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Introduction: In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM., Methods: The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle., Ethics and Dissemination: The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals., Trial Registration Number: NTR6134; Pre-results., Competing Interests: Competing interests: JHD sits on advisory boards for Novo Nordisk A/S. BWM is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). BWM reports consultancy for ObsEva, Merck KGaA and Guerbet., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Around 12% of pregnant women develop gestational diabetes mellitus (GDM), which is associated with increased health risks for both mother and child and pre- and postpartum depression. Little is known about the relationship of GDM with diabetes-specific emotional distress (diabetes distress). The aims of this study are to assess the prevalence of diabetes distress in GDM and its association with adverse pregnancy outcomes., Methods: A prospective cohort study was carried out in an Amsterdam based teaching hospital with an ethnic diverse population. Women diagnosed with GDM completed a set of questionnaires at three time points. Questionnaires consisted of Problem Areas in Diabetes Scale 5 (PAID-5) for diabetes distress (T0-T1), Patient Health Questionnaire 9 (PHQ-9) for depressive symptoms (T0-T2), and questions to assess adverse pregnancy outcomes (T2). Adverse pregnancy outcomes (collected via self-report and if feasible from the medical records) were defined as hypertension, pre-eclampsia, caesarean section, severe perineal tearing, postpartum hemorrhage, postpartum depression, shoulder dystocia, neonatal hospitalization, macrosomia, jaundice, hypoglycemia and other (among which low heart rate, fever, hypoxia). Adverse pregnancy outcomes were dichotomized into none and 1 or more. Additional information was collected from the medical charts. Missing data were imputed via predictive mean matching and a multivariable logistic regression analysis was performed with diabetes distress, depressive symptoms, socioeconomic status, parity and ethnicity as predictors and age, HbA1c, and BMI as covariates., Results: A total of 100 women were included, mean age 32.5 (4.1), mean BMI 26.7 (4.8), 71% were of non-Dutch ethnic background. Elevated diabetes distress (PAID score ≥ 8) was reported by 36% of the women. Multivariable logistic regression analyses revealed that both high diabetes distress (OR 4.70, p = .02) and parity (OR 0.21, p = .02) but not antepartum depressive symptoms were related to adverse pregnancy outcomes., Conclusions: Diabetes distress is likely in women with GDM and our findings suggest an association between both diabetes distress, parity and adverse pregnancy outcomes in women with GDM. This warrants replication and further research into the underlying mechanisms explaining the impact of diabetes distress in GDM and potential interventions to reduce distress.

Aim: Diabetes is associated with a high risk of adverse pregnancy outcomes. Optimal glycaemic control is fundamental and is traditionally monitored with self-measured glucose profiles and periodic HbA1c measurements. We investigated the effectiveness of additional use of retrospective continuous glucose monitoring (CGM) in diabetic pregnancies., Material and Methods: We performed a nationwide multicentre, open label, randomized, controlled trial to study pregnant women with type 1 or type 2 diabetes who were undergoing insulin therapy at gestational age < 16 weeks, or women who were undergoing insulin treatment for gestational diabetes at gestational age < 30 weeks. Women were randomly allocated (1:1) to intermittent use of retrospective CGM or to standard treatment. Glycaemic control was assessed by CGM for 5-7 days every 6 weeks in the CGM group, while self-monitoring of blood glucose and HbA1c measurements were applied in both groups. Primary outcome was macrosomia, defined as birth weight above the 90th percentile. Secondary outcomes were glycaemic control and maternal and neonatal complications., Results: Between July 2011 and September 2015, we randomized 300 pregnant women with type 1 (n = 109), type 2 (n = 82) or with gestational (n = 109) diabetes to either CGM (n = 147) or standard treatment (n = 153). The incidence of macrosomia was 31.0% in the CGM group and 28.4% in the standard treatment group (relative risk [RR], 1.06; 95% CI, 0.83-1.37). HbA1c levels were similar between treatment groups., Conclusions: In diabetic pregnancy, use of intermittent retrospective CGM did not reduce the risk of macrosomia. CGM provides detailed information concerning glycaemic fluctuations but, as a treatment strategy, does not translate into improved pregnancy outcome., (© 2018 John Wiley & Sons Ltd.)

The aim of the present study was to compare the effectiveness and safety of add-on treatment with dapagliflozin to placebo in patients with prednisone-induced hyperglycaemia during treatment for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We enrolled 46 patients hospitalized for an AECOPD in a multicentre double-blind randomized controlled study in which add-on treatment with dapagliflozin 10 mg was compared with placebo. Glycaemic control and incidence of hypoglycaemia were measured through a blinded subcutaneous continuous glucose monitoring device. Participants in the dapagliflozin group spent 54 ± 27.7% of the time in target range (3.9-10 mmol/L) and participants in the placebo group spent 53.6 ± 23.4% of the time in target range (P = .96). The mean glucose concentration was 10.1 mmol/L in the dapagliflozin group and 10.4 mmol/L in the placebo group (P = .66). One participant using dapagliflozin and 2 participants using placebo experienced symptomatic hypoglycaemia. Treatment with dapagliflozin was safe and there was no difference in risk of hypoglycaemia compared with placebo. Dapagliflozin did not result in better glycaemic control compared with placebo in participants with prednisone-induced hyperglycaemia during AECOPD., (© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective . To determine the association between ethnicity, diabetes-distress, and depressive and anxiety symptoms in adult outpatients with diabetes. Research Design and Methods . Diabetes-distress (Problem Areas in Diabetes Scale, PAID5), depressive and anxiety symptoms (Extended Kessler-10, EK10), and quality of life (Short-Form 12, SF12) were assessed in an ethnic diverse diabetes outpatient population of a teaching hospital in Amsterdam. Descent of one's parents and self-classified ethnicity were obtained to define ethnicity. HbA1c, clinical data, and socioeconomic status were derived from the medical charts. Based on established cut-offs for PAID5- and EK10-scores, emotional distress was dichotomized for the purpose of logistic regression analyses. Results . Of 1007 consecutive patients approached, 575 participated. Forty-nine percent were of non-Dutch ethnicity and 24.7% had type 1 diabetes. Diabetes-distress was reported by 12.5% of the native Dutch patients and by 22.0%, 34.5%, and 42.6% of the Surinamese, Turkish, and Moroccan patients, respectively. Prevalence of depressive symptoms was 9.4% in native Dutch patients and 20.4%, 34.5%, and 27.3% in the other groups mentioned. Diabetes-distress and Moroccan origin were significantly associated (OR = 3.60, p < .01) as well as depressive symptoms and Turkish origin (OR = 4.23, p = .04). Conclusions . Different ethnic minorities with diabetes vary in their vulnerability for emotional distress, warranting clinical attention. Future research should elucidate explanatory factors and opportunities for tailored interventions.

Secondary hyperparathyroidism is an almost inevitable complication of advanced kidney failure. The introduction of the calcimimetic cinacalcet for the treatment of secondary hyperparathyroidism in patients on dialysis was based on its ability to reduce elevated levels of parathyroid hormone (PTH). Subsequent clinical studies confirmed the beneficial effects of cinacalcet on biochemical parameters reflecting mineral disturbances and bone disease. In this review we summarise the impact of cinacalcet on biochemical, intermediate and clinical outcomes. We also present previously unpublished mineral metabolism data from 144 Dutch dialysis patients treated with cinacalcet who participated in the pan-European ECHO observational study. Although secondary hyperparathyroidism tended to be more severe in our Dutch cohort, compared with the entire ECHO cohort, cinacalcet was nevertheless effective in reducing PTH in these patients. Two recent clinical studies evaluated, respectively, the efficacy of cinacalcet in improving the intermediate endpoint of cardiovascular calcifications (ADVANCE trial), and its impact on clinical outcomes, including all-cause mortality and cardiovascular events (EVOLVE trial). The ADVANCE trial provided evidence that cinacalcet may indeed improve calcification in both large arteries and cardiac valves. The EVOLVE trial, however, did not meet its clinical primary endpoint (time to all-cause mortality, myocardial infarction, hospitalisation for unstable angina, heart failure or a peripheral vascular event), although secondary and sensitivity analysis suggested a beneficial effect. The clinical implications of these important studies are also addressed in this review.

Familial Mediterranean fever (FMF) is common among Turkish and Moroccan migrants. We describe three patients with FMF. A 3-year-old girl with recurrent fever and abdominal pain who was diagnosed early with FMF and treated effectively with colchicine. An adolescent girl who required interleukin (IL)-1 blockade to achieve disease remission. And a 37-year-old woman in whom the attacks of FMF had not been recognised, but who developed end-stage kidney failure due to AA amyloidosis. Mutations in the MEFV gene underlie the disease in most but not all patients. Therefore, FMF remains a clinical diagnosis. FMF patients suffer recurrent bouts of inflammation, often with fever, serositis or arthritis. The major complication is AA amyloidosis. The inflammatory process is mediated by IL-1β. When started early, colchicine prophylaxis can prevent amyloidosis. When colchicine fails, IL-1 blockade has shown promising results. Timely diagnosis and treatment can make the difference between near normal health and end-stage kidney failure.

Familial LCAT deficiency (FLD) is a recessive lipid disorder ultimately leading to end-stage renal disease (ESRD). We present two brothers with considerable variation in the age at which they developed ESRD. Kidney biopsies revealed both tubular and glomerular pathology. To date, no causal therapy is available, yet enzyme replacement therapy is in development.

Dialysis hypotension occurs frequently and is associated with increased morbidity, mortality, and may influence quality of life. We investigated the influence of blood volume (BV)-controlled ultrafiltration on hemodynamic stability and quality of life in a prospective multiple crossover study. Nineteen patients were consecutively treated with standard hemodialysis (HD), BV-controlled ultrafiltration, and again with standard ultrafiltration during 3-week phases, during which different hemodynamic parameters, ultrafiltrate quantities, dry weight, and quality of life were measured. Blood volume-controlled ultrafiltration resulted in increased hemodynamic stability: systolic blood pressure was significantly higher after treatment with BV-controlled HD compared with both standard treatments (p=0.018 and 0.043, respectively). Also, systolic blood pressure reduction, as a measure of blood pressure stability, was significantly smaller during the BV-controlled phase (-3.9 mmHg) compared with both standard phases (-13.7 and -11.0 mmHg): p=0.003 and 0.035, respectively. No difference was found in the occurrence of large decreases of blood pressure (>30 mmHg), decreases below 90 mmHg systolic pressure, or subjective complaints during treatment or after treatment between both treatment modalities. During the course of the study, the dry weight decreased significantly from mean 73.3 to mean 70.9 kg, and the amount of ultrafiltrate was significantly larger using BV-controlled HD compared with standard treatment (mean 2407 vs. mean 2266 mL; p=0.035). Quality of life, measured by visual analog scales (VAS), showed discrete but no consistent differences between study phases. We conclude that BV-controlled HD increases hemodynamic stability and ultrafiltrate amount compared with a standard treatment. No consistent change in quality of life is found between both treatment modalities.

Background and Purpose: Diabetes mellitus (DM) type 2 has been associated with poor cognitive performance and dementia, particularly in elderly patients. The exact mechanisms underlying the cognitive dysfunction in DM remain unclear. Imaging studies of the brain could be helpful to give more insight into possible structural brain lesions underlying these cognitive dysfunctions. Therefore, we performed a study in independently living patients with DM type 2 in order to investigate the association between DM and brain imaging abnormalities., Methods: The study population consisted of 45 patients with DM type 2 without hypertension (mean age 73.4 +/- 5.1 years, mean duration 16.5 +/- 11.5 years), 45 patients with DM type 2 and hypertension (mean age 73.5 +/- 6.1 years, mean duration 11.9 +/- 9.2 years) and 44 control subjects (mean age 73.1 +/- 5.4 years). All patients and control subjects underwent an MRI of the brain. White matter lesions (WML), cerebral atrophy and medial temporal lobe atrophy were rated by a standardized visual rating scale. Lacunar infarcts were defined as focal hypo-intensities on fluid-attenuated inversion recovery sequences with a hyperintense rim around it., Results: WML occurred more frequently in diabetic patients with hypertension as well as without hypertension. Significantly more deep WML were found in DM patients with and without hypertension when compared to control subjects, whereas no difference was found in the occurrence of periventricular hyperintensities. In all 3 groups, lacunar infarcts occurred sporadically. A trend towards higher atrophy scores was seen in patients with DM compared to control subjects., Conclusions: The data of this cross-sectional study suggest that type 2 DM is an independent risk factor for deep WML in the independently living elderly patients., (Copyright 2007 S. Karger AG, Basel.)

Background: The standard diagnostic approach in patients with suspected deep vein thrombosis is to repeat the compression ultrasonography after 1 week in all patients with an initial normal result. We hypothesized that a normal finding of a D-dimer assay safely obviates the need for repeated ultrasonography. In addition, we evaluated the potential value of a pretest probability assessment for this purpose., Methods: At presentation, consecutive outpatients with suspected thrombosis underwent independent assessment by means of ultrasonography of the proximal veins, a whole-blood D-dimer assay, and a pretest clinical model. Patients with normal ultrasonographic findings and an abnormal D-dimer assay result were scheduled for repeated ultrasonography. We evaluated the incidence of symptomatic venous thromboembolic complications during a 3-month follow-up, and the value of clinical pretest probability with ultrasonography or D-dimer assay in scenario analyses., Results: We studied 1756 patients with prevalence of thrombosis of 22%. At entry, results of the D-dimer assay and ultrasonography were normal in 828 patients (47%). Of these, 6 returned with confirmed symptomatic venous thromboembolism (complication rate, 0.7%; 95% confidence interval [CI], 0.3%-1.6%). Repeated ultrasonography was avoided in 61% of the patients with an initial normal test result. Scenario analyses disclosed that the complication rate was 1.6% (95% CI, 0.8%-2.6%) in those with a low clinical pretest probability and a normal result of ultrasonography at referral, whereas this figure was 1.8% (95% CI, 0.9%-3.3%) in patients with a low clinical probability result and a normal result of the D-dimer assay at referral., Conclusions: It is safe to withhold repeated ultrasonography in patients with suspected deep vein thrombosis who have normal results of ultrasonograpy and the SimpliRED D-dimer assay at presentation. The combination of a low clinical pretest probability with a normal result of compression ultrasonography or the D-dimer assay appears to be equally safe in refuting the diagnosis of deep vein thrombosis.

A patient with acute cardiorespiratory failure caused by hyperleukocytosis due to chronic lymphocytic leukaemia (CLL) is described. Although acute pulmonary failure due to leukostasis is a known and often postmortem finding in patients with acute myelocytic leukaemia (AML) or chronic myelocytic leukaemia (CML) in blastic crises, it is rare in CLL.

Obesity-associated hyperaminoacidemia is traditionally interpreted as a consequence of insulin resistance. We performed two different experiments to investigate the effects of both obesity-associated insulin resistance and the insulin resistance of non-insulin-dependent diabetes mellitus (NIDDM) on amino acid metabolism. In the first experiment, we measured postabsorptive amino acid concentrations and their decline in response to an oral carbohydrate load in 19 obese nondiabetic women and 19 normal-weight nondiabetic controls. Obese subjects were more resistant to insulin with respect to its effects on glucose metabolism than normal-weight controls, as calculated by the method described by Matthews. However, postabsorptive plasma concentrations of the so-called large neutral amino acids (LNAA), namely phenylalanine, tyrosine, valine, leucine, and isoleucine, and their decrease in response to carbohydrate consumption were similar in both groups. In the second experiment, we compared the decrease of plasma concentrations of LNAA during a euglycemic, hyperinsulinemic clamp in obese subjects with and without NIDDM. Peripheral glucose uptake (PGU) was more impaired in NIDDM subjects compared with obese controls. Furthermore, hepatic glucose production (HGP) was less attenuated by insulin infusion in NIDDM than in control subjects. Postabsorptive plasma LNAA concentrations were not different in the two groups. Values obtained in either group were not different from the postabsorptive concentrations in the normal-weight control subjects of experiment 1. All amino acid levels decreased substantially in response to insulin infusion. The magnitude of the decrease was not significantly different in the two groups, except for a slightly greater decrease of the plasma isoleucine concentration in obese control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

The cardiovascular risk factor plasminogen activator inhibitor type 1 (PAI-1) has been associated with abdominal obesity, hypertension, hypertriglyceridemia, hyperinsulinemia, glucose intolerance, and type II diabetes, conditions known to be linked with insulin resistance. To determine whether PAI-1 is related to insulin resistance, we studied nine obese nondiabetics and 10 obese type II diabetics by means of a sequential hyperinsulinemic euglycemic clamp study. Plasma PAI-1 antigen (Ag) correlated significantly with peripheral insulin resistance, represented by the insulin level at which peripheral glucose uptake (PGU) is half-maximal ([ED50PGU] r = .87, P < .001). Multiple regression analysis including indices of hepatic and peripheral insulin action, fasting plasma insulin levels, triglyceride levels, blood pressure (BP), waist to hip ratio (WHR), and body mass index (BMI) disclosed ED50PGU to account for 76% of the variance of PAI-1 Ag. We suggest that PAI-1 contributes to the increased cardiovascular risk encountered with insulin resistance.

Several studies have suggested that ACE-inhibition may be effective in postponing the onset of nephropathy in insulin-dependent diabetic subjects. In contrast, other drugs might have opposing effects. To study the long term effects of either captopril or nifedipine in normotensive, microalbuminuric patients with insulin-dependent diabetes mellitus, eighteen subjects received either placebo (n = 5, P), 20 mg nifedipine daily (n = 7, N) or 50 mg captopril daily (n = 6, C) for one year. Baseline clinical and laboratory variables were comparable in the three groups. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and blood pressure did not differ between groups before and after one years medication. UAER did not change in the captopril and the placebo group (C: -12.6% (-58.1 to 51.8%)' P: -17.3 (-55.9 to 99.3%), medians and ranges. In contrast, in the patients that received nifedipine, UAER rose by 43.1% (-8.5 to 261.8%), (p < 0.05 Baseline vs one year, and one year nifedipine vs captopril and placebo). We therefore conclude, that long-term use of nifedipine increases UAER in normotensive microalbuminuric insulin-dependent subjects, in contrast to captopril or placebo. Whether this enhancement of microalbuminuria exerts an adverse effect on renal function in the long-term is yet unknown, but caution seems warranted.

Insulin resistance contributes to the metabolic defects in non-insulin dependent diabetes mellitus (NIDDM). Anorectic agents have been shown to improve insulin action in NIDDM, irrespective of weight reduction. In a double-blind placebo-controlled cross-over study, we examined hepatic and peripheral insulin action by the sequential hyperinsulinaemic-euglycaemic clamp technique with infusion of 3-[3H]-glucose in eight obese NIDDM patients and in eight obese non-diabetics, matched for age, sex and body mass index. Body weight was kept constant. After 14 days of fluoxetine, 60 mg daily, in NIDDM half-maximal peripheral glucose uptake was achieved at a lower insulin level than after placebo (ED50pgu: 180.5 +/- 25.8 vs. 225.3 +/- 39.9 mU/l, P < 0.05), but not in non-diabetics (140 +/- 15.3 vs. 135.3 +/- 22.2 mU/l, n.s.). Maximal peripheral glucose uptake (Vmaxpgu) did not change significantly. Multivariate analysis disclosed no differences in the effect of fluoxetine between NIDDM and non-diabetics. When non-diabetics and NIDDM were considered together, only the most insulin-resistant individuals demonstrated a decrease in ED50pgu (P < 0.001). Likewise, only the individuals with the most outspoken hepatic insulin resistance demonstrated a decrease in insulin level, at which hepatic glucose production (HGP) is completely suppressed (HGP0) (P < 0.01). In conclusion, fluoxetine improves peripheral and hepatic insulin action in obese insulin-resistant subjects irrespective of its weight lowering effect.

Insulin resistance contributes to the metabolic defects in non-insulin-dependent diabetes mellitus (NIDDM). Anorectic agents have been shown to improve insulin action in NIDDM, irrespective of weight reduction. The serotonin-reuptake inhibiting agent fluoxetine has recently been recognized as an anorectic agent. The effect of fluoxetine on insulin action has not yet been determined. In a double blind placebo controlled crossover study, we examined hepatic and peripheral insulin action by the sequential hyperinsulinemic euglycemic clamp technique with infusion of 3-3H-glucose in eight obese NIDDM and in eight obese nondiabetics, matched for age, sex and body mass index. Body weight was kept constant. After 14 days of fluoxetine, 60 mg daily, in NIDDM half-maximal peripheral glucose uptake was achieved at a lower insulin level than after placebo (ED50pgu 180.5 +/- 25.8 vs 225.3 +/- 39.9 mU/l, P less than 0.05), but not in nondiabetics (140 +/- 15.3 vs 135.3 +/- 22.2 mU/l, n.s.). Maximal peripheral glucose uptake (Vmaxpgu) did not change significantly. Basal hepatic glucose production (HGP) was reduced after fluoxetine in both NIDDM (9.45 vs 10.37 mumol/kg/min) and in nondiabetics (8.57 vs 9.16 mumol/kg/min), although the difference was only significant in nondiabetics (P less than 0.05). Multivariate analysis disclosed no differences in the effect of fluoxetine between NIDDM and nondiabetics. When nondiabetics and NIDDM were considered together, only the most insulin-resistant individuals demonstrated a decrease in ED50pgu (P less than 0.001). Likewise, only the individuals with the most outspoken hepatic insulin resistance demonstrated a decrease in insulin level, at which hepatic glucose production is completely suppressed (HGP0) (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Thrombolytic therapy successfully reopens obstructed blood vessels in the majority of cases. However, it is not known why a substantial amount of thrombi are resistant to lysis by a fibrinolytic agent. In vitro studies have demonstrated that tissue-type plasminogen activator (t-PA) and plasminogen incorporated in the clot (during formation) increase lysibility. To test whether lysibility of in vivo formed human thrombi is related to their composition, we studied 25 venous thrombi obtained at autopsy and 21 arterial thrombi obtained during embolectomy. Plasminogen activator inhibitor-1 (PAI-1) antigen was measured in a phosphate-buffered saline (PBS) extract of each thrombus; t-PA antigen and plasminogen antigen were determined in a 6 M urea extract of the thrombus, representing bound proteins. Lysibility was measured as weight reduction during 8 h of incubation in PBS containing streptokinase (SK) 100 U/ml, corrected for spontaneous lysis, reflected by weight loss in PBS without SK. In addition, lysibility in SK was compared with lysibility in urokinase (UK) 100 U/ml and in t-PA 200 U/ml. Spontaneous lysis amounted to 29 +/- 5% (mean +/- SEM) and 33 +/- 5% in venous and arterial thrombi, respectively, and inversely correlated with the PAI-1 content of thrombi (r = -0.43, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Recently, we described a leprechaun patient with a genetically transmitted severe insulin resistance due to the absence of functional insulin receptors as inferred from the loss of insulin binding to the patients' fibroblasts and the impaired autophosphorylation of the beta-chain of the receptor. This patient was homozygous for the genetic defect which was recently found to be a leucine to proline mutation at position 233 in the alpha-chain of the insulin receptor. In the present study we have examined insulin receptor functions in relatives of this patient. Some of these individuals are heterozygous for the genetic defect and have only one allele coding for a functional insulin receptor. Insulin binding to cultured fibroblasts from the heterozygous individuals is only 20-40% of control values indicating a Mendelian mode of inheritance of the binding defect. In contrast, insulin stimulated autophosphorylation of the beta-chain of the insulin receptor shows normal values, indicating compensation mechanisms operating on this process. The stimulation of the basal level of 2-deoxyglucose uptake by insulin in fibroblasts from the homozygous patient is 1.2 fold whereas the heterozygous and control individuals show stimulation values of approximately 1.65 fold. Basal levels of 2-deoxyglucose uptake are similar in these fibroblasts. Oral glucose tolerance tests on the heterozygous individuals indicate an increased requirement for insulin of the target tissues as concluded from the tendency towards hyperinsulinaemia with no observed hyperglycaemia.(ABSTRACT TRUNCATED AT 250 WORDS)