Low serum 25-hydroxyvitamin D level predicts progression to type 2 diabetes in individuals with prediabetes but not with normal glucose tolerance.

AIMS/HYPOTHESIS: Vitamin D deficiency may increase the risk of type 2 diabetes. We therefore investigated whether serum concentrations of 25-hydroxyvitamin D [25(OH)D] would predict the development of prediabetes (impaired fasting glucose, impaired glucose tolerance or the two combined) and type 2 diabetes, either on their own or when combined with serum concentrations of IGF-1 or IGF-binding protein-1 (IGFBP-1), which may interact with 25(OH)D. METHODS: At baseline, participants aged 35-56 years without known type 2 diabetes were examined using OGTTs, 25(OH)D and IGF peptide measurements, and anthropometric and lifestyle data. Participants who had prediabetes or type 2 diabetes at follow-up 8-10 years later were selected as cases; these were then age- and sex-matched to controls with normal glucose tolerance (NGT) at both baseline and follow-up, giving a total of 980 women and 1,398 men. RESULTS: Men but not women in the highest quartile of 25(OH)D level had a decreased OR for developing type 2 diabetes after adjustment for confounders (OR 0.52, 95% CI 0.30, 0.90), an effect accounted for by individuals with prediabetes, but not with NGT, at baseline. In both sexes, progression from prediabetes to type 2 diabetes was reduced by about 25% per 10 nmol/l increase in 25(OH)D. A high IGFBP-1 value was a better predictor of a reduced risk of type 2 diabetes than high 25(OH)D for both sexes, whereas high IGF-1 concentrations predicted a decreased risk only in men. CONCLUSIONS/INTERPRETATION: High serum 25(OH)D concentrations predict a reduced risk of type 2 diabetes in individuals with prediabetes, but not NGT. There were no significant interactions between 25(OH)D and IGFBP-1 or IGF-1 in terms of risk of diabetes. Our data suggest that vitamin D supplementation should be evaluated for the prevention of type 2 diabetes in prediabetic individuals.

Alcohol consumption and risk of pre-diabetes and type 2 diabetes development in a Swedish population.

AIMS: Alcohol is a potential risk factor of Type 2 diabetes. However, more detailed information on effects of alcohol types and early phases of Type 2 diabetes development seems warranted. The aim of this study was to investigate the influence of alcohol consumption and specific alcoholic beverages on the risk of developing pre-diabetes and Type 2 diabetes in middle-aged Swedish men and women. METHODS: Subjects, who at baseline had normal glucose tolerance (2070 men and 3058 women) or pre-diabetes (70 men and 41 women), aged 35-56 years, were evaluated in this cohort study. Logistic regression was performed to estimate the risk [odds ratio (OR) and 95% confidence interval (CI)] to develop pre-diabetes and Type 2 diabetes at 8-10 years follow-up, in relation to self-reported alcohol intake at baseline. Adjustment was performed for several risk factors. RESULTS: Total alcohol consumption and binge drinking increased the risk of pre-diabetes and Type 2 diabetes in men (OR 1.42, 95% CI 1.00-2.03 and OR 1.67, 95% CI 1.11-2.50, respectively), while low consumption decreased diabetes risk in women (OR 0.41, 95% CI 0.22-0.79). Men showed higher risk of pre-diabetes with high beer consumption (OR 1.84, 95% CI 1.13-3.01) and of Type 2 diabetes with high consumption of spirits (OR 2.03, 95% CI 1.27-3.24). Women showed a reduced risk of pre-diabetes with high wine intake (OR 0.66, 95% CI 0.43-0.99) and of Type 2 diabetes with medium intake of both wine and spirits (OR 0.46, 95% CI 0.24-0.88 and OR 0.55, 95% CI 0.31-0.97, respectively), whereas high consumption of spirits increased the pre-diabetes risk(OR 2.41, 95% CI 1.47-3.96). CONCLUSION: High alcohol consumption increases the risk of abnormal glucose regulation in men. In women the associations are more complex: decreased risk with low or medium intake and increased risk with high alcohol intake.

Factors determining normalization of glucose intolerance in middle-aged Swedish men and women: a 8-10-year follow-up.

AIMS: To examine factors in middle-aged Swedish men and women predicting the conversion from a state of abnormal glucose regulation to normal glucose tolerance (NGT) after 8-10 years. METHODS: At baseline 3128 men and 4821 women, aged 35-56 years, without previously diagnosed diabetes underwent an oral glucose tolerance test and completed a questionnaire. At follow-up, 2383 men and 3329 women were re-examined. The study group consisted of 156 men and 124 women with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both at baseline. RESULTS: The rate of reversal to NGT from IFG or IGT was similar regardless of gender. In participants having IFG or IGT, reversal to NGT was predicted by low fasting and 2-h insulin, homeostasis model assessment of insulin resistance and of pancreatic beta cell function, body mass index and waist circumference without differences between gender and baseline glucose tolerance group. Low 2-h glucose, however, predicted reversal to NGT in men with IFG at baseline, but not in men with IGT at baseline, or in women with either IFG or IGT at baseline. Men reverting to NGT had higher coffee consumption and women had higher baseline leisure-time physical activity. In multiple logistic regression, including all participants, low fasting and 2-h glucose remained independent predictors of reverting to NGT. CONCLUSIONS: Factors predicting reversal to NGT were measures correlated with low insulin resistance, but also lower insulin secretion, perhaps indicating a lower pancreatic beta cell workload in those who reverted. In men, but not in women, low 2-h glucose was of predictive value.

Genetic variation of the adenylyl cyclase 3 (AC3) locus and its influence on type 2 diabetes and obesity susceptibility in Swedish men.

OBJECTIVE: Our previous study using the Goto-Kakizaki rat implicates that the adenylyl cyclase 3 (AC3) is a candidate gene for genetic study of metabolic disorders. The present study aimed to investigate the susceptibility of genetic variation of the AC3 gene in type 2 diabetes (T2D) patients and obese subjects. SUBJECTS AND METHODS: Variation screening in the putative promoter and validation of single nucleotide polymorphisms (SNPs) covering the AC3 gene were performed. In total, 630 Swedish men, including 243 T2D patients (BMI from 18.4 to 45.6 kg m(-2)), 199 obese subjects with normal glucose tolerance (NGT, BMI> or =30 kg m(-2)) and 188 control subjects (NGT, BMI< or =26 kg m(-2)), were genotyped. RESULTS: A novel variant -17A/T in the promoter was identified, but no significant association of this polymorphism with T2D was found. SNPs rs2033655 C/T and rs1968482 A/G were found to be significantly associated with obesity when T2D patients had BMI> or =30 kg m(-2) (P=0.003 and 0.005). The significance was borderline in T2D patients with BMI<30 kg m(-2) (P=0.051 and 0.084) and disappeared in T2D patients with BMI< or =26 kg m(-2). Importantly, analysis in obese subjects with NGT demonstrated that these two polymorphisms were strongly associated with obesity per se (P=0.028 and 0.003). Furthermore, analyses for diplotypes (haplotypic genotypes) predicted an association with BMI in obese subjects. CONCLUSIONS: The present study provides the first evidence that AC3 polymorphisms confer the risk susceptibility to obesity in Swedish men with and without type 2 diabetes.

Psychological distress and risk of pre-diabetes and Type 2 diabetes in a prospective study of Swedish middle-aged men and women.

AIMS: To determine the role of psychological distress as a predictor of pre-diabetes and Type 2 diabetes. METHODS: This cohort study comprised 2127 Swedish middle-aged men and 3100 women with baseline normal glucose tolerance measured by oral glucose tolerance test. At follow-up 8-10 years later, 245 men and 177 women had pre-diabetes [impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and IFG + IGT] and Type 2 diabetes was detected in 103 men and 57 women. Baseline psychological distress was measured by an index of five questions concerning anxiety, apathy, depression, fatigue and insomnia. Odds ratios (ORs) were estimated for pre-diabetes and Type 2 diabetes in association with total psychological distress. In addition, ORs of the single-item questions were calculated. RESULTS: In men, adjusted ORs (95% confidence interval) in the highest index group of psychological distress compared with the lowest group were 1.9 (1.2-2.8) and 2.2 (1.2-4.1) for pre-diabetes and Type 2 diabetes, respectively. Corresponding estimates in women were 1.2 (0.7-2.1) and 0.5 (0.2-1.2). In the middle symptoms groups, adjusted ORs in men were 1.1 (0.8-1.4) for pre-diabetes and 1.2 (0.7-2.0) for Type 2 diabetes and in women 1.8 (1.1-3.0) and 0.7 (0.3-1.4). When analysed separately, the associations with each of the five single factors were similar. CONCLUSIONS: The results indicate that psychological distress, including symptoms of anxiety, apathy, depression, fatigue and insomnia, increases the risk of pre-diabetes and Type 2 diabetes in Swedish middle-aged men. Increased risks were not present in women, except for pre-diabetes in the middle index group.

Serum levels of insulin-like growth factor binding proteins (IGFBP)-4 and -5 correlate with bone mineral density in growth hormone (GH)-deficient adults and increase with GH replacement therapy.

Adults with growth hormone deficiency (GHD) exhibit low bone mineral density (BMD) which improves by growth hormone (GH) replacement therapy. The insulin-like growth factor (IGF) system has an established role in mediating the effects of GH on bone and IGF binding proteins (IGFBP)-4 and IGFBP-5 have been shown to modulate the effects of IGFs in bone. Therefore, we studied serum levels of IGFBP-4 and IGFBP-5 and their relationship to serum levels of bone biochemical markers and BMD in adults with GH deficiency (GHD) before and during GH therapy. Serum levels of IGFBP-5 and IGFBP-4 were measured on samples from 20 patients (11 males) 22-57 years of age. All had IGF-I serum values below -2 standard deviation score. The first 6 months were placebo controlled and all received 3 years of active treatment with the mean dose 0.23 +/- 0.01 IU/kg/week divided into daily subcutaneous injections. Serum IGFBP-5 levels in GHD adults were low at baseline and positively related to total body, femoral neck, trochanter, and Ward's triangle BMD (r = 0.471, 0.549, 0.462, and 0.470, respectively, p < 0.05). The mean serum IGFBP-5 level increased by about 2-fold within 3 months after the initiation of GH therapy and was correlated with serum IGF-I (r = 0.719, 0.801, and 0.722 before and after 18 and 36 months, respectively,p < 0.001). A positive correlation between serum IGFBP-5 levels and lumbar spine BMD was found during GH treatment but not before. The percentage increase of serum IGFBP-5 after GH therapy showed a positive correlation with the percentage increase of total alkaline phosphate activity (r = 0.347 p < 0.05). In contrast to IGFBP-5, serum IGFBP-4 levels were positively related to body mass index (r = 0.607, p < 0.01). Baseline serum IGFBP-4 levels also correlated with total body, femoral neck, trochanter, and Ward's triangle BMD (r = 0.502, 0.590, 0.612, and 0.471, respectively,p < 0.05). The mean serum IGFBP-4 level was increased by 25% within 3 months after initiation of GH therapy and did not correlate with serum IGF-I levels. Although the above findings are consistent with the idea that GH-induced changes in serum IGFBP-5 and IGFBP-4 levels may in part mediate the anabolic effects of GH on bone tissue in adults with GHD, further studies are needed to establish the cause and effect relationship.

Glucagon stimulates insulin-like growth factor binding protein-1 secretion in healthy subjects, patients with pituitary insufficiency, and patients with insulin-dependent diabetes mellitus.

Glucagon (1-1.5 mg) was administrated iv as a bolus dose to healthy individuals (n = 7), patients with GH deficiency (n = 14), and patients with insulin-dependent diabetes mellitus (IDDM; n = 6). Thereafter, blood samples for determination of serum glucose, insulin, insulin-like growth factor-binding protein-1 (IGFBP-1), GH, and insulin-like growth factor-I (IGF-I) concentrations were collected for 180 min. IGFBP-1 concentrations increased significantly in response to glucagon, with maximal values observed at 90 min [in healthy subjects from 36 +/- 6 to 58 +/- 10 micrograms/L (P < 0.05), in GH-deficient patients from 36 +/- 4 to 54 +/- 6 micrograms/L (P < 0.001), and in IDDM patients from 115 +/- 18 to 167 +/- 27 micrograms/L (P < 0.05)]. The IGFBP-1 elevation was delayed in relation to the glucagon-induced increase in glucose and insulin concentrations. When the groups were combined, the individual IGFBP-1 peak value observed at 90 min was inversely correlated to the individual peak value of insulin observed at 15-30 min (r = -0.743; P < 0.001). In GH-deficient patients, serum GH concentrations remained undetectable (< 0.2 micrograms/L), and IGF-I concentrations were unchanged after the glucagon injection. In healthy subjects and IDDM patients, mean GH levels did not change significantly, whereas mean IGF-I concentrations decreased slightly at 30 min. In conclusion, glucagon increased serum IGFBP-1 concentrations in spite of increases in glucose and insulin. These results suggest that glucagon is a stimulator of IGFBP-1.

Altered relation between circulating levels of insulin-like growth factor-binding protein-1 and insulin in growth hormone-deficient patients and insulin-dependent diabetic patients compared to that in healthy subjects.

To investigate whether previously reported increased levels of insulin-like growth factor-binding protein-1 (IGFBP-1) in GH-deficient patients only reflect decreased levels of insulin or are elevated in relation to insulin, diurnal profiles of IGFBP-1 and insulin were determined in plasma from patients with GH levels below 0.2 microgram/L throughout 24 h (n = 23) and compared to profiles from patients with insulin-dependent diabetes mellitus (IDDM; n = 9) and healthy subjects (n = 12). Samples were drawn using a continuous withdrawal technique at 20-min intervals. Levels of IGF-I were determined in one morning sample. As in healthy subjects, serum IGFBP-1 displayed a diurnal variation in GH-deficient as well as in IDDM patients, with lowest levels in the afternoon and evening and a rise with maximum levels during the night and morning. Fasting and 24-h mean levels of IGFBP-1 were significantly higher in GH-deficient patients [61 +/- 12 (P < 0.01) and 39 +/- 6 micrograms/L (P < 0.01), respectively] and IDDM patients [72 +/- 18 (P < 0.01) and 45 +/- 9 micrograms/L (P < 0.01), respectively] compared to those in healthy subjects (27 +/- 4 and 18 +/- 2 micrograms/L, respectively). Fasting levels of IGFBP-1 correlated to 24-h mean values of IGFBP-1 in all groups separately and in the combined group (r = 0.931; P < 0.001). An inverse relationship was found between IGFBP-1 and insulin in GH-deficient patients, both between 24-h mean values (r = -0.756; P < 0.001) and between fasting values (r = -0.721; P < 0.001). Corresponding values for healthy subjects were r = -0.548; P = 0.065 and r = -0.712; P < 0.01, respectively, whereas in IDDM patients the relationship was nonsignificant. Moreover, in GH-deficient patients, the diurnal mean levels of IGFBP-1 were inversely correlated to IGF-I (r = -0.477; P < 0.05) and body mass index (r = -0.450; P < 0.05). When insulin was taken into account, a tendency for a negative correlation between IGFBP-1 and IGF-I (P = 0.054) remained, whereas the relationship to body mass index disappeared. However, IGFBP-1 levels were elevated in relation to insulin levels in GH-deficient patients compared to healthy subjects (F = 48.7; P < 0.001 and F = 32.5; P < 0.001, diurnal mean values and fasting values, respectively). The majority of the IDDM patients had values in the same range as the GH-deficient patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Influence of circulating epinephrine and norepinephrine on insulin-like growth factor binding protein-1 in humans.

The aim of the present study was to investigate the influence of circulating epinephrine (Epi) and norepinephrine (Norepi) on serum insulin-like growth factor binding protein-1 (IGFBP-1) concentrations. Healthy men received 0.3 nmol.kg.min Epi iv (n = 6), 0.5 nmol.kg.min Norepi iv (n = 7), or saline (n = 5) during 30 min. Arterial blood samples were obtained before, during, and 120 min after infusion. During the catecholamine infusion arterial Epi and Norepi plasma concentrations reached 6.35 +/- 0.53 and 15.65 +/- 2.71 nmol/L, respectively, which resulted in significant increases in glucose concentrations. When Epi was infused, IGFBP-1 increased from 45 +/- 6 micrograms/L to 76 +/- 10 micrograms/L (P < 0.05) 60 min after the infusion. Epi was also followed by increases in insulin, C-peptide, and glucagon. Norepi resulted in a slight increase in circulating IGFBP-1 (43 +/- 6 to 54 +/- 8 nmol/L, NS). The findings suggest that Epi, at plasma concentrations similar to those reached during physical stress, stimulates the production of IGFBP-1 in humans.

Growth hormone replacement therapy improves body composition and increases bone metabolism in elderly patients with pituitary disease.

Although a specific GH deficiency (GHD) syndrome in the adult and the response to GH replacement therapy are well recognized, there are few data available on the effect of GH replacement therapy in elderly GH-deficient patients. We studied the effect of GH therapy on body composition and bone mineral density measured by dual energy x-ray absorptiometry, markers for bone metabolism, insulin-like growth factors (IGFs), and IGF-binding proteins (IGFBPs) in 31 patients (6 women and 25 men; aged 60-79 yr; mean, 68 yr) with multiple pituitary hormone deficiencies. The GH response to arginine or insulin was below 3 microg/L (9 mU/L) in all subjects. They were randomized to GH (Humatrope, Eli Lilly & Co.) or placebo for 6 months, followed by 12 months of open treatment. The dose was 0.05 IU/kg x week for 1 month, and after that it was 0.1 IU/kg x week divided into daily sc injections (0.75-1.25 IU/day). There were no changes in any of the measured variables during placebo treatment. GH treatment normalized serum IGF-I in a majority of the patients and increased IGFBP-3 and -5 as well as IGFBP-4 and IGF-II to values within normal range. Lean body mass was increased, and the increase at 6 and 12 months correlated with the increase in IGF-I (r = 0.46; P = 0.010 and r = 0.54, respectively; P = 0.003). GH treatment caused a modest, but highly significant, reduction of total body fat. Mean bone mineral density was not different from that in healthy subjects of the same age and did not change during the observation period. Markers for bone formation (bone-specific alkaline phosphatase activity, osteocalcin, and procollagen I carboxyl-terminal peptide in serum) increased within the normal range, and levels were sustained throughout the study. The bone resorption marker (pyridinoline in urine) was significantly elevated for 12 months. Side-effects were mild, mostly attributed to fluid retention. In two patients with normal glucose tolerance at the start of the study, pathological glucose tolerance occurred in one patient and was impaired in one. In conclusion, elderly patients with GHD respond to replacement therapy in a similar manner as younger subjects, with an improvement in body composition and an increase in markers for bone metabolism. Side-effects are few, and elderly GHD patients can be offered treatment. As long-term risks are unknown, GH doses should be titrated to keep IGF-I within the age-related physiological range.

Serum insulin-like growth factor I (IGF-I), IGF-binding protein-1 and -3, and the acid-labile subunit as serum markers of body composition during growth hormone (GH) therapy in adults with GH deficiency.

Serum levels of insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), the acid-labile subunit (ALS), insulin, and IGFBP-1 were evaluated as indicators of body composition during GH replacement therapy in 20 GH-deficient patients (9 women and 11 men), aged 22-57 yr, with IGF-I levels below -2 SD. The mean GH dose was 0.128 +/- 0.003 IU/kg.week during the first month and thereafter 0.23 +/- 0.01 IU/kg.week, divided into daily doses (0.7-4.3 IU/day). Serum levels of IGF-I, ALS, and IGFBP-3 above the normal range were reached in seven, five, and three subjects, respectively, after 12 months of GH therapy. IGF-I and ALS levels, but not IGFBP-3 levels, correlated with the total daily GH dose (r = 0.676; P = 0.001 and r = 0.631; P = 0.003). The mean increase in lean body mass (LBM) measured by dual energy x-ray absorptiometry was 3.0 +/- 0.5 kg (P < 0.001). At 12 months, the LBM values were significantly correlated to the IGF-I levels (r = 0.718; P < 0.001), but not to ALS or IGFBP-3 levels. No correlation was found before therapy, and the increase in LBM at 12 months correlated with the IGF-I increase (r = 0.514; P = 0.029) only after exclusion of two nonresponders. Both before and during therapy, LBM was inversely related to IGFBP-1 (r = -0.715; P < 0.004 at 12 months). None of the GH-induced proteins could be used as indicators of body fat changes. In conclusion, both IGF-I and ALS can be used as indicators to avoid GH excess during replacement therapy, but only IGF-I relates to changes in LBM.

Serum levels of insulin-like growth factor I in 152 patients with growth hormone deficiency, aged 19-82 years, in relation to those in healthy subjects.

Serum insulin-like growth factor I (IGF-I) levels within normal range for age have been reported to be common in adults with GH deficiency (GHD). Therefore, serum IGF-I levels were determined in 152 consecutive patients (71 women and 81 men) with evidence of hypothalamic-pituitary disorders or previous cranial radiation, who fulfilled the presently used criteria for GHD i.e. peak GH response below 3 microg/L at stimulation test. Patients treated for acromegaly were excluded. Forty-three patients, aged 19-63 yr, had childhood onset GHD, and 109, aged 23-82 yr, had adult-onset GHD. Their IGF-I levels were expressed in SD scores in relation to normal reference values based on 448 healthy subjects, aged 20-96 yr (247 women and 201 men). In healthy subjects a linear inverse correlation, without gender difference, was found between logarithmic transformed IGF-I levels and age (r = -0.774; P < 0.001). In contrast, no age dependency was found in GHD patients. All patients with childhood-onset GHD had IGF-I values below -2 SD, significantly lower than those in adult-onset GHD patients (-6.2 +/- 0.3 vs. -3.2 +/- 0.2 SD score; P < 0.001). In patients with adult-onset GHD, 34% of the IGF-I levels were within normal range, increasing to 40% in the subgroup above 60 yr of age, in whom 86% were diagnosed with hypothalamic-pituitary tumors. Normal IGF-I was more common in men than in women, but no difference was observed between patients with panhypopituitarism and those with partial pituitary insufficiency. High frequencies of IGF-I levels within the normal range were found in GHD patients with pituitary tumors (20 of 57 nonsecreting pituitary adenomas, 5 of 15 prolactinomas, 6 of 12 Cushing's disease, and 4 of 25 craniopharyngiomas), but in only 2 of 43 patients with GHD due to other causes. In conclusion, an IGF-I level below -2 SD seems to be of diagnostic value in GHD with onset in childhood or early adulthood, whereas values within normal range are common in patients over 60 yr of age, especially those with pituitary tumors. The outcome of GH replacement therapy may reveal whether the addition of IGF-I as a diagnostic criterion is of predictive value in older patients.

Acute and short-term effects of growth hormone on insulin-like growth factors and their binding proteins: serum levels and hepatic messenger ribonucleic acid responses in humans.

We investigated the acute (4-5 h) and short-term (5 days) effects of GH treatment on hepatic messenger RNA (mRNA) levels of the genes for the insulin-like growth factors (IGFs), insulin-like growth factor binding protein-1, -2, and -3 (IGFBPs), and the acid labile subunit (ALS), as well as serum levels of these proteins in humans. At the mRNA level, we observed an increase in IGF-1 transcription (+173%) following GH treatment in the acute group, which remained elevated in the short-term treatment group. IGFBP-2 mRNA decreased after short-term GH treatment, without changes in IGFBP-1 or -3 expression. The ALS transcript level increased after 5 days. In serum, we found increased levels of IGF-I and insulin, and decreased levels of IGF-II, in the short-term treatment group. IGFBP-1 decreased in both treatment groups, whereas IGFBP-2 was reduced after 5 days treatment. ALS increased in the short-term group. We observed increased IGFBP-3 serum levels after 5 days of GH treatment, likely due to increased formation of the ternary complex. Our results show that the metabolic effects by GH on the IGF axis are complex. In addition to a direct stimulation of IGF-I and ALS expression, GH inhibits IGFBP-1 serum levels and IGFBP-2 expression in an indirect manner, possibly facilitating enhanced IGF bioavailability to target tissues.

Tamoxifen-induced cell death in malignant melanoma cells: possible involvement of the insulin-like growth factor-1 (IGF-1) pathway.

Recent data indicate that the estrogen receptor (ER) blocker tamoxifen (TAM) can induce cell death in malignant melanoma cells. However, as shown in the present study and several other studies melanoma cells usually do not express classical ERs. In the present study we investigated whether the cytotoxic effect of TAM on melanoma cells could depend on interference with the expression or function of the insulin-like growth factor-1 receptor (IGF-1R), a plasma membrane receptor important for cell survival in this tumor cell type. Several melanoma cell lines were included in the analysis. Administration of TAM at a concentration of 15 microm or more resulted in cell death of the melanoma cells within 48 h. TAM treatment was correlated to a slight to moderate inhibition of IGF-1 binding to IGF-1R. Since it has been reported that TAM can increase the release of IGF binding proteins (IGFBPs) we then investigated whether this mechanism could underly the decreased IGF-1 binding. However, we could demonstrate that the amount of released IGFBPs were unchanged or decreased in TAM-treated cells. Whereas TAM did not have any strong effect on IGF-1 binding and the expression of IGF-1R at the cell surface, it was was found to efficently block tyrosine phosphorylation of IGF-1R beta-subunit. Taken together, our data suggest that TAM-induced cytotoxicity of malignant melanoma cells can be due to inactivation of IGF-1R.

Growth hormone treatment of osteoporotic postmenopausal women - a one-year placebo-controlled study.

OBJECTIVES: To study the effect of 12 months of growth hormone (GH) treatment on bone markers, bone mineral density (BMD), lean body mass (LBM) and body fat mass (BF) in postmenopausal osteoporotic women. DESIGN: Sixteen patients were randomised to a double-blind randomised placebo-controlled one-year study with daily s.c. injections of GH or placebo. After the first year 14 patients (8 placebo treated, 6 GH treated) were recruited to GH treatment during the second year. All patients were also supplemented with 0.5 g calcium per oral. METHODS: Bone mineral density and body composition were assessed by dual energy X-ray absorptiometry. Biochemical bone markers were analysed by RIA or HPLC techniques. Diurnal GH profiles were performed with continuous venous blood sampling. RESULTS: Sixteen patients started in the placebo-controlled study. In all, twelve patients completed one year and only four patients completed two years of GH treatment. At baseline 3 patients had serum insulin-like growth factor-I (S-IGF-I) levels below -2 S.D. for age. Maximal diurnal GH levels tended to correlate negatively with S-IGF-I (P=0.076). S-IGF-I was unrelated to BMD. Serum IGF-binding protein-1 (S-IGFBP-1) correlated negatively with femoral neck BMD (r=-0.61, P=0.012). The intended GH dose of 0.05U/kg/day or a maximum of 3U/day s.c. was reduced to 0.024+/-0.004U/kg/day, equal to 0.5-2.7U/day due to frequent side effects, and four patients were excluded. After one year of GH treatment BF increased slightly, LBM and BMD in total body and lumbar spine were unchanged but femoral neck BMD had decreased 3.4+/-1.6% (P<0.05). The mean S-IGF-I increase was 32% (range -38-138%). Mean levels of the bone formation markers S-osteocalcin and S-procollagen type I propeptide increased maximally by 88 and 36% respectively after 9-12 months while the bone resorption markers were unchanged. In the placebo-treated group there were no significant alterations. CONCLUSIONS: The effects on S-IGF-I, bone markers and LBM were small although GH-related side effects were common. The reason for this apparent partial resistance to the anabolic effects of GH is not clear but nutritional deficits may be involved. Assessment of the effects of GH on bone mass and fracture rate requires longer study periods than one year.

Different effects of antipsychotic drugs on insulin release in vitro.

The aim of this study was to examine the influence of antipsychotic drugs on insulin release from pancreatic beta cells in vitro. The effect of seven antipsychotics (i.e. chlorpromazine, haloperidol, perphenazine, zuclopenthixol, clozapine, olanzapine and risperidone) in a concentration of 10(-6) M was investigated on basal and glucose-stimulated insulin release. Clozapine increased basal insulin release, whereas haloperidol inhibited glucose-stimulated release and the other five antipsychotics had no significant effects. A possible stimulatory effect of clozapine on insulin release may explain its ability to increase appetite and induce weight gain.

Biological effects of ingested amosite asbestos, taconite tailings, diatomaceous earth and Lake Superior water in rats.

Because amphibole fibers were found in Lake Superior and in Duluth municipal water, this study was initiated to evaluate the carcinogenicity of ingested asbestos. Groups of 22-30 Sprague-Dawley rats were fed asbestos and related materials during their lifetime and were examined at autopsy after spontaneous death. Test materials were unfiltered Duluth city tap water, municipal water reservoir sediment suspension, taconite plant tailings, amosite asbestos (a "low-dose" group at 20 mg/rat . day an a high-dose group at 300 mg/rat . day) and diatomaceous earth; a control group drank fiber-free well water or filtered city tap water. Autopsy studies revealed no significant increase in the incidence of malignant tumors in any experimental group compared with that in the control group.

Oral contraceptive use and abnormal glucose regulation in Swedish middle aged women.

AIM: To investigate the association between oral contraceptive (OC) use and abnormal glucose regulation in Swedish middle aged women. METHODS: A prospective population-based study including 4794 women, aged 36-56 at baseline. None had previously diagnosed diabetes. At both baseline and follow-up 8 years later, the women were examined by oral glucose tolerance test. Information regarding lifestyle factors and anthropometric measurements were collected. RESULTS: At baseline, current use of OCs was associated with pre (Odds ratio, OR 4.1, 95%CI 2.2-7.8) but not with type 2 diabetes. The association to prediabetes was entirely linked to IGT (OR 7.1, 3.3-15.8) in current users of OCs and in former users (OR 2.1, 1.1-3.9). Women who used OC at baseline had a better cardiovascular disease risk profile; lower body mass index (BMI), more physically active and less smoking. At follow-up, the increased risk did not persist. CONCLUSION: Current use of OC was associated with a four times increased risk of having prediabetes and seven times of having impaired glucose tolerance. No increased risk persisted at the follow-up, suggesting that the risk due to prior use of OC is decreasing with time. The healthier lifestyle in women who used OCs may have contributed to reduced long-term risk of prediabetes.