Early postnatal growth in children with HLA-conferred susceptibility to type 1 diabetes.

AIMS/HYPOTHESIS: An association between increased length/height and weight gain and risk of type 1 diabetes (T1D) has been reported in children. We set out to investigate the potential contribution of T1D human leukocyte antigen (HLA) risk genotypes to this association in two countries with a contrasting disease incidence. METHODS: In Estonia and Finland, length and weight were monitored up to the age of 24 months in 688 subjects. According to their HLA genotypes, the children were divided into four groups, those with very high, high or moderate risk for T1D, as well as a neutral/control group. Relative length and weight (SDS) were assessed and compared at 3, 6, 12, 18 and 24 months using World Health Organization (WHO) growth curves. RESULTS: The mean relative length at the age of 24 months was lower in the group with the very high risk HLA genotype compared to the controls (p < 0.05). The mean relative weight differed between those two groups at the age of 12, 18 and 24 months (p < 0.05). When Estonian and Finnish cohorts were analyzed separately, the relative length showed similar but non-significant trends in both countries, while in Estonia the changes in weight at some time points still remained significant (p < 0.05). CONCLUSIONS: Children with the highest HLA-conferred risk for T1D gained less weight and length during the first 24 months of life, and this feature was more pronounced in the Estonian children.

Feasibility and compliance in a nutritional primary prevention trial in infants at increased risk for type 1 diabetes.

AIM: The international Trial to Reduce IDDM in the Genetically at Risk (TRIGR) was launched to determine whether weaning to a highly hydrolysed formula in infancy reduces the incidence of type 1 diabetes in children at increased genetic disease susceptibility. We describe here the findings on feasibility and compliance from the pilot study. METHODS: The protocol was tested in 240 children. The diet of the participating children was assessed by self-administered dietary forms, a structured questionnaire and a food record. Blood samples were taken and weight and height measured at birth and at 3, 6, 9, 12, 18 and 24 months. RESULTS: A majority of the subjects (84%) were exposed to the study formula at least for 2 months. Linear growth or weight gain over the first 2 years of life was similar in the two study groups. The levels of IgA and IgG antibodies to cow's milk and casein were higher in the cow's milk-based formula group than in the hydrolysed formula group during the intervention period (p<0.05), reflecting the difference in the intake of cow's milk protein. CONCLUSION: This randomized trial on infant feeding turned out to be feasible, and dietary compliance was acceptable. Valuable experience was gained for the planning and sample size estimation of the study proper.

Inter- and intra-specific responses to elevated ozone and chamber climate in northern birches.

We studied the responses of micropropagated, northern provenances of downy, mountain and silver birches to elevated ozone (O(3)) and changing climate using open-top chambers (OTCs). Contrary to our hypothesis, northern birches were sensitive to O(3), i.e. O(3) levels of 31-36 ppb reduced the leaf and root biomasses by -10%, whereas wood biomass was affected to a lesser extent. The warmer and drier OTC climate enhanced growth in general, though there were differences among the species and clones, e.g. in bud burst and biomass production. Inter- and intra-specific responses to O(3) and changing climate relate to traits such as allocation patterns between the above- and belowground parts (i.e. root/shoot ratio), which further relate to nutrient and water economy. Our experiments may have mimicked future conditions quite well, but only long-term field studies can yield the information needed to forecast responses at both tree and ecosystem levels.

Apolipoprotein E epsilon 4 allele is associated with increased atrophy in progressive mild cognitive impairment: a voxel-based morphometric study.

BACKGROUND: The apolipoprotein E (APOE) epsilon4 allele is a risk factor for Alzheimer's disease. Earlier studies have shown differences in brain structure according to the APOE epsilon4 status. OBJECTIVE: To assess possible differences in brain structure according to the APOE epsilon4 status in mild cognitive impairment (MCI) subjects in relation to conversion to dementia. METHODS: In a follow-up study of 56 MCI subjects, 13 MCI subjects progressed to dementia (PMCI) during a mean follow-up time of 31 months. Brain structure differences in both stable MCI (SMCI) and PMCI epsilon4 carriers and noncarriers in the baseline MRI scan were assessed with voxel-based morphometry. RESULTS: The SMCI epsilon4 carriers had atrophy in the amygdala and hippocampus compared to the SMCI noncarriers. The PMCI epsilon4 carriers revealed atrophy of the left inferior frontal gyrus and parietal cortex compared to the PMCI noncarriers. CONCLUSION: The rate of brain atrophy in certain brain areas may be increased in epsilon4-positive MCI subjects progressing to dementia.

Dietary manipulation of beta cell autoimmunity in infants at increased risk of type 1 diabetes: a pilot study.

AIMS/HYPOTHESIS: We aimed to assess the feasibility of a dietary intervention trial with weaning to hydrolysed formula in infants at increased risk of type 1 diabetes and to study the effect of the intervention on the emergence of diabetes-associated autoantibodies in early childhood. METHODS: We studied 242 newborn infants who had a first-degree relative with type 1 diabetes and carried risk-associated HLA-DQB1 alleles. After exclusive breastfeeding, the infants underwent a double-blind, randomised pilot trial of either casein hydrolysate (Nutramigen; Mead Johnson) or conventional cow's milk-based formula until the age of 6-8 months. During a mean observation period of 4.7 years, autoantibodies to insulin, anti-glutamic acid decarboxylase and insulinoma-associated antigen-2 were measured by radiobinding assays, and islet cell antibodies (ICA) by immunofluorescence. RESULTS: The feasibility of screening and identifying a cohort of first-degree relatives with HLA-conferred disease susceptibility, enrolling them in a dietary intervention trial and following them for seroconversion to autoantibody positivity is established. The cumulative incidence of autoantibodies was somewhat smaller in the casein hydrolysate vs control formula group, suggesting the need for a larger well-powered study. After adjustment for duration of study formula feeding, life-table analysis showed a significant protection by the intervention from positivity for ICA (p=0.02) and at least one autoantibody (p=0.03). CONCLUSIONS/INTERPRETATION: The present study provides the first evidence ever in man, despite its limited power, that it may be possible to manipulate spontaneous beta cell autoimmunity by dietary intervention in infancy.

Enterovirus infections as a risk factor for type I diabetes: virus analyses in a dietary intervention trial.

This study evaluated the possible role of enterovirus infections in the pathogenesis of type I (insulin-dependent) diabetes in a prospective dietary intervention trial. Children participated in the second pilot of the Trial to Reduce IDDM in Genetically at Risk (TRIGR) project. They were randomized into two groups receiving either a casein hydrolysed formula (Nutramigen) or a regular formula, whenever breast milk was not available over the first 6-8 months of life. Altogether 19 children who turned positive for autoantibodies associated with type I diabetes by 2 years of age and 84 matched control children were analysed for enterovirus antibodies and enterovirus RNA in serum. Enterovirus infections were common during the first 2 years of life and more frequent among boys than girls (P = 0.02). Autoantibody-positive children had more enterovirus infections than autoantibody-negative children before the appearance of autoantibodies (0.83 versus 0.29 infection per child, P = 0.01). The average levels of IgG antibodies to echovirus antigen were also higher in autoantibody-positive than in autoantibody-negative children (P = 0.0009). No difference was found in the frequency of enterovirus infections between children receiving the casein hydrolysed formula or regular formula. These results suggest that enterovirus infections are associated with the induction of beta-cell autoimmunity in young children with increased genetic susceptibility to type I diabetes.

Disease-associated autoantibodies during pregnancy and at birth in families affected by type 1 diabetes.

We studied the pattern of type 1 diabetes-associated autoantibodies during pregnancy and the transplacental transfer of these autoantibodies to the fetal circulation and searched for possible signs of prenatal induction of beta-cell autoimmunity in newborn infants. The population comprised 208 mothers and their newborn infants. Seventy-four of the mothers (36%) had type 1 diabetes and 134 (64%) of the infants had an affected father or sibling. Blood samples were obtained from the mother at the end of the first trimester and at delivery, and from the cord blood of the newborn infant. Close to 40% of the mothers with type 1 diabetes had antibodies to islet cells (ICA), 55% to glutamic acid decarboxylase (GADA) and 54% to the IA-2 protein (IA-2A) in early pregnancy, whereas the corresponding frequencies in the nonaffected mothers were 5.2%, 5.2% and 3.0%. No significant changes could be seen in autoantibody levels during pregnancy, and there was a close correlation between the two maternal samples. One third of the infants of mothers with type 1 diabetes tested positive for ICA, 50% for GADA and 51% for IA-2A. Six percent of the infants of nondiabetic mothers had ICA, 2.2% GADA and none had IA-2A. None of the infants of the antibody negative mothers had antibodies in their cord blood. These observations indicate that the immunomodulatory effect of pregnancy on signs of beta-cell autoimmunity is weak, but if diabetes-associated autoantibodies are present in the mother, most of them are transferred to the fetal circulation. Our data do not provide any support for fetal induction of beta-cell autoimmunity.

The first signs of beta-cell autoimmunity appear in infancy in genetically susceptible children from the general population: the Finnish Type 1 Diabetes Prediction and Prevention Study.

Little is known about the timing of the etiological events and the preclinical process of type 1 diabetes during the first years of life in the general population. In this population-based prospective birth cohort study, the appearance of diabetes-associated autoantibodies as a sign of beta-cell autoimmunity and the development of type 1 diabetes were monitored from birth. Of 25,983 newborn infants, 2,448 genetically susceptible children were monitored for islet cell antibodies (ICA) at 3- to 6-month intervals. If an infant seroconverted to ICA positivity, all his/her samples were also analyzed for insulin autoantibodies (IAA), antibodies to the 65-kDa isoform of glutamic acid decarboxylase, and antibodies to the protein tyrosine phosphatase-related IA-2 molecule. Fifteen children of those who carried the high-risk genotype (2.7%) and 23 of those who carried the moderate-risk genotype (1.2%; P = 0.019) tested positive for ICA at least once. Among those who showed positivity for at least 2 antibodies during the observation period (25 of 38), IAA appeared as the first or among the first antibodies in 22 children (88%) and emerged earlier than the other antibodies (P < 0.019 or less). The first autoantibodies appeared in the majority of the children in the fall and winter (30 of 38 vs. 8 of 38 in the spring and summer, P < 0.001). These observations suggest that young children in the general population with a strong human-leukocyte-antigen-DQ-defined genetic risk of type 1 diabetes show signs of beta-cell autoimmunity proportionally more often than those with a moderate genetic risk. IAA emerge as the first detectable antibody more commonly than any other antibody specificity, implying that insulin may be the primary antigen in most cases of human type 1 diabetes associated with the DR4-DQB1*0302 haplotype. The seasonal variation in the emergence of the first signs of beta-cell autoimmunity suggests that infectious agents may play a role in the induction of such autoimmunity.

Pregnancy induces nonimmunoglobulin insulin-binding activity in both maternal and cord blood serum.

To evaluate whether pregnancy has any effect on insulin antibody levels and to test the concordance between a conventional radioimmunoassay and a new microassay for the detection of insulin antibodies, insulin antibodies were analysed in 104 mothers in early pregnancy and at delivery and in their newborn infants. Thirty-eight of the mothers had type 1 diabetes. The concordance between the assays was high in the samples taken in early pregnancy (95%), but substantially lower in the samples taken at delivery (40%) and in the cord blood samples (68%). A considerable proportion of the mothers at delivery, especially the unaffected mothers (71%), and the newborn infants of the unaffected mothers (32%) were positive for insulin antibodies in the conventional assay but not in the microassay. Insulin antibody levels increased in the mothers, significantly so in the unaffected mothers (P < 0.001), during pregnancy in the conventional assay, whereas in the microassay they decreased significantly (P < 0.01) in affected mothers and remained negative in the unaffected mothers. Since immune complexes are precipitated with protein A specific for IgG in the microassay and with polyethylene glycol lacking specificity for immunoglobulins in the conventional assay, our data indicate that insulin antibody levels decrease on average during pregnancy and that the increasing non-IgG anti-insulin activity observed in the conventional assay is induced by pregnancy and is present in both the maternal and the foetal circulation.

Feasibility of genetic and immunological prediction of type I diabetes in a population-based birth cohort.

AIMS/HYPOTHESIS: Population-wide genetic screening of susceptibility to multifactorial diseases will become relevant as knowledge of the pathogenesis of these diseases increases and preventive interventions are identified. METHODS: Feasibility and acceptance of neonatal genetic screening for Type I (insulin-dependent) diabetes mellitus susceptibility and adherence of the at-risk children to frequent autoantibody follow-up were studied. Screening was offered to all families. The infants with HLA-DQB1 genotypes *02/*0302 and *0302/x (x not equal to *02, *0301, *0602) were invited to autoantibody follow-up. The children who developed signs of beta-cell autoimmunity were invited to a separate prevention trial. RESULTS: The parents of 31,526 babies born between November 1994 and April 1999 (94.4% of those eligible) agreed to genetic screening. We found that 4651 infants (14.8%) had increased genetic risk (2.5 to 15 times that of the general population) for Type I (insulin-dependent) diabetes mellitus, and 80% of them joined the autoantibody surveillance. At the age of 1, 2, 3 and 4 years, 74, 69, 68 and 76% of the at-risk children, respectively, attended the follow-up. A total of 17 of the 22 children (77%) who were born during the study period and have developed diabetes carry the risk genotypes we currently use for screening. CONCLUSIONS/INTERPRETATION: Population-based screening of genetic susceptibility for Type I diabetes, linked with a possibility to participate later in a prevention trial, is highly accepted in Finland and identifies about 75% of those developing diabetes at an early age. Families adhere well to the frequent measurement of signs of beta-cell autoimmunity in the children at-risk.

Postnatal elimination of transplacentally acquired disease-associated antibodies in infants born to families with type 1 diabetes. The Finnish TRIGR Study Group. Trial to Reduce IDDM in the Genetically at Risk.

The elimination of maternally acquired, diabetes-associated antibodies from the peripheral circulation of infants was studied in a population of 47 mothers and their newborn infants from families in which at least 1 first degree relative had type 1 diabetes. Blood samples were taken from the placental cord; from the infant at follow-up visits at the ages of 3, 6, 9, 12, 18, and 24 months; and from the mother at the time of delivery. The samples were analyzed for cytoplasmic islet cell antibodies (ICA), insulin antibodies (IA), autoantibodies to the 65-kDa isoform of glutamic acid decarboxylase (GADA), and autoantibodies to the protein tyrosine phosphatase-related IA-2 antigen (IA-2A). The mean elimination times for ICA, IA, GADA, and IA-2A were 3.1, 3.1, 4.5, and 4.3 months (P = NS), respectively. The initial levels of IA, GADA, and IA-2A in the cord blood correlated closely with the elimination time (r(s) = 0:84-0.91; P < 0.001). The mean proportions of ICA, IA, GADA, and IA-2A still detectable were 18%, 21%, 30%, and 20%, respectively, at 3 months; 2.2%, 14%, 10%, and 6% at 6 months; and 0.3%, 15%, 2.3%, and 5.1% at 9 months. One infant still tested positive for GADA at the age of 12 months, whereas all of the other antibodies had been eliminated by that age. When observing the natural history of beta-cell autoimmunity or when screening for secondary prevention in young children, cross-sectional autoantibody analyses do not provide sufficient information. Repeated testing is to be recommended in young children. In infancy, increasing antibody levels most likely reflect de novo synthesis of diabetes-associated autoantibodies.

Cerebral hemodynamics in human acute ischemic stroke: a study with diffusion- and perfusion-weighted magnetic resonance imaging and SPECT.

Nineteen patients with acute ischemic stroke (<24 hours) underwent diffusion-weighted and perfusion-weighted (PWI) magnetic resonance imaging at the acute stage and 1 week later. Eleven patients also underwent technetium-99m ethyl cysteinate dimer single-photon emission computed tomography (SPECT) at the acute stage. Relative (ischemic vs. contralateral control) cerebral blood flow (relCBF), relative cerebral blood volume, and relative mean transit time were measured in the ischemic core, in the area of infarct growth, and in the eventually viable ischemic tissue on PWI maps. The relCBF was also measured from SPECT. There was a curvilinear relationship between the relCBF measured from PWI and SPECT (r = 0.854; P < 0.001). The tissue proceeding to infarction during the follow-up had significantly lower initial CBF and cerebral blood volume values on PWI maps (P < 0.001) than the eventually viable ischemic tissue had. The best value for discriminating the area of infarct growth from the eventually viable ischemic tissue was 48% for PWI relCBF and 87% for PWI relative cerebral blood volume. Combined diffusion and perfusion-weighted imaging enables one to detect hemodynamically different subregions inside the initial perfusion abnormality. Tissue survival may be different in these subregions and may be predicted.

Human brain activity during exposure to radiofrequency fields emitted by cellular phones.

OBJECTIVES: The aim of this study was to explore the possible influence of radiofrequency (RF) radiation exposure on human brain function. METHODS: The electroencephalographic (EEG) activity of 19 volunteers was quantitatively analyzed. Ten of the subjects were men (28-48 years of age) and 9 were women (32-57 years of age). The sources of exposure were 5 different cellular phones (analogue and digital models) operating at a frequency of 900 MHz or 1800 MHz. The EEG activity was recorded in an awake, closed-eyes situation. Six 30-minute experiments, including 1 sham exposure, were made for each subject. The duration of a real exposure phase was 20 minutes. RESULTS: Exposure to one of the phones caused a statistically significant change in the absolute power at the delta band of the EEG recording. However, no difference was seen in the relative power of the same band, and no changes occurred during exposure to other phones at any frequency bands. CONCLUSIONS: The findings of this study suggest that exposure to radiofrequency fields emitted by cellular phones has no abnormal effects on human EEG activity. The observed difference in 1 parameter was probably caused by statistical chance.

Human surfactant protein--A gene locus for genetic studies in the Finnish population.

Lung surfactant lowers the surface tension but surfactant proteins also have other functions. Surfactant protein A (SP-A) has a well-defined role in innate immunity. The gene locus for human SP-A genes is in chromosome 10q21 through q24 and consists of two highly homologous functional SP-A genes (SP-A1 and SP-A2) and a pseudogene. Several alleles that differ by a single amino acid have been identified for both SP-A genes. The SP-A gene locus has been shown to be sufficiently polymorphic for genetic studies in the American population. In this study, we analysed the SP-A allele frequencies in a Finnish population (n = 790) and found them to differ from the frequencies observed in US. Furthermore, we describe several new alleles for both SP-A genes. The heterozygosity indices and polymorphism information content values ranged between 0.50--0.62 indicating that SP-A gene locus is polymorphic enough for studies associating the locus with pulmonary diseases.

Cow's milk formula feeding induces primary immunization to insulin in infants at genetic risk for type 1 diabetes.

Insulin autoantibodies (IAAs) often appear as the first sign of islet cell autoimmunity in prediabetic children. Because cow's milk contains bovine insulin, we followed the development of insulin-binding antibodies in children fed with cow's milk formula. Bovine insulin- and human insulin-binding antibodies by enzyme immunoassay and IAA by radioimmunoassay were analyzed in 200 infants carrying HLA-DQB1*0302 but no protective alleles who participated in a Finnish population-based birth-cohort study. Based on the prospectively registered information, the first 100 infants enrolled in the study who were exposed to cow's milk formula before age 12 weeks and the first 100 infants enrolled in the study who were exclusively breast-fed for longer than their first 12 weeks of life were selected for the present study. Also, 11 children from the birth cohort who developed at least two diabetes-associated autoantibodies, 98 children with newly diagnosed type 1 diabetes, and 92 healthy children were studied. We found that the amount of IgG-antibodies binding to bovine insulin was higher at age 3 months in infants who were exposed to cow's milk formula than in infants who were exclusively breast-fed at that age (median 0.521 vs. 0.190; P < 0.0001). The antibodies binding to bovine insulin cross-reacted with human insulin. None of these infants tested positive for IAA. The levels of bovine insulin-binding antibodies declined in both groups at ages 12 and 18 months, whereas in the 11 children with at least two diabetes-associated autoantibodies the levels increased during the follow-up period (P < 0.0001). IgG antibodies correlated with IgG2 antibodies binding to bovine insulin (r = 0.43, P = 0.004) and IAA (r = 0.27, P = 0.02) in diabetic children, but not in healthy children. Cow's milk feeding is an environmental trigger of immunity to insulin in infancy that may explain the epidemiological link between the risk of type 1 diabetes and early exposure to cow's milk formulas. This immune response to insulin may later be diverted into autoaggressive immunity against beta-cells in some individuals, as indicated by our findings in children with diabetes-associated autoantibodies.

The biopsychosocial disease consequence model in rehabilitation: model development in the Finnish 'work hardening' programme for chronic pain.

To compare the effectiveness of diverse rehabilitation programmes, comparable data about their effects on maintaining or improving the residual function of the rehabilitation patients should be gathered. Current rehabilitation theories and assessment procedures for functioning are not consistent enough for valid comparisons. The rehabilitation theory should be developed to produce coherence and generalizability to the rehabilitation process. The biopsychosocial disease consequence (BPSDC) model for functioning is presented for this purpose. The model describes the rehabilitation process of patients with chronic pain as a three-axial (biopsychosocial) and three-dimensional (disease consequences) assessment and intervention grid for functioning. It emphasizes the strict mutual relationship between the assessment procedures and intervention plans. Application of the BPSDC model in the Finnish AKSELI project studying the effects of two different programmes on patients with chronic low-back pain is described. Although the AKSELI studies indicated that in addition to the assessment procedures other factors also contributed to valid evaluation of outcomes, and it is hoped that the BPSDC model will encourage researchers to look for definitions of functioning, to assess functioning according to theoretical assumptions about the sub-areas of functioning, and to provide comparable outcome data for the evaluation of various programmes.

An empirical investigation of the 'Biopsychosocial Disease Consequence model': psychological impairment, disability and handicap in chronic pain patients.

The purpose of this study is to emphasize the meaningfulness of a global, functional rather than a narrow medical view in the efficacy evaluation of chronic pain treatment. Therefore, the 'Biopsychosocial Disease Consequence (BPSDC) model' to assess function more globally than before, is presented in this article. The model is based on two theories: (1) the biopsychosocial approach and (2) WHO's classification of impairments, disabilities and handicaps. In addition to the presentation of the conceptual model, the development of the hypothetical criteria and assessment models for psychological impairments, disabilities and handicaps, and the validity testing of the psychological assessment axis are described. Within each of the three classes, i.e. psychological impairments, disabilities and handicaps, the results supported the independence of the hypothetical criteria from each other. On the other hand, results suggested that some changes to the hypothetical assessment models for some of the criteria might be valuable. It was concluded that although the most adequate psychological assessment models for function, found in this study, can be considered as robust and recommendable as one set of tools for functional assessment, the main aim of this article is to encourage multidisciplinary team efforts to develop and systematize the assessment procedures of function in patients suffering from chronic diseases.

Mental health and functioning: a case analysis of rehabilitation patients.

The relationship between mental health and functioning has been inconsistently described. Here, the role of mental health in determining functioning was studied from a large multi-axial (biopsychosocial) and multi-dimensional (impairments, disabilities and handicaps) point of view. Case-analysis of rehabilitation patients indicated that inconsistent findings may be due to an incorrect linearity assumption. Results indicated that: (1) good mental health may aid the patient to benefit from rehabilitation. However, (2) it does not guarantee good future functioning, because the impact of mental health on functioning varies in interaction with other functional aspects. On the other hand, (3) poor mental health does not necessarily impede good future functioning, whereas (4) poor mental health, associated with other aspects of poor functioning, quite reliably predicts poor functioning after rehabilitation. It was concluded that single psychological factors cannot predict functioning. To improve prediction, broader models of functional assessment in rehabilitation should be used.

Psychologists' role in functional assessment of rehabilitation patients.

In this study attention was paid to the psychological criteria that clinicians may use when assessing global functioning of rehabilitation patients. Global functioning was understood to be determined by physical, psychological and social factors and was operationally defined as performance in three different areas of life: work, daily activities and human relations. The psychological factors whose relationships to global functioning were studied were three components of personality dynamics:--mental health, cognitive skills and motivation. Patients' mental health, cognitive abilities, motivation and global functioning were clinically rated on the basis of data given by psychological interview, psychological test-results and other information. Correlation analysis showed that the clinicians tend to use the mental health state, the level of cognitive performance and the degree of motivation as criteria when assessing the functioning of rehabilitation patients during the rehabilitation examination. However, multiple regression analysis showed that these psychological variables explained as little as 32% of the variance in follow-up functioning. This is in agreement with the biopsychosocial view that psychological factors are only one class of events manifesting in illness, functioning and behavior.

The effect of liver microsomal enzyme inducing and inhibiting drugs on insulin mediated glucose metabolism in man.

The effects of hepatic microsomal enzyme inducing (phenobarbitone and flumecinol), and inhibiting (cimetidine) drugs, and placebo treatment on insulin mediated glucose metabolism (M) were investigated in 29 healthy volunteers. Phenobarbitone (50 mg for 10 days) increased M (30%), metabolic clearance rate of glucose (MCRg), and antipyrine clearance rate (33%). Fasting immunoreactive insulin (IRI) decreased while fasting blood glucose (BG) remained unaltered. Flumecinol, another inducer, tested in two doses (200 mg and 600 mg for 6 days), did not alter glucose or antipyrine metabolism. Fasting IRI reduced on treatment with 600 mg of flumecinol, but not with the smaller dose. Cimetidine (600 mg for 6 days) decreased M (19.5%), MCRg (26%), and antipyrine clearance rate (20%). The placebo did not alter glucose or antipyrine metabolism. The results indicate that the insulin mediated glucose disposal rate can be altered by drugs influencing hepatic microsomal enzyme activity.