The association between body mass index groups and metabolic comorbidities with healthcare and medication costs: a nationwide biobank and registry study in Finland.

BACKGROUND: The increasing prevalence of obesity imposes a significant cost burden on individuals and societies worldwide. OBJECTIVE: In this nationally representative study, the association between body mass index (BMI) groups and the number of metabolic comorbidities (MetC) with total direct costs was investigated in the Finnish population. STUDY DESIGN, SETTING, AND PARTICIPANTS: The study cohort included 5,587 adults with BMI ≥18.5 kg/m2 who participated in the cross-sectional FinHealth 2017 health examination survey conducted by the Finnish Institute for Health and Welfare. Data on healthcare resource utilization (HCRU) and drug purchases were collected from national healthcare and drug registers. MAIN OUTCOME MEASURE: The primary outcome was total direct costs (costs of primary and secondary HCRU and prescription medications). RESULTS: Class I (BMI 30.0-34.9 kg/m2) and class II - III (BMI ≥35.0 kg/m2) obesity were associated with 43% and 40% higher age- and sex-adjusted direct costs, respectively, compared with normal weight, mainly driven by a steeply increased comorbidity in the higher BMI groups. In all BMI groups combined, individuals with ≥2 MetCs comprised 39% of the total study population and 60% of the total costs. CONCLUSION: To manage the cost burden of obesity, treatment should be given equal consideration as other chronic diseases, and BMIs ≥30.0 kg/m2 should be considered in treatment decisions.

Obesity and metabolic state are associated with increased healthcare resource and medication use and costs: a Finnish population-based study.

AIM: To characterize healthcare resource (HCRU) and medication use and associated costs in individuals with obesity compared with individuals with normal weight or overweight in a population-based cohort of Finnish adults. The association between metabolic state and direct costs was also assessed. METHODS: The study cohort included 5587 randomly selected individuals who participated in the national FinHealth 2017 health examination survey. Data on healthcare visits and hospital stays, including diagnoses (ICD-10), and purchases and costs of prescription medicines were collected from the nationwide registers by the Finnish Institute for Health and Welfare and Social Insurance Institution of Finland. The healthcare costs were calculated based on standard unit costs reported by the Finnish Institute for Health and Welfare. RESULTS: The total annual direct costs were €2665 (SD €5673) and €1799 (SD €3874) per person with obesity and with normal weight or overweight, respectively. Obesity was associated with significantly increased total direct (age- and sex-adjusted cost rate ratio, RR, 1.356; p < 0.001), HCRU-related (1.273; p = 0.002), and medication (1.669; p < 0.001) costs. A vast majority (90%) of individuals with obesity were classified as metabolically unhealthy based on clinical measurements. The metabolically unhealthy state was associated with increased costs in individuals with obesity but not in individuals with normal weight or overweight. CONCLUSION: Obesity is associated with a significant and complex direct cost burden to society, arising primarily from increased comorbidity. Metabolically healthy obesity is uncommon and obesity prevention and timely treatment should be of high priority to tackle the increasing burden of obesity.

The association of body mass index with quality of life and working ability: a Finnish population-based study.

PURPOSE: The impact of obesity on quality of life (QoL) and working ability vary in different dimensions. This study investigated the association of obesity with QoL and working ability in Finnish adults. Comorbidities as associative factors were also characterised. METHODS: This cross-sectional study included 4956 randomly selected adults. QoL (EUROHIS-QOL 8 total score and individual components), perceived physical and psychological working ability, and sick leave days were analysed in different body mass index (BMI) groups. Regression models were used to study the role of comorbidities as associative factors. RESULTS: EUROHIS-QOL 8 total score was significantly lower in BMI group 25.0-29.9 kg/m2 (4.01; 95% confidence interval 3.97-4.05), BMI 30.0-34.9 kg/m2 (3.85; 3.79-3.91), BMI 35.0-39.9 kg/m2 (3.75; 3.66-3.85), and BMI ≥ 40.0 kg/m2 (3.73; 3.46-4.00) compared to individuals with normal (18.5-24.9 kg/m2) BMI (4.08; 4.04-4.12). Individuals with obesity (BMI ≥ 30.0 kg/m2) rated their QoL lower than individuals with normal BMI in seven of the eight EUROHIS-QOL 8 components. A lesser proportion of individuals (53-73%) with obesity rated their physical working ability as very or fairly good compared to individuals with normal BMI (90%, p values < 0.001). The psychological working ability was rated as very or fairly good by 71-75% of individuals with obesity compared to 85% of individuals with normal BMI (p = 0.008 and p = 0.001 in individuals with BMI 30.0-34.9 and BMI 35.0-39.9 kg/m2, respectively). CONCLUSIONS: Obesity was negatively associated with both physical and psychological components of QoL, even after accounting for obesity-related comorbidities. Obesity treatment can benefit from a holistic approach that considers these multifaceted associations.

Insulins NPH, glargine, and detemir, and risk of severe hypoglycemia among working-age adults.

INTRODUCTION: The longer acting basal insulin analogs glargine and detemir have shown a lower incidence of hypoglycemia compared to insulin NPH in clinical studies. We evaluated the real-life risk of severe hypoglycemia among new users of insulins in the working-age population in Finland. METHODS: All persons aged 18-65 years with diabetes mellitus who were newly prescribed with insulins NPH, glargine, or detemir during 2006-2009, were identified from national registers. Risk of severe hypoglycemia requiring hospital care was compared between insulin types. RESULTS: A total of 16,985 persons initiated basal insulin treatment (5586, 7499, and 3900 patients started NPH, glargine, and detemir, respectively) during follow-up. Five hundred and thirty-six persons were hospitalized because of severe hypoglycemia. Absolute rate (per 1000 patient-years) was 20.6 (95% CI 17.9, 23.8), 17.8 (15.6, 20.3), and 12.4 (9.9, 15.5) for NPH, glargine, and detemir initiators, respectively. With NPH as reference, the adjusted hazard ratio (HR) was 0.92 (95% CI 0.74, 1.15, p = 0.47) for glargine, and 0.70 (0.51, 0.94, p= 0.018) for detemir. The HR for detemir compared to glargine was 0.76 (0.58, 0.99, p = 0.040). CONCLUSIONS: Initiating insulin treatment with detemir, but not with glargine, was associated with a significantly lower risk of severe hypoglycemia compared to NPH, among working-age adults. KEY MESSAGES The comparative safety of modern basal insulins regarding hypoglycemia among the working-age population is unclear. Large reductions in the incidence of severe hypoglycemia were seen among real-life patients who started insulin detemir, as compared to patients who initiated glargine or especially NPH insulin. Given the large amount of patients using insulin, these findings may have considerable clinical consequences at the population level.

The effects of a HTR2B stop codon and testosterone on energy metabolism and beta cell function among antisocial Finnish males.

Herein, we examined insulin resistance (IR), insulin sensitivity (IS), beta cell activity, and glucose metabolism in subjects with antisocial personality disorder (ASPD), and whether the serotonin 2B (5-HT2B) receptor and testosterone have a role in energy metabolism. A cohort of subjects belonging to a founder population that included 98 ASPD males, aged 25-30, was divided into groups based on the presence of a heterozygous 5-HT2B receptor loss-of-function gene mutation (HTR2B Q20*; n = 9) or not (n = 89). Serum glucose and insulin levels were measured in a 5 h oral glucose tolerance test (75 g) and indices describing IR, IS, and beta cell activity were calculated. Body mass index (BMI) was also determined. Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were measured in cerebrospinal fluid, and testosterone levels from serum. An IR-like state comprising high IR, low IS, and high beta cell activity indices was observed among ASPD subjects without the HTR2B Q20* allele. By contrast, being an ASPD HTR2B Q20* carrier appeared to be preventive of these pathophysiologies. The HTR2B Q20* allele and testosterone predicted lower BMI independently, but an interaction between HTR2B Q20* and testosterone lead to increased insulin sensitivity among HTR2B Q20* carriers with low testosterone levels. The HTR2B Q20* allele also predicted reduced beta cell activity and enhanced glucose metabolism. Reduced 5-HT2B receptor function at low or normal testosterone levels may be protective of obesity. Results were observed among Finnish males having an antisocial personality disorder, which limits the generality.

Bone marrow fat unsaturation in young adults is not affected by present or childhood obesity, but increases with age: A pilot study.

OBJECTIVES: Obesity increases bone marrow fat (BMF) content. The association between early obesity and bone marrow fatty acid composition is unknown. We measured BMF unsaturation index (UI) in normal-weight and overweight young adults with a known weight status in early childhood and tested the relationship between BMF UI and exercise history, glycemic state, and other clinical characteristics. METHODS: The study included 18 normal-weight (BMI <25 kg/m(2); 2 males, 16 females) and 17 overweight (BMI ≥25 kg/m(2); 9 males, 8 females) young adults aged 15-27 years. BMF UI was assessed with magnetic resonance proton spectroscopy optimized to reduce water interference. Exercise information was obtained with a pedometer accompanied with the history of recent physical activity. Blood samples (insulin, glucose, HbA1c) and body characteristics (BMI, waist-to-hip ratio, body fat composition) were assessed. RESULTS: BMF UI was not affected by obesity at the time of study or before age 7 years. BMF UI increased with age in normal-weight and overweight subjects (R=0.408, p=0.015) but did not associate with gender, physical activity or body fat composition; a suggestive association was observed with glucose (R=-0.289, p=0.10). CONCLUSIONS: The association of BMF UI with age in early adulthood may represent normal maturation of bone marrow. There was a trend toward an association with blood glucose, warranting further studies.

Suppressed bone turnover in obesity: a link to energy metabolism? A case-control study.

CONTEXT: Observations in rodents suggest that osteocalcin (OC) participates in glucose metabolism. Based on human studies, it remains unclear whether circulating OC is simply a bone turnover marker (BTM) or also a mediator in interactions between the skeleton and glucose homeostasis. OBJECTIVE: The objective of the study was to determine the responses of BTMs, including OC, to oral glucose tolerance test (OGTT) in a case-control setting. DESIGN AND PATIENTS: Thirty-four normoglycemic young adults [mean age 19 y (SD 2.3)] with severe childhood-onset obesity and their gender- and age-matched nonobese controls underwent a standard 2-hour OGTT. MAIN OUTCOME MEASURES: Glucose, insulin, and six BTMs including total and carboxylated OC (cOC) were determined at baseline and at 30, 60, 90, and 120 minutes during OGTT. RESULTS: The obese and control subjects were similar in height; the mean body mass indices were 40.4 and 21.9 kg/m(2), respectively. The homeostasis model assessment index was 2.7 times greater in the obese subjects. All BTMs, except bone-specific alkaline phophatase, were lower in the obese subjects compared with the controls: the differences at baseline were 40%, 35%, 17%, 31%, and 32% for N-terminal propeptides of type I collagen, cross-linked telopeptides of type I collagen, tartrate-resistant acid phosphatase, total OC, and carboxylated OC (P < .05 for all) after adjusting for whole-body bone area. All BTMs decreased during OGTT. The relative values for the OGTT responses for total, but not for cOC (measured as area under the curve) differed between the two groups (P = .029 and P = .139, respectively): the decrease in total OC during the OGTT was less pronounced in the obese subjects. Responses in other BTMs were similar between the groups. No associations were observed between glucose metabolism and OCs during OGTT with linear regression. CONCLUSIONS: Bone turnover markers were substantially lower in obese subjects compared with controls. Total OC and cOC showed less pronounced decrease during the OGTT in obese subjects compared with controls, whereas other BTMs responded similarly in the two groups. The role of OC, if anything, in glucose homeostasis is indirect and may be mediated via other factors than glucose or insulin.

Evaluation of the incidence and risk of hypoglycemic coma associated with selection of basal insulin in the treatment of diabetes: a Finnish register linkage study.

OBJECTIVE: Long-acting basal insulin analogs have demonstrated positive effects on the balance between effective glycemic control and risk of hypoglycemia versus neutral protamine Hagedorn (NPH) insulin in randomized controlled trials. Evidence of severe hypoglycemic risk with insulin detemir, insulin glargine, or NPH insulin is presented from a nationwide retrospective database study. RESEARCH DESIGN AND METHODS: Data from hospital and secondary healthcare visits due to hypoglycemic coma from 75 682 insulin-naïve type 1 or 2 diabetes patients initiating therapy with NPH insulin, insulin glargine, or insulin detemir in Finland between 2000 and 2009 were analyzed. Incidence rates with 95% confidence intervals (CIs) were calculated using Poisson regression. Hazard ratios were estimated using Cox's regression with adjustments for relevant background variables. RESULTS: The adjusted risk of hospital/secondary healthcare visits due to the first severe hypoglycemic event was 21.7% (95% CI 9.6-32.1%, p < 0.001) lower for insulin detemir and 9.9% (95% CI 1.5-17.6%, p = 0.022) lower for insulin glargine versus NPH insulin. Risk of hypoglycemic coma recurrence was 36.3% (95% CI 8.9-55.5%, p = 0.014) lower for detemir and 9.5% but not significantly (95% CI -10.2 to 25.7%, p = 0.318) lower for glargine versus NPH insulin. Risk of all hypoglycemic coma events was 30.8% (95% CI 16.2-42.8%, p-value <0.001) lower for detemir and 15.6% (95% CI 5.1-25.0%, p-value 0.005) lower for glargine versus NPH. Insulin detemir had a significantly lower risk for first (13.1% lower [p = 0.034]), recurrent (29.6% lower [p = 0.021]), and all (17.9% lower [p = 0.016]) severe hypoglycemic events than insulin glargine. CONCLUSIONS: There were considerable differences in risk of hospitalization or secondary healthcare visits due to hypoglycemic coma between basal insulin treatments in real-life clinical practice.

Starting or switching to biphasic insulin aspart 30 (BIAsp 30) in type 2 diabetes: a multicenter, observational, primary care study conducted in Finland.

AIMS: Assess safety and glycaemic control in patients initiating insulin with, or switching from basal insulin to, biphasic insulin aspart 30/70 (BIAsp 30) in primary care in Finland. METHODS: A non-randomised, non-interventional, open-label, 26-week study of type 2 diabetes (T2D) patients prescribed BIAsp 30 by their physician, who determined starting dose, titration and injection frequency. RESULTS: 496 patients provided safety data (insulin-naïve n=197; prior insulin n=299 [84.9% received NPH insulin]). Three patients (0.6%) reported four SADRs (three hypoglycaemia, one hypoglycaemia with unconsciousness). HbA1c was significantly (p<0.0001) reduced after 26 weeks' BIAsp 30 therapy (final dose): insulin-naïve -1.4% (44.4 IU); prior insulin -1.1% (77.4 IU). HbA1c<7.0% was achieved by 10% of insulin-naïve patients at baseline and 51% at 26-week follow-up. In the prior insulin group, 7% and 30% of patients had HbA1c<7.0% at baseline and 26 weeks, respectively. Minor hypoglycaemia increased significantly from baseline to study end: insulin-naïve 0.66-6.45 events/patient/year (p<0.0001); prior insulin 5.11-8.58 events/patient/year (p<0.05). Weight increased by 1.0 kg (insulin-naïve) and 1.3 kg (previous insulin). CONCLUSION: BIAsp 30, initiated and titrated in T2D patients in primary care in Finland, showed a good safety profile and significantly improved glycaemic control.

Association of intramyocellular, intraperitoneal and liver fat with glucose tolerance in severely obese adolescents.

OBJECTIVE: Impaired glucose tolerance (IGT) is common among obese adolescents. The aim of the present study was to investigate the association between glucose tolerance and intramyocellular, intra-abdominal and liver fat in adolescents presenting with early-onset severe obesity. DESIGN AND METHODS: We studied 21 adolescents (mean age 13.5 years, range 11.5-15.9 years) referred to secondary care due to severe obesity (relative weight for height > +60% or body mass index > 98th percentile for age and sex, before the age of 10 years) and their eight non-obese siblings (mean age 14.4 years, range 11.8-16.7 years). All subjects underwent oral glucose tolerance tests, followed by magnetic resonance spectroscopy (MRS) to measure the intramyocellular fat content in mainly oxidative soleus and mainly glycolytic tibialis anterior muscles. MRS was also used to measure liver fat. Abdominal fat (subcutaneous, intraperitoneal and retroperitoneal) was measured using MR imaging. RESULTS: Compared with their non-obese siblings, the obese adolescents had increased fat deposition in all anatomic locations studied. Eight obese adolescents had IGT, and they also had increased intramyocellular fat in the soleus (P=0.03) and increased intraperitoneal fat (P=0.04) compared with obese subjects with normal glucose tolerance (NGT). In contrast, no significant difference was seen between obese adolescents with NGT and IGT in liver fat (P=0.9) or intramyocellular fat in the tibialis anterior (P=0.13). In logistic regression analysis, increased soleus intramyocellular fat and intraperitoneal fat were significant predictors of IGT. CONCLUSIONS: IGT in obese adolescents is associated with increased intramyocellular and intraperitoneal fat rather than liver fat.

Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia.

OBJECTIVE: Mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) underlie osteoporosis-pseudoglioma syndrome. Animal models implicate a role for LRP5 in lipid and glucose homeostasis. The objective was to evaluate metabolic consequences of LRP5 mutations in humans. DESIGN AND PATIENTS: Thirteen Finnish individuals with homozygous or heterozygous LRP5 mutations were assessed for bone health, glucose and lipid metabolism, and for serum serotonin concentration. Results were compared with findings in family members without mutations. MEASUREMENTS: Bone mineral density (BMD), vertebral morphology, oral and intravenous glucose tolerance tests, lipid profile and serum serotonin concentrations. RESULTS: Two individuals were homozygous for R570W, one compound heterozygous for R570W and R1036Q, and 10 were heterozygous (six for R570W, three for R1036Q and one for R925C). Subjects with two LRP5 mutations had multiple spinal fractures and low BMD. Subjects with one mutation had significantly lower median lumbar spine (P = 0.004) and femoral neck (P = 0.005) BMD Z-scores, and more often vertebral fractures than the 18 individuals without mutations. Of the 12 subjects with LRP5 mutation six had diabetes and one had impaired glucose tolerance. Intravenous glucose tolerance tests suggested impaired beta-cell function; no insulin resistance was observed. Prevalence of hypercholesterolaemia was similar in mutation positive and negative subjects. Serum serotonin concentrations showed a trend towards higher concentrations in subjects with LRP5 mutation. CONCLUSIONS: We found high prevalence of osteoporosis and abnormal glucose metabolism in subjects with LRP5 mutation(s). Further studies are needed to establish the role of LRP5 in glucose and lipid metabolism.

Fasting plasma glucose variability as a marker of nocturnal hypoglycemia in diabetes: evidence from the PREDICTIVE study.

The relationship between fasting glucose (FG) variability and nocturnal hypoglycemia was assessed using longitudinal data from PREDICTIVE, the large-scale observational study of insulin detemir. An HbA(1c)-corrected correlation was found between these endpoints, suggesting FG variability can serve as a useful marker for this risk in clinical practice.

Effects of recombinant human IGF-I/IGF-binding protein-3 complex on glucose and glycerol metabolism in type 1 diabetes.

Recombinant human IGF-I (rhIGF-I) complexed with its natural binding protein IGF-binding protein (IGFBP)-3 (rhIGF-I/IGFBP-3) is a novel formulation that has been shown to improve insulin sensitivity in type 1 diabetes, yet the mechanisms are not clear. We used stable isotopes to investigate the effects of rhIGF-I/IGFBP-3 on glucose and glycerol metabolism in type 1 diabetes. Fifteen subjects (age 13-24 years; 10 males) were studied on three occasions in random order. Each study period lasted for two days, and an injection of either placebo or rhIGF-I/IGFBP-3 (0.1-0.8 mg x kg(-1) x day (-1)) was given subcutaneously at 6:00 p.m. on days 1 and 2. Following the second injection, the subjects were kept euglycemic overnight by a variable rate insulin infusion, followed by a 4-h, two-step (insulin 0.6 and 1.5 mU x kg(-1) x min (-1)) hyperinsulinemic-euglycemic clamp. During the overnight basal steady state, rhIGF-I/IGFBP-3 dose-dependently reduced endogenous glucose production rate (R(a)) (P = 0.004), while peripheral glucose uptake (R(d)) was not different from placebo. The increase in glucose R(d) during hyperinsulinemic clamp was greater following rhIGF-I/IGFBP-3 than placebo, both during the first (P = 0.008) and second step (P = 0.008) of the clamp. No significant differences were found in glycerol R(a), a measure of lipolysis, between rhIGF-I/IGFBP-3 and placebo. In conclusion, rhIGF-I/IGFBP-3 enhances glucose metabolism by controlling both endogenous glucose output and peripheral glucose uptake.

Dose-dependent effects of recombinant human insulin-like growth factor (IGF)-I/IGF binding protein-3 complex on overnight growth hormone secretion and insulin sensitivity in type 1 diabetes.

GH hypersecretion in type 1 diabetes has been implicated in the pathogenesis of insulin resistance, and microangiopathic complications, and may result from reduced circulating IGF levels. We examined the effects of recombinant human (rh)IGF-I [complexed in equimolar ratio with rhIGF binding protein (BP)-3 (rhIGF-I/IGFBP-3)] replacement on overnight GH levels and insulin sensitivity in type 1 diabetes. Fifteen subjects, 13-24 yr old (10 male), were given rhIGF-I/IGFBP-3 or placebo as a daily sc injection for 2 d. After the second injection overnight, insulin requirements for euglycemia were determined (0400-0800 h), followed by a 4-h, two-step (insulin, 0.6 and 1.5 mU/kg.min) hyperinsulinemic euglycemic [90 mg/dl (5 mmol/liter)] clamp. In each subject, the protocol was repeated on three occasions in random order. Seven subjects received placebo and rhIGF-I/IGFBP-3 (0.1 mg/kg.d and 0.4 mg/kg.d), and eight subjects received placebo and rhIGF-I/IGFBP-3 (0.2 mg/kg.d and 0.8 mg/kg.d). We found dose-dependent increases in circulating IGF-I and IGFBP-3 concentrations after rhIGF-I/IGFBP-3. These were paralleled by significant reductions in mean overnight GH levels and GH pulse amplitude. We also observed dose-dependent effects of rhIGF-I/IGFBP-3 on overnight insulin requirements for euglycemia, with reductions of up to 41%. Insulin sensitivity, defined by M-values, was improved with rhIGF-I/IGFBP-3 (0.4 and 0.8 mg/kg.d). Thus, restoration of circulating IGF-I and IGFBP-3 levels with rhIGF-I/IGFBP-3 suppresses GH secretion in adolescents with type 1 diabetes, leading to reduced insulin requirements and improvements in insulin sensitivity.

Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene.

The type 1 IGF receptor (IGF1R) is required for normal embryonic and postnatal growth. The aim of this study was to determine whether we could detect abnormal IGF1R function in skin fibroblasts from children with an abnormal copy number of the IGF1R gene. We report two children with altered copy number of the IGF1R gene who presented with abnormal growth. Case 1 is a girl with intrauterine growth retardation, postnatal growth failure, and recurrent hypoglycemia. Pituitary function tests were normal. Routine karyotype analysis identified a deletion on 15q26.2, and a fluorescence in situ hybridization study using IGF1R probes showed only a single IGF1R gene. Case 2 was large for gestational age, with birth weight and length at or above 97th percentile, and showed rapid early postnatal growth. He was found to have a recombinant chromosome 15 containing a partial duplication at 15q (q25-qter). A fluorescence in situ hybridization study using the same probes showed three copies of the IGF1R gene. In a mitochondrial activity assay, skin fibroblasts from the subject with only one copy of IGF1R showed slower growth, whereas cells from the subject with three copies of IGF1R showed accelerated growth compared with controls. IGF1R phosphorylation, as assessed by Western blot, and IGF1R binding studies were decreased compared with controls in the child with one copy of the IGF1R and increased in the child with three copies of the gene. Our data are consistent with the concept that IGF1R gene copy number is of functional and clinical importance in humans.

The role of sex steroids in the regulation of insulin sensitivity and serum lipid concentrations during male puberty: a prospective study with a P450-aromatase inhibitor.

OBJECTIVE: Our purpose was to study the sex steroid-mediated changes in serum insulin and lipid concentrations in boys during puberty. DESIGN AND METHODS: We treated boys with constitutional delay of puberty either with testosterone plus placebo or with testosterone plus an aromatase inhibitor, letrozole, which inhibits the conversion of androgens to oestrogens. We demonstrated previously that during treatment with testosterone plus letrozole the increase in testosterone concentration was more than 5-fold higher than during treatment with testosterone plus placebo. The concentrations of 17beta-oestradiol, IGF-I and IGF-binding protein-3 increased during testosterone-plus-placebo treatment, but during testosterone-plus-letrozole treatment the concentrations remained unchanged. These divergent changes in the two groups enabled us to study the effects of sex steroids and GH on insulin sensitivity and lipid concentrations. RESULTS: The insulin concentration in the testosterone-plus-placebo-treated group did not change. In contrast, in the testosterone-plus-letrozole-treated group, the concentration decreased during letrozole treatment, indicating improved insulin sensitivity. Changes in insulin and IGF-I concentrations within 12 and 18 months were correlated. In the testosterone-plus-placebo-treated group, the high-density lipoprotein cholesterol concentration did not change but in the testosterone-plus-letrozole-treated group the concentration decreased. The concentrations of low-density lipoprotein cholesterol (LDL-cholesterol) and triglycerides did not change in either of the groups. CONCLUSIONS: The findings indicate that androgens do not directly alter insulin sensitivity in boys during puberty. In contrast, the observations suggest tight regulation of glucose--insulin homeostasis by GH in boys at this stage. Furthermore, our findings indicate that sex steroids do not significantly participate in the regulation of serum concentrations of LDL-cholesterol or triglycerides in boys during early and mid-puberty.

Intestinal permeability to mannitol and lactulose in children with type 1 diabetes with the HLA-DQB1*02 allele.

Food antigens and enteroviruses are possible triggers of type 1 diabetes. Because permeability of the intestinal epithelium may facilitate contact of these antigens with the mucosal immune system, we set out to study intestinal permeability in patients with type 1 diabetes. Children with type 1 diabetes (n = 26, mean age 12 years, mean duration of disease 4 years) and 24 healthy age-matched control children were given mannitol and lactulose orally, and their intestinal permeability was measured as a percentage of this dose recovered in urine. Patients with type 1 diabetes did not differ in their permeability to lactulose, nor was their lactulose/mannitol ratio any different from that of controls. However, patients with type 1 diabetes who had the HLA-DQB 1*02 allele and, therefore, a higher risk for celiac disease (CD) absorbed significantly more mannitol (mean + 95% CI): 17.7% (15.2-20.2) than did those negative for this allele: 12.3% (8.2-16.4), p = 0.04. Their lactulose permeability was also higher: 0.30 (0.16-0.44) and 0.09% (0-0.18), respectively, p = 0.02. Although the differences in permeability reach statistical significance, there was still much overlap between the two groups in terms of actual laboratory values. The higher permeability of patients with the HLA-DQB1*02 allele suggests that these patients may be more prone to develop abnormal immune responses to food antigens.