Soluble Klotho: a possible predictor of quality of life in acromegaly patients.

PURPOSE: Although quality of life (QoL) is improved in patients with acromegaly after disease control, QoL correlates only weakly with traditional biomarkers. Our objective is to investigate a potential relation between the new serum biomarker soluble Klotho (sKlotho), GH and insulin-like growth factor 1 (IGF-1) levels, and QoL. METHODS: In this prospective cohort study, we investigated 54 acromegaly patients biochemically well-controlled on combination treatment with first-generation somatostatin receptor ligands (SRLs) and pegvisomant (PEGV) at baseline and 9 months after switching to pasireotide LAR (PAS-LAR; either as monotherapy, n = 28; or in combination with PEGV, n = 26). QoL was measured by the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) and Acromegaly Quality of Life (AcroQoL) questionnaire. RESULTS: Switching to PAS-LAR treatment significantly improved QoL without altering IGF-1 levels. QoL did not correlate with GH or IGF-1 levels, but sKlotho correlated with the observed improvements in QoL by the AcroQoL global (r = -0.35, p = 0.012) and physical subdimension (r = -0.34, p = 0.017), and with PASQ headache (r = 0.28, p = 0.048), osteoarthralgia (r = 0.46, p = 0.00080) and soft tissue swelling score (r = 0.29, p = 0.041). Parallel changes in serum sKlotho and IGF-1 (r = 0.31, p = 0.023) suggest sKlotho and IGF-1 to be similarly dependent on GH. Comparing the PAS-LAR combination therapy and the monotherapy group we did not observe a significant difference in improvement of QoL. CONCLUSIONS: Patients experienced improved QoL during PAS-LAR, either as monotherapy or in combination with PEGV. Soluble Klotho concentrations appear to be a useful marker of QoL in acromegaly patients but the underlying mechanisms remain to be investigated.

Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies.

BACKGROUND: Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer. PURPOSE: To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer. DATA SOURCES: Studies identified in PubMed, Web of Science, and CancerLit. STUDY SELECTION: The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate. DATA EXTRACTION: Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom. DATA SYNTHESIS: The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% CI, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake. LIMITATIONS: Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies. CONCLUSION: High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.

Improved Glucose Tolerance in a Kidney Transplant Recipient With Type 2 Diabetes Mellitus After Switching From Tacrolimus To Belatacept: A Case Report and Review of Potential Mechanisms.

The introduction of immunosuppressant belatacept, an inhibitor of the CD28-80/86 pathway, has improved 1-year outcomes in kidney transplant recipients with preexistent diabetes mellitus and has also reduced the risk of posttransplant diabetes mellitus. So far, no studies have compared a tacrolimus-based with a belatacept-based immunosuppressive regimen with regard to improving glucose tolerance after kidney transplantation. Here, we present the case of a 54-year-old man with type 2 diabetes mellitus who was converted from belatacept to tacrolimus 1 year after a successful kidney transplantation. Thereafter, he quickly developed severe hyperglycemia, and administration of insulin was needed to improve metabolic control. Six months after this episode, he was converted back to belatacept because of nausea, diarrhea, and hyperglycemia. After switching back to belatacept and within 4 days after stopping tacrolimus glucose tolerance improved and insulin therapy could be discontinued. Although belatacept is considered less diabetogenic than tacrolimus, the rapid improvement of glucose tolerance after switching to belatacept is remarkable. In this article, the potential mechanisms of this observation are discussed.

Intravenous glucose administration in fasting rats has differential effects on acylated and unacylated ghrelin in the portal and systemic circulation: a comparison between portal and peripheral concentrations in anesthetized rats.

Ghrelin is produced by the gastrointestinal tract, and its systemic concentrations are mainly regulated by nutritional factors. Our aim was to investigate: 1) endogenous portal and systemic acylated and unacylated ghrelin levels (AG and UAG, respectively); 2) whether an iv glucose tolerance test (IVGTT) modifies AG and UAG; and 3) whether the liver passage plays a role in regulating systemic AG and UAG. To elucidate this, we evaluated the effects of IVGTT or saline injection on endogenous portal and systemic concentrations of glucose, insulin, AG, and UAG in anesthetized fasting rats. Hepatic extraction of insulin, AG, and UAG and the ratio of AG to UAG were also measured. IVGTT suppressed both portal (P < 0.03) and peripheral (P < 0.05) UAG, whereas it only blunted prehepatic, but not peripheral, AG. During fasting, hepatic clearance of UAG was 11%, and it was decreased to 8% by IVGTT. AG was cleared by the liver by 38% but unaffected by glucose. The AG to UAG ratio was higher in the portal than the systemic circulation, both in the saline (P < 0.004) and IVGTT (P < 0.0005) rats. In conclusion, this study shows that: 1) the ratio of AG to UAG is very low in the portal vein and decreases further in the systemic circulation; 2) IVGTT in anesthetized fasting rats inhibits UAG, whereas it only blunts prehepatic, but not systemic, AG; and 3) hepatic clearance of AG is much higher than that of UAG. Thus, our results suggest that peripheral AG metabolic regulation and action are mainly confined within the gastrointestinal tract.

Long-term efficacy and safety of combined treatment of somatostatin analogs and pegvisomant in acromegaly.

BACKGROUND: We previously reported the efficacy of a combined treatment of active acromegaly with both long-acting somatostatin analogs (SSA) and pegvisomant (PEG-V). OBJECTIVE: Our objective was to assess long-term efficacy and safety in a larger group of acromegalic patients after a period of 138 (35-149) wk [median (range)]. DESIGN: PEG-V was added to high-dose SSA treatment in 32 subjects (13 females) who had not shown a normalization in serum IGF-I concentrations during SSA monotherapy. PEG-V dosage was increased until IGF-I concentration normalized. The maximal dose was 80 mg twice weekly. RESULTS: After dose finding, IGF-I remained within the normal range in all subjects with PEG-V administered once (n = 24) or twice (n = 8) weekly, on a total weekly dose of 60 (40-160) mg. Baseline IGF-I levels were positively correlated with the required dosage of PEG-V (r = 0.48; P = 0.006). PEG-V-dependent liver enzyme disturbances were observed in 11 (6 diabetic) subjects, of which symptomatic gallstones explained two cases. These liver enzyme disturbances were transient in all subjects without discontinuation or dose adaptation of PEG-V. In our series, diabetic patients had a 5.1 times (odds ratio) (confidence interval, 1.02-25.54; P < 0.05) higher risk for developing liver enzyme disturbances. These liver enzyme disturbances seemed to occur earlier. Pituitary adenoma size decreased in four patients. No increase in tumor size was observed in any of the patients. CONCLUSION: Long-term combined treatment with long-acting SSA and (twice) weekly PEG-V for active acromegaly seems to be effective and safe. Patients with acromegaly and diabetes seem to have a higher risk of developing transient liver enzyme disturbances.

An igf-I gene polymorphism modifies the risk of diabetic retinopathy.

The role of IGF-I in the pathogenesis of diabetic retinopathy is unclear. We studied, prospectively, the relationship between an IGF-I gene polymorphism, retinal vessel diameters, and incident diabetic retinopathy in subjects with impaired glucose tolerance (IGT) or type 2 diabetes. In all 5,505 participants of the population-based Rotterdam Study (775 with IGT, 394 with type 2 diabetes, and 4,336 control subjects), fundus color transparencies were taken at baseline (between 1990 and 1993) and at follow-up (from 1997 to 1999). The wild-type genotype (i.e., carriers of the 192- or 194-bp alleles) was present in 72.7% of the participants, while 27.3% were variant carriers. Variant carriers with IGT or type 2 diabetes appeared to have larger retinal arteriolar and venular diameters at baseline than individuals with the wild-type genotype, but these differences did not reach statistical significance. This trend was especially observed in subjects who developed retinopathy at follow-up. In variant carriers with IGT/diabetes, an increase (odds ratio 1.8 [95% CI 1.0-3.2]; P = 0.04) in the risk of retinopathy was observed compared with participants with the wild-type genotype. In conclusion, our findings suggest that this IGF-I gene polymorphism is associated with an increased risk of diabetic retinopathy.

Retinal vessel diameters and risk of impaired fasting glucose or diabetes: the Rotterdam study.

The association between a smaller retinal arteriolar-to-venular ratio (AVR) and incident diabetes may be due to arteriolar narrowing, venular dilatation, or both. We investigated associations between baseline vessel diameters and incident impaired fasting glucose or diabetes in a population-based cohort (aged > or =55 years). Baseline retinal vessel diameters (1990-1993) were measured on digitized images of 2,309 subjects with a normal glucose tolerance test (postload glucose <7.8 mmol/l). At follow-up (1997-1999), impaired fasting glucose was defined as 6.1-7.0 mmol/l and diabetes as > or =7.0 mmol/l and/or antidiabetic medication use. Odds ratios (ORs) per SD increase in venular diameters were 1.13 (95% CI 1.00-1.29) for impaired fasting glucose and 1.09 (0.90-1.33) for diabetes. ORs per SD decrease in arteriolar diameters were 1.12 (0.98-1.27) and 1.08 (0.89-1.31) and per SD decrease in AVR were 1.29 (1.13-1.46) and 1.19 (0.98-1.45). After adjustment for cardiovascular risk factors, the associations were unaltered for venules and disappeared for arterioles. After stratification on age, associations between venular dilatation and impaired fasting glucose (1.23 [1.02-1.47]) or diabetes (1.18 [0.89-1.56]) were mainly present in participants aged <70 years. In conclusion, in our study, the risk of impaired fasting glucose and diabetes with AVR was explained by venular dilatation rather than arteriolar narrowing, warranting more focus on the causes of this dilatation.

The alpha-adducin gene is associated with macrovascular complications and mortality in patients with type 2 diabetes.

We examined the association between alpha-adducin 1 (ADD1) gene polymorphism (Gly460Trp) with macrovascular complications and mortality in type 2 diabetes in a Caucasian population aged >or=55 years. The study was part of the Rotterdam Study, a prospective population-based cohort study. ADD1 polymorphism was determined in 6,471 participants, including 599 patients with type 2 diabetes at baseline. The prevalence of hypertension in type 2 diabetic patients was 2.57 times higher in ADD1 TT carriers compared with GG carriers (95% CI 1.05-6.32, P = 0.03). Homozygous T carriers also had a higher mean common carotid intima media thickness (IMT) compared with GG carriers (mean difference 0.05 mm, P for trend = 0.03). In diabetic patients with hypertension, the risk of mortality was 1.83 times higher in homozygous T carriers compared with the GG genotype group (95% CI 1.07-3.16, P = 0.03). The increased risk was only present among TT carriers who did not use antidiabetes medication (hazard ratio 2.18 [95% CI 1.12-4.24], P = 0.02). The results of this population-based cohort study suggest that the ADD1 gene contributes to the risk of hypertension and increases mean common carotid IMT in patients with type 2 diabetes. Furthermore, the study indicates that the ADD1 polymorphism could be useful in identifying hypertensive type 2 diabetic patients with a high risk of mortality.

An IGF-I gene polymorphism modifies the risk of developing persistent microalbuminuria in type 1 diabetes.

OBJECTIVE: Derangements of the GH-IGF-I axis have been associated with microalbuminuria (MA) in type 1 diabetes. The aim of this study was to investigate whether an IGF-I gene promoter polymorphism influenced the development of persistent MA in type 1 diabetes. DESIGN: A prospective follow-up study of a cohort of 277 patients with newly diagnosed type 1 diabetes consecutively enrolled between September 1979 and August 1984. METHODS: Urinary albumin excretion rate over 24 h was measured in each patient at least once a year. Persistent MA was defined as a urinary albumin excretion rate between 30 and 300 mg/24 h. RESULTS: During a median follow-up of 18.0 years (range 1.0-21.5), 79 of 277 patients developed persistent MA. IGF-I gene genotype was available for 216 subjects; in 73% of the subjects, the wild-type genotype of this IGF-I gene polymorphism was present, while 27% had the variant type. At baseline, there were no differences in IGF-I levels and HbA(1c) values between subjects with the wild type and subjects with variant type. By Kaplan-Meier analysis, subjects with the variant type of this polymorphism had during follow-up a higher risk of development of MA compared subjects with the wild type (P = 0.03). CONCLUSIONS: Subjects with the variant type of an IGF-I gene polymorphism had a significantly increased risk of developing MA. This risk was not mediated through changes in circulating IGF-I levels. Our study suggests that in type 1 diabetes, this IGF-I gene polymorphism is a risk factor of MA.

An insulin-like growth factor-I promoter polymorphism is associated with increased mortality in subjects with myocardial infarction in an elderly Caucasian population.

We investigated whether an insulin-like growth factor I (IGF-I) promoter polymorphism is associated with excess mortality in elderly subjects with myocardial infarction (MI). This association was assessed in 7,983 subjects of the Rotterdam Study during 14 years of follow-up. Among 345 subjects who developed a MI, the risk of mortality was 1.49 times higher in the variant carriers of the IGF-I promoter polymorphism than in the nonvariant carriers (95% confidence interval 1.10 to 2.10, p = 0.02). The risk of death increased with the number of variant alleles. Our study suggests that genetically determined low IGF-I activity is an important determinant of mortality in subjects with MI.

Unacylated ghrelin is active on the INS-1E rat insulinoma cell line independently of the growth hormone secretagogue receptor type 1a and the corticotropin releasing factor 2 receptor.

Both unacylated ghrelin (UAG) and acylated ghrelin (AG) exert metabolic effects. To investigate the interactions between AG and UAG on ghrelin receptors we evaluated the effects of AG and UAG on INS-1E rat insulinoma cells, using insulin secretion after 30min static incubation as a read-out. A possible involvement of the growth hormone secretagogue receptor type 1a (GHS-R1a) or the corticotropin-releasing factor 2 (CRF2) receptor (CRF2R), as a putative receptor for UAG, was also studied determining their mRNA expression and the functional effects of receptor antagonists on insulin release. Both UAG and AG stimulated insulin release dose-dependently in the nanomolar range. The AG-induced insulin output was antagonized by two GHS-R1a antagonists ([d-Lys(3)]GHRP-6 and BIM28163), which did not block UAG actions. These effects occurred in the presence of low levels of GHS-R1a mRNA. Neither CRF2R expression nor effects of the CRF2R antagonist (astressin(2)B) on insulin output were observed. In conclusion, we provide a sensitive and reproducible assay for specific effects of UAG, which in this study is responsible for insulin release by INS-1E cells. Our data support the existence of a specific receptor for UAG, other than the CRF2R and GHS-R1a. The stimulatory effect on insulin secretion by AG in this cell line is mediated by the GHS-R1a.

Short-term administration of an angiotensin-receptor antagonist in patients with impaired fasting glucose improves insulin sensitivity and increases free IGF-I.

OBJECTIVE: Blocking the renin-angiotensin system (RAS) may reduce the risk of developing type-2 diabetes, but data are inconclusive and the mechanisms involved are unclear. RAS and RAS inhibition also influence the IGF-I system, which is important in glucose homeostasis. We investigated the effects of the angiotensin-receptor antagonist, losartan, on insulin resistance and IGF-I levels DESIGN AND METHODS: In this hypothesis-generating study, five individuals with impaired fasting glucose received 100 mg losartan during 8 weeks. Before and after the treatment period, insulin sensitivity was assessed using the homeostasis model assessment of insulin resistance (HOMA), as well as the 2-h continuous infusion of glucose with model assessment (CIGMA). Furthermore, serum levels of free and total IGF-I, IGF-binding protein-3 (IGFBP-3), lipids and HbAlc were measured. RESULTS: After the treatment period, the HOMA score for insulin resistance had decreased from 5.3+/-1.1 to 3.7+/-0.9 (P=0.004) and the 2-h CIGMA score from 23.4+/-3.1 to 15.9+/-2.1 (P=0.07). The serum levels of free IGF-I had increased from 57+/-18.8 to 134+/-31.3 pmol/l (P=0.04). In terms of percentage, the decrease of HOMA correlated with the increase in free IGF-I levels (Pearson's correlation coefficient r=-0.8; P=0.07). A trend in the same direction was observed with 2-h CIGMA. No differences were observed in lipids, total IGF-I, IGFBP-3 or HbAlc. CONCLUSIONS: Losartan raised serum levels of free IGF-I, which might contribute to the improvement of insulin resistance associated with losartan treatment. These observations, if confirmed in broader studies, will help our understanding of the pathogenesis of type-2 diabetes mellitus, as well as the role of angiotensin-receptor antagonists in its prevention.

IGF-I gene promoter polymorphism is a predictor of survival after myocardial infarction in patients with type 2 diabetes.

OBJECTIVE: Previously we observed that non-carriers of the most common alleles of an IGF-I promoter polymorphism have low circulating IGF-I levels and an increased risk of developing myocardial infarction (MI), particularly in patients with type 2 diabetes. DESIGN: We investigated whether this IGF-I promoter polymorphism is associated with survival of type 2 diabetes in a Caucasian population aged 55 years and older. METHODS: The study was embedded in the Rotterdam Study, a prospective population-based cohort study. At baseline, 668 patients with type 2 diabetes were diagnosed, among which, 55 incident MI were ascertained during follow-up. For the present study, we used two genotype groups: non-variant carriers (homozygous for 192, 194, or 192/194 bp genotypes), and variant carriers. RESULTS: During a median follow-up of 8.8 years, 396 out of the 668 patients with type 2 diabetes (59.3%) died of various causes. The frequency of type 2 diabetes variant carrier and non-variant carriers was 28.7 and 71.3% respectively. The survival in patients with type 2 diabetes without an MI did not differ between the IGF-I genotype groups (hazard ratio (HR) = 0.8, 95% confidence interval (CI): 0.7-1.1, P = 0.1). In contrast, in those who developed an MI, variant carriers had a 2.4 times higher risk of mortality than non-variant carriers (95% CI: 1.2-4.8, P = 0.01). CONCLUSION: Our study suggests that genetically determined low IGF-I activity is an important determinant of survival in patients with type 2 diabetes who developed an MI. The IGF-I promoter polymorphism, therefore, may help to predict the future mortality risk in this group of patients.

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits.

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.

A polymorphism in type I deiodinase is associated with circulating free insulin-like growth factor I levels and body composition in humans.

The interaction between the GH-IGF-I axis and thyroid hormone metabolism is complex and not fully understood. T(4) stimulates IGF-I activity in animals in the absence of GH. On the other hand, GH replacement therapy results in an increase in serum T(3) and a decrease in T(4) and rT(3) levels, suggesting a stimulation of type I deiodinase (D1) activity. Recently, we demonstrated the association of two polymorphisms in D1 (D1a-C/T; T = 34%, and D1b-A/G; G = 10%) with serum iodothyronine levels. Haplotype alleles were constructed, suggesting a lower activity of the D1 haplotype 2 allele (aT-bA) and a higher activity of the haplotype allele 3 (aC-bG). In this study, we investigated whether genetic variations in D1 are associated with the IGF-I system. In 156 blood donors and 350 elderly men, the association of the D1 haplotype alleles with circulating IGF-I and free IGF-I levels was studied. In addition, potential associations with muscle strength and body composition were investigated in the elderly population. Finally, the relation between serum iodothyronine levels and IGF-I levels was studied. In blood donors, haplotype allele 2 was associated with higher levels of free IGF-I (302.9 +/- 22.9 vs. 376.3 +/- 19.1 pg/ml, P = 0.02). In elderly men, haplotype allele 2 also showed an allele dose increase in free IGF-I levels (P(trend) = 0.01) and an allele dose decrease in serum T(3) levels (P(trend) = 0.01), independent of age. Carriers of the D1a-T variant also had a higher isometric grip strength (P = 0.047) and maximum leg extensor strength (P = 0.07) as well as a higher lean body mass (P = 0.03). In blood donors, T(4) and free T(4) were negatively correlated with total IGF-I levels (R = -0.18, P = 0.03 and R = -0.24, P = 0.003), whereas T(3) to T(4) and T(3) to reverse T(3) ratios were positively correlated with total IGF-I (R = 0.31, P < 0.001 and R = 0.18, P = 0.03). Free IGF-I showed a negative correlation with T(4) (R = -0.26, P = 0.001) and T(4)-binding globulin (R = -0.31, P < 0.001) and a positive correlation with T(3) to T(4) ratio (R = 0.21, P = 0.01). In conclusion, a polymorphism that results in a decreased D1 activity is associated with an increase in free IGF-I levels. The pathophysiological significance of this association with IGF-I is supported by an increased muscle strength and muscle mass in carriers of the D1 haplotype 2 allele in a population of elderly men. The association of D1 haplotype allele 2 with serum T(3) levels in the elderly population suggests a relative increase in its contribution to circulating T(3) in old age.

Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes.

Ghrelin exerts various metabolic activities, including regulation of glucose levels in humans. To verify whether the glucose response to ghrelin reflects a modulation of an insulin-independent hepatic phenomenon, we studied glucose output by primary porcine hepatocytes in suspension culture, after incubation with acylated ghrelin (AG), unacylated ghrelin (UAG), and hexarelin (HEX). AG induced glucose output dose dependently after 20 min of incubation (P < 0.001), whereas HEX, a GH secretagogue receptor type 1a (GHS-R1a) agonist, had no effect. UAG inhibited glucose release also dose dependently and after 20 min (P < 0.001). Moreover, UAG completely reversed AG-induced glucose output (P < 0.01). Using real-time PCR, GHS-R1a gene expression was undetectable in all the hepatocyte preparations studied. The lack of efficacy of HEX, the efficacy of UAG, and the absence of GHS-R1a expression indicate the involvement of a yet uncharacterized ghrelin receptor type. In conclusion, glucose output by primary hepatocytes is time- and dose-dependently stimulated by AG and inhibited by UAG. Moreover, UAG counteracts the stimulatory effect of AG on glucose release. These actions might be mediated by a different receptor than GHS-R1a, and apparently, we must consider AG and UAG as separate hormones that can modify each other's actions on glucose handling, at least in the liver.

A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels.

We investigated whether a polymorphism in codons 22 and 23 of the glucocorticoid (GC) receptor gene [GAGAGG(GluArg) --> GAAAAG(GluLys)] is associated with altered GC sensitivity, anthropometric parameters, cardiovascular risk factors, and sex steroid hormones. In a subgroup of 202 healthy elderly subjects of the Rotterdam Study, we identified 18 heterozygotes (8.9%) for the 22/23EK allele (ER22/23EK carriers). In the highest age group, the number of ER22/23EK carriers was higher (67-82 years, 12.9%) than in the youngest age group (53-67 years, 4.9%; P < 0.05). Two dexamethasone (DEX) suppression tests with 1 and 0.25 mg DEX were performed, and serum cortisol and insulin concentrations were compared between ER22/23EK carriers and noncarriers. After administration of 1 mg DEX, the ER22/23EK group had higher serum cortisol concentrations (54.8 +/- 18.3 vs. 26.4 +/- 1.4 nmol/l, P < 0.0001), as well as a smaller decrease in cortisol (467.0 +/- 31.7 vs. 484.5 +/- 10.3 nmol/l, P < 0.0001). ER22/23EK carriers had lower fasting insulin concentrations (P < 0.001), homeostasis model assessment- insulin resistance (IR) (index of IR, P < 0.05), and total (P < 0.02) and LDL cholesterol concentrations (P < 0.01). Our data suggest that carriers of the 22/23EK allele are relatively more resistant to the effects of GCs with respect to the sensitivity of the adrenal feedback mechanism than noncarriers, resulting in a better metabolic health profile.

Limited predictive value of an acute test with subcutaneous octreotide for long-term IGF-I normalization with Sandostatin LAR in acromegaly.

OBJECTIVES: To study whether the growth hormone (GH) response after the subcutaneous administration 50 microg of octreotide (acute octreotide test) has any predictive value for long-term IGF-I normalization with Sandostatin LAR. DESIGN: Twenty four therapy-naive patients with active acromegaly were studied. RESULTS: > 75% GH decrease in the acute octreotide test predicted long-term IGF-I normalization with Sandostatin LAR in 8/11 (73%) of patients. 3/13 (23%) patients with < 75% GH decrease in the acute octreotide test were long-term biochemically controlled with Sandostatin LAR. Using the > 75% GH reduction criterion, the sensitivity and specificity of this test for predicting long-term normalization of serum IGF-I with Sandostatin LAR treatment were 73% and 77%, respectively (positive and negative predictive values: 73% and 77%, respectively). 6/8 (75%) patients with GH suppression to levels < 1.1 microg/l and 9/16 (56%) patients with GH suppression to levels < 2 microg/l in the acute octreotide test showed normalization of serum IGF-I with long-term Sandostatin LAR treatment. The sensitivity and specificity of GH suppression < 1.1 microg/l for predicting of the long-term normalization of serum IGF-I with Sandostatin LAR therapy were 55% and 85%, respectively (positive and negative predictive values: 75% and 69%, respectively). The sensitivity and specificity of GH suppression < 2 microg/l for predicting of the long-term normalization of serum IGF-I with Sandostatin LAR therapy were 82% and 46%, respectively (positive and negative predictive values: 56% and 75%, respectively). CONCLUSION: The acute octreotide is not recommended for clinical decision making with regard to long-term treatment using the long-acting somatostatin analog Sandostatin LAR in acromegaly.

The 'bio-assay' quality of life might be a better marker of disease activity in acromegalic patients than serum total IGF-I concentrations.

OBJECTIVES: To investigate the quality of life (QoL) in acromegalic patients in relation to biochemical parameters. DESIGN AND METHODS: Single-center, open label study in 14 acromegalic patients (eight woman and six men, age 33-77 years), with normal serum IGF-I levels during long-term treatment with monthly injections of 20 mg of long-acting octreotide. We investigated which biochemical parameter might reflect optimal QoL, using the SF-36 questionnaire. RESULTS: We observed that six patients had a low QoL score at baseline in the same range as observed in cancer patients. The other eight patients had a normal QoL. GH, IGF-I nor free IGF-I could discriminate these two subgroups at baseline. After skipping one monthly injection, all six subjects with the low QoL escaped in their free IGF-I concentrations. Also total IGF-I concentrations escaped in four of these six. In the subjects with normal QoL, free IGF-I levels remained normal in all, while total IGF-I levels only escaped in one. CONCLUSIONS: This study tells us that the currently used biochemical criteria for disease control in acromegaly might be sufficient in assessing long-term mortality and morbidity, but they are insufficient in addressing the most important parameter from the patient's perspective--QoL.

An early diagnostic tool for diabetic peripheral neuropathy in rats.

The skin's rewarming rate of diabetic patients is used as a diagnostic tool for early diagnosis of diabetic neuropathy. At present, the relationship between microvascular changes in the skin and diabetic neuropathy is unclear in streptozotocin (STZ) diabetic rats. The aim of this study was to investigate whether the skin rewarming rate in diabetic rats is related to microvascular changes and whether this is accompanied by changes observed in classical diagnostic methods for diabetic peripheral neuropathy. Computer-assisted infrared thermography was used to assess the rewarming rate after cold exposure on the plantar skin of STZ diabetic rats' hind paws. Peripheral neuropathy was determined by the density of intra-epidermal nerve fibers (IENFs), mechanical sensitivity, and electrophysiological recordings. Data were obtained in diabetic rats at four, six, and eight weeks after the induction of diabetes and in controls. Four weeks after the induction of diabetes, a delayed rewarming rate, decreased skin blood flow and decreased density of IENFs were observed. However, the mechanical hyposensitivity and decreased motor nerve conduction velocity (MNCV) developed 6 and 8 weeks after the induction of diabetes. Our study shows that the skin rewarming rate is related to microvascular changes in diabetic rats. Moreover, the skin rewarming rate is a non-invasive method that provides more information for an earlier diagnosis of peripheral neuropathy than the classical monofilament test and MNCV in STZ induced diabetic rats.