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Sublimation growth of cubic silicon carbide (3C–SiC) with diameters of 50 and 100 mm was performed on freestanding homoepitaxial grown seeds. For both seeds and sublimation grown crystals, two different relaxation axes with varying curvature could be observed with the higher bent axis aligned perpendicular to the original wafer flat. A general reduction in the wafer bow independent of the starting curvature and size of the seeds could be observed. Using the X-ray imaging, we could observe in situ that the bow reduction is linked to the growth of new material and cannot be initiated by heat up or cool down processes alone. Raman spectroscopy of the grown crystals revealed that the observed flattening goes along with a tensing of the seeding layers while the surface of the crystals remains free of a stress gradient. A slight concave bending of lattice planes along the main relaxation axis could be observed by high-resolution XRD rocking curve measurements while for the lower bent axis, no lattice plane bending occurred. Full width half maximum values of the (002) reflection showed values as low as 67 arcseconds proofing the possibility to grow large-area, high-quality 3C–SiC using sublimation growth.

AIMS: To compare data on cardiovascular risk factor changes in lipids, insulin, proinsulin, fibrinolysis, leptin and C-reactive protein, and on diabetes incidence, in relation to changes in lifestyle. METHODS: The study was a randomized lifestyle intervention trial conducted in northern Sweden between 1995 and 2000, in 168 individuals with impaired glucose tolerance (IGT) and body mass index above 27 at start. The intensive intervention group (n = 83) was subjected to a 1-month residential lifestyle programme. The usual care group (n = 85) participated in a health examination ending with a single counselling session. Follow-up was conducted at 1, 3 and 5 years. RESULTS: At 1-year follow-up, an extensive cardio-metabolic risk factor reduction was demonstrated in the intensive intervention group, along with a 70% decrease of progress to type 2 diabetes. At 5-year follow-up, most of these beneficial effects had disappeared. Reported physical activity and fibre intake as well as high-density lipoprotein cholesterol were still increased, and fasting insulin and proinsulin were lower. CONCLUSIONS: The intervention affected several important cardio-metabolic risk variables beneficially, and reduced the risk for type 2 diabetes, but the effects persisted only as long as the new lifestyle was maintained. Increased physical activity seemed to be the behaviour that was most easy to preserve. [ABSTRACT FROM AUTHOR]

The aims of this study were to estimate incidence of diabetic ketoacidosis and mortality from diabetic ketoacidosis using data from public health registries. Four thousand eight hundred and seven admissions in the period 1996-2002 and 137 deaths in the period 1996-2000 with a diagnosis of diabetic ketoacidosis were identified from the Danish National Patient Registry and Danish Cause of Death Registry, respectively. Annual incidence of diabetic ketoacidosis in the general population was estimated to 12.9 per 100,000, being higher in males than in females (14.4 versus 11.4 per 100,000, p<0.0001). Twelve percent of all patients were classified as Type 2 diabetes, predominantly in patients >50 years. Overall mortality was 4%, being higher in patients >70 years than in patients < or =70 years (15% versus 2%, p<0.0001). One or more additional somatic diagnoses were stated on 77% of the death certificates, most often a diagnosis of cardiovascular (47%) or infectious (30%) diseases. Compared to previous studies, the incidence in the general population seems to have remained unaltered the past 25 years, but may have decreased in younger patients. Older patients with diabetic ketoacidosis differed from younger patients in having a higher mortality and a larger proportion of patients classified as Type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: The evidence on the effects of metformin and insulin in type 2 diabetes patients on quality of life, patient satisfaction, and cardiovascular outcomes is unclear., Methods: The Copenhagen Insulin and Metformin Therapy (CIMT) trial is an investigator-initiated multicentre, randomised, placebo-controlled trial with a 2 × 3 factorial design conducted at eight hospitals in Denmark. Participants with type 2 diabetes were randomised to metformin (n = 206) versus placebo (n = 206); in combination with open-label biphasic insulin aspart one to three times daily (n = 137) versus insulin aspart three times daily in combination with insulin detemir once daily (n = 138) versus insulin detemir once daily (n = 137).We present a detailed description of the methodology and statistical analysis of the clinical CIMT outcomes including a detailed description of tests of the assumptions behind the statistical analyses. The outcomes are quality of life (Short Form Health Survey (SF-36)), Diabetes Medication Satisfaction Questionnaire, and Insulin Treatment Satisfaction Questionnaire (assessed at entry and 18 months after randomisation) and cardiovascular outcomes including time to a composite of either myocardial infarction, stroke, peripheral amputation, coronary revascularisation, peripheral revascularisation, or death., Discussions: This statistical analysis plan ensure the highest possible quality of the subsequent post-hoc analyses., Trial Registration: The protocol was approved by the Regional Committee on Biomedical Research Ethics (H-D-2007-112), the Danish Medicines Agency (EudraCT: 2007-006665-33 CIMT), and registered within ClinicalTrials.gov (NCT00657943, 8 th of April 2008)., Competing Interests: Sten Madsbad: Advisory boards: AstraZeneca; Boehringer Ingelheim; Eli Lilly; Intarcia Therapeutics; Merck Sharp & Dohme; Novartis; Novo Nordisk; Sanofi. Lecture fees: AstraZeneca; Boehringer Ingelheim; Merck Sharp & Dohme; Novo Nordisk; Sanofi. Research Grant Recipient: Novo Nordisk; Boehringer Ingelheim. Leif Breum: Advisory boards: AstraZeneca; Boehringer Ingelheim; Merck Sharp & Dohme; Novo Nordisk; Sanofi. Lecture fees: AstraZeneca; Lundbeck, Otsuka. Louise Lundby-Christensen, Christian Ovesen, Thomas Almdal: own shares in Novo Nordisk A/S. Elisabeth R Mathiesen: Advisory board: Novo Nordisk. Markus Harboe Olsen. Janus C Jakobsen, Christian Gluud, Simone B Sneppen, Christoffer Hedetoft, Michael E. Røder, Henrik Vestergaard, Niels Wiinberg, Thure Krarup: none declared., (© 2023 The Authors.)

Purpose: The aim of this study was to explore the factor structure of the Danish translation of the eating disorder quality of life scale and evaluate the internal reliability and convergent validity of the scale in a Danish cohort of women with AN., Methods: The total sample comprised 211 patients diagnosed with anorexia nervosa age 13-40 years. Patients completed questionnaires assessing eating disorder psychopathology, physical and social functioning, and well-being., Results: Factor analyses were not able to support the current division of the scale into 12 factors. We found excellent internal consistency of the eating disorder quality-of-life scale total score. We found relevant associations between quality of life and pre-determined variables., Conclusion: This study supports the use of the total score of the eating disorder quality of life scale in assessing quality of life in patients with anorexia nervosa. However, future studies should explore the factor structure of the scale further., Level of Evidence: III: Evidence obtained from cohort or case-control analytic studies., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

A better understanding of explanatory factors for disease-specific health-related quality of life (HRQoL) in anorexia nervosa (AN) could help direct treatment providers to aspects of the most relevance for patient wellbeing and recovery. We aimed to investigate whether factors associated with HRQoL are the same for women with AN and normal-weight controls. The participants in this study were women with AN recruited from specialized eating disorder centers in Denmark and healthy, normal-weight controls invited via online social media. Participants completed online questionnaires on medical history, disease-specific HRQoL (Eating Disorders Quality of Life Scale, EDQLS) and generic HRQoL (SF-36), eating disorder symptomatology, depression, psychological wellbeing, and work and social adjustment. Questionnaires were fully completed by 211 women with AN (median age 21.7 years) and 199 controls (median age 23.9 years). Women with AN had poorer scores on all measures, i.e., worse HRQoL, psychological health, and work/social functioning. Eating disorder symptomatology affected EDQLS score in both groups, but poorer HRQoL in women with AN was also significantly associated with worse scores on bulimia, maturity fears, depression, vitality, and with older age. The factors investigated together explained 79% of the variance in EDQLS score. Management of disordered self-assessment and thought processes may be of particular importance to women with AN. Greater emphasis on these aspects alongside weight gain could enhance patient-clinician alliance and contribute to better treatment outcomes.

Background: Treating patients with anorexia nervosa (AN) remains a major challenge. The choice between an inpatient or an outpatient care setting is an essential issue for the patients and for their relatives with major health economic implications. However, health services-related studies are lacking. The present study was a descriptive exploration of time-trends in treatment modes of patients with free and equal access to health services., Methods: The study was based on a nationwide cohort of patients diagnosed for the first time with AN, each followed for 5 years in the registers covering the years 1994-2018. The per patient number of hospital admissions, cumulated number of days of hospitalization and number of outpatient visits during the first 5 years after initial diagnosis were considered., Results: The cohort of patients with AN with at least 5 years of follow-up amounted to N = 7,505. A clear trend was observed in the per patient five-year cumulated number of inpatient days, decreasing by 6% per year after adjustment for age at diagnosis, parental mental diagnosis, and family income. The five-year number of hospital admissions after initial diagnosis decreased by 2% per year, while no trend was observed for outpatient visits., Conclusions: The per patient number of hospitalizations and cumulated days of hospitalization during 5 years after diagnosis were reduced for patients initially diagnosed with AN while there was no change in the number of outpatient visits. The factors contributing to these changes of treatment modes over time are in need of further study., (© 2020 The Authors. International Journal of Eating Disorders published by Wiley Periodicals LLC.)

Glucagon-like receptor agonists (GLP-1RAs) are included in current national and international guidelines as second-line treatment especially in patients with type 2 diabetes and concomitant cardiovascular disease (CVD). First-generation GLP-1RAs were two- or once-daily injectables, but longer-acting GLP-1RAs have now been developed for once-weekly administration - e.g., exenatide ER, dulaglutide and semaglutide. With semaglutide, the same prolongation principle as designed in liraglutide is used (spacer and fatty acid chain). However, the similarity to endogenous human GLP-1 is well preserved, sharing 94% homology. It is administered with a simple device and without resuspension before use. The efficacy and safety of semaglutide have been investigated in an extensive clinical development program including more than 9,000 patients with type 2 diabetes. Semaglutide has been compared head-to-head with a dipeptidyl peptidase-4 (DPP4)-inhibitor, GLP-1RAs and basal insulin. Further head-to-head studies are awaiting that compare semaglutide against a sodium-dependent-glucose transporter-2 (SGLT2)-inhibitor. In these studies, semaglutide was found to provide significant and clinically relevant reductions in HbA1c, fasting plasma glucose (FPG), glucose excursions, body weight and blood pressure. The reduction in glycaemic parameters was more pronounced than that in the comparator GLP-1RAs. The rate of hypoglycemia is very low during treatment with semaglutide if not combined with sulphonylureas or insulin. A cardiovascular outcome trial (CVOT) was performed before the approval of semaglutide, at the request of legal authorities. Not only non-inferiority was confirmed, but also superiority compared with placebo used in a population of patients with type 2 diabetes and CVD treated with oral antihyperglycaemic drugs (OADs) and/or insulin with regard to the primary composite endpoint: death from cardiovascular (CV) causes, nonfatal myocardial infarction or nonfatal stroke. The safety of treatment with semaglutide in patients with type 2 diabetes has been extensively investigated. Overall, gastrointestinal side effects dominate, as observed with other GLP-1RAs, and was observed in the same range as for comparator GLP-1RAs. As observed with other GLP-1RAs, side effects such as nausea and vomiting diminished over time during continuous treatment. Regarding microvascular complications, an unexpected increase in diabetes-related retinopathy was observed in the CVOT; Semaglutide Unabated Sustainability in Treatment of Type 2 diabetes' [SUSTAIN 6]), but not in other studies. The reason for this increase is not finally elucidated, but may be due to a nonspecific effect of a rapid decrease in glycaemic parameters in patients with preexisting retinopathy with high HbA1c at the start of the treatment. There is currently a warning in the Summary of Product Characteristics (SmPC) for semaglutide concerning treatment in patients with preexisting retinopathy. Further studies are needed to clarify this., Competing Interests: Disclosure and potential conflicts of interest: The author declares that they have no conflicts of interest. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at http://www.drugsincontext.com/wp-content/uploads/2019/10/dic.212585-COI.pdf, (Copyright © 2019 Røder ME.)

Aim: To evaluate whether management of people with Type 2 diabetes shared between a specialized outpatient clinic and primary health care has noninferior HbA 1c outcomes compared with mono-sectorial management in a specialized outpatient clinic., Methods: A randomized controlled, noninferiority study. People with moderate hyperglycaemia, hypertension and/or incipient complications were eligible for the study. All participants had annual comprehensive check-ups at the outpatient clinic. Quarterly check-ups were conducted by general practitioners (GPs) for the shared care group and by endocrinologists at the outpatient clinic for the control group. The primary outcome was the mean difference in HbA 1c from baseline to 12 months of follow-up. The noninferiority margin for HbA 1c was 4.4 mmol/mol., Results: A total of 140 people were randomized [age 65.0 ± 0.9 years, HbA 1c 52 ± 0.8 mmol/mol (6.9 ± 0.1%), systolic BP 135.6 ± 1.1 mmHg; all mean ± sem]. Peripheral neuropathy was present in 68% of participants and microalbuminuria in 19%; 15% had history of a previous major cardiovascular event. Among study completers (n = 133), HbA 1c increased by 2.3 mmol/mol (0.2%) in the shared care group and by 1.0 mmol/mol (0.1%) in the control group, with a between-group difference of 1.3 mmol/mol [90% confidence interval (CI) -1.3, 3.9] (0.1%, 90% CI -0.1, 0.4). Noninferiority was confirmed in both per protocol and intention to treat analyses., Conclusion: We found that our shared care programme was noninferior to specialized outpatient management in maintaining glycaemic control in this group of people with Type 2 diabetes. Shared care should be considered for the future diabetes management of Type 2 diabetes., (© 2019 Diabetes UK.)

Background: Digitalization of health services ensures greater availability of services and improved contact to health professionals. To ensure high user adoption rates, we need to understand the indicators of use and nonuse. Traditionally, these have included classic sociodemographic variables such as age, sex, and educational level. Electronic health literacy (eHL) describes knowledge, skills, and experiences in the interaction with digital health services and technology. With our recent introduction of 2 new multidimensional instruments to measure eHL, the eHL questionnaire (eHLQ) and the eHL assessment (eHLA) toolkit, eHL provides a multifaceted approach to understand use and nonuse of digital health solutions in detail., Objective: The aim of this study was to investigate how users and nonusers of digital services differ with respect to eHL, in a group of patients with regular contact to a hospital outpatient clinic. Furthermore, to examine how usage and nonusage, and eHL levels are associated with factors such as age, sex, educational level, and self-rated health., Methods: Outpatients were asked to fill out a survey comprising items about usage of digital services, including digital contact to general practitioner (GP) and communication via the national health portal sundhed.dk, the eHLQ, and the eHLA toolkit, as well as items on age, sex, education, and self-rated health. In total, 246 patients completed the survey. A Mann-Whitney test was used to test for differences between users and nonusers of digital services. Correlation tests described correlations between eHL scales (eHEALSs) and age, education, and self-rated health. A significance level of .0071 was used to reject the null hypothesis in relation to the eHEALSs and usage of digital services., Results: In total, 95.1% (234/246) of the participants used their personal digital ID (NemID), 57.7% (142/246) were in contact with their GPs electronically, and 54.0% (133/246) had used the national health portal (sundhed.dk) within the last 3 months. There were no differences between users and nonusers of sundhed.dk with respect to age, sex, educational level, and self-rated health. Users of NemID scored higher than nonusers in 6 of the 7 dimensions of eHLQ, the only one which did not differ was dimension 2: Understanding of health concepts and language. Sundhed.dk users had a higher score in all of the 7 dimensions except for dimension 4: Feel safe and in control. The eHLA toolkit showed that users of sundhed.dk and NemID had higher levels of eHL with regard to tools 2, 5, 6, and 7. Furthermore, users of sundhed.dk had higher levels of eHL with regard to tools 3 and 4., Conclusions: Information about patients' eHL may provide clinicians an understanding of patients' reasons for not using digital health services, better than sociodemographic data or self-rated health., (©Kamila Adellund Holt, Astrid Karnoe, Dorthe Overgaard, Sidse Edith Nielsen, Lars Kayser, Michael Einar Røder, Gustav From. Originally published in the Interactive Journal of Medical Research (http://www.i-jmr.org/), 05.04.2019.)

Monoclonal antibodies inhibiting proprotein convertase subtilisin-kexin type 9 constitute a new class of lipid-lowering drugs. Currently, evolocumab and alirocumab are marketed. A recent cardiovascular outcome study with evolocumab has shown a cardiovascular (CV) event reduction of 15% in high-risk individuals at very low levels of low-density lipoproteins. The adverse event profile up to two years is mild. Treatment is very costly, and data on CV endpoints are still limited. Treatment is restricted to patients at very high risk of getting CV diseases and on a maximal tolerated statin and ezetimibe treatment in addition to dietary intervention.

Decreased quality of life is described more often in hypothyroid patients, who are treated with a synthetic form of thyroxine (L-T4), than in euthyroid controls. A combination of L-T4 and a synthetic form of triiodothyronine (L-T3) has been suggested; however, previous meta-analyses on unselected patients did not find any effect. Recent studies demonstrate, that the overall hypothalamic-pituitary-thyroid-tissue homeostasis could be more complex than previously suggested. Polymorphisms in deiodinase and thyroid hormone transporter genes could theoretically explain, why a minor subgroup of hypothyroid patients seem to have an effect of L-T4/L-T3 combination therapy.

To optimize medical care, Danish guidelines for type 2 diabetes emphasize cross-sectoral collaboration. Risk stratification is recommended as a model of organizing care in terms of distributing tasks and responsibilities between primary and secondary healthcare sectors. Collaboration between the sectors is expected to be beneficial for patients and ensure rational utilization of resources. Challenges such as inter-sectoral communication, sharing of data and unambiguous responsibility underline the need for continuous optimization of the organization of cross-sectorial diabetes management.

Treatment of patients with type 2 diabetes is directed against treating symptoms of hyperglycemia, minimizing the risk of hypoglycemia, and the risk of microvascular and macrovascular complications. The majority of patients with type 2 diabetes die from cardiovascular or cerebrovascular disease. Future therapies should therefore focus on reducing cardiovascular morbidity in this high-risk population. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are two drug classes with proven antihyperglycemic effect in type 2 diabetes. However, these drugs seem to have other effects such as weight reduction, low risk of hypoglycemia, and blood pressure reduction. Emerging evidence suggests pleiotropic effects, which potentially could be important in reducing cardiovascular risk. Prompted by regulatory authorities demanding cardiovascular outcome trials (CVOTs) assessing the cardiovascular safety of new antihyperglycemic drug candidates, many CVOTs are ongoing and a few of these are finalized. Somewhat surprising recent CVOTs in both drug classes have shown promising data on cardiovascular morbidity and mortality in patients with a very high risk of cardiovascular events. It is uncertain whether this is a class effect of the two drug classes, and it is yet unproven whether long-term cardiovascular benefits of these drugs can be extrapolated to populations at lower risk of cardiovascular disease. The aim of the present review is to give an overview of our current knowledge of the GLP-1RA and SGLT2-i classes, with specific focus on mechanisms of action, effects on cardiovascular risk factors and cardiovascular morbidity and mortality from the CVOTs presently available. The clinical potential of these data is discussed., Competing Interests: Conflict of interest statement: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Type 2 diabetes and its management affect the patient and the close family potentially causing either psychological distress or increased sense of responsibility and collaboration in these families. Interactions between patient and family play an important role in maintaining lifestyle changes and diabetes self-management. The purpose of this integrative review was to summarise and assess published studies on the intra-family perspective of supportive and non-supportive interactions in families with a type 2 diabetes patient., Methods: Included in the review were published qualitative and quantitative studies that examined the intra-family perspective on supportive and non-supportive interactions. We searched the literature from 2000 to 2016 and the search strategy comprised the following databases: Cochrane, PubMed, CINAHL, Web of Science, PsycINFO and Psyc-ARTICLES as well as hand searching of reference lists. Quality assessment, data extraction and analysis were undertaken on all included studies., Results: We identified five eligible research papers. Employing content analysis three categories describing interactions were refined: Impact of practical action, impact of emotional involvement, and impact of communication content. Supportive interactions included encouraging communication and family collaboration in managing diet, medications, and blood glucose checking. Non-supportive interactions were visible irritation, nagging behaviour and refusing to share the burden of living with diabetes., Conclusion: The findings stress the importance of including both patient and family in clinical practice to target diabetes self-management adherence and well-being of the whole family. The majority of self-management occurs within the family environment. Therefore, the intra-family perspective of supportive and non-supportive interactions should be understood and addressed as the family members are interdependent and affected by each other. Future research assessing the impact of professional support and the family function will have the potential to improve the daily life and well-being of patients with type 2 diabetes as well as the whole family.

Introduction: Disproportionately elevated fasting levels of proinsulin immunoreactive material (PIM)relative to insulin immunoreactivity (IRI) are a well-established abnormality in type 2 diabetes. Thesignificance of this abnormality has been investigated and discussed in several studies. Areas covered: The present review focuses on the role of proinsulin and its conversion intermediates inthe development of type 2 diabetes, obesity and insulin resistance, and the potential role as a marker ofcardiovascular risk, including the most important studies in this field. Expert commentary: The composition of plasma PIM is heterogeneous comprising des(31,32)-proinsulin,intact proinsulin and small amounts of des(64,65)-proinsulin. Disproportionate hyperproinsulinemiaseems to occur early in the development and before the diagnosis of type 2 diabetes, and seemsassociated to disease progression. Obesity and insulin resistance does not influence fasting PIM/IRI levels in type 2 diabetes. Fasting PIM/IRI levels in type 2 diabetes are closely associated with the degree of impairment in insulin secretory capacity. Different type 2 diabetes alleles have been described associated with elevated PIM/IRI levels. Recent data suggests that proinsulin and its conversion intermediates may have a role as markers of increased risk of cardiovascular disease in glucose intolerance and type 2 diabetes.

The sodium-glucose cotransporter 2 inhibitor (SGLT-2i)-class is efficacious as monotherapy and as add-on therapy with an expected lowering of the glycated haemoglobin (HbA1c) concentration of approximately 7 mmol/mol. Side effects relate to the mode of action, genital infections are the main problem. Extremely rare cases of ketoacidosis are reported, mostly in patients with Type 1 diabetes. One SGLT-2i, empagliflozin, has been shown to reduce cardiovascular mortality and progression of kidney disease in patients with Type 2 diabetes and cardiovascular disease. Outcome trials for other SGLT-2i are pending. SGLT-2i are now in guidelines as a possible second-line therapy or in case of metformin intolerance.

Background: The prevalence of type 2 diabetes (T2D) is growing globally and hospital-based outpatient clinics are burdened with increasing numbers of patients. To ensure high quality treatment and care, it is necessary to structurally reorganise the management of patients with T2D. The objective of this study is to test if T2D patients (who are at intermediate risk of or are already having incipient diabetic complications) jointly managed by a hospital-based outpatient clinic and general practitioners (shared care programme) have a non-inferior outcome compared to an established programme in a specialised (hospital based) outpatient diabetes clinic., Methods: The study is designed as a randomised controlled trial. The shared care model will be tested during a period of 3 years, with data collection at baseline and at 12, 24 and 36 months. All patients will be offered four medical visits a year; the shared care intervention consists of one annual comprehensive check-up at the outpatient clinic and three quarterly visits at the general practitioners' office. The control group will be followed with four quarterly visits at the outpatient clinic, including an annual comprehensive check-up. In the outpatient clinic, the patients will be treated by a specialised diabetes team, including an endocrinologist. On the basis of a predefined stratification model, we will recruit patients stratified to be at intermediate risk of or already having incipient diabetic complications. We plan to include 140 patients. The primary outcome is glycated haemoglobin. Other outcome measures include (1) the proportion of patients who meet the Danish standard indicators reflecting quality of care; (2) quality of life measured by Short Form 36; and (3) the functionality of the patients' families measured by Family Assessment Measure III. The experiences of the patients and families when participating in the shared care program will be explored by collecting dyadic interviews., Discussion: This study will evaluate the quality of a shared care programme for patients with T2D, and provide evidence about advantages and disadvantages compared with a programme in a specialised outpatient clinic. The results may provide important information on how to organise the care for patients with T2D in the future., Trial Registration: This trial was registered with Clinicaltrials.gov on 21 October 2015, registration number: NCT02586545 .

Background: To target optimised medical care the Danish guidelines for diabetes recommend stratification of patients with type 2 diabetes (T2D) into three levels according to risk and complexity of treatment. The aim was to describe the T2D population in an outpatient clinic, measure the compliance of the endocrinologists' to perform risk stratification, and investigate the level of concordance between stratification performed by the endocrinologists and objective assessments., Methods: A cross-sectional study with data collected from medical records and laboratory databases. The Danish risk stratification model contained the following criteria: HbA1c, blood pressure, metabolic complications, microvascular and macrovascular complications. Stratification levels encompassed: level 1 (uncomplicated), level 2 (intermediate risk) and level 3 (high risk). Objective assessments were conducted independently by two health professionals, and compared with the endocrinologists' assessments. In order to test the degree of concordance, we conducted Cohen's kappa, McNemar's test for marginal homogeneity, and Bowker's test for symmetry., Results: Of 245 newly referred patients, 209 (85%) were stratified by the endocrinologists to level 1 (16%), level 2 (55%) and level 3 (29%). By objective assessments, 4% were stratified to level 1, 51% to level 2 and 45% to level 3. Of 419 long-term follow-up patients, 380 (91%) were stratified by the endocrinologists to level 1 (5%), level 2 (57%), level 3 (38%). By objective assessments, 3% were stratified to level 1, 58% to level 2 and 39% to level 3. The concordance rate between endocrinologists' and objective assessments was 63% among newly referred (kappa 0.39; fair agreement) and 67% for long-term follow-up (kappa 0.45; moderate agreement). Among newly referred patients, the endocrinologists stratified less patients at level 3 compared to objective assessments (p < 0.0001). There were no significant differences in marginal distribution within long-term follow-up patients., Conclusion: Type 2 diabetes patients, newly referred to or allocated for long-term follow-up in the out-patient clinic, were mainly intermediate and high-risk, complicated patients (96% and 95 %, respectively). Compliance of stratification by endocrinologists was high. The concordance between endocrinologists' and objective assessments was not strong. Our data suggest that clinician-support for stratification level categorisation might be needed.

Aims: Sulphonylureas (SU) are currently recommended as a well-established second line treatment in guidelines for type 2 diabetes (T2DM). In the Capital Region of Denmark 16,865 patients were given SU as part of their treatment of T2DM in 2010-2011. To what extent SU are associated with hospitalizations due to severe hypoglycaemic episodes, defined as episodes with a need for external assistance, was investigated. The prevalence and characteristics of these patients and potential risk factors were studied., Methods: ICD-10 diagnosis codes were used to identify patients hospitalized due to hypoglycaemia and T2DM for a period of 2 years (2010-2011). Inclusion criteria were T2DM, hospitalization due to hypoglycaemia and treatment with SU as monotherapy or in combination with other glucose-lowering drugs except insulin treatment., Results: We identified 161 patients fulfilling the inclusion criteria. Their mean age was 76 (53-97) years and 54% were males. Sixty percent of the patients had diabetic complications, including 19% with diabetic nephropathy. The major reason for severe hypoglycaemia was an unchanged dose of SU despite of a significant decline in food intake (45%). In 22% of the patients more than one reason was listed, most commonly a concomitant infection associated with decreased food intake and unchanged dose of SU., Conclusion: The incidence of hospital admission-requiring severe hypoglycaemia in patients treated with SU was 0.48 episodes per 100 patient-years of SU-treated patients. It was mainly older patients with diminished food intake, excessive alcohol use or other medications, concomitant infection, and with diabetic complications., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Neutral Protamine Hagedorn insulin with an intermediate action profile has been in use for many years for the treatment of Type 1 diabetes and as an option for Type 2 diabetes. It is efficacious in reducing blood sugars, but shows substantial variability and risk of hypoglycemia. Basal insulin analogs have been developed in recent years to overcome these issues. Three basal insulin analogs are currently in the market in Europe. PEGylated insulin lispro is a new second-generation basal insulin analog which most likely will undergo review in 2016 by the US FDA and EMA in Europe for possible approval for marketing. Phase III trials are finalized, but not yet published. Phase II studies suggest antiglycemic efficacy, possible with a preferential hepato-specific action, a low rate of hypoglycemia, minor weight loss and acceptable tolerability. The benefit-risk profile needs, however, to be established.

The aims of this study were to investigate management routines of diabetic ketoacidosis (DKA) in adult patients in departments of internal medicine in Denmark and to relate current routines of treatment to available evidence. A questionnaire requesting information on management routines of DKA was sent to all departments of internal medicine in Denmark responsible of managing DKA. Fifty-nine departments (88%) returned the questionnaire and/or a copy of their management protocol. At 19 departments (32%), all patients with DKA were managed in an intensive care unit (ICU). Twenty-four different insulin regimens and 21 fluid protocols were identified. Routines of insulin therapy varied in terms of doses and routes of administration. Fifty-eight departments (97%) used isotonic saline for hydration. Potassium supplements were administered as a separate infusion of either isotonic potassium-sodium-chloride (83%) or isotonic potassium-chloride (10%). Recommended volumes to be administered during the first 8h of treatment varied significantly (median 4800ml, range 3750-7700ml). Use of bicarbonate was endorsed by 80%. This study shows significant variations in management routines of DKA in Denmark. In many cases, the treatment routines employed are not supported by evidence from clinical trials. We recommend implementation of national and/or European guidelines for management of DKA in adult patients.

The aim of this study was to estimate the incidence of diabetic ketoacidosis (DKA) and mortality from DKA using data from public health registries. We extracted information on 4807 admissions during the period 1996-2002 and 137 deaths during the period 1996-2000 with a diagnosis of DKA from the Danish National Patient Registry (NPR) and the Danish Cause of Death Registry (CDR) respectively. The annual incidence of DKA in the general population was estimated to 12.9 per 100,000. Overall mortality was 4%. Death from DKA was associated with increasing age and with somatic comorbidity.

This study examines variations in treatment routines for diabetic ketoacidosis (DKA) in Denmark. All departments of internal medicine in Denmark managing DKA were invited to complete a questionnaire. 88% replied. The study shows significant variations in management routines of DKA in Denmark. In many cases, the routines are not supported by evidence from clinical trials. National guidelines for the management of DKA in adult patients are needed.

Following the introduction of highly active antiretroviral therapy (HAART), a number of metabolic and morphologic alterations, known as HIV-associated lipodystrophy syndrome (HALS), have been increasingly common in HIV-infected patients being treated with this therapy. The use of protease inhibitors (PI), in particular, has been associated with insulin resistance and hyperglycaemia, but only infrequently with diabetic ketoacidosis. We report a case of diabetic ketoacidosis in an HIV-infected woman after 1(1/2) years of a PI-containing regimen, demonstrating reduced beta cell function and insulin resistance.

Objective: To explore the role of tissue plasminogen activator (tPA) activity and plasminogen activator inhibitor type 1 (PAI-1) in survivors of a first myocardial infarction (MI). Insulin and proinsulin were analysed as potential risk factors., Design: Case-control study in northern Sweden., Subjects: A total of 115 patients under 65 years of age with a first MI were enrolled and recalled for further examination 3 months later. Twenty-seven patients were excluded, 17 with known diabetes and 10 who did not come to the follow-up, giving a final number of 88 patients, 73 men and 15 women. Patients were age- and sex-matched with control subjects drawn from the local cohort in the MONICA population survey 1994., Main Outcome Measures: We compared MI patients and controls using univariate and multiple regression analyses including odds ratios (OR)., Results: PAI-1 activity, fibrinogen, postload insulin and -proinsulin were significantly higher and tPA activity significantly lower in MI patients in the univariate analysis. In a multiple regression analysis, including also age, sex and cardiovascular risk factors, these parameters were divided in quartiles. The lowest quartile of tPA activity was significantly associated with MI (OR = 19.1; CI 3.0-123) together with the highest quartiles of fibrinogen (OR = 25; CI 5.2-120) but other variables were not., Conclusion: Low tPA activity, i.e. low fibrinolytic activity, characterized nondiabetic subjects after a first MI which is not explained by concomitant disturbances in metabolic and anthropometric variables.

Disproportionate hyperproinsulinemia is a feature of beta-cell dysfunction in type 2 diabetes. It has been hypothesized that this abnormality represents an intrinsic abnormality of the beta-cell and/or may result from an increase in beta-cell secretory demand. To address this, six patients with type 2 diabetes and six age- and BMI-matched normal subjects received a combined 3-h insulin and somatostatin clamp to decrease beta-cell secretory demand. An arginine stimulation test was performed before and at the end of the clamp to measure beta-cell peptide release. In keeping with the reduction in secretory demand, C-peptide levels were suppressed by 60-80% during the clamp, as were proinsulin (PI) levels. The arginine-stimulated PI/C-peptide ratio decreased in the diabetic subjects from 4.4 +/- 1.5% before to 1.8 +/- 0.5% after the clamp (P < 0.01). This latter ratio was similar to that observed in the normal subjects before the somatostatin infusion (1.5 +/- 0.3%). In the normal subjects, after the clamp the PI/C-peptide ratio had decreased to 0.8 +/- 0.3% (P <0.01). Thus, the postclamp PI/C-peptide ratio in the subjects with type 2 diabetes was elevated compared with that in the normal subjects (P <0.05). Based on these observations, while relief of secretory demand on beta-cells by somatostatin decreases the disproportionate elevation in PI levels in patients with type 2 diabetes, the failure to normalize this measure suggests that an intrinsic abnormality of beta-cell function exists in subjects with type 2 diabetes that may be aggravated by increased secretory demand.

Type 2 diabetes mellitus is associated with insulin resistance, reduced B cell function, and an increase in the proinsulin (PI) to immunoreactive insulin (IRI) ratio (PI/IRI); the latter is thought to be an indication of B cell dysfunction. Normal aging is associated with insulin resistance and reduced B cell function, but it is not known whether changes in PI and the PI/IRI ratio are also a feature of the aging-associated B cell dysfunction. Therefore, we tested whether the aging-associated changes in insulin sensitivity and B cell function result in changes in PI and IRI levels that are proportionate or whether they are disproportionate as in type 2 diabetes. Twenty-six healthy older (mean +/- SEM age, 67 +/- 1 yr) and 22 younger (28 +/- 1 yr) subjects with similar body mass indexes (27.9 +/- 0.6 vs. 26.3 +/- 1.0 kg/m2) were studied. PI was measured by a RIA recognizing both intact PI and its conversion intermediates. The insulin sensitivity index (SI) was quantified using the minimal model, and B cell function was measured as fasting insulin levels, the acute insulin response to glucose (AIRglucose), and as the acute insulin response to arginine at maximal glycemic potentiation (AIRmax). B cell function was also adjusted for SI based on the known hyperbolic relationship between these two variables. Older and younger subjects had similar fasting glucose (5.3 +/- 0.1 vs. 5.2 +/- 0.1 mmol/L), IRI (83 +/- 8 vs. 76 +/- 9 pmol/L), PI (8.9 +/- 0.8 vs. 10.6 +/- 2.0 pmol/L), and PI/IRI ratio (12.3 +/- 1.3% vs. 13.9 +/- 1.6%; all P = NS) despite a 50% reduction of insulin sensitivity (SI, 1.94 +/- 0.21 vs. 3.88 +/- 0.38 x 10(-5) min(-1)/pmol x L; P < 0.001) and in B cell function [SI x fasting IRI, 139 +/- 18 vs. 244 +/- 24 x 10(-5)(P < 0.001); SI x AIRglucose, 0.75 +/- 0.13 vs. 1.70 +/- 0.15 x 10(-2) min(-1) (P < 0.001); SI x AIRmax, 3.63 +/- 0.53 vs. 6.81 +/- 0.70 x 10(-2) min(-1) (P < 0.001)] in the older subjects. These findings suggest that the B cell dysfunction in older subjects is not associated with disproportionate proinsulinemia. However, in older subjects the B cell response to the insulin resistance of aging is reduced whether measured as fasting levels of PI or IRI or as the acute response to secretagogues. Thus, when examined in terms of the degree of insulin sensitivity, the lower fasting IRI levels in older subjects suggest that the utility of fasting insulin levels as a surrogate measure of insulin resistance in older individuals may be limited.

Objective: Type 2 diabetes is a heterogeneous disease in which both beta-cell dysfunction and insulin resistance are pathogenetic factors. Disproportionate hyperproinsulinemia (elevated proinsulin/insulin) is another abnormality in type 2 diabetes whose mechanism is unknown. Increased demand due to obesity and/or insulin resistance may result in secretion of immature beta-cell granules with a higher content of intact proinsulin., Research Design and Methods: We investigated the impact of obesity on beta-cell secretion in normal subjects and in type 2 diabetic patients by measuring intact proinsulin, total proinsulin immunoreactivity (PIM), intact insulin, and C-peptide (by radioimmunoassay) by specific enzyme-linked immunosorbent assays in the fasting state and during a 120-min glucagon (1 mg i.v.) stimulation test. Lean (BMI 23.5 +/- 0.3 kg/m2) (LD) and obese (30.1 +/- 0.4 kg/m2) (OD) type 2 diabetic patients matched for fasting glucose (10.2 +/- 0.6 vs. 10.3 +/- 0.4 mmol/l) were compared with age- and BMI-matched lean (22.4 +/- 0.6 kg/m2) (LC) and obese (30.8 +/- 0.9 kg/m2) (OC) normal control subjects., Results: Diabetic patients (LD vs. LC and OD vs. OC) had elevated fasting levels of intact proinsulin 6.6 +/- 1.0 vs. 1.6 +/- 0.3 pmol/l and 7.7 +/- 2.0 vs. 1.2 +/- 0.2 pmol/l; PIM: 19.9 +/- 2.5 vs. 5.4 +/- 1.0 pmol/l and 29.6 +/- 6.1 vs. 6.1 +/- 0.9 pmol/l; and total PIM/intact insulin: 39 +/- 4 vs. 15 +/- 2% and 35 +/- 5 vs. 13 +/- 2%, all P < 0.01. After glucagon stimulation, PIM levels were disproportionately elevated (PIM/intact insulin based on area under the curve analysis) in diabetic patients (LD vs. LC and OD vs. OC): 32.6 +/- 6.7 vs. 9.2 +/- 1.1% and 22.7 +/- 5.2 vs. 9.1 +/- 1.1%, both P < 0.05. Intact insulin and C-peptide net responses were significantly reduced in type 2 diabetic patients, most pronounced in the lean group. The ratio of intact proinsulin to PIM was higher in diabetic patients after stimulation in both LD versus LC: 32 +/- 3 vs. 23 +/- 2%, and OD versus OC: 28 +/- 4 vs. 16 +/- 2%, both P < 0.01. In obese normal subjects, intact proinsulin/PIM was lower both in the fasting state and after glucagon stimulation: OC versus LC: 22 +/- 3 vs. 33 +/- 3% (fasting) and 16 +/- 2 vs. 23 +/- 2% (stimulated), both P < 0.05., Conclusions: Increased secretory demand from obesity-associated insulin resistance cannot explain elevated intact proinsulin and disproportionate hyperproinsulinemia in type 2 diabetes. This abnormality may be an integrated part of pancreatic beta-cell dysfunction in this disease.

An increased proportion of fasting proinsulin (PI) relative to immunoreactive insulin (IRI; increased PI/IRI) occurs in noninsulin-dependent diabetes mellitus (NIDDM). To determine whether the magnitude of the increase in PI/IRI is an indicator of the degree of reduced B cell secretory capacity, we measured fasting plasma glucose, PI, IRI, and PI/IRI and related them to maximal B cell secretory capacity (AIRmax) in 9 subjects with NIDDM [age, 61 +/- 3 yr; body mass index (BMI), 27.5 +/- 1.3 kg/m2; duration of NIDDM, 10.8 +/- 1.8 yr; mean +/- SEM] and in 10 healthy subjects matched for age and BMI (age, 61 +/- 6 yr; BMI, 27.9 +/- 1.5 kg/m2). AIRmax was quantified as the incremental insulin response to i.v. arginine at maximal glycemic potentiation (plasma glucose > 25 mmol/L). Mean fasting plasma glucose was 13.7 +/- 1.4 mmol/L (range, 7.5-18.3 mmol/L) in NIDDM subjects and 5.0 +/- 0.1 mmol/L in the controls. Fasting PI was higher in NIDDM (33.1 +/- 5.2) than in controls (9.4 +/- 2.5 pmol/L; P < 0.01), but IRI levels were similar (93.4 +/- 10.9 vs. 82.8 +/- 23.4 pmol/L; P = NS). The PI/IRI ratio was significantly elevated in NIDDM compared to control subjects (35.9 +/- 4.1% vs. 12.8 +/- 0.8%; P < 0.01). After elevation of the glucose level to 30.3 +/- 0.4 mmol/L (NIDDM) and 30.3 +/- 0.5 mmol/L (controls), AIRmax was quantified as 622 +/- 71 pmol/L in NIDDM and 1997 +/- 315 pmol/L in controls, (P < 0.001). The PI/IRI ratio correlated inversely with AIRmax in the NIDDM patients (r = -0.76; P < 0.01). We conclude that the magnitude of the elevation in fasting PI/IRI is related to the reduction in AIRmax. Thus, the fasting PI/IRI ratio appears to be a marker of the degree of reduced AIRmax in NIDDM.

Objective: To follow proinsulin immunoreactive material (PIM) in healthy siblings from the time of diagnosis of insulin-dependent diabetes mellitus (IDDM) in the proband, for at least 2 years., Design and Methods: The study comprised 148 siblings representing 112 families. The siblings were recruited from the nationwide 'Childhood Diabetes in Finland' study and tested for immunological markers. If a sibling was found positive for islet cell antibodies (ICA) or insulin autoantibodies (IAA), PIM sampling was extended beyond 2 years., Results: Of the 148 siblings, 12 developed IDDM 3-53 months after the diagnosis in the proband. Eleven of these siblings exhibited initially normal PIM concentrations. In nine siblings, samples were available both more than 6 months and during the last 6 months before the diagnosis of IDDM; PIM concentrations increased in seven, remained unchanged in one, and decreased in one in the period up to the diagnosis of IDDM (P < 0.05). Median PIM concentration did not change significantly during the examination period of 2 years in the 136 siblings who did not contract IDDM. Constantly increased PIM concentrations were found in 12 of the 136 siblings who did not develop IDDM. These 12 siblings were all ICA negative., Conclusion: In healthy siblings of IDDM patients exhibiting an initially low PIM concentration, an abrupt increase in PIM seems to precede the clinical manifestation of IDDM within 0-6 months. However, there were too few patients available to close follow-up to allow calculation of any predictive value of this increase. Persistently increased PIM concentrations were present in some healthy siblings who did not develop IDDM. The reason for that finding remains unclear, but it could be associated with previous B cell damage.

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.

Increased concentrations of proinsulin immunoreactive material (PIM) absolutely or relative to insulin is a characteristic finding in patients with non-insulin-dependent diabetes mellitus (NIDDM). The aim of this study was to test if 8 h or mild hyperglycemia (7-9 mmol/l) in healthy subjects could induce a preferential secretion of PIM from B cells. Serum concentrations of insulin, C-peptide and PIM were measured every 10 min during the 8 h of continuous glucose infusion in nine normal-weight healthy subjects without diabetes among their first-degree relatives. After a gradual rise in B-cell peptides, a steady state was reached. From 4 to 8 h no further difference in insulin, C-peptide or PIM concentration was found. Fasting PIM/C-peptide and PIM/insulin ratios of 0.5% and 2.3% increased during the glucose clamp to levels of 1.4% and 7.6%, respectively. Neither testing the regression slope nor comparing individual time points showed any significant difference for the PIM/C-peptide ratio from 2 to 8 h and for the PIM/insulin ratio from 3 to 8 h. These results do not support the hypothesis that an increased glucose drive per se results in an altered B-cell function with increasing PIM/C-peptide ratio. At least 8 h of mild hyperglycemia in healthy subjects does not progressively alter B-cell function.

Objective: To study the natural history of fasting proinsulin immunoreactivity (PIM) during the first 30 months of IDDM and its relationship to fasting C-peptide and insulin antibodies., Research Design and Methods: An incidence cohort of 204 consecutive newly diagnosed IDDM patients were followed prospectively, having blood drawn for measurements at diagnosis and at 1, 3, 6, 9, 12, 18, 24, and 30 months. A sensitive enzyme-linked immunosorbent assay was used for the determination of PIM., Results: All patients had detectable fasting PIM in plasma at diagnosis, with a median value and interquartile range of 3.5 pmol/l (2.2-6.2). The median PIM level increased during the first months of IDDM to reach a peak at 9-12 months (9.9-10.3 pmol/l). PIM then declined gradually to 5.6 pmol/l (1.9-13.5) at 30 months without reaching baseline. PIM at each time point was widely scattered in a skewed log-normal distribution without signs of bimodality. After the onset of insulin treatment, median insulin antibody level increased and declined in a similar pattern. Both PIM and antibody level were significantly higher in children and adolescents compared with adults. However, stepwise multiple regression analysis showed that age was only of minor importance for the PIM variation during the study period. Insulin antibody level and fasting C-peptide were the major determinants at 3-30 months, accounting for approximately 40% of the variation (R2). Blood glucose was of minor importance, and insulin dose, HbA1c, and BMI were of no importance. The correlation between fasting PIM and fasting C-peptide improved (R2 doubled) if the insulin antibody level was accounted for. Further, the slope of the correlation curve between PIM and C-peptide increased threefold when antibody binding was > 4%. At diagnosis, insulin autoantibodies could be detected in 19% of the patients. Their presence predicted higher proinsulin at 1-3 months, a higher insulin dose the 1st year, and higher levels of insulin antibodies later in the study., Conclusions: Circulating insulin antibodies may affect the level of PIM in IDDM, probably by adding a pool of IgG-bound PIM thereby increasing half-life and plasma concentration. This may explain why C-peptide and PIM levels do not change in concert during the 1st years of IDDM. Unlike C-peptide, PIM can not therefore quantitate beta-cell secretion unless the presence of insulin antibodies is ruled out.

Administration of exogenous insulin during an intravenous glucose tolerance test allows the use of the minimal model technique to determine the insulin sensitivity index in subjects with reduced endogenous insulin responses. To study the effect of different insulin administration protocols, we performed three intravenous glucose tolerance tests in each of seven obese subjects (age, 20-41 yr; body mass index, 30-43 kg/m2). Three different insulin administration protocols were used: a low-dose (0.025 U/kg) infusion given over 10 min, a low-dose (0.025 U/kg) bolus injection, and a high-dose (0.050 U/kg) bolus injection, resulting in peak insulin concentrations of 1,167 +/- 156, 3,014 +/- 483, and 6,596 +/- 547 pM, respectively. The mean insulin sensitivity index was 4.80 +/- 0.95 x 10(-5), 3.56 +/- 0.53 x 10(-5), and 2.42 +/- 0.40 x 10(-5) min-1/pM respectively (chi +/- SEM; P = 0.01). The association of higher peak insulin concentrations with lower measured insulin sensitivity values suggested the presence of a saturable process. Because results were not consistent with the known saturation characteristics of insulin action on tissue, a second saturable site involving the transport of insulin from plasma to interstitium was introduced, leading to a calculated Km of 807 +/- 165 pM for this site, a value near the 1/Kd of the insulin receptor. Thus, the kinetics of insulin action in humans in these studies is consistent with two saturable sites, and supports the hypothesis for transport of insulin to the interstitial space. Saturation may have an impact on minimal model results when high doses of exogenous insulin are given as a bolus, but can be minimized by infusing insulin at a low dose.

Objective: Abnormal glucose metabolism with impaired glucose tolerance has been documented in patients with thyrotoxicosis but the pathogenesis is not fully understood. Therefore, the aim of the present study was to study the beta-cell function and the meal induced oxidative glucose and lipid metabolism in patients with thyrotoxicosis., Design: After an overnight fast the impact of hyperthyroidism on standard mixed meal induced glucose oxidation, lipid oxidation and beta-cell function was studied., Patients: Nine untreated patients with Graves' disease were compared to 9 age and weight matched healthy controls., Measurements: Glucose and lipid oxidation were studied by indirect calorimetry before and after the meal. The insulin secretion rate was calculated by the 'combined model' approach, after which the insulin secretion rates and the ambient glucose levels were cross-correlated. The slope of these regression lines was used as a measure of beta-cell sensitivity to glucose and denotes the insulin secretory capacity. beta-Cell function was further evaluated by measurement of proinsulin and its conversion intermediates. Glucoregulatory hormones were also measured. The findings were correlated to the thyroid hormone levels., Results: Fasting blood glucose and post-prandial glucose response were increased in patients (P < 0.01). The hyperthyroid patients displayed a 'dual' beta-cell defect: (a) inability to increase the insulin response appropriately to hyperglycaemia and (b) increased proinsulin levels both in the fasting state and in response to a meal. Indirect calorimetry showed increased lipid oxidation in the fasting state and at the end of the meal (P < 0.01). No difference in glucose oxidation was demonstrated in the fasting state but the post-prandial glucose oxidation was enhanced in the patients (P < 0.01). The adrenaline response was normal, whereas the noradrenaline response was impaired or absent in the patients. The thyroid hormone levels were significantly correlated to fasting levels of blood glucose, insulin, free fatty acids and lipid oxidation, but not to fasting C-peptide, glucose oxidation or catecholamines., Conclusions: Untreated Graves' disease was associated with glucose intolerance due to quantitative as well as qualitative beta-cell defects. The lipid oxidation was increased in the fasting state and at the end of the meal; after the meal the increase in glucose oxidation was more pronounced in the patients. Thyroid hormones thus increased the oxidation but not by an increase in catecholamines. Indeed, the post-prandial sympathetic response was blunted.

Disproportionate elevation [increased proinsulin/insulin (PI/INS) ratio] of PI immunoreactivity is associated with noninsulin-dependent diabetes mellitus (NIDDM). The nature of this abnormality is not known. To address the question of whether genetic factors contribute to hyperproinsulinemia, we measured fasting levels of PI immunoreactivity, intact INS, and C peptide (CP) in 12 pairs of monozygotic twins discordant for NIDDM for a mean (+/- SEM) period of 9 +/- 3 yr. Thirteen age- and body mass index-matched healthy subjects without any family history of NIDDM acted as controls. The nondiabetic twins had levels of fasting INS, CP, PI, PI/CP, and PI/INS similar to those of control subjects. Fasting levels of PI, and PI/CP and PI/INS ratios were significantly 2- to 3-fold elevated in NIDDM twins compared to those in both nondiabetic twins and control subjects. To investigate whether hyperproinsulinemia in these NIDDM patients was due to a differential elevation of intact PI or conversion intermediates, we analyzed PI profiles in NIDDM twins and normal subjects by high pressure liquid chromatography. PI was heterogeneous and consisted mainly of des(31,32)-PI and intact PI in both NIDDM patients and normal subjects, with no major difference in composition between the groups. Small amounts of des(64,65)-PI (0-11%) were measured in some patients and normal subjects. The results suggest that hyperproinsulinemia is not a genetically determined trait per se in NIDDM. Disproportionately elevated PI levels seem to be related to the actual disease process. Further conversion of intact PI and des(31,32)-PI may be equally impaired in NIDDM.

Congenital muscle fiber type disproportion myopathy (CFTDM) is a chronic, nonprogressive muscle disorder characterized by universal muscle hypotrophy and growth retardation. Histomorphometric examination of muscle shows a preponderance of smaller than normal type 1 fibers and overall fiber size heterogeneity. Concomitant endocrine dysfunctions have not been described. We report the findings of altered insulin secretion and insulin action in two brothers affected with CFTDM and glucose intolerance as well as in their nonconsanguineous glucose-tolerant parents. Results are compared with those of six normoglycemic control subjects. All study participants underwent an oral glucose tolerance test to estimate insulin secretion. The oldest boy and his parents volunteered for studies of whole-body insulin sensitivity consisting of a 4-h euglycemic hyperinsulinemic clamp in combination with indirect calorimetry. Insulin receptor function and glycogen synthase (GS) activity and expression were examined in biopsies of vastus lateralis muscle. Despite a 45-90-fold increase in both fasting and postprandial serum insulin levels, both CFTDM patients had diabetes mellitus. Clamp studies revealed that the oldest boy had severe insulin resistance of both liver and peripheral tissues. The impaired insulin-stimulated glucose disposal to peripheral tissues was primarily due to reduced nonoxidative glucose metabolism. These changes were paralleled by reduced basal values of muscle GS total activity, allosterical activation of GS by glucose-6-phosphate, GS protein, and GS mRNA. The father expressed a lesser degree of insulin resistance, and studies of muscle insulin receptor function showed a severe impairment of receptor kinase activity. In conclusion, CFTDM is a novel form of severe hyperinsulinemia and insulin resistance. Whether insulin resistance is causally related to the muscle disorder awaits to be clarified.

The objective of this study was to test whether levels of proinsulin immunoreactivity (PIM) relative to those of insulin immunoreactivity (IRI) or C-peptide are changed and related to subclinical beta-cell dysfunction in siblings of insulin-dependent diabetes mellitus (IDDM) patients. Twenty-three siblings, previously found positive for islet cell antibodies and/or insulin autoantibodies, were divided into 2 groups according to their first phase insulin response (FPIR) to i.v. glucose tolerance tests (IVGTTs) sequentially performed during an observation period of 2 yr. Eleven siblings had diminished FPIR on at least 1 occasion (group 1), whereas 12 siblings had a normal FPIR on all occasions studied (group 2). All underwent a further IVGTT (0.5 g glucose/kg BW), and serum samples were taken at 0, 1, 3, 6, 10, 20, 30, 40, 50, and 60 min. The 2 groups had comparable median age, female/male ratio, weight, height, fasting blood glucose, immunoreactive insulin, C-peptide, and insulin autoantibodies levels, but group 1 had significantly higher islet cell antibodies levels. Fasting median PIM/IRI and PIM/C-peptide ratios were 2- to 3-fold higher in group 1 [10.5% (range, 1.8-93.8%) vs. 5.2% (range, 1.9-14.3%) and 3.3% (range, 0.4-23.1%) vs. 1.3% (range, 0.7-2.6%; P < 0.05]. Fasting PIM/C-peptide ratios correlated inversely with FPIRs (rs = -0.68; P < 0.01). During glucose stimulation, maximal responses of IRI and C-peptide were 4-fold lower in group 1, and the time of maximal responses of IRI and C-peptide occurred later in group 1 than in group 2. In contrast, no difference in maximal responses of PIM was found, but the time of maximal responses of PIM occurred later in group 1. Nine of 11 siblings in group 1 presented with IDDM 1-28 months after the test, compared to none in group 2. In group 1 a paradoxical inhibitory response of PIM was observed during the first 6 min of the IVGTT. These data indicate that fasting PIM/IRI and/or PIM/C-peptide ratio reflects subclinical beta-cell dysfunction in prediabetic subjects with evidence of immunological beta-cell assault and suggests that an elevated ratio may be an additional marker for later development of IDDM.

Objective: We studied glucose metabolism and insulin kinetics in cystic fibrosis patients with diabetic and normal glucose tolerance., Design: Measurements of blood glucose and serum free insulin concentrations during hyperinsulinaemic normoglycaemic clamp and post-clamp insulin decay, followed by the calculation of insulin sensitivity (M-value and M/I ratio), insulin clearance rate, serum half-life and apparent distribution space for insulin., Subjects: Cystic fibrosis patients, age range 20-29 years, with diabetes mellitus (n = 10) and normal glucose tolerance (n = 10), and 10 age-matched control subjects., Results: During the glucose clamp, diabetic cystic fibrosis patients needed less glucose than cystic fibrosis patients with normal glucose tolerance and control subjects (M-value), and steady-state serum insulin concentrations were lower in cystic fibrosis patients with diabetic and normal glucose tolerance than in control subjects. The quantity of glucose metabolized per unit of serum insulin concentration (M/I ratio) was similar in the three study groups (median approximately 145 (mumol/kg/min)/(nmol/l); range 70-252). Insulin clearance rates were higher in cystic fibrosis patients with diabetic (24.4 (19.3-29.9) ml/kg/min) and normal (22.6 (14.9-28.4) ml/kg/min) glucose tolerance than in control subjects (17.5 (15.9-24.2) ml/kg/min). Although insulin clearance rates were inversely related to body mass index (R(S) = -0.59, P < 0.001), the higher insulin clearance rates in CF patients cannot be accounted for solely by differences in body mass index since the insulin clearance rates were similarly increased in patients with body mass index above and below 20 kg/m2 (22.7 (14.9-28.4) and 24.4 (19.3-29.9) ml/kg/min, respectively). Serum half-lives for insulin were shorter in cystic fibrosis patients (approximately 4.3 (3.2-7.2) min) than in control subjects (5.9 (3.8-12.5) min), whereas the apparent distribution spaces for insulin were similar in the three study groups (approximately 150 (88-391) ml/kg)., Conclusions: Insulin sensitivity, calculated as the quantity of glucose metabolized per kg body weight per unit of serum insulin concentration, is normal in cystic fibrosis patients with normal glucose tolerance and with well controlled diabetes mellitus. The insulin clearance rate is increased in cystic fibrosis patients with diabetic and normal glucose tolerance, owing to a shorter serum half-life of insulin, whereas the apparent distribution space for insulin is normal.

A highly sensitive two-site sandwich ELISA measuring total proinsulin immunoreactive material in serum or plasma was developed. The assay was based on two monoclonal antibodies, an anti-C-peptide antibody bound to a microtest plate and a biotin-labeled anti-insulin antibody. The detection limit (3 SD above zero value) in buffer was 0.05 pmol/L, corresponding to 0.25 pmol/L in human serum (diluted 1:5). The linear calibrator range was 0.05-20 pmol/L. Interassay CVs were 4.7% at a median (range) of 2.3 pmol/L (1.4-2.8 pmol/L, n = 8), 6.7% at 5.1 pmol/L (3.3-8.0 pmol/L, n = 8), and 8.7% at 10.0 pmol/L (8-12 pmol/L, n = 10). Mean analytical recovery of added human proinsulin (hPI) (2, 5, and 10 pmol/L) to serum was 84% (range 68-128%, n = 9). Human insulin and human C-peptide did not cross-react at 5000 and 10,000 pmol/L, respectively. The four major proinsulin conversion intermediates reacted 65-99%: split(32-33)hPI 74%, des-(31,32)hPI 65%, split(65-66)hPI 78%, and des(64,65)hPI 99%. All serum values from 38 fasting healthy subjects were above the detection limit: median (range) 4.0 (2.1-12.6) pmol/L.

We describe an enzyme-linked two-site immunoassay for quantitation of intact insulin in human serum and plasma. The method uses two murine monoclonal antibodies that bind to two different epitopes on the insulin molecule. The immunoassay is specific. Human proinsulin is not bound by the antibodies, and the binding of partially processed proinsulin intermediates is believed to be of minor clinical importance. The relative response of human, bovine, and porcine insulin is 1, 1, and 3, respectively. The assay is sensitive (detection limit 5 pmol/L), accurate (101% recovery with 50 pmol/L insulin added to samples, 95% with 100 pmol/L, and 89% with 300 pmol/L), and fast (results within 3 h), and has a high analytical capacity (done in microtiter plates). The working assay range selected is 5-600 pmol/L, corresponding to a clinically useful range. Because of its specificity, this two-site immunoassay gives results that are lower than those obtained by using a competitive radioimmunoassay, both in normal individuals and in non-insulin-dependent diabetics.

Pancreatic and gut hormone responses to oral glucose, and insulin sensitivity were studied in cystic fibrosis patients with normal (N = 14), impaired (N = 4), and diabetic (N = 12) glucose tolerance, and in 10 control subjects, and beta cell responses to oral glucose and intravenous glucagon were compared. Compared to control subjects, initial insulin and C-peptide responses to oral glucose were lower in all patient groups, and decreased with decreasing glucose tolerance. Insulin sensitivity in patients with impaired and diabetic glucose tolerance was lower than in control subjects. The 6 min post-glucagon C-peptide concentration was positively correlated with the initial insulin response to oral glucose. Fasting levels of pancreatic polypeptide, pancreatic glucagon, total glucagon, glucagon-like peptide-1 7-36 amide, and gastric inhibitory polypeptide were normal in all patient groups. Following oral glucose, pancreatic polypeptide responses were absent in all patients, suppressibility of pancreatic glucagon secretion was increasingly impaired with decreasing glucose tolerance, and gut hormone levels were normal. In conclusion, at cystic fibrosis (a) insulin secretion is impaired even when glucose tolerance and insulin sensitivity are within the normal range, (b) the glucagon test gives valid estimates of residual beta cell function, (c) pancreatic polypeptide response to oral glucose is absent, (d) glucagon suppressibility decreases with decreasing glucose tolerance, and (e) the enteroinsular axis is intact.

Elevated fasting proinsulin immunoreactive material (PIM) has previously been found in patients with type 2 (non-insulin-dependent) diabetes mellitus. It is not known whether this is a genetic trait or whether it is related to the manifestation of type 2 diabetes. Neither is it clear whether the raised fasting insulin immunoreactivity previously observed in first-degree relatives of patients with type 2 diabetes is due to raised PIM. Furthermore, it has not been investigated whether first-degree relatives have altered PIM responses to different secretagogues. To study this, PIM, insulin and C-peptide were measured in patients with type 2 diabetes, in their first-degree relatives and in healthy control subjects in the fasting state and in relatives and controls during a hyperglycemic clamp. At the end of the hyperglycemic clamp, 0.5 mg of glucagon was given intravenously to stress the beta cells further. Fasting PIM concentrations were significantly higher in patients with type 2 diabetes (P < 0.05). These patients did not have significantly elevated fasting insulin levels when corrected for PIM. In the relatives, fasting insulin concentrations were elevated but PIM levels were normal suggesting that the increase in fasting insulin concentrations reflected an increase in true insulin. The incremental PIM, insulin and C-peptide responses to glucose and glucagon in the relatives were not different from those in the controls. We conclude that elevated fasting PIM levels in patients with type 2 diabetes seem not to be a genetic trait.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperglycemia, hyperinsulinemia, and insulin resistance cause vascular disease in type 2 diabetes mellitus. Dietary treatment alone often fails and oral drugs or insulin enhance hyperinsulinemia. In previous studies, an intravenous bolus of recombinant human insulin-like growth factor-I (rhIGF-I) caused normoglycemia in insulin-resistant diabetics whereas rhIGF-I infusions lowered insulin and lipid levels in healthy humans, suggesting that rhIGF-I is effective in insulin-resistant states. Thus, eight type 2 diabetics on a diet received on five treatment days subcutaneous rhIGF-I (2 x 120 micrograms/kg) after five control days. Fasting and postprandial glucose, insulin, C-peptide, proinsulin, glucagon, triglyceride, insulin-like growth factor-I and -II, and growth hormone levels were determined. RhIGF-I administration increased total IGF-I serum levels 5.3-fold above control. During the control period mean (+/- SD) fasting glucose, insulin, C-peptide, and total triglyceride levels were 11.0 +/- 4.3 mmol/liter, 108 +/- 50 pmol/liter, 793 +/- 250 pmol/liter, and 3.1 +/- 2.7 mmol/liter, respectively, and decreased during treatment to a nadir of 6.6 +/- 2.5 mmol/liter, 47 +/- 18 pmol/liter, 311 +/- 165 pmol/liter, and 1.6 +/- 0.8 mmol/liter (P < 0.01), respectively. Postprandial areas under the glucose, insulin, and C-peptide curve decreased to 77 +/- 13 (P < 0.02), 52 +/- 11, and 60 +/- 9% (P < 0.01) of control, respectively. RhIGF-I decreased the proinsulin/insulin ratio whereas glucagon levels remained unchanged. The magnitude of the effects of rhIGF-I correlated with the respective control levels. Since rhIGF-I appears to improve insulin sensitivity directly and/or indirectly, it may become an interesting tool in type 2 diabetes and other states associated with insulin resistance.

Two reversed-phase high-performance liquid chromatographic (RP-HPLC) systems were developed for the separation of human insulin, proinsulin and the major proinsulin intermediates. The individual components were quantified using two enzyme-linked immunosorbent assays for insulin and proinsulin immunore-active material (PIM) after (passive) evaporation of the organic modifier. Serum samples from normal subjects and patients with non-insulin-dependent diabetes mellitus were immunopurified and analysed in one of the RP-HPLC systems. The proportion of PIM relative to insulin immunoreactive material was higher in the diabetic patient compared with that in the normal subject. In both, PIM was heterogeneous, consisting of intact proinsulin and des-proinsulin intermediates.