Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and type 2 diabetes susceptibility.

AIMS: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic ß-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to type 2 diabetes in humans. METHODS: Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for type 2 diabetes susceptibility in up to 25 000 people (8148 with type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort. In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis. RESULTS: rs1800497 at the DRD2/ANKK1 locus was associated with a significantly increased risk for type 2 diabetes in women (odds ratio 1.14 (1.06-1.23); P = 4.1*104) but not in men (odds ratio 1.00 (95% CI 0.93-1.07); P = 0.92) or the combined group. Although rs1800497 was not associated with insulin secretion, we did find another single nucleotide polymorphism in this locus, rs6275, to be associated with increased first-phase glucose-stimulated insulin secretion in women (P = 5.5*104) but again not in men (P = 0.34). CONCLUSION: The present data identify DRD2/ANKK1 as a potential sex-specific type 2 diabetes susceptibility gene.

Glucocorticoid receptor gene polymorphisms are associated with reduced first-phase glucose-stimulated insulin secretion and disposition index in women, but not in men.

AIM: Glucocorticoids are efficacious anti-inflammatory agents, but, in susceptible individuals, these drugs may induce glucose intolerance and diabetes by affecting ß-cell function and insulin sensitivity. We assessed whether polymorphisms in the glucocorticoid receptor gene NR3C1 associate with measures of ß-cell function and insulin sensitivity derived from hyperglycaemic clamps in subjects with normal or impaired glucose tolerance. METHODS: A cross-sectional cohort study was conducted in four academic medical centres in the Netherlands and Germany. Four hundred and forty-nine volunteers (188 men; 261 women) were recruited with normal glucose tolerance (n=261) and impaired glucose tolerance (n=188). From 2-h hyperglycaemic clamps, first- and second-phase glucose-stimulated insulin secretion, as well as insulin sensitivity index and disposition index, were calculated. All participants were genotyped for the functional NR3C1 polymorphisms N363S (rs6195), BclI (rs41423247), ER22/23EK (rs6189/6190), 9ß A/G (rs6198) and ThtIIII (rs10052957). Associations between these polymorphisms and ß-cell function parameters were assessed. RESULTS: In women, but not in men, the N363S polymorphism was associated with reduced disposition index (P=1.06 10(-4) ). Also only in women, the ER22/23EK polymorphism was associated with reduced first-phase glucose-stimulated insulin secretion (P=0.011) and disposition index (P=0.003). The other single-nucleotide polymorphisms were not associated with ß-cell function. Finally, none of the polymorphisms was related to insulin sensitivity. CONCLUSION: The N363S and ER22/23EK polymorphisms of the NR3C1 gene are negatively associated with parameters of ß-cell function in women, but not in men.

Waist circumference and metabolic risk factors have separate and additive effects on the risk of future Type 2 diabetes in patients with vascular diseases. A cohort study.

AIMS: To assess the effect of various measures of adiposity and of metabolic risk factors, both separately and in combination, on the risk of future Type 2 diabetes in patients with manifest vascular diseases. METHODS: This was a prospective cohort study in 2924 patients (mean age 59 ± 12 years) with manifest atherosclerosis. Metabolic risk factors were defined according to National Cholesterol Education Program criteria for the metabolic syndrome. Incidence of Type 2 diabetes was assessed by questionnaire and subsequent verification. RESULTS: During a median follow-up of 4.9 years (range 3.0-7.6 years) there were 178 cases (6.1%) of incident Type 2 diabetes. An increase with 1 sd waist circumference showed a strong association with incident Type 2 diabetes in both men (hazard ratio 2.45, 95% CI 1.97-3.04) and women (hazard ratio 1.77, 95% CI 1.38-2.26). Compared with patients with normal (i.e. below the National Cholesterol Education Program criteria for abdominal adiposity) waist circumference and < 3 metabolic risk factors, both patients with normal waist circumference and ≥ 3 metabolic risk factors and patients with high (i.e. above the National Cholesterol Education Program criteria for abdominal adiposity) waist circumference and < 3 metabolic risk factors had an increased risk of Type 2 diabetes (hazard ratio 2.44, 95% CI 1.37-4.36 and hazard ratio 3.61, 95% CI 2.23-5.85, respectively). Patients with both high waist circumference and ≥ 3 metabolic risk factors had the highest risk of developing Type 2 diabetes (hazard ratio 10.76, 95% CI 6.95-16.64). CONCLUSIONS: In patients with manifest atherosclerosis, both presence of ≥ 3 metabolic risk factors and presence of a high waist circumference alone are associated with increased risk for developing Type 2 diabetes. The combined presence of ≥ 3 metabolic risk factors and high waist circumference, which is present in 15% of patients, is associated with a 10-fold increased risk of future Type 2 diabetes. To identify patients with manifest atherosclerosis at the highest risk of developing Type 2 diabetes, fat distribution in combination with metabolic risk factors should be considered.

Genetic association analysis of LARS2 with type 2 diabetes.

AIMS/HYPOTHESIS: LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study was to establish the true contribution of this variant and common variants in LARS2 (MAF > 5%) to type 2 diabetes risk. METHODS: We combined genome-wide association data (n = 10,128) from the DIAGRAM consortium with independent data derived from a tagging single nucleotide polymorphism (SNP) approach in Dutch individuals (n = 999) and took forward two SNPs of interest to replication in up to 11,163 Dutch participants (rs17637703 and rs952621). In addition, because inspection of genome-wide association study data identified a cluster of low-frequency variants with evidence of type 2 diabetes association, we attempted replication of rs9825041 (a proxy for this group) and the previously identified H324Q variant in up to 35,715 participants of European descent. RESULTS: No association between the common SNPs in LARS2 and type 2 diabetes was found. Our replication studies for the two low-frequency variants, rs9825041 and H324Q, failed to confirm an association with type 2 diabetes in Dutch, Scandinavian and UK samples (OR 1.03 [95% CI 0.95-1.12], p = 0.45, n = 31,962 and OR 0.99 [0.90-1.08], p = 0.78, n = 35,715 respectively). CONCLUSIONS/INTERPRETATION: In this study, the largest study examining the role of sequence variants in LARS2 in type 2 diabetes susceptibility, we found no evidence to support previous data indicating a role in type 2 diabetes susceptibility.

Sex hormone-binding globulin concentrations before conception as a predictor for gestational diabetes in women with polycystic ovary syndrome.

BACKGROUND: Low plasma sex hormone-binding globulin (SHBG) concentrations during pregnancy have been associated with the risk of developing gestational diabetes mellitus (GDM). Women presenting with polycystic ovary syndrome (PCOS) often exhibit low plasma SHBG concentration and are at increased risk of developing GDM. In this study, we investigate whether SHBG levels before conception are predictive of GDM in women with PCOS. METHODS: A total of 50 women with PCOS were enrolled and followed up during pregnancy. Initial endocrine, metabolic and physical features were assessed according to a standardized preconception screening program. At 24-26 weeks of gestational age a 100-g glucose tolerance test was performed to screen for GDM. RESULTS: Of the 50 women, 21 (42%) were diagnosed with GDM by a 100-g glucose tolerance test. Waist circumference, BMI, blood pressure, plasma glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR) and SHBG levels before conception were significantly different between women who did and did not develop GDM. Stepwise logistic regression analysis showed that SHBG was the most significant predictive parameter for GDM (odds ratio 0.92; 95% confidence interval 0.87-0.97), without significant contribution of waist circumference and HOMA-IR. Receiver operator characteristic (ROC) analysis indicated that plasma SHBG (area under the curve 0.86) had the highest predictive value for subsequent development of GDM, however, the limited group size did not allow for calculation of a threshold value of SHBG. CONCLUSIONS: In women with PCOS, preconception SHBG levels are strongly associated with subsequent development of GDM. Regression and ROC analysis show that preconception SHBG levels may be a better predictor for GDM in PCOS women compared with waist circumference or HOMA-IR. CLINICAL TRIAL REGISTRATION NUMBER: NCT00821379.

Type 2 Diabetes Mellitus: New Genetic Insights will Lead to New Therapeutics.

Type 2 diabetes is a disorder of dysregulated glucose homeostasis. Normal glucose homeostasis is a complex process involving several interacting mechanisms, such as insulin secretion, insulin sensitivity, glucose production, and glucose uptake. The dysregulation of one or more of these mechanisms due to environmental and/or genetic factors, can lead to a defective glucose homeostasis. Hyperglycemia is managed by augmenting insulin secretion and/or interaction with hepatic glucose production, as well as by decreasing dietary caloric intake and raising glucose metabolism through exercise. Although these interventions can delay disease progression and correct blood glucose levels, they are not able to cure the disease or stop its progression entirely. Better management of type 2 diabetes is sorely needed. Advances in genotyping techniques and the availability of large patient cohorts have made it possible to identify common genetic variants associated with type 2 diabetes through genome-wide association studies (GWAS). So far, genetic variants on 19 loci have been identified. Most of these loci contain or lie close to genes that were not previously linked to diabetes and they may thus harbor targets for new drugs. It is also hoped that further genetic studies will pave the way for predictive genetic screening. The newly discovered type 2 diabetes genes can be classified based on their presumed molecular function, and we discuss the relation between these gene classes and current treatments. We go on to consider whether the new genes provide opportunities for developing alternative drug therapies.

Effect of octreotide on plasma concentrations of glucose, insulin, glucagon, growth hormone, and cortisol in healthy dogs and dogs with insulinoma.

The inhibitory effect of the somatostatin analogue octreotide on the secretion of insulin could be used in the treatment of insulinoma. However, current information on the effectiveness of octreotide in dogs is conflicting. Therefore, the endocrine effects of a single subcutaneous dose of 50 microg octreotide were studied in healthy dogs in the fasting state (n=7) and in dogs with insulinoma (n=12). Octreotide did not cause any adverse effects. In healthy dogs in the fasting state, both plasma insulin and glucagon concentrations declined significantly. Basal (non-pulse related) GH and ACTH concentrations were not affected. A slight but significant decrease in the plasma glucose concentrations occurred. Dogs with insulinoma had significantly higher baseline insulin concentrations and lower baseline glucose concentrations than healthy dogs in the fasting state. Plasma glucagon, GH, ACTH, and cortisol concentrations did not differ from those in healthy dogs. Baseline plasma insulin concentrations decreased significantly in dogs with insulinoma after octreotide administration, whereas plasma concentrations of glucagon, GH, ACTH, and cortisol did not change. In contrast to the effects in the healthy dogs, in the dogs with insulinoma plasma glucose concentrations increased. Thus, the consistent suppression of plasma insulin concentrations in dogs with insulinoma, in the absence of an suppressive effect on counter-regulatory hormones, suggests that further studies on the effectiveness of slow-release preparations in the long-term medical treatment of dogs with insulinoma are warranted.

Adverse effects of insulin antibodies on postprandial plasma glucose and insulin profiles in diabetic patients without immune insulin resistance. Implications for intensive insulin regimens.

To assess the possible influence of moderate titer insulin antibodies on diabetic glycemic control, we examined insulin-antibody equilibrium binding characteristics, postprandial glucose tolerance, and plasma free-insulin profiles after subcutaneous injection of both porcine and human insulin (0.15 U/kg) in 12 patients with insulin-dependent diabetes mellitus under conditions stimulating intensive insulin therapy. The patients' antibodies bound porcine and human insulin indistinguishably, and their plasma glucose and free-insulin profiles after ingestion of a standard meal were similar with both insulins. Initial increases in plasma free-insulin levels after injection of both insulins were negatively correlated with both insulin-antibody binding (r = -.55, P less than .006) and postprandial hyperglycemia (peak level r = -.56, P less than .006); the latter was positively correlated with insulin-antibody binding (r = .48, P less than .02). The effects of insulin antibodies on postprandial plasma free-insulin and glucose levels could be accounted for substantially by the association constant of the high-affinity insulin-antibody binding sites (K1); patients in the highest quartile for K1 had significantly slower initial increments in plasma free insulin (0.31 +/- 0.04 vs. 0.46 +/- 0.06 microU/min, P less than .05) and greater postprandial hyperglycemia (peak value 237 +/- 10 vs. 166 +/- 12 mg/dl, P less than .001) than patients in the lowest quartile. We conclude that moderate insulin-antibody titers commonly found in insulin-treated patients can slow the early increase in plasma free insulin after subcutaneous injection and that this impairs postprandial glucose tolerance; such an effect may limit the effectiveness of intensive insulin therapy.

Defining the genetic contribution of type 2 diabetes mellitus.

Type 2 diabetes mellitus is a common multifactorial genetic syndrome, which is determined by several different genes and environmental factors. It now affects 150 million people world wide but its incidence is increasing rapidly because of secondary factors, such as obesity, hypertension, and lack of physical activity. Many studies have been carried out to determine the genetic factors involved in type 2 diabetes mellitus. In this review we look at the different strategies used and discuss the genome wide scans performed so far in more detail. New technologies, such as microarrays, and the discovery of SNPs will lead to a greater understanding of the pathogenesis of type 2 diabetes mellitus and to better diagnostics, treatment, and eventually prevention.

Cardiac tamponade from misplaced central venous line in pericardiophrenic vein.

A patient in whom a left internal jugular vein catheter had first migrated into the left pericardiophrenic vein, and subsequently had perforated into the pericardium leading to a cardiac tamponade is described. Although this malposition has rarely been reported, it does not seem to be so infrequent, as three other similar misplacements have occurred in our institution. This malposition can be prevented by a high degree of suspicion, preferential use of the right internal jugular vein for catheterization, routine use of a J-tipped guidewire, limiting the depth of insertion of the guidewire during cannulation, routine roentgenographic control of radiopaque catheters, and (slow) injection of a small volume of radiopaque dye through the central venous catheter.

Clinical significance of insulin antibodies in insulin-treated diabetic patients.

The prevalence and titers of insulin antibodies in insulin-treated patients have markedly decreased, mainly as a consequence of the improvements in the purity of insulin preparations and to a lesser degree because of the changes of species of insulin (human insulin). However, numerous patients still produce antibody levels that may alter insulin pharmacokinetics, leading to higher postprandial blood glucose levels and to an increased risk for delayed hypoglycemia. Although the effects of antibodies on long-term glycemic control are less clear, the metabolic consequences of altered pharmacokinetics are clinically evident in patients in whom near normoglycemia is the goal and who are treated predominantly with short-acting insulin. Lipoatrophy and immunological insulin resistance, which are also antibody-induced phenomena, have become rare. Whether pregnancies in diabetic mothers with antibodies carry an increased risk for serious or fatal complications is not clear; neonates of these mothers are probably at increased risk for neonatal hypoglycemia.

Prolonged fasting hypoglycemia due to insulin antibodies in patient with non-insulin-dependent diabetes mellitus: effect of insulin withdrawal on insulin-antibody-binding kinetics.

Fasting hypoglycemia, which persisted for 3 days after insulin treatment was stopped, occurred in a patient with non-insulin-dependent diabetes mellitus who had inappropriate plasma free-insulin levels (18-25 microU/ml) and extremely high antibody-bound insulin (greater than 20,000 microU/ml) but normal counter-regulatory hormone secretion and plasma C-peptide levels. The amount of antibody-bound insulin decreased in a biphasic pattern over 13 mo of observation with an initial half-life of 35 days and a more gradual decrease with a half-life of 160 days. The number of high-affinity antibody binding sites was virtually identical to the amount of antibody-bound insulin in the patient's plasma. We conclude that the patient's fasting hyperinsulinemia and hypoglycemia were due to release of antibody-bound insulin.

Insulin secretion in normal glucose-tolerant relatives of type 2 diabetic subjects. Assessments using hyperglycemic glucose clamps and oral glucose tolerance tests.

OBJECTIVE: To assess insulin secretion in normal glucose-tolerant Caucasian first-degree relatives of type 2 diabetes subjects and in matched normal glucose-tolerant control subjects and to compare insulin secretion as assessed using a hyperglycemic glucose clamp with insulin secretion as assessed using an oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: Twenty-one first-degree relatives of type 2 diabetic subjects and 21 control subjects without a family history of type 2 diabetes, who were matched for sex, age, BMI, waist-to-hip ratio, and aerobic capacity, underwent a hyperglycemic glucose clamp (10 mmol/l, 180 min). An OGTT (75 g glucose in 300 ml water) was also performed. RESULTS: First-phase insulin release (plasma insulin, 0-10 min) was not different (multiple analysis of variance [MANOVA]: F = 2.63, P = 0.11). Second-phase insulin release was lower (MANOVA: F = 4.18, P = 0.047). Separate analyses of variance showed decreased plasma insulin levels from 120 min onward (all P < 0.05), decreasing to geometric mean (95% CI) levels of 330 (270-402) and 462 (366-582) pmol/l at 180 min in relatives and control subjects, respectively. The insulin sensitivity index (ISI) as assessed using a hyperglycemic clamp was not different between the two groups. Mean +/- SE ISI during the 3rd hour was 27.5 +/- 2.2 and 30.5 +/- 3.0 micrograms.kg-1.min-1.pmol-1.l-1 in relatives and control subjects, respectively (P > 0.20). At 90 min after the OGTT, log plasma insulin levels correlated significantly with second-phase insulin release as assessed using the hyperglycemic glucose clamp. CONCLUSIONS: Normal glucose-tolerant first-degree relatives of type 2 diabetic subjects have a decreased second-phase insulin release, compared with matched control subjects. After an OGTT, 90-min values of log plasma insulin and 90-min values of the ratio of log plasma insulin to blood glucose may be good indicators of insulin secretory properties in normal glucose-tolerant family members of type 2 diabetic subjects.

Clinical characteristics of type 1 diabetic patients with and without severe hypoglycemia.

OBJECTIVE: To investigate the frequency of severe hypoglycemia (SH) and hypoglycemic coma and to identify clinical and behavioral risk indicators in a nonselected population of type 1 diabetic patients. RESEARCH DESIGN AND METHODS: This study involved a retrospective clinical survey of 195 consecutive patients using a questionnaire addressing the frequency of SH (i.e., help from others required) and hypoglycemic coma during the previous year, general characteristics, behavior, hypoglycemia awareness, and the Hypoglycemia Fear Survey Data regarding diabetes, treatment, long-term complications, comorbidity, and comedication were obtained from the patients' medical records. RESULTS: A total of 82% of subjects were receiving intensive insulin treatment, and mean +/- SD HbA(1c) was 7.8 +/- 1.2%. Mean duration of diabetes was 20 +/- 12 years. The occurrence of SH (including hypoglycemic coma) was 150 episodes/100 patient-years and affected 40.5% of the population. Hypoglycemic coma occurred in 19% of subjects (40 episodes/100 patient-years). SH without coma was independently related to nephropathy (odds ratio [OR] 4.8 [95% CI 1.5-15.1]), a threshold for hypoglycemic symptoms of <3 mmol/l (4.8 [1.8-12.0]), and a daily insulin dose 0.1 U/kg higher (1.3 [1.0-1.6]) (all ORs were adjusted for diabetes duration and use of comedication). Hypoglycemic coma was independently related to neuropathy (3.9 [1.5-10.4]), (nonselective) beta-blocking agents (14.9 [2.1-107.4]), and alcohol use (3.5 [1.3-9.1]) (all ORs were adjusted for diabetes duration). CONCLUSIONS: SH and hypoglycemic coma are common in a nonselected population with type 1 diabetes. The presence of long-term complications, a threshold for symptoms of <3 mmo/l, alcohol use, and (nonselective) beta-blockers were associated with SH during the previous year. If prospectively confirmed, these results may have consequences for clinical practice.

Determining the association between adipokine expression in multiple tissues and phenotypic features of non-alcoholic fatty liver disease in obesity.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is an obesity-associated disease, and in obesity adipokines are believed to be involved in the development of NAFLD. However, it is still not clear whether adipokines in the liver and/or adipose tissues can be related to the development of specific characteristics of NAFLD, such as steatosis and inflammation. We aimed to address this question by simultaneously examining the adipokine expression in three tissue types in obese individuals. METHODS: We enrolled 93 severely obese individuals with NAFLD, varying from simple steatosis to severe non-alcoholic steatohepatitis. Their expression of 48 adipokines in the liver, visceral and subcutaneous adipose tissue (SAT) was correlated to their phenotypic features of NAFLD. We further determined whether the correlations were tissue specific and/or independent of covariates, including age, sex, obesity, insulin resistance and type 2 diabetes (T2D). RESULTS: The expression of adipokines showed a liver- and adipose tissue-specific pattern. We identified that the expression of leptin, angiopoietin 2 (ANGPT2) and chemerin in visceral adipose tissue (VAT) was associated with different NAFLD features, including steatosis, ballooning, portal and lobular inflammation. In addition, the expression of tumor necrosis factor (TNF), plasminogen activator inhibitor type 1 (PAI-1), insulin-like growth factor 1 (somatomedin C) (IGF1) and chemokine (C-X-C motif) ligand 10 (CXCL10) in the liver tissue and the expression of interleukin 1 receptor antagonist (IL1RN) in both the liver and SAT were associated with NAFLD features. The correlations between ANGPT2 and CXCL10, and NAFLD features were dependent on insulin resistance and T2D, but for the other genes the correlation with at least one NAFLD feature remained significant after correcting for the covariates. CONCLUSIONS: Our results suggest that in obese individuals, VAT-derived leptin and chemerin, and hepatic expression of TNF, IGF1, IL1RN and PAI-1 are involved in the development of NAFLD features. Further, functional studies are warranted to establish a causal relationship.

Dose-response characteristics for arginine-stimulated insulin secretion in man and influence of hyperglycemia.

To test the hypothesis that glucose only affects the responsiveness (maximum velocity) of the beta-cell to arginine without changing the sensitivity (ED50) of the beta-cell to arginine, we investigated the influence of hyperglycemia on the responsiveness and sensitivity of arginine-induced insulin secretion in eight healthy male volunteers. Plasma C-peptide and insulin levels achieved during infusions of five doses of arginine (30 min) with and without a 60-min hyperglycemic clamp (17 mmol/L) were analyzed using a modified Michaelis-Menten equation. At euglycemia, the ED50 (half-maximally stimulating serum arginine concentration) was significantly less for first phase than for second phase plasma C-peptide secretion (0.7 +/- 0.1 vs. 2.7 +/- 0.4 mmol/L; P less than 0.002). Hyperglycemia significantly increased arginine-induced insulin secretion at all arginine infusion rates (P less than 0.01) without significantly altering the ED50 for either phase. We conclude 1) that the regulation of arginine-induced insulin secretion differs between both phases of insulin secretion, and 2) that a 1-h infusion with glucose significantly potentiates arginine-induced insulin secretion without influencing the difference in regulation of both phases of arginine-induced insulin secretion, supporting the validity of the use of arginine as a secretagogue in studies involving hyperglycemia.

A genome-wide scan in type 2 diabetes mellitus provides independent replication of a susceptibility locus on 18p11 and suggests the existence of novel Loci on 2q12 and 19q13.

A genome-wide scan was performed, using nonparametric linkage analyses, to find susceptibility loci for type 2 diabetes mellitus in the Dutch population. We studied 178 families from The Netherlands, who constituted 312 affected sibling pairs. The first stage of the genome scan consisted of 270 DNA markers, with an average intermarker spacing of 13 cM. Because obesity and type 2 diabetes mellitus are interrelated, the data set was stratified for the subphenotype body mass index, corrected for age and gender. This resulted in a suggestive maximum multipoint LOD score of 2.3 (single-point P value, 9.7 x 10(-4); genome-wide P value, 0.028) for the most obese 20% pedigrees of the data set, between marker loci D18S471 and D18S843. In the lowest 80% obese pedigrees, two interesting loci on chromosome 2 and 19 were found, with LOD scores of 1.5 and 1.3. We provide independent evidence that the chromosome 18p11 locus, reported earlier from a Finnish/Swedish population, is of definite interest for type 2 diabetes mellitus in connection with obesity. Subsequently, our results indicate that two novel loci may reside on chromosomes 2 and 19, with minor effects involved in the development of type 2 diabetes mellitus in the Dutch population.

Prevention of complications in non-insulin-dependent diabetes mellitus (NIDDM).

It is expected that the number of patients with diabetes mellitus will increase in the near future. The high rate of microvascular and macrovascular complications developing in these patients will place an even higher burden on our healthcare systems. Several pathophysiological factors are involved in the development of complications, among which are hyperglycaemia per se, the consequent formation of advanced glycation end-products (AGEs) and the intracellular accumulation of sorbitol. In addition, hypertension and dyslipidaemia also play an important role, especially in the development of coronary heart disease and stroke. The major therapeutic goals in patients with non-insulin-dependent diabetes mellitus (NIDDM) are to reduce obesity and normalise lipid disturbances and increased blood pressure, in order to improve the well-being of the patient and reduce the risk of the development of late diabetic complications. Often, pharmacological treatment of the hyperglycaemia is necessary, in which case sulphonylureas, metformin, alpha-glucosidase inhibitors such as acarbose, or insulin may be employed. It is believed that medical interventions, by their effect on improving metabolic control, reduce the incidence and severity of diabetic complications, especially when considering the toxic effects of glucose and the accumulation of AGEs as a consequence of raised tissue glucose levels. This concept is also based on extrapolation of the finding of the Diabetes Control and Complications Trial that intensive glycaemic control in IDDM will prevent the progression of at least the microvascular complications like retinopathy and nephropathy. There are, however, no long term studies in NIDDM patients to show that treatment with oral antihyperglycaemic agents helps to postpone or prevent complications. It is expected that the UK Prospective Diabetes Study will show whether better metabolic control, either with oral antihyperglycaemics or with insulin, will indeed improve outcome. Several other studies aiming at specific risk factor intervention (hypertension, hyperlipidaemia, lipid oxidation) in NIDDM patients are currently ongoing.

Determinants of insulin sensitivity in chronic heart failure.

OBJECTIVE: To describe the determinants of insulin sensitivity (IS) in chronic heart failure (CHF), we created a model in which the influence of lifestyle factors and etiology of heart failure on IS were incorporated concomitantly with age, left ventricular ejection fraction (LVEF) and parameters of body composition. DESIGN: Observational cohort study. SETTING: Outpatient clinic for chronic heart failure. PATIENTS: Fifty-seven male CHF patients [NYHA class II-III, age 61+/-9 years, body mass index (BMI) 26.9+/-3.3 kg/m2 (mean+/-S.D.)]. INTERVENTIONS: Euglycemic hyperinsulinemic clamp, cycle ergometry, anthropometric measurements, LVEF and a physical activity questionnaire. MAIN OUTCOME MEASURES: A model explaining the variance of IS in CHF. RESULTS: IS was 18.2+/-8.6 microg.kg(-1).min(-1).mU(-1).l(-1), fasting insulin level was 15.9+/-11.0 mU/l and fasting glucose level was 5.5+/-0.6 mmol/l. Peak VO2 was 19.1+/-4.9 ml.kg(-1).min(-1) and LVEF 26.2+/-7.1%. IS was inversely associated with fasting insulin concentration (r=-0.50, P<0.001) and BMI (r=-0.54, P<0.001). After controlling for BMI, IS also revealed a correlation with age (r=-0.36, P<0.01). The model explained 60% of variance in IS: BMI contributed 20%, smoking 17%, age 17% and physical activity in daily life (DPA) 16% (all P<0.05) to the variance of IS, whereas LVEF (9%) and etiology of heart failure (8%) contributed moderately. CONCLUSIONS: In CHF patients, IS is for a major part predicted by BMI, smoking, age, daily physical activity, LVEF and etiology of heart failure.

Lower beta-cell secretion in physically active first-degree relatives of type 2 diabetes patients.

Regular physical activity may prevent or postpone type 2 diabetes, and is thought to be related to an increase of insulin sensitivity. We studied whether physically active, glucose-tolerant first-degree relatives of type 2 diabetes patients differ in glucose tolerance (oral glucose tolerance test [OGTT]) and insulin secretion (hyperglycemic glucose clamp) from less active first-degree relatives. A group of 37 relatives was split into 2 subgroups according to the sex-specific median of the sports index, assessed by a questionnaire, as the cutoff point. Blood glucose levels during the OGTT were lower in the highly active subgroup versus the less active counterparts (multivariate ANOVA [MANOVA], P = .011), but the plasma insulin levels were similar. First-phase secretion was not different in the highly active group versus the less active group, but second-phase secretion (average plasma insulin in the third hour) was significantly lower (P = .016). As expected, the insulin sensitivity index (ISI) was higher in the highly active subgroup (P= .011). Subdivision into subgroups with high or low maximal O2 consumption (VO2max) resulted in similar differences, but these were not significant. In a group of 21 controls, the results resembled the values in the relatives but were less often statistically significant. In conclusion, regular physical activity not only is associated with increased insulin sensitivity but also downregulates the pancreatic beta cell. This downregulation may provide an extra mechanism by which physical activity diminishes the development of type 2 diabetes.