagonism Is Reduced in Patients With IDDM

Interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α) have been implicated as immune effector molecules in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Recently, an increased frequency of the A1/A1 genotype of an IL-1 receptor antagonist (IL-1Ra) gene polymorphism was observed in patients with IDDM. Therefore, we investigated plasma IL-1Ra and soluble TNF p55 receptor (TNFsRp55) levels in 18 men with recent-onset IDDM, 10 men with long-standing IDDM, and 35 age-matched healthy men. No differences in plasma IL-1Ra were found among the three groups. However, when the plasma IL-1Ra levels in the subjects with IDDM and the control subjects were analyzed according to IL-1Ra genotypes, we found a 30% lower level of plasma IL-1Ra in subjects with IDDM carrying the A1/A1 genotype compared with the levels in those carrying the A1/A2 genotype (372 ± 40 vs. 530 ± 54 ng/l, respectively, P = 0.025). In contrast, no significant association was seen between plasma IL-1Ra and IL-1Ra genotype in the control subjects. The TNFsRp55 level in heparinized plasma was 17% lower in patients with IDDM than in control subjects (3.93 ± 0.22 vs. 4.72 ± 0.24 μg/l, respectively, P = 0.038). These findings could not be explained by metabolic derangement in the IDDM patients. Although based on a limited number of patients, these preliminary findings suggest that μ-cells in IDDM patients may be more sensitive to the cytotoxic effects of TNF-α and IL-1 because of less production of TNFsRp55 and, in a subset of IDDM patients, of IL-IRa during the inflammatory challenge of insulitis.

Lifestyle intervention for type 2 diabetes patients – trial protocol of The Copenhagen Type 2 Diabetes Rehabilitation Project

BackgroundCurrent guidelines recommend education, physical activity and changes in diet for type 2 diabetes patients, yet the composition and organization of non-pharmacological care are still controversial. Therefore, it is very important that programmes aiming to improve non-pharmacological treatment of type 2 diabetes are developed and evaluated. The Copenhagen Type 2 Diabetes Rehabilitation Project aims to evaluate the effectiveness of a new group-based lifestyle rehabilitation programme in a Health Care Centre in primary care.Methods/DesignThe group-based diabetes rehabilitation programme consists of empowerment-based education, supervised exercise and dietary intervention. The effectiveness of this multi-disciplinary intervention is compared with conventional individual counselling in a Diabetes Outpatient Clinic and evaluated in a prospective and randomized controlled trial. During the recruitment period of 18 months 180 type 2 diabetes patients will be randomized to the intervention group and the control group. Effects on glycaemic control, quality of life, self-rated diabetes symptoms, body composition, blood pressure, lipids, insulin resistance, beta-cell function and physical fitness will be examined after 6, 12 and 24 months.DiscussionThe Copenhagen Type 2 Diabetes Rehabilitation Project evaluates a multi-disciplinary non-pharmacological intervention programme in a primary care setting and provides important information about how to organize non-pharmacological care for type 2 diabetes patients.Trail RegistrationClinicalTrials.gov registration number: NCT00284609.

Proinsulin, intact insulin, and fibrinolytic variables and fibrinogen in healthy subjects : A population study

OBJECTIVE As high serum insulin predicts impaired fibrinolysis and proinsulin reacts in most conventional insulin assays, we hypothesized that proinsulin could link low fibrinolytic activity and hyperinsulinemic conditions. RESEARCH DESIGN AND METHODS We explored the relationship between fibrinolysis and plasma fibrinogen on the one hand and specific insulin and proinsulin on the other, in a healthy population sample of 165 men and women, 25–74 years of age, from the Northern Sweden MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) Study. Specific insulin and proinsulin were measured by enzyme-linked immunosorbent assay. Partial correlation coefficients, adjusted for age and sex, were calculated. RESULTS Plasma fibrinogen levels were related to insulin (r = 0.25, P < 0.01) and proinsulin (r = 0.29, P < 0.001), as was plasminogen activator inhibitor (PAI)-1 activity (r = 0.36 and r = 0.29, respectively; P < 0.001). Tissue Plasminogen activator (tPA) activity correlated inversely to insulin (r = −0.35, P < 0.001) and proinsulin (r = −0.36, P < 0.001). In a multivariate analysis taking also smoking and anthropometric and metabolic measurements into account, fasting proinsulin was a significant predictor of high plasma fibrinogen level. Insulin and proinsulin levels were not related to tPA activity. High levels of postload insulin, triglycerides, and diastolic blood pressure, but not proinsulin, predicted high PAI-l activity. CONCLUSIONS In a healthy population, the relationship previously described between high insulin levels and impaired fibrinolysis is not attributable to confounding from proinsulin. Elevated proinsulin levels are associated with high fibrinogen levels.

Metformin versus placebo in combination with insulin analogues in patients with type 2 diabetes mellitus-the randomised, blinded Copenhagen Insulin and Metformin Therapy (CIMT) trial.

Objective To assess the effect of metformin versus placebo both in combination with insulin analogue treatment on changes in carotid intima-media thickness (IMT) in patients with type 2 diabetes. Design and setting Investigator-initiated, randomised, placebo-controlled trial with a 2×3 factorial design conducted at eight hospitals in Denmark. Participants and interventions 412 participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥7.5% (≥58 mmol/mol); body mass index >25 kg/m2) were in addition to open-labelled insulin treatment randomly assigned 1:1 to 18 months blinded metformin (1 g twice daily) versus placebo, aiming at an HbA1c ≤7.0% (≤53 mmol/mol). Outcomes The primary outcome was change in the mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight and hypoglycaemic and serious adverse events were other prespecified outcomes. Results Change in the mean carotid IMT did not differ significantly between the groups (between-group difference 0.012 mm (95% CI −0.003 to 0.026), p=0.11). HbA1c was more reduced in the metformin group (between-group difference −0.42% (95% CI −0.62% to −0.23%), p<0.001)), despite the significantly lower insulin dose at end of trial in the metformin group (1.04 IU/kg (95% CI 0.94 to 1.15)) compared with placebo (1.36 IU/kg (95% CI 1.23 to 1.51), p<0.001). The metformin group gained less weight (between-group difference −2.6 kg (95% CI −3.3 to −1.8), p<0.001). The groups did not differ with regard to number of patients with severe or non-severe hypoglycaemic or other serious adverse events, but the metformin group had more non-severe hypoglycaemic episodes (4347 vs 3161, p<0.001). Conclusions Metformin in combination with insulin did not reduce carotid IMT despite larger reduction in HbA1c, less weight gain, and smaller insulin dose compared with placebo plus insulin. However, the trial only reached 46% of the planned sample size and lack of power may therefore have affected our results. Trial registration number NCT00657943; Results.

Effect of a group-based rehabilitation programme on glycaemic control and cardiovascular risk factors in type 2 diabetes patients: The Copenhagen Type 2 Diabetes Rehabilitation Project

OBJECTIVE To compare the effectiveness of a group-based rehabilitation programme with an individual counselling programme at improving glycaemic control and cardiovascular risk factors among patients with type 2 diabetes. METHODS We randomised 143 adult type 2 diabetes patients to either a 6-month multidisciplinary group-based rehabilitation programme or a 6-month individual counselling programme. Outcome measures included glycated haemoglobin (HbA(1c)), blood pressure, lipid profile, weight, and waist circumference. RESULTS Mean HbA(1c) decreased 0.3%-point (95% confidence interval [CI] = -0.5, -0.1) in the rehabilitation group and 0.6%-point (95% CI = -0.8, -0.4) among individual counselling participants (p<0.05). Within both groups, equal reductions occurred in body weight, waist circumference, systolic blood pressure and diastolic blood pressure, but no significant between-group differences between occurred for any of the cardiovascular outcomes. The group-based rehabilitation programme consumed twice as many personnel resources. CONCLUSION The group-based rehabilitation programme resulted in changes in glycaemic control and cardiovascular risk factor reduction that were equivalent or inferior to those of an individual counselling programme. PRACTICE IMPLICATIONS The group-based rehabilitation programme, tested in the current design, did not offer additionally improved outcomes and consumed more personnel resources than the individual counselling programme; its broad implementation is not supported by this study. Trial registration Clinicaltrials.gov NCT00284609.

Effects of biphasic, basal-bolus or basal insulin analogue treatments on carotid intima-media thickness in patients with type 2 diabetes mellitus: the randomised Copenhagen Insulin and Metformin Therapy (CIMT) trial

Objective To assess the effect of 3 insulin analogue regimens on change in carotid intima-media thickness (IMT) in patients with type 2 diabetes. Design and setting Investigator-initiated, randomised, placebo-controlled trial with a 2×3 factorial design, conducted at 8 hospitals in Denmark. Participants and interventions Participants with type 2 diabetes (glycated haemoglobin (HbA1c)≥7.5% (≥58 mmol/mol), body mass index >25 kg/m2) were, in addition to metformin versus placebo, randomised to 18 months open-label biphasic insulin aspart 1–3 times daily (n=137) versus insulin aspart 3 times daily in combination with insulin detemir once daily (n=138) versus insulin detemir alone once daily (n=137), aiming at HbA1c≤7.0% (≤53 mmol/mol). Outcomes Primary outcome was change in mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight, and hypoglycaemic and serious adverse events were other prespecified outcomes. Results Carotid IMT change did not differ between groups (biphasic −0.009 mm (95% CI −0.022 to 0.004), aspart+detemir 0.000 mm (95% CI −0.013 to 0.013), detemir −0.012 mm (95% CI −0.025 to 0.000)). HbA1c was more reduced with biphasic (−1.0% (95% CI −1.2 to −0.8)) compared with the aspart+detemir (−0.4% (95% CI −0.6 to −0.3)) and detemir (−0.3% (95% CI −0.4 to −0.1)) groups (p<0.001). Weight gain was higher in the biphasic (3.3 kg (95% CI 2.7 to 4.0) and aspart+detemir (3.2 kg (95% CI 2.6 to 3.9)) compared with the detemir group (1.9 kg (95% CI 1.3 to 2.6)). Insulin dose was higher with detemir (1.6 IU/kg/day (95% CI 1.4 to 1.8)) compared with biphasic (1.0 IU/kg/day (95% CI 0.9 to 1.1)) and aspart+detemir (1.1 IU/kg/day (95% CI 1.0 to 1.3)) (p<0.001). Number of participants with severe hypoglycaemia and serious adverse events did not differ. Conclusions Carotid IMT change did not differ between 3 insulin regimens despite differences in HbA1c, weight gain and insulin doses. The trial only reached 46% of planned sample size and lack of power may therefore have affected our results. Trial registration number NCT00657943.

Measurement of Insulin Immunoreactivity in Human Plasma and Serum

Featured article: Andersen L, Dinesen B, Jorgensen PN, Poulsen F, Roder ME. Enzyme immunoassay for intact human insulin in serum or plasma. Clin Chem 1993;39:578–82.1 Our 1993 report described a monoclonal antibody–based ELISA for insulin that had greater specificity than existing RIAs. This specificity allowed determination of intact insulin only, without comeasurement of proinsulin and the conversion intermediate des(31,32)-proinsulin. In patients with type 2 diabetes or with high concentrations of insulin precursors in the blood, the assay measured intact insulin immunoreactivity from plasma and serum samples. The assay was also suitable for large-scale studies. Immunochemical methods for estimating insulin concentrations have been used for 50 years. In 1959 Berson and Yalow introduced the RIA method for the determination of insulin (1), which led to a Nobel Prize in 1977. Competitive insulin RIAs based on polyclonal antibodies had many limitations, however, including limited stability of the radioactive isotope, limited amounts of the antibodies, and unspecific determination of insulin precursors and insulin degradation products together with insulin. The assays were laborious for large-scale use. The discovery of monoclonal antibodies made it possible to produce potentially unlimited amounts of …

Management of Patients with Type 2 Diabetes Shared between a Specialized Outpatient Clinic and General Practice Was Noninferior to Mono Management in a Specialized Outpatient Clinic—A Prospective, Randomized, Noninferiority Trial

To ensure high-quality care for patients with type 2 diabetes (T2D), it is necessary to consider how clinical management is organized. We investigated if management of patients with T2D shared between a specialized outpatient clinic and primary health care has a non-inferior outcome of HbA1c compared to ‘mono’ management in a specialized outpatient clinic.The study was a 12-month randomized controlled, non-inferiority trial. Non-inferiority margin for HbA1c was 4.4 mmol/mol. Patients with T2D and incipient complications were eligible for the study. The shared care intervention consisted of one annual comprehensive check-up at the outpatient clinic and three quarterly visits at the primary health care physician. The control group was offered four quarterly visits at the outpatient clinic, including an annual comprehensive check-up.We randomized 140 patients (age: 65.0±0.9 years (mean±SEM), BMI: 30.8±0.5 kg/m2, diabetes duration: 9.1±0.5 years, HbA1c: 51.9±0.8 mmol/mol, systolic blood pressure: 135.6±1.1 mmHg) with no significant baseline differences between the groups. Ninety-five (68%) patients had peripheral neuropathy, 26 (19%) microalbuminuria, and 21 (15%) previous major cardiovascular event. At end-of-trial, mean HbA1c change from baseline was 2.0 mmol/mol in the intervention group and 0.9 mmol/mol in the control group. The between-group difference of 1.1 mmol/mol (95% confidence interval: -2.0, 4.1) met the pre-specified non-inferiority criterion. Our study shows that a shared care program is non-inferior to an established program in a specialized outpatient clinic in maintenance of glycemic control of T2D patients with incipient complications. Shared care could be part of future T2D management, as more patients will benefit from the specialized diabetes team while keeping close contact with the primary care physician. Disclosure L. Munch: None. B.B. Bennich: None. D. Overgaard: None. H. Konradsen: None. H.V. Middelfart: None. N. Kaarsberg: None. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker9s Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker9s Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker9s Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker9s Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker9s Bureau; Self; Sanofi. T. Vilsb ll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker9s Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. M. R der: None.