A six-month low-carbohydrate diet high in fat does not adversely affect endothelial function or markers of low-grade inflammation in patients with type 2 diabetes: an open-label randomized controlled trial.

BACKGROUND: While a low-carbohydrate diet (LCD) reduces HbA1c in patients with type 2 diabetes (T2D), the associated high intake of fat may adversely affect cardiovascular risk factors. To address this, we examined the effect of a non-calorie-restricted LCD high in fat on endothelial function and markers of low-grade inflammation in T2D over 6 months. METHODS: In an open-label randomized controlled trial, 71 patients with T2D were randomized 2:1 to either a LCD (< 20 E% carbohydrates, 50-60 E% fat) or a control diet (50-60 E% carbohydrates, 20-30 E% fat) for six months. Flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) were assessed by ultrasound in the brachial artery together with plasma interleukin-6 (IL-6) and serum high-sensitivity C-reactive protein (hsCRP) in the participants at baseline (n = 70) and after six months (n = 64). RESULTS: The FMD and NID were unaltered in both groups after six months, and there were no between-group differences in change of either FMD (p = 0.34) or NID (p = 0.53) in response to the interventions. The circulating hsCRP and IL-6 levels decreased only in response to LCD (both p < 0.05). However, comparing changes over time with the control diet, the LCD did not reduce either IL-6 (p = 0.25) or hsCRP (p = 0.07) levels. The lack of changes in FMD and NID in response to LCD persisted after adjustment for cardiovascular risk factors. CONCLUSION: A LCD high in fat for six months does not adversely affect endothelial function or selected markers of low-grade inflammation, which suggests that this nutritional approach does not increase the risk of cardiovascular disease. Trial registration ClinicalTrials.gov (NCT03068078).

Insulin resistance.

Insulin resistance is an essential metabolic phenomenon that plays an important part in the pathophysiological development of a number of common diseases, such as obesity, type 2 diabetes, arterial hypertension, polycystic ovary syndrome, Alzheimer's disease, fatty liver disease, and several types of cancer. It is therefore important for the clinician to understand the nature of insulin resistance. The purpose of this article is to provide a status of today's knowledge on the subject that applies to diagnosis and treatment of patients with insulin resistance in the daily clinic.

Diabetic Polyneuropathy Early in Type 2 Diabetes Is Associated With Higher Incidence Rate of Cardiovascular Disease: Results From Two Danish Cohort Studies.

OBJECTIVE: Symptoms indicative of diabetic polyneuropathy (DPN) early in type 2 diabetes may act as a marker for cardiovascular disease (CVD) and death. RESEARCH DESIGN AND METHODS: We linked data from two Danish type 2 diabetes cohorts, the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Denmark) and the Danish Centre for Strategic Research in Type 2 Diabetes (DD2), to national health care registers. The Michigan Neuropathy Screening Instrument questionnaire (MNSIq) was completed at diabetes diagnosis in ADDITION-Denmark and at a median of 4.6 years after diagnosis of diabetes in DD2. An MNSIq score ≥4 was considered as indicative of DPN. Using Poisson regressions, we computed incidence rate ratios (IRRs) of CVD and all-cause mortality comparing MNSIq scores ≥4 with scores <4. Analyses were adjusted for a range of established CVD risk factors. RESULTS: In total, 1,445 (ADDITION-Denmark) and 5,028 (DD2) individuals were included in the study. Compared with MNSIq scores <4, MNSIq scores ≥4 were associated with higher incidence rate of CVD, with IRRs of 1.79 (95% CI 1.38-2.31) in ADDITION-Denmark, 1.57 (CI 1.27-1.94) in the DD2, and a combined IRR of 1.65 (CI 1.41-1.95) in a fixed-effect meta-analysis. MNSIq scores ≥4 did not associate with mortality; combined mortality rate ratio was 1.11 (CI 0.83-1.48). CONCLUSIONS: The MNSIq may be a tool to identify a subgroup within individuals with newly diagnosed type 2 diabetes with a high incidence rate of subsequent CVD. MNSIq scores ≥4, indicating DPN, were associated with a markedly higher incidence rate of CVD, beyond that conferred by established CVD risk factors.

Metabolic Factors, Lifestyle Habits, and Possible Polyneuropathy in Early Type 2 Diabetes: A Nationwide Study of 5,249 Patients in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Cohort.

OBJECTIVE: To investigate the association of metabolic and lifestyle factors with possible diabetic polyneuropathy (DPN) and neuropathic pain in patients with early type 2 diabetes. RESEARCH DESIGN AND METHODS: We thoroughly characterized 6,726 patients with recently diagnosed diabetes. After a median of 2.8 years, we sent a detailed questionnaire on neuropathy, including the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), to identify possible DPN (score ≥4) and the Douleur Neuropathique en 4 Questions (DN4) questionnaire for possible associated neuropathic pain (MNSIq ≥4 + pain in both feet + DN4 score ≥3). RESULTS: Among 5,249 patients with data on both DPN and pain, 17.9% (n = 938) had possible DPN, including 7.4% (n = 386) with possible neuropathic pain. In regression analyses, central obesity (waist circumference, waist-to-hip ratio, and waist-to-height ratio) was markedly associated with DPN. Other important metabolic factors associated with DPN included hypertriglyceridemia ≥1.7 mmol/L, adjusted prevalence ratio (aPR) 1.36 (95% CI 1.17; 1.59); decreased HDL cholesterol <1.0/1.2 mmol/L (male/female), aPR 1.35 (95% CI 1.12; 1.62); hs-CRP ≥3.0 mg/L, aPR 1.66 (95% CI 1.42; 1.94); C-peptide ≥1,550 pmol/L, aPR 1.72 (95% CI 1.43; 2.07); HbA1c ≥78 mmol/mol, aPR 1.42 (95% CI 1.06; 1.88); and antihypertensive drug use, aPR 1.34 (95% CI 1.16; 1.55). Smoking, aPR 1.50 (95% CI 1.24; 1.81), and lack of physical activity (0 vs. ≥3 days/week), aPR 1.61 (95% CI 1.39; 1.85), were also associated with DPN. Smoking, high alcohol intake, and failure to increase activity after diabetes diagnosis associated with neuropathic pain. CONCLUSIONS: Possible DPN was associated with metabolic syndrome factors, insulin resistance, inflammation, and modifiable lifestyle habits in early type 2 diabetes.

Cohort profile: the Funen Diabetes Database-a population-based cohort of patients with diabetes in Denmark.

PURPOSE: Detailed population-based data are essential to understanding the epidemiology of diabetes and its clinical course. This article describes the Funen Diabetes Database (FDDB). The purpose of the FDDB was to serve as a shared electronic medical record system for healthcare professionals treating patients with diabetes. The cohort can also be used for research. PARTICIPANTS: The FDDB covers a geographical area of almost 500 000 Danish inhabitants. It currently includes 3691 patients with type 1 diabetes, 19 085 patients with type 2 diabetes, 292 patients with other types of diabetes and 5992 patients with an unknown type of diabetes. Patients have been continuously enrolled from general practitioners and endocrinology departments in the Funen area in Denmark since 2003. Patients undergo a clinical work-up at their first diabetes contact and during follow-up visits. The information collected includes type of diabetes contact, blood pressure, height, weight, lifestyle factors (smoking, exercise), laboratory records (eg, haemoglobin A1c and cholesterol levels), results from foot examinations (eg, pulse, cutaneous sensitivity and ankle brachial index), results from eye examinations (eg, degree of retinopathy assessed by retinal photo and eye examination), glucose-lowering drugs and diabetic complications. FINDINGS TO DATE: The FDDB cohort was followed for a total of 212 234 person-years up to 2016. A cross-sectional study described the prevalence of diabetic retinopathy and its associated risk factors. The clinical outcomes of patients with type 1 diabetes, type 2 diabetes and latent autoimmune diabetes in adults have been assessed. Linkage to population-based medical registries with complete follow-up has enabled the collection of extensive continuous data on general practice contacts, diagnoses and procedures from hospital contacts, medication use and mortality. FUTURE PLANS: The FDDB serves as a strong data resource that will be used in future studies of diabetes epidemiology with focus on occurrence, risk factors, treatment, complications and prognosis.

Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project cohort of newly diagnosed patients with type 2 diabetes: a cohort profile.

PURPOSE: The aim of this article is to provide a detailed description of the ongoing nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project cohort and biobank. The DD2 cohort continuously enrols newly diagnosed patients with type 2 diabetes (T2D) throughout Denmark. The overall goal of the DD2 project is to establish a large and data-rich T2D cohort that can serve as a platform for exhaustive T2D research including (1) improved genotypic and phenotypic characterisation of T2D, (2) intervention studies of more individualised T2D treatment, (3) pharmacoepidemiological studies and (4) long-term follow-up studies on predictors of T2D complications and prognosis. PARTICIPANTS: Between 2010 and 2016, 7011 individuals with T2D have been enrolled and assessed at baseline. Information collected include interview data (eg, body weight at age 20 years, physical activity and alcohol consumption), clinical examination data (eg, hip-waist ratio and resting heart rate) and biological samples (whole blood, DNA, plasma and urine) stored at -80°C and currently analysed for a range of biomarkers and genotypes. FINDINGS TO DATE: Registry linkage has provided extensive supplemental continuous data on glycosylated haemoglobin A, lipids, albuminuria, blood pressure, smoking habits, body mass index, primary care contacts, hospital diagnoses and procedures, medication use, cancer and mortality. Cross-sectional associations between biomarkers, family history, anthropometric and lifestyle measures and presence of complications at baseline have been reported. FUTURE PLANS: During 2016, a detailed follow-up questionnaire has been answered by 85% of initial participants, providing follow-up information on baseline variables and on presence of diabetic neuropathy. The DD2 cohort has now been followed for a total of 18 862 person-years, and nested intervention trials and follow-up studies are ongoing. In the future, the cohort will serve as a strong national and international resource for recruiting patients to nested case studies, clinical trials, postmarketing surveillance, large-scale genome studies and follow-up studies of T2D complications.

Effects of metformin, rosiglitazone and insulin on bone metabolism in patients with type 2 diabetes.

BACKGROUND: Fracture risk is increased in individuals with type 2 diabetes (T2D). The pathophysiological mechanisms accentuating fracture risk in T2D are convoluted, incorporating factors such as hyperglycaemia, insulinopenia, and antidiabetic drugs. The objectives of this study were to assess whether different insulin regimens, metformin and rosiglitazone influence bone metabolism. We explored if the concentration of metformin and rosiglitazone in blood or improved glycaemic control altered bone turnover. METHODS: Two-year clinical trial designed to investigate effects of antidiabetic treatment in 371 T2D patients. Participants were randomized to short or long-acting human insulin (non-blinded) and then further randomized to metformin + placebo, rosiglitazone + placebo, metformin + rosiglitazone or placebo + placebo (blinded). Fasting bone turnover markers (BTM) representing bone resorption (CTX) and formation (PINP) including HbA1c were measured at baseline and after 3, 12 and 24 months. Trough steady-state plasma concentrations of metformin and rosiglitazone were measured after 3, 6 and 9 months of treatment. Associations between treatments and BTMs during the follow-up of the trial were analysed in mixed-effects models that included adjustments for age, gender, BMI, renal function and repeated measures of HbA1c. RESULTS: BTMs increased from baseline to month 12 and remained higher at month 24, with CTX and PINP increasing 28.5% and 23.0% (all: p < 0.001), respectively. Allocation of insulin regimens was not associated with different levels of BTMs. Metformin and metformin + rosiglitazone but not rosiglitazone alone were associated with lower bone formation (PINP). Neither metformin nor rosiglitazone plasma concentrations was associated with BTMs. HbA1c was inversely associated with CTX but not P1NP. CONCLUSIONS: The choice of insulin treatment is not influencing BTMs, metformin treatment may decrease BTMs, and improvement of glycaemic control may influence bone resorption activity.

[Metformin and surgery before general anaesthesia].

Danish national guidelines recommend discontinuation of metformin 48 h prior to general anaesthesia due to the presumed increased risk of lactic acidosis. By reviewing recent studies concerning the risk of metformin-associated lactic acidosis it is found, that studies indicate, that metformin does not increase the risk of lactic acidosis. However, comorbidities such as cardiovascular insufficiency, sepsis, dehydration and impaired kidney function are risk factors. New guidelines propose discontinuation of metformin on the day of surgery. Patients with Type 2 diabetes and comorbidities should have the levels of arterial pH and lactate monitored.

Prevalence of micro- and macrovascular diabetes complications at time of type 2 diabetes diagnosis and associated clinical characteristics: A cross-sectional baseline study of 6958 patients in the Danish DD2 cohort.

AIMS: To examine the prevalence of micro- and macrovascular complications and their associated clinical characteristics at time of type 2 diabetes (T2D) diagnosis. METHODS: We examined the prevalence of complications and associated clinical characteristics among 6958 newly diagnosed T2D patients enrolled in the prospective Danish Center for Strategic Research in T2D cohort during 2010-2016. We calculated age- and gender-adjusted prevalence ratios (aPRs) of complications using log-binomial and Poisson regression. RESULTS: In total, 35% (n=2456) T2D patients had diabetic complications around diagnosis; 12% (n=828) had microvascular complications, 17% (n=1186) macrovascular complications, and 6% (n=442) had both. HbA1c levels of ≥7% were associated with microvascular complications [HbA1c 7%-8%; aPR: 1.35, 95% confidence interval (CI): 1.12-1.62] but not macrovascular complications [aPR: 0.91, 95% CI: 0.76-1.08]. High C-peptide≥800pmol/L was associated with macrovascular [aPR 1.34, 95% CI: 1.00-1.80] but not microvascular [aPR 0.97, 95% CI: 0.71-1.33] complications. Macrovascular complications were associated with male sex, age>50years, obesity, hypertriglyceridemia, low HDL cholesterol, smoking, elevated CRP levels, and anti-hypertensive therapy. Microvascular complications were associated with high blood pressure, hypertriglyceridemia, and absence of lipid-lowering therapy. CONCLUSIONS: One-third of patients with T2D had diabetes complications around time of diagnosis. Our findings suggest different pathophysiological mechanisms behind micro- and macrovascular complications.

[Squamous cell carcinoma developing in necrobiosis lipoidica in a diabetic patient]. / Recidiverende tilfælde af spinocellulær karcinom i necrobiosis lipoidica-sår hos en patient med diabetes.

The development of squamous cell carcinoma in chronic and/or non-healing ulcers associated with necrobiosis lipoidica (NL) is rare, but should be considered in diabetic patients. NL is a non-infectious granulomatous degenerative skin disease. The prevalence of NL in diabetic patients is estimated to 0,3-1,2%. Awareness of malignant transformation potential within a plaque of NL is crucial for early diagnosis and easy radical treatment. A case from our outpatient diabetes clinic is presented.

Diabetes mellitus prevalence in tuberculosis patients and the background population in Guinea-Bissau: a disease burden study from the capital Bissau.

BACKGROUND: Data regarding the association between diabetes mellitus (DM) and tuberculosis (TB) in Africa are scare. We did a DM screening survey among TB patients and non-TB controls in Guinea-Bissau. METHODS: The study was conducted at the Bandim Health Project (BHP) in the capital Bissau. From July 2010 to July 2011, newly diagnosed TB cases were identified through a TB notification system. Concurrently, non-TB controls were selected randomly from the BHP's demographic surveillance database and visited at home. Participants were tested using fasting blood glucose (FBG) measurements. DM was diagnosed as FBG ≥ 7 mmol/l. Our survey was linked to the patient database at the only existing Diabetes Clinic in Bissau. RESULTS: TB patients (n=110) were older than the controls (n=572) (35 vs 31 years; p=0.02), more often male (55% vs 37%; p<0.001) and had a lower body mass index (18.7 vs 24.2 kg/m(2); p<0.001). The prevalence of DM was 2.8% (3/107) for TB patients and 2.1% (11/531) for controls (p=0.64). Excluding two controls already receiving anti-diabetic treatment, the prevalence of DM was 2.8% (3/107) vs 1.7% (9/529) (p=0.44). CONCLUSIONS: The prevalence of DM was low, also among TB patients. No association between DM and TB was found.

Elevated atherosclerosis-related gene expression, monocyte activation and microparticle-release are related to increased lipoprotein-associated oxidative stress in familial hypercholesterolemia.

OBJECTIVE: Animal and in vitro studies have suggested that hypercholesterolemia and increased oxidative stress predisposes to monocyte activation and enhanced accumulation of oxidized LDL cholesterol (oxLDL-C) through a CD36-dependent mechanism. The aim of this study was to investigate the hypothesis that elevated oxLDL-C induce proinflammatory monocytes and increased release of monocyte-derived microparticles (MMPs), as well as up-regulation of CD36, chemokine receptors and proinflammatory factors through CD36-dependent pathways and that this is associated with accelerated atherosclerosis in subjects with heterozygous familial hypercholesterolemia (FH), in particular in the presence of Achilles tendon xanthomas (ATX). APPROACH AND RESULTS: We studied thirty FH subjects with and without ATX and twenty-three healthy control subjects. Intima-media thickness (IMT) and Achilles tendon (AT) thickness were measured by ultrasonography. Monocyte classification and MMP analysis were performed by flow cytometry. Monocyte expression of genes involved in atherosclerosis was determined by quantitative PCR. IMT and oxLDL-C were increased in FH subjects, especially in the presence of ATX. In addition, FH subjects had elevated proportions of intermediate CD14++CD16+ monocytes and higher circulating MMP levels. Stepwise linear regression identified oxLDL-C, gender and intermediate monocytes as predictors of MMPs. Monocyte expression of pro-atherogenic and pro-inflammatory genes regulated by oxLDL-C-CD36 interaction was increased in FH, especially in ATX+ subjects. Monocyte chemokine receptor CX3CR1 was identified as an independent contributor to IMT. CONCLUSIONS: Our data support that lipoprotein-associated oxidative stress is involved in accelerated atherosclerosis in FH, particularly in the presence of ATX, by inducing pro-inflammatory monocytes and increased release of MMPs along with elevated monocyte expression of oxLDL-C-induced atherosclerosis-related genes.

Poor pregnancy outcome after octreotide treatment during pregnancy for familial hyperinsulinemic hypoglycemia: a case report.

BACKGROUND: Late familial hyperinsulinemic hypoglycemia is characterized by recurrent episodes of hypoglycemia and an inappropriate insulinemic response. Treatment with octreotide (somatostatin analogue) reduces the prevalence of clinical significant hypoglycemia and might be beneficial during pregnancy. To our knowledge this is the first report of a woman with late familial hyperinsulinemic hypoglycemia experiencing pregnancies with and without octreotide treatment. CASE PRESENTATION: A 35-year-old Caucasian woman known to suffer from late familial hyperinsulinemic hypoglycemia due to a well-known mutation in the insulin receptor gene has been pregnant 6 times. The patient was treated with injections of Sandostatin LAR® (octreotide) during the first four pregnancies. Her first pregnancy in 1999 was unknown until approximately 25th gestational weeks with fatal intrauterine growth retardation. The following two pregnancies were terminated on parental request after a chorion villus biopsy revealed the mutation causing late familial hyperinsulinemic hypoglycemia. During the fourth pregnancy, in which the fetus also had the mutation, serial ultrasound examinations showed a small fetus with appropriate growth. At birth the girl was small for gestational age. She was admitted to the neonatal special care unit due to low blood glucose and intravenous glucose and early feeding was initiated. One day old, her condition deteriorated with signs of an abdominal catastrophe indicating necrotizing enterocolitis. After two laparotomies - both confirming necrotizing enterocolitis - the child died 8 days after birth.In the following two pregnancies Sandostatin LAR® was stopped before pregnancy and the patient was treated only with diet restriction and intensive glucose monitoring. Both pregnancies ended successfully. One child carried the mutation and was small for gestational age at birth while the other child did not carry the mutation and had normal birth weight. CONCLUSION: In a woman with late familial hyperinsulinemic hypoglycemia octreotide was given during the first four pregnancies resulting in 2 cases of early termination of pregnancy on parental request and 2 cases of inappropriate fetal growth and unviable outcome. The following two pregnancies treated with diet only had a successful outcome.

A novel oral dual amylin and calcitonin receptor agonist (KBP-042) exerts antiobesity and antidiabetic effects in rats.

The present study investigated a novel oral dual amylin and calcitonin receptor agonist (DACRA), KBP-042, in head-to-head comparison with salmon calcitonin (sCT) with regard to in vitro receptor pharmacology, ex vivo pancreatic islet studies, and in vivo proof of concept studies in diet-induced obese (DIO) and Zucker diabetic fatty (ZDF) rats. In vitro, KBP-042 demonstrated superior binding affinity and activation of amylin and calcitonin receptors, and ex vivo, KBP-042 exerted inhibitory action on stimulated insulin and glucagon release from isolated islets. In vivo, KBP-042 induced a superior and pronounced reduction in food intake in conjunction with a sustained pair-fed corrected weight loss in DIO rats. Concomitantly, KBP-042 improved glucose homeostasis and reduced hyperinsulinemia and hyperleptinemia in conjunction with enhanced insulin sensitivity. In ZDF rats, KBP-042 induced a superior attenuation of diabetic hyperglycemia and alleviated impaired glucose and insulin tolerance. Concomitantly, KBP-042 preserved insulinotropic and induced glucagonostatic action, ultimately preserving pancreatic insulin and glucagon content. In conclusion, oral KBP-042 is a novel DACRA, which exerts antiobesity and antidiabetic efficacy by dual modulation of insulin sensitivity and directly decelerating stress on the pancreatic α- and ß-cells. These results could provide the basis for oral KBP-042 as a novel therapeutic agent in type 2 diabetes.

The role of genetic variants in CYP2C8, LPIN1, PPARGC1A and PPARγ on the trough steady-state plasma concentrations of rosiglitazone and on glycosylated haemoglobin A1c in type 2 diabetes.

OBJECTIVE: The aim of this study was to examine the effect of single nucleotide polymorphisms in CYP2C8, LPIN1, PPARGC1A and PPARγ on rosiglitazone's (i) trough steady-state plasma concentration (C(ss,min)), (ii) on glycosylated haemoglobin A1c (HbA1c) and (iii) the risk of developing adverse events, mainly oedema, in patients with type 2 diabetes mellitus (T2D). METHODS: The data used in this study were obtained from the South Danish Diabetes Study including 371 T2D patients with a focus on the 187 patients who were treated with rosiglitazone. The study was a placebo-controlled, partly blinded and multicentre clinical trial. The C(ss,min) of rosiglitazone and HbA1c was determined and the genotype of the patients was identified. RESULTS: The mean C(ss,min) of rosiglitazone was 21.3 ng/ml (95% confidence interval 18.8; 24.2 ng/ml), with observations ranging from 1 to 296 ng/ml. Carriers of CYP2C8*3 (n=32) (rs10509681 and rs11572080) had a statistically significantly lower mean C(ss,min) than wild types (n=106), and they also had a statistically significantly lower mean absolute difference in HbA1c during rosiglitazone treatment. Finally, the carriers of CYP2C8*3 had a lower odds ratio of developing oedema. CONCLUSION: We showed that CYP2C8*3 was associated with lower plasma levels of rosiglitazone and hence a reduced therapeutic response but also a lower risk of developing oedema during treatment with rosiglitazone. Individualized treatment with rosiglitazone on the basis of the CYP2C8 genotype may therefore be possible.

Akt2 influences glycogen synthase activity in human skeletal muscle through regulation of NH2-terminal (sites 2 + 2a) phosphorylation.

Type 2 diabetes is characterized by reduced muscle glycogen synthesis. The key enzyme in this process, glycogen synthase (GS), is activated via proximal insulin signaling, but the exact molecular events remain unknown. Previously, we demonstrated that phosphorylation of Thr³°8 on Akt (p-Akt-Thr³°8), Akt2 activity, and GS activity in muscle were positively associated with insulin sensitivity. Here, in the same study population, we determined the influence of several upstream elements in the canonical PI3K signaling on muscle GS activation. One-hundred eighty-one nondiabetic twins were examined with the euglycemic hyperinsulinemic clamp combined with excision of muscle biopsies. Insulin signaling was evaluated at the levels of the insulin receptor, IRS-1-associated PI3K (IRS-1-PI3K), Akt, and GS employing activity assays and phosphospecific Western blotting. The insulin-stimulated GS activity was positively associated with p-Akt-Thr³°8 (P = 0.01) and Akt2 activity (P = 0.04) but not p-Akt-Ser47³ or IRS-1-PI3K activity. Furthermore, p-Akt-Thr³°8 and Akt2 activity were negatively associated with NH2-terminal GS phosphorylation (P = 0.001 for both), which in turn was negatively associated with insulin-stimulated GS activity (P < 0.001). We found no association between COOH-terminal GS phosphorylation and Akt or GS activity. Employing whole body Akt2-knockout mice, we validated the necessity for Akt2 in insulin-mediated GS activation. However, since insulin did not affect NH2-terminal phosphorylation in mice, we could not use this model to validate the observed association between GS NH2-terminal phosphorylation and Akt activity in humans. In conclusion, our study suggests that although COOH-terminal dephosphorylation is likely necessary for GS activation, Akt2-dependent NH2-terminal dephosphorylation may be the site for "fine-tuning" insulin-mediated GS activation in humans.

[Type 2 diabetes in Denmark]. / Type 2-diabetes i Danmark.

Our vision is that the opportunistic screening system will be improved in order to find patients with occult type 2 diabetes (T2D), since an early treatment based on a correct phenotyping is the goal. Individual goals for HbA1c, blood pressure and lipids must be set up, and the number of drugs used must fit with the patient's phenotype to avoid polypharmacy. A new flow chart for the organisation of T2D has been formulated giving the general practitioners the role as co-ordinators.

[Treatment of insulinomas with alcoholic ablation]. / Behandling af insulinom med alkoholsklerosering.

The efficacy and safety of endoscopic ultrasound (EUS)-guided alcohol ablation of an insulinoma in a patient not candidate for surgery is being evaluated. A 89 year-old male patient with insulinoma and serious cardiac disease was treated with EUS-guided alcohol ablation. The only complication was a slight degree of pancreatitis. Two months after the ablation values of plasma glucose and serum pro-insulin were normalized. EUS-guided alcohol ablation is a safe and efficient alternative to surgical resection of insulinomas in poor surgical candidates.

The LiP (Lifestyle in Pregnancy) study: a randomized controlled trial of lifestyle intervention in 360 obese pregnant women.

OBJECTIVE: To study the effects of lifestyle intervention on gestational weight gain (GWG) and obstetric outcomes. RESEARCH DESIGN AND METHODS: The LiP (Lifestyle in Pregnancy) study was a randomized controlled trial in 360 obese women allocated in early pregnancy to lifestyle intervention or control. The intervention program included dietary guidance, free membership in fitness centers, physical training, and personal coaching. RESULTS: A total of 360 obese pregnant women were included, and 304 (84%) were followed up until delivery. The intervention group had a significantly lower median (range) GWG compared with the control group of 7.0 (4.7-10.6) vs. 8.6 kg (5.7-11.5; P = 0.01). The Institute of Medicine (IOM) recommendations on GWG were exceeded in 35.4% of women in the intervention group compared with 46.6% in the control group (P = 0.058). Overall, the obstetric outcomes between the two groups were not significantly different. CONCLUSIONS: Lifestyle intervention in pregnancy resulted in limited GWG in obese pregnant women. Overall obstetric outcomes were similar in the two groups. Lifestyle intervention resulted in a higher adherence to the IOM weight gain recommendations; however, a significant number of women still exceeded the upper threshold.

Plasma osteoprotegerin is related to carotid and peripheral arterial disease, but not to myocardial ischemia in type 2 diabetes mellitus.

BACKGROUND: Cardiovascular disease (CVD) is frequent in type 2 diabetes mellitus patients due to accelerated atherosclerosis. Plasma osteoprotegerin (OPG) has evolved as a biomarker for CVD. We examined the relationship between plasma OPG levels and different CVD manifestations in type 2 diabetes. METHODS: Type 2 diabetes patients without known CVD referred consecutively to a diabetes clinic for the first time (n = 305, aged: 58.6 ± 11.3 years, diabetes duration: 4.5 ± 5.3 years) were screened for carotid arterial disease, peripheral arterial disease, and myocardial ischemia by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy (MPS). In addition, plasma OPG concentrations and other CVD-related markers were measured. RESULTS: The prevalence of carotid arterial disease, peripheral arterial disease, and myocardial ischemia was 42%, 15%, and 30%, respectively. Plasma OPG was significantly increased in patients with carotid and peripheral arterial disease compared to patients without (p < 0.001, respectively), however, this was not the case for patients with myocardial ischemia versus those without (p = 0.71). When adjusted for age, HbA1c and U-albumin creatinine ratio in a multivariate logistic regression analysis, plasma OPG remained strongly associated with carotid arterial disease (adjusted OR: 2.12; 95% CI: 1.22-3.67; p = 0.008), but not with peripheral arterial disease or myocardial ischemia. CONCLUSIONS: Increased plasma OPG concentration is associated with carotid and peripheral arterial disease in patients with type 2 diabetes, whereas no relation is observed with respect to myocardial ischemia on MPS. The reason for this discrepancy is unknown.