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Formation of reactive oxygen species has been linked to the development of diabetes complications. Treatment with metformin has been associated with a lower risk of developing diabetes complications, including when used in combination with insulin. Metformin inhibits Complex 1 in isolated mitochondria and thereby decreases the formation of reactive oxygen species. Thus, we post-hoc investigated the effect of metformin in combination with different insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes. Four hundred and fifteen individuals with type 2 diabetes were randomized (1:1) to blinded treatment with metformin (1,000 mg twice daily) versus placebo and to (1:1:1) open-label biphasic insulin, basal-bolus insulin, or basal insulin therapy in a 2 × 3 factorial design. RNA and DNA oxidation were determined at baseline and after 18 months measured as urinary excretions of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), respectively. Urinary excretion of 8-oxoGuo changed by +7.1% (95% CI: 0.5% to 14.0%, P = 0.03) following metformin versus placebo, whereas changes in 8-oxodG were comparable between intervention groups. Biphasic insulin decreased urinary excretion of 8-oxoGuo (within-group: −9.6% (95% CI: −14.4% to −4.4%)) more than basal-bolus insulin (within-group: 5.2% (95% CI: −0.5% to 11.2%)), P = 0.0002 between groups, and basal insulin (within-group: 3.7% (95% CI: −2.0% to 9.7%)), P = 0.0007 between groups. Urinary excretion of 8-oxodG decreased more in the biphasic insulin group (within-group: −9.9% (95% CI: −14.4% to −5.2%)) than basal-bolus insulin (within group effect: −1.2% (95% CI: −6.1% to 3.9%)), P = 0.01 between groups, whereas no difference was observed compared with basal insulin. In conclusion, eighteen months of metformin treatment in addition to different insulin regimens increased RNA oxidation, but not DNA oxidation. Biphasic insulin decreased both RNA and DNA oxidation compared with other insulin regimens.

Summary: Some studies indicate potential beneficial effects of metformin on body composition and bone. This trial compared metformin + insulin vs placebo + insulin. Metformin treatment had a small but positive effect on bone quality in the peripheral skeleton, reduced weight gain, and resulted in a more beneficial body composition compared with placebo in insulin-treated patients with type 2 diabetes. Introduction: Glucose-lowering medications affect body composition. We assessed the long-term effects of metformin compared with placebo on whole body bone and body composition measures in patients with type 2 diabetes mellitus. Methods: This was a sub-study of the Copenhagen Insulin and Metformin Therapy trial, which was a double-blinded randomized placebo-controlled trial assessing 18-month treatment with metformin compared with placebo, in combination with different insulin regimens in patients with type 2 diabetes mellitus (T2DM). The sub-study evaluates the effects on bone mineral content (BMC), density (BMD), and body composition from whole body dual-energy X-ray absorptiometry (DXA) scans which were assessed at baseline and after 18 months. Results: Metformin had a small, but positive, (p < 0.05) effect on subtotal, appendicular, and legs BMC and BMD compared with placebo. After adjustment for sex, age, vitamin D, smoking, BMI, T2DM duration, HbA1c, and insulin dose, the effects on appendicular BMC and BMD persisted (p < 0.05 for both). The changes in appendicular BMC and BMD corresponded approximately to a 0.7% and 0.5% increase in the metformin group and 0.4% and 0.4% decrease in the placebo group, respectively. These effects were mostly driven by an increase in BMC and BMD in the legs and a loss of BMC and BMD in the arms. During 18 months, all participants increased in weight, fat mass (FM), FM%, and lean mass (LM), but decreased in LM%. The metformin group increased less in weight (subtotal weight (weight-head) − 2.4 [− 3.5, − 1.4] kg, p value < 0.001) and FM (− 1.5 [− 2.3, − 0.8] kg, p value < 0.001) and decreased less in LM% (0.6 [0.2, 1.1] %, p value < 0.001) compared with the placebo group. Conclusion: Metformin treatment had a small positive effect on BMC and BMD in the peripheral skeleton and reduced weight gain compared with placebo in insulin-treated patients with T2DM.

Preclinical studies have shown a potential osteoanabolic effect of metformin but human studies of how metformin affects bone turnover are few. A post hoc sub-study analysis of an 18-month multicenter, placebo-controlled, double-blinded trial in type 2 diabetes mellitus (T2DM), randomizing participants to metformin versus placebo both in combination with different insulin analogue regimens (Metformin + Insulin vs. Placebo + Insulin). Patients were not treatment naive at baseline, 83% had received metformin, 69% had received insulin, 57.5% had received the combination of metformin and insulin before entering the study. Bone formation and resorption were assessed by measuring, N-terminal propeptide of type I procollagen (P1NP) and C-terminal telopeptide of type I collagen (CTX) at baseline and end of study. The influence of gender, age, smoking, body mass index (BMI), T2DM duration, glycosylated hemoglobin A1c (HbA1c), c-reactive protein (CRP) and insulin dosage was also included in the analyses. The levels of bone formation marker P1NP and bone resorption marker CTX increased significantly in both groups during the trial. P1NP increased less in the Metformin + Insulin compared to the placebo + insulin group (p = 0.001) (between group difference change), while the increases in CTX levels (p = 0.11) were not different. CRP was inversely associated (p = 0.012) and insulin dosage (p = 0.011) was positively related with change in P1NP levels. BMI (p = 0.002) and HbA1C (p = 0.037) were inversely associated with change in CTX levels. During 18 months of treatment with metformin or placebo, both in combination with insulin, bone turnover increased in both groups. But the pattern was different as the bone formation marker (P1NP) increased less during Metformin + Insulin treatment, while change in bone resorption (CTX) was not significantly different between the two groups.

Aims To investigate measures of carotid intima-media thickness (IMT) and conventional cardiovascular (CV) risk factors as predictors of future carotid IMT, and the prediction of CV events during follow-up based on measures of carotid IMT. Methods Observational longitudinal study including 230 persons with type 2 diabetes (T2D). Results Mean age at follow-up was 66.7 (SD 8.5) years, 30.5% were women and mean body mass index (BMI) was 31.8 (4.4) kg/m2. Carotid IMT was measured at baseline, after 18 months of intervention in the Copenhagen Insulin and Metformin Therapy (CIMT) trial and after a mean follow-up of 6.4 (1.0) years. Baseline carotid IMT, carotid IMT after 18 months' intervention, and CV risk factors (age, sex and baseline systolic blood pressure) gave the best prediction of carotid IMT (root mean-squared error of prediction of 0.106 and 95% prediction error probability interval of −0.160, 0.204). Conclusions Measures of carotid IMT combined with CV risk factors at baseline predicts attained carotid IMT better than measures of carotid IMT or CV risk factors alone. Carotid IMT did not predict CV events, and the present results do not support the use of carotid IMT as a predictor of CV events in persons with T2D.

Summary: Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS) in patients with type 2 diabetes. Metformin had no significant effect on BMD in the spine and hip or TBS compared with a placebo. Introduction: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures despite a high bone mass. Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS). Methods: This was a sub-study of a multicenter, randomized, 18-month placebo-controlled, double-blinded trial with metformin vs. placebo in combination with different insulin regimens (the Copenhagen Insulin and Metformin Therapy trial) in patients with T2DM. BMD in the spine and hip and TBS in the spine were assessed by dual-energy X-ray absorptiometry at baseline and after 18 months follow-up. Results: Four hundred seven patients were included in this sub-study. There were no between-group differences in BMD or TBS. From baseline to 18 months, TBS decreased significantly in both groups (metformin group, − 0.041 [− 0.055, − 0.027]; placebo group − 0.046 [− 0.058, − 0.034]; both p < 0.001). BMD in the spine and total hip did not change significantly from baseline to 18 months. After adjustments for gender, age, vitamin D, smoking, BMI, duration of T2DM, HbA1c, and insulin dose, the TBS between-group differences increased but remained non-significant. HbA 1c was negatively associated with TBS (p = 0.009) as was longer duration of diabetes, with the femoral neck BMD (p = 0.003). Body mass index had a positive effect on the hip and femoral neck BMD (p < 0.001, p = 0.045, respectively). Conclusions: Eighteen months of treatment with metformin had no significant effect on BMD in the spine and hip or TBS in patients with T2DM compared with a placebo. TBS decreased significantly in both groups. Trial registration: ClinicalTrials.gov (NCT00657943).

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/m(2)) 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 (pCONCLUSIONS: 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.

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%), pCONCLUSIONS: 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.

Patients with affective disorder have higher mortality not only because of their affective illness but also because of a higher risk of death from physical illness especially cardiovascular diseases.To investigate the prevalence in a naturalistic cohort of patient treated at a Mood Disorder Clinic.Patients were evaluated for the presence of metabolic syndrome (MeS) according to modified NCEP ATP III criteria.Of the 143 patients eligible for participation, 100 patients participated in the study (32% male, mean age 43.6 ± 14.2); the prevalence of MeS was 26%. Higher age and high body mass index (BMI) were significantly associated with MeS. No association between present medication and MeS was seen.More than a quarter of affectively ill patients had MeS, which emphasizes the importance of integrated somatic and psychiatric care in order to reduce this group of patients' risk profile concerning cardiovascular diseases and diabetes. Clinically, it seems reasonable to prioritize overweight and obese patients for further examination.

The incidence of the metabolic syndrome, a major risk factor for diabetes and cardiovascular disease, is increasing worldwide and is suggested to be higher among psychiatric patients, especially those on antipsychotic treatment.To assess the prevalence of the metabolic syndrome in Danish psychiatric outpatients and compare it with the general population.In a cross-sectional, observational study in 2007-08, 170 Danish outpatients on antipsychotic drug treatment were monitored for the prevalence of the metabolic syndrome based on the International Diabetes Federation (IDF) definition and compared with a general population group of 3303 randomly selected Danes.Of the antipsychotic-treated patients 48.2% fulfilled the IDF criteria for the metabolic syndrome, compared with 29.6% of the general population. The antipsychotic-treated patients had higher rates of increased waist circumference, triglyceride and glucose levels, and lower high-density lipoprotein cholesterol. Compared with the general population, the odds ratio (OR) of the metabolic syndrome among antipsychotic-treated patients was 2.2. After adjustment for age and sex, the OR increased to 2.7. In the antipsychotic-treated group, statistically different rates of the metabolic syndrome for patients in monopharmacy vs. polypharmacy, and for patients in monotherapy with first-generation vs. second-generation antipsychotics, could not be found.The metabolic syndrome is highly prevalent among a Danish outpatient population treated with antipsychotics compared with the general population. Monitoring of lipid and glucose levels, blood pressure and waist circumference before start-up and during treatment with antipsychotic medication is of pivotal importance in order to prevent diabetes and cardiovascular disease in this patient population.

OBJECTIVE: To investigate tolerability and glycemic control over 26 weeks in patients with type 2 diabetes (T2D) who initiated insulin with, or switched to, biphasic insulin aspart 30/70 (BIAsp 30) in routine clinical care. METHODS: This was a non-randomized, non-interventional, open-label, observational study involving patients under the care of approximately 150 insulin-prescribing physicians in Denmark. All patients enrolled were prescribed BIAsp 30 in routine care. Starting dose, dose titration and injection frequency were determined individually by each physician. Information on serious adverse drug reactions (SADR), glycemic parameters and hypoglycemic events were obtained from patients’ notes, patients’ diaries and recall, and transferred to case report forms by physicians at baseline (during 4 weeks prior to BIAsp 30 therapy) and after 12 and 26 weeks of treatment. RESULTS: 421 subjects were recruited and 392 provided safety data. The age (mean ± SD) was 62.0 ± 11.4 years, body mass index (BMI) 30.4 ± 6.4 kg/m2, duration of diabetes 9.1 ± 8.1 years and HbA1c (%) 9.4 ± 1.7. 199 subjects were prior insulin users and 193 were insulin-naïve patients. Four patients reported a SADR (3 hypoglycemia, 1 severe hypoglycemia). HbA1c was significantly reduced after 26 weeks of BIAsp 30 therapy: prior insulin users -1.2%, insulin-naïve patients -2.2% (both p < 0.001). 28% and 41% of patients, respectively, reached target HbA1c < 7%. Overall the hypoglycemia rate was lower for insulin-naïve patients than for prior insulin users: 5.0 vs. 6.6 episodes/patient-year (p < 0.05). CONCLUSION: Initiating insulin with, or switching insulin to, BIAsp 30 in routine care was safe and effective in patients with T2D.

Background Plasma tryptophan concentrations and the ratio of tryptophan to other large neutral amino acids (plasma tryptophan ratio) are reportedly low in obese subjects. The plasma tryptophan ratio predicts brain tryptophan uptake and serotonin production. If this ratio is low in obese subjects, serotonin function may also be low. Plasma tryptophan concentrations and ratios have been measured only at single time points in obese subjects; it is not known whether low values for these 2 variables persist throughout a 24-h period. Objective Our objective was to determine whether plasma tryptophan concentrations and ratios in obese subjects are lower than those in normal-weight subjects throughout a 24-h period and whether they increase when body weight is reduced. Design Plasma tryptophan concentrations and ratios were examined in obese subjects before and after weight loss and in nonobese control subjects. Blood samples were drawn frequently throughout the 24-h period. An insulin tolerance test was also used to determine whether weight loss altered the ability of insulin to modify plasma concentrations of tryptophan and of the other large neutral amino acids. Results Plasma tryptophan concentrations and ratios in obese subjects were low at all times; these effects persisted after weight reduction. Plasma concentrations of all the large neutral amino acids decreased during insulin infusion in all the groups. Conclusions The low 24-h plasma tryptophan ratios in obese and formerly obese subjects suggest that brain tryptophan uptake may be continuously diminished and may remain below normal despite weight reduction.

Lymphoma may occasionally involve the adrenal glands, but primary adrenal lymphoma (PAL) is very rare and only few cases have been reported. We present a case of a 60-year-old, otherwise healthy, woman, with bilateral PAL presenting with adrenal insufficiency. The patient responded initially upon administration of large doses of intravenously hydrocortisone with total remission of symptoms. An abdominal computerized tomography scan demonstrated bilateral adrenal lesions but did not demonstrate any other pathology. Since metastatic malignant disease was suspected a positron-emission-tomography scan was performed only showing significant uptake in the adrenal glands. Endocrine evaluation did not reveal abnormal function of any hormonal system and the patient was scheduled for bilateral adrenalectomy. However the clinical condition deteriorated rapidly and the patient was readmitted to hospital before surgery was performed. A new computerized tomography scan showed rapid progression of disease with further enlargement of the adrenal masses and both pulmonary and hepatic metastasis. Needle biopsy was performed but the patient refused further treatment and died before a diagnosis was obtained. The immuneohistochemical diagnosis was large B-cell lymphoma. This case should remind clinicians that PAL may be a cause of bilateral adrenal incidentaloma especially if the patient presents with adrenal insufficiency.

OBJECTIVE--To describe mortality by suicide and other causes of death in a group of patients who attempted suicide, and to identify predictive factors. DESIGN--10 year follow up study based on records of suicide attempters in 1980. SETTING--Poisoning treatment centre at a general hospital. SUBJECTS--974 patients aged 15 and over referred to the poisoning treatment centre after deliberate self poisoning. MAIN OUTCOME MEASURES--Death by different causes registered in the Danish death cause register. RESULTS--In 10 years of follow up 306 patients died: 103 by suicide, 131 from natural causes, and 31 by accident; five were murdered, and in 36 cases the cause of death was uncertain. The standard mortality ratio was 550. Cause specific standardised mortality rates were 2960 for suicide, 236 for natural causes, 1256 for accidents, and 5459 for uncertain causes. In a Cox regression analysis, high risk factors for subsequent suicide were: more than one previous suicide attempt (relative risk 2.25), living alone (2.28), and age (1.03 per year). Predictors of death by natural causes were receiving a pension (1.69), drug misuse (2.72), more than one previous suicide attempt (2.25), age (1.06 per year), and male sex (2.49). The group of patients fulfilling at least one high risk criterion for later suicide differed significantly from the rest of the patient group in incidence of suicide, but both sensitivity and specificity were low. CONCLUSIONS--Most patients who attempted suicide were at high risk of succeeding because the risk factors, though significant, are not very specific. A strategy to prevent suicide must be directed toward the majority of those who attempt suicide.

Nine male marathon runners were investigated during habitual training (week 0), after 3 weeks of training break (week 3), and after 2 weeks (week 5) and 4 weeks (week 7) of retraining. Maximal oxygen uptake, body fat (BF), and plasma levels of 25(OH)D3, 1,25(OH)2D3, parathyroid hormone (PTH), calcitonin (CT), albumin, and albumincorrected calcium were determined throughout weeks 0–7. The maximal oxygen uptake decreased after training break and increased during retraining (P=0.002). BF did not change significantly. Plasma 1,25(OH)2D3 was elevated after training break and decreased after 2 and 4 weeks of retraining [week 0: 44.0±3.7 (SEM) pg×1-1; week 3: 52.4±6.0 pg×1-1; week 5: 42.0±2.8 pg×1-1; week 7: 36.9±2.3 pg×1-1; P=0.03]. Plasma 25(OH)D3 did not change significantly. Plasma PTH increased throughout the training break and retraining (week 0: 1.36±0.25 pmol×1-1; week 3: 2.02±0.43 pmol×1-1; week 5: 2.23±0.60 pmol×1-1; week 7: 2.63±0.34 pmol×1-1; P=0.03). Albumincorrected calcium values were transiently decreased during retraining (week 3: 2.77±0.08 mM; week 5: 2.47±0.05 mM; week 7: 2.66±0.07 mM; P=0.01). Plasma CT did not change during training break, but was transiently decreased during retraining (week 0: 9.97±0.39 pmol×1-1; week 3: 9.91±0.37 pmol×1-1; week 5: 8.19±0.50 pmol×1-1; week 7: 9.02±0.45 pmol×1-1; P=0.01). Plasma CT was correlated to albumin (r=0.46, P=0.005), albumin-corrected calcium (r=0.34, P=0.04), and maximal oxygen uptake (r=0.45, P=0.006). Plasma 1,25(OH)2D3 was correlated to 25(OH)D3 (r=0.04, P=0.02), and BF (r=0.50, P=0.002). The described endurance training induced significant changes of plasma 1,25(OH)2D3 and PTH despite only transient changes of albumin-corrected calcium and CT.

Abdominal obesity is associated with type 2 diabetes, cardiovascular disease, dyslipidemia and hypertension. The prevalence of abdominal obesity and its relationship with these comorbidities have not previously been examined in Danish primary care patients.The IDEA study was an international cross sectional study including 168,159 patients worldwide. In Denmark, 47 randomly selected general practitioners included 847 consecutive patients. Age, gender, waist circumference, body mass index (BMI) and the presence of known comorbidities were recorded for all patients.The prevalence of abdominal obesity (waist circumference = 80 cm for women and = 94 cm for men) was 66% among women and 60% among men. There was a significant relationship between the degree of abdominal obesity and the prevalence of diabetes, dyslipidemia and hypertension for both sexes. There was a trend towards an increased prevalence of cardiovascular disease with increased waist circumference.Abdominal obesity is very frequently found in Danish primary care patients, and it is associated with an increased prevalence of diabetes, dyslipidemia and hypertension. Patients with increased waist circumference should be screened to diagnose comorbidities related to the abdominal obesity.

This study was initiated to elucidate the mechanisms behind valproate-induced weight gain. Eight patients with epilepsy were studied with identical examination programs before and during the end of the first month of treatment with sodium valproate (VPA). The measurements included registration of food intake, indirect calorimetry, and determination of pancreatic and thyroid hormones, catecholamines, albumin, electrolytes, glycerol, and free fatty acids. Measurements were performed both at the basal condition and during a 3-hour oral glucose tolerance test (OGTT). After the start of VPA treatment, the mean levels during the OGTT of plasma glucose and catecholamines were significantly decreased by 7% and 25%, respectively (P less than .05). The mean ratio of insulin to glucagon decreased by 37% (P less than .01). During the glucose load, the decreases in free fatty acids were less pronounced after the start of VPA treatment, whereas the mean levels of glycerol were found to be unchanged. We detected no differences between the two periods with regard to total energy intake or macronutrient selection, energy expenditure, or thyroid hormones. As VPA is known to affect the concentration of carnitine in humans, it is hypothesized that a possible VPA-induced deficiency of the beta-oxidation of fatty acids is important for the development of obesity in epileptic patients in long-term treatment with VPA, but changes in catecholamines or other hormones might also be of importance.

Results from a phase II trial with Tesofensine for treatment of obesity are presented. In total 203 obese persons were randomised to treatment with Tesofensine 0.25, 0.5, or 1.0 mg, or placebo daily for 24 weeks. Treatment with Tesofensine resulted in a mean weight reduction of 4.5, 9.2 and 10.6% higher than that of placebo for 0.25, 0.5 and 1.0 mg, respectively. Tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved anti-obesity drugs. Findings of safety and efficacy of 0.5 mg Tesofensine need confirmation in phase III trials.

Background: Patients with type 2 diabetes (T2DM) have an increased mortality rate primarily because of macrovascular disease. Where T2DM patients cannot be managed sufficiently through diet, exercise and peroral antidiabetic drugs, that is when haemoglobin A1c (HbA1c) is above 7.0%, it is yet unknown whether a combination of metformin and insulin analogues is superior to insulin analogues alone. Nor is it known which insulin analogue regimen is the optimal. Objective: The primary objective of this trial is to evaluate the effect of an 18-month treatment with metformin vs. placebo in combination with one of three insulin analogue regimens, the primary outcome measure being carotid intima-media thickness (CIMT) in T2DM patients. Design: A randomized, stratified, multicentre trial having a 2 × 3 factorial design. The metformin part is double masked and placebo controlled. The insulin treatment is open. The intervention period is 18 months. Patient Population: Nine hundred and fifty patients with T2DM and HbA1c ≥ 7.5% on treatment with oral hypoglycaemic agents or on insulin treatment and deemed able, by the investigator, to manage once-daily insulin therapy with a long-acting insulin analogue. Randomization: Central randomization stratified for age (above 65 years), previous insulin treatment and treatment centre. Interventions: Metformin 1 g × two times daily vs. placebo (approximately 475 patients vs. 475 patients) in combination with • Insulin detemir before bedtime (approximately 315 patients) or • Biphasic insulin aspart 30 before dinner with the possibility to increase to two or three injections daily (approximately 315 patients) or • Insulin aspart before the main meals (three times daily) and insulin detemir before bedtime (approximately 315 patients). Intervention follows a treat-to-target principle in all six arms aiming for an HbA1c ≤ 7.0%. Outcome measures: Primary outcome measure is the change in CIMT from baseline to 18 months. Secondary outcome measures comprises the composite outcome of death, acute myocardial infarction, stroke or amputation assessed by an adjudication committee blinded to intervention, other cardiovascular clinical outcomes, average postprandial glucose increment from 0 to 18 months, hypoglycaemia and any inadvertent medical episodes. In addition, change in plaque formation in the carotids, HbA1c, cardiovascular biomarkers, body composition, progression of microvascular complications and quality of life will be assessed as tertiary outcome measures. Time schedule: Patient enrolment started May 2008. Follow-up is expected to finish in March 2011. Conclusion: CIMT is designed to provide evidence as to whether metformin is advantageous even during insulin treatment and to provide evidence regarding which insulin analogue regimen is most advantageous with regard to cardiovascular disease.

1. Obesity may be associated with a decreased activity of the sympathetic nervous system and also with a deficiency of the response to stimuli activating the sympathetic nervous system. As insulin activates the sympathetic nervous system, the present study was undertaken to measure the plasma noradrenaline concentration in the fasting state and after 75 g of oral glucose in simple-obese patients (n = 13), in non-insulin-dependent (type 2) diabetic patients (n = 37) and in normal control subjects (n = 12). 2. The fasting plasma noradrenaline concentration was similarly reduced in the simple-obese group and in the diabetic obese group compared with the control group (P = 0.005). The glucose-induced increase in plasma noradrenaline concentration was normal in the simple- obese group, but was abolished in the obese diabetic patients (P = 0.008). 3. Step-wise regression analysis indicated that independent effects on the fasting plasma noradrenaline concentration were exerted by age (r = + 0.32, P = 0.002), glucose concentration (r = −0.32, P = 0.02) and the degree of obesity (r = −0.37, P = 0.007), but not by plasma insulin concentration. 4. These results show that obese patients have a reduced fasting plasma noradrenaline concentration independently of accompanying diabetes, but that the response of noradrenaline to oral glucose is only abolished in the obese diabetic patients.

In humans caffeine stimulates thermogenesis by unknown mechanisms and its effect on body weight has not been studies. The effect of placebo and 100, 200, and 400 mg oral caffeine on energy expenditure, plasma concentrations of substrates and hormones, blood pressure, and heart rate was investigated in a double-blind study in healthy subjects who had a moderate habitual caffeine consumption. Caffeine increased energy expenditure dose dependently and the thermogenic response was positively correlated with the response in plasma caffeine (r = 0.52; p less than 0.018), plasma lactate (r = 0.79; p less than 0.000001), and plasma triglyceride (r = 0.53; p less than 0.02). Stepwise regression analysis with the thermogenic response as the dependent variable excluded plasma caffeine and yielded the following equation: thermic effect (kcal/3 h) = -0.00459 X heart rate + 0.30315 X (triglyceride) + 0.53114 X (lactate) + 15.34 (r = 0.86; p = 0.0001). The results suggest that lactate and triglyceride production and increased vascular smooth muscle tone may be responsible for the major part of the thermogenic effect of caffeine.

A reduced thermic response and an impaired activation of the sympathetic nervous system (SNS) has been reported after oral glucose in human obesity. It is, however, not known whether the reduced SNS activity returns to normal along with weight reduction. The thermic effect ofglucose was lower in eight obese patients than in matched control subjects (1 .7% vs 9.2%, p < 0.002). The increase in arterial norepineph- rine after glucose was also blunted in the obese patients. After a 30-kg weight loss their glucose and lipid profiles were markedly improved but the thermic effect ofglucose was still lower than that of the control subjects (4.2%, p < 0.001). The glucose-in- duced arterial norepinephrine response remained diminished in the reduced obese patients whereas the changes in plasma epinephrine were similar in all three groups. The results suggest that a defective SNS may be a cause in the development of obesity. Am J Clin Nutr 1990:51:331-7.

We report a case of Lemierre's syndrome caused by Fusobacterium necrophorum and discuss characteristics of this potentially fatal condition which, though rare, may have a rising frequency. Familiarity with the signs and symptoms of Lemierre's syndrome is therefore of great importance.

Acceptable adverse effects and a clinical relevant weight loss of 3 to 5 kilograms have been found in long-term randomized clinical trials for sibutramine (Reductil) and orlistat (Xenical); these drugs may be prescribed for treatment of obesity for a duration of one and four years, respectively. This also seems to be the case for rimonabant (Acomplia), which is expected to receive approval in 2005 or 2006. However, until data on morbidity and mortality are available from RCTs, there is no absolute indication for prescribing drugs for treatment of obesity.

Weight gain is a common, but often overlooked side effect to many widely used drugs. In susceptible individuals the weight gain may result in clinically significant obesity and associated comorbidities. Both tricyclic antidepressant medications and antipsychotic compounds are those prominently cited for producing persistent and problematic body weight gain in many treated patients and have a serious impact on medication compliance to an otherwisebeneficial treatment.Furthermore,weight gain is often seen as an improvement of the psychiatric disease and therefore not recognized before the initial body weight is exceeded by several kilos. The mechanisms behind the weight gain are poorly understood.Many of these drugs interfere with central appetite-regulating neurotransmitters and may also produce sedative and anticholinergic effects, ultimately contributing to changes in energy expenditure. The incidence of weight gain during acute and chronic treatment with different classes of frequently prescribed drugs will be reviewed (Table 19.1), as will the possiblemechanisms by which such drugs alter energy intake and expenditure, contributing to drug-induced weight gain (Table 19.2). Newer, effectivemedication classes, without the side effect of weight gain will also be discussed. ANTIDEPRESSANT MEDICATIONS

Fluoxetine (F) is a specific serotonin-reuptake inhibitor that has been shown to promote weight loss and improve glycemic control in obese diabetic patients. To study its long-term metabolic effect, 40 obese patients with non-insulin -dependent diabetes mellitus (NIDDM) or impaired glucose tolerance (IGT) were included in a 12-month, randomized, placebo controlled study. Patients were assigned to receive either 60 mg F or placebo (P) daily in conjunction with a 5.0-MJ/d diet (> 50% carbohydrate). Both groups showed a significant weight loss, with a nadir after 6 months without group differences (mean +/- SD: F, 10.1 +/- 10.0 kg; P, 9.4 +/- 11.5 kg). Fifteen patients from the F group and 14 from the P group completed the 12-month study without weight loss differences. Glycemic regulation improved along with the weight loss, but with a larger decline in plasma C-peptide and fasting glucose levels on the F group (P < .05). Total skeletal muscle glycogen synthase (GS) activity increased by 31% in the F group (P < .01) and by 17% in the P group (nonsignificant) after 6 months of treatment, but was still less than the activity in normal-weight controls (aged 28.0 +/- 6.3 years; body mass index, 23.5 +/- 2.2). After adjustment for fasting glucose, insulin, weight loss, and diabetic state, a positive effect of F remained on the total GS activity, which accounted for 27% of the variation (P < .05). The waist to hip ratio was reduced in P subjects as compared with F subjects (P < .05). Fat-free mass (FFM) tended to be more reduced in the F group as compared with P subjects (4.9 v 1.9 kg), although the difference did not reach statistical significance. In conclusion, F seems to improve insulin sensitivity beyond the effect mediated through weight loss by a possible effect on GS activity in skeletal muscle tissue.

When given as a supplement to an energy restricted diet the sympathomimetic agent ephedrine, in combination with methylxanthines such as caffeine, improves fat loss by dual actions: a central suppression of appetite and peripheral stimulation of energy expenditure covered by fat oxidation. Mean weight loss was found to be 16.6 kg after 6 months when E+C was given as an adjuvant to an efficient hypoenergetic diet, which was 3.4 kg higher than in the placebo group. An additional 24 weeks treatment with E+C prevented relapse. In the first weeks of treatment E+C offset the hypotensive effect of energy restriction and weight loss, but the effect was transient, and after 8 weeks blood pressures were indistinguishable from those of the placebo group. E+C has no adverse effect on glucose and lipid metabolism, but has been shown to prevent the decline in HDL-cholesterol caused by weight loss. In a comparative trial the weight loss produced by E+C was similar to that of dexfenfluramine. More research on sympathomimetics and methylxanthines should be carried out to identify combinations with improved efficiency and safety. Moreover, more long-term trials and studies in males are required.

Chronic meningococcaemia is a rare disorder. A patient was admitted to hospital with intermittent fever and arthralgia of a migratory nature for 1 week. Maculopapular lesions were present. His temperature was 38.5 degrees C. Physical examination revealed a patient without any signs of severe illness. Blood cultures grew Neisseria meningitides.

The aim of this study was to characterize the association between serum insulin-like growth factor-1 (IGF-1) and obesity, as well as fat distribution, before and during moderate energy restriction (1,200 kcal/d). In 51 females and nine males having a body mass index (BMI) between 27 and 39 kg/m2, relationships between serum IGF-1, IGF-binding protein-3 (IGFBP-3), insulin, growth hormone (GH), blood glucose, and anthropometric measurements of body fat were examined. The patients were studied before treatment and again after 8 and 16 weeks of dieting. Visceral adipose tissue (AT) was estimated by anthropometric computed tomography (CT)-calibrated equations. In females, IGF-1 was inversely associated with the abdominal sagittal diameter (SagD) and with the visceral AT (r = −.41, P = .006). No significant correlations were found between IGF-1 and BMI or other indices of adiposity. Weight loss caused a temporary increase in IGF-1 concentrations (P = .03) and continued decrements in blood glucose levels (P = .0004 at 16 weeks). A statistically significant inverse correlation between IGF-1 and blood glucose levels was present before (r = −.30, P = .02) and after 8 (r = −.37, P = .007) and 16 (r = .02, P = .02) weeks of dietary treatment. Both serum IGF-1 and insulin levels were positively correlated with serum IGFBP-3 levels (r = .34, P = .009 and r = .34, P = .008, respectively). We conclude that IGF-1 levels in obese females reflect the intraabdominal fat mass rather than obesity per se. IGF-1 and blood glucose levels are inversely correlated in obesity before and during energy restriction.

OBJECTIVE--To study the effect of cimetidine suspension compared with placebo suspension on weight loss in moderately obese patients taking a 5 MJ/day diet supplemented with dietary fibre. To determine the relation between the effectiveness of the blinding and weight loss. DESIGN--Randomised double blind study with an eight week parallel group phase and a subsequent eight week crossover or continuation phase. SETTING--Outpatient clinic. SUBJECTS--60 patients (51 women) aged 18-60. MAIN OUTCOME MEASURE--Weight loss. RESULTS--After eight weeks of treatment the mean weight loss in the cimetidine group (5.7 kg) was similar to that of the placebo group (5.9 kg; p = 0.78, 95% confidence interval -2.0 to 1.5 kg). Body mass index, waist and hip measurements, waist-hip ratio, and systolic and diastolic blood pressures decreased similarly in the two groups. No association was found between weight loss and the patients9 ability to guess if they were being given drug or placebo. Correct guesses of current drug were more prevalent than expected by chance (25/37 correct, p = 0.05 for the parallel group phase; 26/30, p = 0.0001 for the crossover phase). CONCLUSIONS--Cimetidine had no effect on weight loss in moderately obese patients. The study underlines the potential problem that blinding of patients to treatment can be compromised.

• Serum concentrations of magnesium, potassium, calcium, and sodium were determined on admission of 224 patients to the hospital and after 2, 4, and 6 days in hospital; all were admitted to the hospital with suspected acute myocardial infarction (AMI). On admission, the patients were randomly allocated to 48 hours of treatment with magnesium intravenously or placebo. One hundred twenty-three patients had AMI (of whom 53 [43%] were treated with magnesium) and 101 had their suspected AMI disproven (of whom 51 [50%] were treated with magnesium). In a supplementary study, serum and urine levels of magnesium, potassium, calcium, and sodium, together with serum levels of parathyroid hormone, were determined before and after intravenous magnesium treatment in six patients with AMI and six patients with ischemic heart disease but without AMI. In both studies, magnesium therapy was associated with significant alterations in extracellular ion homeostasis. Serum concentrations of potassium decreased during the initial days of hospitalization in the patients treated with placebo, but increased slightly in the patients treated with magnesium infusions. These increments in the serum concentrations of magnesium and potassium correlated significantly. The increase in the serum concentration of potassium after magnesium infusions was due to a reduced renal potassium excretion level (from 71.3 to 49.4 mmol/24 h), indicating the existence of a divalent-monovalent cation exchange mechanism in the nephron. This hypothesis was supported by the observation that renal sodium excretion likewise decreased after magnesium infusions (from 83.2 to 59.2 mmol/24 h). Serum concentration of calcium decreased significantly after magnesium treatment (from 2.35 mmol/L on admission to 2.15 mmol/L after 24 hours in the hospital) in the AMI group, in contrast to the placebotreated patients, where no significant fluctuations in serum concentration of calcium were detected during the initial six days. This decrease in serum concentration of calcium was due to a marked increase in renal calcium excretion (from 3.43 mmol/24 h before to 6.59 mmol/24 h after magnesium infusion). A correlation between increments in serum magnesium concentration and decrements in serum calcium concentration was detected. No change in serum levels of parathyroid hormone was found before and after magnesium infusions. Both serum and urine levels of magnesium significantly increased after magnesium treatment to levels above the upper normal limits (serum magnesium concentration increased from 0.81 to 1.21 mmol/L, urine magnesium excretion levels from 3.57 to 16.57 mmol/24 h for both serum and urine changes). No changes were found in serum sodium concentration. It is concluded that the magnesium infusions significantly influence serum levels of potassium and calcium by changes in the renal threshold for tubular reabsorption. Theoretically, such changes in extracellular ion homeostasis are suppressant of arrhythmias, and it is suggested that this might be one mechanism for the antiarrhythmic effect of magnesium therapy in patients with AMI. ( Arch Intern Med 1988;148:1801-1805)