Colesevelam-induced hypoglycaemia in a patient with type 1 diabetes mellitus.

Colesevelam possesses antidiabetic properties, which could potentiate sulphonylurea or insulin-induced hypoglycemia; clinically significant hypoglycemia, as a side effect to bile acid sequestrants, may be under-recognized in clinical practice.

Insulin-like growth factor-I response to a single bolus of growth hormone is increased in obesity.

Reduced GH levels are found in obesity; despite which IGF-I levels are reported as low normal or normal. Previously peripheral responsiveness to GH has been investigated and reported to be increased in obese men and premenopausal women; however, the use of weight-based GH doses in these studies made data interpretation difficult. GH binding protein (GHBP) measurement constitutes an indirect estimate of GH receptor number. GHBP has been reported to be elevated in obesity; however, results from a recent study implied that this was only in men and premenopausal but not postmenopausal women. Therefore, we pursued this question further by challenging a cohort of healthy normal-weight and obese subjects with a non-weight-based dose of GH and examined the relationship of GHBP with the IGF-I response in the context of their body composition. Ninety-eight (40 male) healthy subjects with a wide range of ages and body mass index (BMI) were studied. Ninety-one (34 male) of these subjects were divided into groups of similar age: men and women with a BMI less than 30 [normal-weight men (NM), BMI 26 (22-29) kg/m(2) (n = 19) and women (NW), BMI 24 (19-29) kg/m(2) (n = 23) and with a BMI > 30 (obese men (OM), 41 (30-72) kg/m(2) (n = 15) and women (OW), 43 (30-68) kg/m(2) (n = 34)]. Fat mass and percentage fat were measured by a bioelectrical impedance analyzer. An IGF-I generation test, which involved a sc injection of 21 IU (7 mg) GH, was performed. At baseline serum samples were assayed for GHBP; serum IGF-I and IGFBP3 levels were measured both at baseline and 24 h after GH administration. There was a higher increment IGF-I in obese men and women, compared with the equivalent normal-weight subjects [NM vs. OM: 245 (33-342) vs. 291 (192-427) ng/ml (P < 0.05); NW vs. OW: 220 (103-435) vs. 315 (144-450) ng/ml (P < 0.0005)]. Increment IGF-I was negatively correlated with baseline IGF-I (F = 12.1) and positively correlated with GHBP (F = 18.2) (R(2) = 0.29). GHBP levels were significantly higher in OM and OW (pre- and postmenopausal) than in the equivalent normal-weight groups [NM vs. OM: 2175 (995-4190) vs. 3030 (1540-5470) pmol/liter (P < 0.05); NW vs. OW: 2131 (1010-5040) vs. 3585 (1540-5740) pmol/liter (P < 0.0005)]. GHBP levels correlated highly with BMI, percentage fat, and fat mass (R > 0.6, P < 0.0001). Baseline IGF-I was not affected by body composition. In conclusion, in obese compared with normal-weight healthy subjects, there is a larger increment IGF-I to a single bolus of GH in men, and irrespective of menopausal status, women. Increment IGF-I is associated positively with GHBP level, which in turn is associated with markers of increasing obesity in men and women. GH responsiveness is increased in obesity.

The insulin-like growth factor I generation test in adults.

The insulin-like growth factor I (IGF-I) generation test has the potential to assess the ability of an individual to respond to an acute bolus of growth hormone (GH), in terms of IGF-I, IGF-binding protein 3 and acid-labile subunit responses. This article will discuss something of the history of the IGF-I generation test, and review some of the major studies to date. The IGF-I generation test was first used in adults by Lieberman et al., who studied the effects of ageing and oestrogen administration, and suggested that decreased responsiveness to GH occurs with increasing age and oral oestrogen administration. Our results, however, show that, while activity of the GH/IGF-I axis declines with age, peripheral responsiveness to GH is not affected. As in the Lieberman study, we found that oral oestrogen replacement reduces responses of GH-dependent peptides to GH stimulation in healthy post-menopausal women. Transdermal oestrogen administration also reduced responsiveness to GH, although to a lesser degree than orally administered oestrogen. In addition, utilizing a non-weight-based dose of GH we have demonstrated that obese individuals produce greater increases in IGF-I following an acute bolus of GH. In GH deficiency (GHD), data suggesting enhanced peripheral responsiveness should be interpreted with caution, and with awareness of differences between these groups in terms of age and obesity. The IGF-I generation test may allow a fresh approach to unanswered questions in the field of GHD, but as the IGF-I response to GH is not strictly associated with protein anabolism or clinical benefit, the question remains whether this test will predict the effect of longer-term GH administration.

The impact of dose and route of estrogen administration on the somatotropic axis in normal women.

Oral estrogen therapy has reliably been found to reduce levels of serum IGF-I and increase mean 24-h GH levels in postmenopausal women as well as increase GH requirements in patients with GH deficiency. It is thought to act by inhibiting GH-stimulated IGF-I secretion, thus resulting in diminished feedback at the hypothalamic-pituitary axis and, hence, increased GH levels. In contrast, the administration of transdermal estrogen has variably been found to reduce, not change or increase, levels of serum IGF-I. We sought to clarify the effect of transdermal estrogen on the GH/IGF-I axis by using the IGF-I generation test, in which the acute response to a bolus dose of GH is examined. Nine healthy postmenopausal women received three different formulations of estrogen: oral estradiol (1 mg every 12 h), transdermal estradiol (50 micro g/d), and transdermal estradiol (200 micro g/d) for a 6-wk period in random order, separated by an 8-wk washout period. At the start of the study and in the last week of each estrogen formulation treatment, subjects underwent an IGF-I generation test. Oral estradiol reduced baseline (P < 0.05) and GH stimulated (P < 0.05) IGF-I levels, and GH stimulated IGF-binding protein-3 (IGFBP-3) levels (P < 0.05). High dose transdermal estrogen did not affect basal levels of IGF-I or IGFBP-3, but reduced the response of these GH-dependent peptides to GH stimulation (P < 0.05). Low dose transdermal estrogen did not alter either baseline or peak IGF-I levels, but reduced the peak IGFBP-3 response to GH stimulation (P < 0.05). Estradiol levels were lower during both transdermal estrogen preparations than during oral estrogen. It has been suggested that the effect of estrogen on responsiveness to GH is limited to that administered by the oral route. We have demonstrated that transdermal estrogen also has a significant impact on responsiveness to GH despite achieving levels of circulating estrogen lower than those achieved by oral estrogen replacement.

The insulin-like growth factor-I generation test: peripheral responsiveness to growth hormone is not decreased with ageing.

OBJECTIVE: Ageing is accompanied by a reduction in GH secretion, and a decrease in circulating IGF-I. Few data are available on whether the responsiveness of IGF-I to GH stimulation changes with age. SUBJECTS AND METHODS: Therefore we carried out multiple IGF-I generation tests in 26 healthy volunteers (16 male) of normal body mass index (BMI); nine aged 20-40 years, six aged 41-60 years, and 11 aged > 61 years. Each subject received three single doses of GH: 0.8, 2.0 and 21 IU in random order at least 4 weeks apart. Serum samples were taken 0, 18, 24, 48, 72 and 120 h following each dose of GH. RESULTS: Basal serum levels of IGF-I (P < 0.0001) and IGFBP-3 (P < 0.01) declined with age, but serum acid-labile subunit (ALS) levels did not (P = 0.2). Peak IGF-I levels (P < 0.01 for 0.8 IU and P < 0.05 for the 2 IU dose) and area under curve (AUC) IGF-I (P < 0.01 for the 0.8 IU and 2.0 IU doses of GH and P < 0.05 for the 21 IU dose) after GH administration continued to demonstrate a significant trend towards lower values with increasing age. However, the increment in IGF-I, IGFBP-3 and ALS in response to GH did not decline with age. Indeed, the increment in IGF-I after 2 IU of GH, judged by the increase from basal to peak levels, increased with advancing age (P = 0.05), and a positive relationship was seen between the increment in the area under the IGF-I curve following the 21 IU dose of GH and age (P < 0.02). CONCLUSION: These data illustrate that although activity of the GH/IGF-I axis declines with age, peripheral responsiveness to GH is not attenuated. This suggests that a decrease in GH responsiveness does not contribute to the age-related fall in circulating GH-dependent peptides. Thus, for those embarking on trials of GH therapy or GH secretagogues in the elderly, the capacity to generate IGF-I will not limit potential efficacy. Furthermore, the dose of GH replacement required for patients with organic GH deficiency is likely to be lower in the elderly compared with young adults.

Determinants of IGF-I status in a large cohort of growth hormone-deficient (GHD) subjects: the role of timing of onset of GHD.

BACKGROUND: IGF-I standard deviation score (SDS) is widely used in clinical practice; however, factors determining IGF-I SDS in GH-deficient (GHD) individuals remain incompletely understood. Earlier studies have been limited by the small size of cohorts studied. We have used the KIMS database to examine if a true difference exists between subjects who developed GHD in adult life (AO), and those who developed GHD in childhood (CO). PATIENTS: A total of 1317 patients fulfilled the inclusion criteria, 1073 with AO GHD and 244 with CO GHD. METHODS: Serum IGF-I concentrations were determined by a hydrochloric acid-ethanol extraction radioimmunoassay method using synthetic IGF-I for labelling. The reference range was calculated using normative data from healthy Swedish individuals. RESULTS: A total of 86% of patients with CO GHD but only 52% of patients with AO GHD had IGF-I SDS below -2 SDS. The CO cohort had a lower IGF-I SDS (-4.69 vs. -2.24, P < 0.0001), a smaller body mass index (BMI; 26.6 vs. 28.6 kg/m2, P < 0.0001) and waist-hip ratio (WHR; 0.90 vs. 0.92 P < 0.001) than the AO cohort. A stepwise multiple linear regression was performed to examine the principal determinants of IGF-I SDS. Age at onset of GHD was the most important determinant of IGF-I SDS, contributing 17% towards the variability of IGF-I SDS. Timing of onset, gender, BMI, and number of pituitary hormone deficiencies other than GH deficiency were also significant determinants of IGF-I SDS. CONCLUSION: Whilst age at onset of GHD was the most important determinant of IGF-I SDS, individuals with CO GHD had values on average 1.43 lower than those with AO GHD, all other factors being equal. Potential explanations include differences in GH secretory patterns, variation in body composition, and/or suboptimal treatment of GHD in childhood.

Childhood-onset growth hormone (GH) deficiency in adult life.

Over the last decade GH replacement therapy for adults has progressed in status from research study to a mainstream clinical indication. An area ripe for further research, however, is the difference between adults who developed GHD before and after completion of growth and puberty. That differences exist, not only in aetiology, but also in phenotype and response to GH therapy is clear. However, whether these differences are intrinsic to the timing of onset of GHD, or related to secondary factors including the method of assessment or dose of GH employed is uncertain. This chapter discusses the current state of knowledge in this area and poses further questions, not only for the researcher attempting to understand the mechanisms underlying these differences, but also for the physician seeking to ameliorate the impact of GHD in patients who acquired GHD in childhood.