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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.

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.

Recently, low-carbohydrate diets have increased in popularity as a method to achieve glycaemic control and weight loss in Type 2 diabetes patients. However, there is a lack of consistency and long-term results in existing studies on patients with Type 2 diabetes. In this review, we address current knowledge of low-carbohydrate diets and how they affect glycaemic control, diabetic dyslipidaemia, weight and markers of cardiovascular risk, and our aim is to aid medical practitioners in guiding patients with Type 2 diabetes who wish to try a low-carbohydrate diet in order to take control of their disease.

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.

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.

A Cochrane analysis concluded that glucagon-like peptide-1 (GLP-1) analogues were effective for the improvement of glycaemic control in patients with type 2 diabetes. What is the significance for the treatment of Danish patients with type 2 diabetes? In Denmark, two drugs exist, exenatid and liraglutid, and they both reduce HbA1c with approx. 1%. Compared with sulfonylurea and insulin, the advantage of GLP-1 analogues is not only that they rarely induce hypoglycaemia, but also that body weight is reduced. On the other hand, no long-term results exist with regard to impact on the cardiovascular system, and no complete overview of possible side effects has been presented either.

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.

An obesity epidemic has spread all over the world during the past 30-40 years. Persons becoming viscerally obese have a large risk of developing dysmetabolism characterised by ectopic fat accumulation resulting in increased triglyceride content and reduced HDL-cholesterol in the blood, arterial hypertension and type 2 diabetes. Today, this phenotype is designated metabolic syndrome (MS). The International Diabetes Federation (IDF) has presented an operational definition making it possible to intervene against the basal components of the syndrome early in the course of the syndrome in order to reduce its serious consequences in terms of increased morbidity and mortality.

The aim was to estimate and illustrate the weight history of 1,320 newly diagnosed diabetic patients according to patient characteristics at diagnosis. The median recalled weight gain from age 20 to diabetes diagnosis at a median age of 65.3 years was 14.7 kg. The average weight gain from 10 years prior to diabetes diagnosis until diagnosis, however, was only 1 kg and varied with e.g. age, sex, diagnostic plasma glucose, and presence of diabetic retinopathy. The findings contribute to the evidence basis of general practitioners' weight advice both before and after diabetes diagnosis.

We monitored changes in patients' weight during the first 5 years after diabetes diagnosis. Data were from 711 newly diagnosed diabetic patients aged 40 or over managed in general practice. Patients whose only treatment was advice on diet generally maintained an initial weight loss of 5-7 kg over the 5 years. Patients receiving metformin or sulfonylureas maintained an average weight loss of 2-4 kg depending on age and sex, while an acceptable average glycaemic control was achieved. The results indicate that weight reduction is a practicable treatment in diabetic patients.

World wide the prevalence of type 2 diabetes is increasing and 30-50% of patients are undiagnosed. Early detection and intervention may decrease the risk of late diabetic complications, and thus clear guidelines for early detection and diagnosis of type 2 diabetes are needed. We recommend those individuals with either previous gestational diabetes; obesity (BMI > 30 kg/m2) and/or two or more relatives with diabetes should be considered eligible for testing for diabetes. In order to make the diagnosis two diabetic glucose values on separate days are required. The diagnosis may be made using plasma glucose or capillary whole blood, but quality control measures are essential for glucose measurements in general practice as well as in departments of clinical biochemistry.

Insulin resistance is an important issue in the understanding of the metabolic syndrome. Clinical insulin resistance is usually defined by reduced insulin-mediated uptake of glucose in skeletal muscle. However, new studies have shown that liver and fat cells may also develop insulin resistance in subjects with the metabolic syndrome, specifically when these subjects are hyperglycaemic. New investigations also indicate that the endothelial cell itself can be insulin-resistant, reduced blood flow and increased peripheral resistance as the outcome. Insulin resistance may not only induce hyperglycaemia, but also dyslipidaemia (increased plasma levels of free fatty acids and triglyceride, and reduced plasma HDL levels) and arterial hypertension. All these variables may provoke arteriosclerosis and ischaemic heart disease. Specifically, abdominal adiposity seems to be responsible for insulin resistance in subjects with the metabolic syndrome. The mechanism could be intracellular accumulation of acyl CoA and triglyceride. However, an increased production of peptides from the adipose tissue, such as TNF alpha and reduced production of adiponectine may also play a role. The mechanism by which FFA and triglyceride, together with the peptides mentioned, may induce insulin resistance at a cellular level, resulting in reduced glucose transport and intracellular glucose processing, is still being discussed. A change in the insulin signalling cascade is one possibility, but the results so far have been contradictory. Another possibility is, of course, that the cellular accumulation of acyl CoA itself intervenes with gene expression and with phosphorylation of proteins.

Introduction: Interventions against osteoporosis may reduce the incidence of fractures in patients and costs to society, but they also incur additional expenditure and thus call for economic evaluation. The aim of this paper was to evaluate existing literature by applying cost-effectiveness (CEA) and cost-utility analyses (CUA) to pharmacological treatment of osteoporosis., Material and Methods: MEDLINE and the reference lists of relevant papers were searched to identify original papers on the subject. Studies were included if they were peer reviewed, written in English or a Scandinavian language, and reported CEA or CUA for a specified pharmacological intervention., Results: Of the 37 identified studies, 16 met the inclusion criteria (ten CUA and six CEA), and 21 studies were excluded. Of the studies examined, 13 studies concerned hormone replacement therapy (HRT), four bisphosphonate, four calcitonin, and four calcium supplementation and/or vitamin D treatment. All were based on simulations of the long-term effects of the intervention with respect to cost and effect. However, the studies varied widely in patient selection and assumptions about duration and effectiveness of intervention, assessment of quality of life, and mortality following hip fracture., Discussion: The published studies rely on limited empirical data as regards the effect of treatment, costs, and adverse effects. Several, however, indicate that some interventions may be cost-effective in high-risk groups.

In a prospective, controlled, comprehensive cohort trial of 2,016 healthy early postmenopausal women aged 45-58 years we studied fracture prevention through the use of oestrogen. There were two main study arms: a randomised arm (randomised to HRT [n = 502] or not [n = 504]) and a non-randomised arm (on HRT [n = 221] or not [n = 789] by own choice). After five years, an intention-to-treat analysis (n = 2,016) showed a reduction in the overall fracture risk (RR = 0.73, 95% CI: 0.50-1.05) and in the forearm fracture risk (RR = 0.45, 95% CI: 0.22-0.90) with oestrogen. Restriction of the analysis to women who had adhered to their initial allocation of either oestrogen (n = 395) or no oestrogen (n = 977) showed a significant reduction in both the overall fracture risk (RR = 0.61, 95% CI: 0.39-0.97) and the risk of forearm fractures (RR = 0.24, 95% CI: 0.09-0.69). We conclude that it is possible to reduce the number of forearm fractures in early postmenopausal women by the use of oestrogen as primary prevention.

Introduction: We assessed the effect of a multifaceted intervention directed at general practitioners to improve type 2 diabetes care., Materials and Methods: Three hundred and eleven Danish practices with 474 general practitioners were randomised to structured personal care (intervention group) or routine care (comparison group). Of 970 surviving patients (aged 40+ years) diagnosed with diabetes in 1989-1991, 874 (90.1%) were assessed after 6 years. Intervention comprised regular follow-up and individualized goal-setting, supported by reminders to doctors, clinical guidelines, feed-back, and continuing medical education., Results: Predefined non-fatal outcomes and mortality were the same in both groups. The following risk factor levels were lower in the intervention patients than in the comparison patients: fasting plasma glucose (7.9 vs 8.7 mmol/l, medians, P = 0.0007), haemoglobin A1c (8.5 vs 9.0%, P < 0.0001, normal range 5.4-7.4%), systolic blood pressure (145 vs 150 mmHg, P = 0.0004), and cholesterols (6.0 vs 6.1 mmol/l, P = 0.029, baseline-adjusted). Both groups had sustained a weight loss since diagnosis (2.6 vs 2.0 kg). Metformin was the only drug used more frequently in the intervention group (24 vs 15%). Intervention doctors arranged more follow-up consultations, referred fewer patients to diabetes clinics, and were more optimistic in their goal-setting., Discussion: In primary care, individualized goal-setting with educational and surveillance support may for at least six years bring risk factors of patients with type 2 diabetes to a level that in other trials has been shown to reduce diabetic complications, but without adverse weight gain.

Two members of the group, thiazolidinediones, have been approved for the treatment of type 2 diabetes mellitus. These novel oral antihyperglycaemic agents reduce insulin resistance through binding to and activation of the nuclear receptor, PPAR gamma, with subsequent effects on the glucose and lipid homoeostasis. The compounds will probably exhibit beneficial effects on other facets of the metabolic syndrome. Their effectiveness on glycaemic control appears comparable, as assessed by the literature available. HbA1c is lowered by 1.0 to 1.5%. Both drugs are approved for combination therapy with either metformin or sulphonylureas, not as monotherapy or in combination with insulin. Disturbed heart function (NYHA I-IV) is a contra-indication. In contrast to troglitazone, there is so far no evidence of liver toxicity. In spite of the limited literature, it is anticipated that the present class of oral hypoglycaemic agents will turn out to be an important contribution to improving the metabolic control of patients with type 2 diabetes, if the safety profile remains unchanged in long-term studies.

In Denmark, gestational diabetes mellitus (GDM) develops in about 2% of all pregnant women. The discussion of GDM is complicated by lack of consensus regarding screening methods, diagnosis and treatment. Observational studies indicate that untreated GDM is associated with an increased risk of maternal and perinatal morbidity, and that the offspring of GDM mothers tend to be at increased risk of developing diabetes and adiposity as a result of an abnormal intrauterine environment. Several follow-up studies have shown that women with previous GDM run a considerable risk of developing diabetes (especially type 2 diabetes) later in life. Intervention strategies for this high risk group are suggested.

Previous studies have demonstrated an association between low weight at birth and risk of later development of non-insulin dependent diabetes mellitus (NIDDM). It is unknown whether this association may be due to an impact of intrauterine malnutrition per se, or whether it may be due to a coincidence between the putative "NIDDM susceptibility genotype" and a genetically determined low weight at birth. We traced original midwife birthweight record determinations in a group of monozygotic (n = 14 pairs) and dizygotic (n = 14 pairs) twins who phenotypically appeared discordant for NIDDM at a mean age of 67 and 64 years respectively. Birthweights were lower in the NIDDM twins compared with both their identical and non-identical non-diabetic co-twins respectively (p < 0.02 both). Using a similar approach in twin pairs discordant for impaired glucose tolerance (IGT) per se, no significantly decreased birthweight was detected in the IGT twins compared with their non-diabetic co-twins. However, when a larger group of twins with different glucose tolerances were considered, birthweights were lower in twins with abnormal glucose tolerance including both NIDDM and IGT. Furthermore, the twins with the lowest birthweights among the two co-twins had the highest plasma glucose concentrations 120 min after the 75 g oral glucose load (n = 86 pairs, p = 0.02). The study supports the hypothesis that low birthweight and a non-genetically determined intrauterine component such af malnutrition may play a role for the development of NIDDM in twins.

In order to be able to study the aetiology and pathogenesis of diseases with manifestation in childhood and youth a Danish register of young twins has been established. The compilation of the register is based on the Danish Civil Registration System, with the Danish Vital Statistics as source of validation. All twins were sent a one side questionnaire asking about diabetes, willingness to participate in other projects and pairwise similarity in the twins. Comprising 20,888 twin pairs the register covers 74.4% of all twin pairs born 1953-67 (incl.) and 97.4% of those born 1968-82 (incl.). The response rate of the questionnaire study was 92.3%. The responders represented 19 180 twin pairs. Ninety-six percent of the respondent twins declared their willingness to participate in additional studies. An analysis of trends in the twinning rates for the years 1968-82 showed that the rate in monozygotic twinning is increasing and the twinning rate of opposite-sexed twin pairs is decreasing, thus confirming earlier estimated trends in twinning rates. This register provides a valuable resource for future twin studies.

The impact on glycaemic control of soluble insulin injected either intramuscularly into the thigh (IMT), subcutaneously into the abdominal wall (SCA) or subcutaneously into the thigh (SCT) was evaluated in 49 Type 1 diabetic outpatients following a randomised three-month intervention study. Insulin doses were adjusted based on patients' self-monitored blood glucose values and reported hypoglycaemic episodes. More patients in the SCA and IMT groups than in the SCT group had serum fructosamine values within normal limits following intervention. Blood glucose at 03.00 was lower in the SCT group than in the SCA and IMT groups, due to a higher number of low nocturnal blood glucose values (less than 4 mmol/l) in the SCT group. In conclusion, s.c. injection of soluble insulin into the abdominal wall or intramuscularly into the thigh is preferable compared to s.c. injection into the thigh in the basal bolus insulin delivery regimen. Soluble insulin injection s.c. into the thigh during daytime is a risk factor for nocturnal hypoglycaemia.

Diabetics have a higher prevalence of recurrent angina, myocardial infarction and hypertension compared with healthy individuals. This is partly due to the metabolic control, and partly to the development of nephropathy, but inherited factors also seem to contribute to their development. Another factor, to some extent inherited, could be magnesium-deficiency. Up to 30% of all diabetics suffer from magnesiumdepletion, which in other disease entities has been related to angina pectoris, myocardial infarction, and changes in blood lipids. Furthermore, magnesium-deficiency might be related to the development of hypertension. In diabetes, magnesium-depletion has been linked with the development of retinopathy, and an increase in abortions and malformations in diabetic pregnancies. No intervention trials with magnesium, to elucidate the question of magnesium depletion and diabetic late complications have hitherto been made. No methods for assessing magnesium-status in diabetes are available as yet, to select patients for this type of trial.

There are approximately 100,000 non-insulin-dependent diabetics in the Danish population and the incidence appears to be increasing. As the disease is complicated by a series of arteriosclerotic manifestations together with hypertension and eye changes, it presents great problems in the primary and also in the secondary sector. The Danish Association for Internal Medicine has, on this basis, prepared an explanatory report with the main object of establishing guidelines for treatment of the disease both medically and by organisation. The report contains a review of the patho-physiological conditions with emphasis on resistance to insulin and the basic cellular defect. The connections with arteriosclerosis and hypertension are also emphasized. The significance of the diet in the treatment of the condition is also emphasized as approximately 80% of the patients are overweight. Guidelines for treatment with sulphonurea, biguanides and insulin are presented. In order to provide optimal treatment and control of non-insulin-dependent diabetics and to provide them a better quality of life closer cooperation between general practitioners and diabetic clinics is recommended. In particular, it appears to be desirable to involve diabetic clinics at the commencement of the disease when the need for training is great.