Bile acid sequestrants have been used for decades for the treatment of hypercholesterolaemia. Sequestering of bile acids in the intestinal lumen interrupts enterohepatic recirculation of bile acids, which initiate feedback mechanisms on the conversion of cholesterol into bile acids in the liver, thereby lowering cholesterol concentrations in the circulation. In the early 1990s, it was observed that bile acid sequestrants improved glycaemic control in patients with type 2 diabetes. Subsequently, several studies confirmed the finding and recently – despite elusive mechanisms of action – bile acid sequestrants have been approved in the USA for the treatment of type 2 diabetes. Nowadays, bile acids are no longer labelled as simple detergents necessary for lipid digestion and absorption, but are increasingly recognised as metabolic regulators. They are potent hormones, work as signalling molecules on nuclear receptors and G protein-coupled receptors and trigger a myriad of signalling pathways in many target organs. The most described and well-known receptors activated by bile acids are the farnesoid X receptor (nuclear receptor) and the G protein-coupled cell membrane receptor TGR5. Besides controlling bile acid metabolism, these receptors are implicated in lipid, glucose and energy metabolism. Interestingly, activation of TGR5 on enteroendocrine L cells has been suggested to affect secretion of incretin hormones, particularly glucagon-like peptide 1 (GLP1 (GCG)). This review discusses the role of bile acid sequestrants in the treatment of type 2 diabetes, the possible mechanism of action and the role of bile acid-induced secretion of GLP1 via activation of TGR5.
David P Sonne, Morten Hansen and Filip K Knop
K David, C Moyson, D Vanderschueren and B Decallonne
Chronic hypoparathyroidism and its treatment may lead to symptoms and complications affecting quality of life. We determined complications in chronic hypoparathyroid patients.
Retrospective cross-sectional study of patients with chronic hypoparathyroidism treated with active vitamin D supplements in a tertiary care centre during the year 2015. Primary outcome parameters were history of kidney stones and seizures and presence of renal and cerebral calcifications on imaging. Secondary outcome parameters were current symptoms of paraesthesia/cramps, hospitalization due to hyper/hypocalcaemia and hypercalciuria.
One hundred and seventy patients were included – 143 (84%) with post-surgical hypoparathyroidism (PSHP), 16 (9%) with non-surgical hypoparathyroidism (NSHP) and 11 (7%) with pseudo-hypoparathyroidism (PHP).
History of kidney stones and seizures was present in 15 and 9% of patients, respectively. Renal and cerebral imaging was performed in 51 and 26% of the patients, with 22 and 25% of these patients having renal and cerebral calcifications respectively. Both history of seizures and cerebral calcifications were significantly more in NSHP and PHP than in PSHP patients. No association was observed between seizures and cerebral calcifications. Cramps/paraesthesia were present in 16%, and hospitalization related to hypocalcaemia was reported in 5% of the patients. Calciuria was screened in 47% at the time of consultation, and in 76% of the patients during the past 5 years. In 36% of these patients, calciuria was increased.
Patients with chronic hypoparathyroidism frequently develop ectopic calcifications. Non-surgical patients suffer more from seizures and cerebral calcifications than patients that developed hypoparathyroidism post surgery. There is a need for increased screening of long-term complications, according to the guidelines.
Ganapathy K Bhat, Tony M Plant and David R Mann
Objectives: Subnormal leptin levels in low birth weight infants may allow for catch-up growth during infancy. Scant data are available that relate growth with circulating leptin during normal infancy in primates. The current study objective was to examine the association between serum leptin, its soluble receptor (sOB-R), testosterone and IGF-I concentrations, and body weight during infancy in male rhesus monkeys.
Design: Hormone levels were assessed longitudinally in animals (n = 7) from birth until 1 year of age.
Results: Body weight increased during the first 6 months of life and was strongly correlated with rising IGF-I levels and, as IGF-I plateaued and then declined during the second half of the year, body weight gain decelerated. In contrast, leptin levels declined gradually with age during the first year of life in conjunction with increasing body weight. There was no association between body weight gain and serum leptin levels or between serum testosterone and leptin values. Since sOB-R levels also declined with leptin values, it does not appear that levels of bioavailable leptin changed during infancy.
Conclusions: The data do not support the contention that leptin regulates growth during infancy, but the close association between IGF-I levels and body weight suggested that this hormone may regulate growth in infant male monkeys. The failure to observe an association between serum testosterone and leptin concentrations suggested that leptin is not involved in the activation of the hypothalamic–pituitary –testicular axis during this developmental period.
David P Sonne, Jens F Rehfeld, Jens J Holst, Tina Vilsbøll and Filip K Knop
Recent preclinical work has suggested that postprandial flow of bile acids into the small intestine potentiates nutrient-induced glucagon-like peptide 1 (GLP1) secretion via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells. The notion of bile-induced GLP1 secretion combined with the findings of reduced postprandial gallbladder emptying in patients with type 2 diabetes (T2DM) led us to speculate whether reduced postprandial GLP1 responses in some patients with T2DM arise as a consequence of diabetic gallbladder dysmotility.
Design and methods
In a randomised design, 15 patients with long-standing T2DM and 15 healthy age-, gender- and BMI-matched control subjects were studied during 75-g oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals: i) 2.5 g fat, 107 g carbohydrate and 13 g protein; ii) 10 g fat, 93 g carbohydrate and 11 g protein; and iii) 40 g fat, 32 g carbohydrate and 3 g protein. Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP1, glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin and gastrin were measured. Furthermore, gallbladder emptying and gastric emptying were examined.
Gallbladder emptying increased with increasing meal fat content, but no intergroup differences were demonstrated. GIP and GLP1 responses were comparable among the groups with GIP levels being higher following high-fat meals, whereas GLP1 secretion was similar after both OGTT and meals.
In conclusion, patients with T2DM exhibited normal gallbladder emptying to meals with a wide range of fat content. Incretin responses were similar to that in controls, and an association with postprandial gallbladder contraction could not be demonstrated.
Vita Birzniece, Margot A Umpleby, Anne Poljak, David J Handelsman and Ken K Y Ho
In hypopituitary men, oral delivery of unesterified testosterone in doses that result in a solely hepatic androgen effect enhances protein anabolism during GH treatment. In this study, we aimed to determine whether liver-targeted androgen supplementation induces protein anabolism in GH-replete normal women.
Eight healthy postmenopausal women received 2-week treatment with oral testosterone at a dose of 40 mg/day (crystalline testosterone USP). This dose increases portal concentrations of testosterone, exerting androgenic effects on the liver without a spillover into the systemic circulation.
The outcome measures were whole-body leucine turnover, from which leucine rate of appearance (LRa, an index of protein breakdown) and leucine oxidation (Lox, a measure of irreversible protein loss) were estimated, energy expenditure and substrate utilization. We measured the concentration of liver transaminases as well as of testosterone, SHBG and IGF1.
Testosterone treatment significantly reduced LRa by 7.1±2.5% and Lox by 14.6±4.5% (P<0.05). The concentration of liver transaminases did not change significantly, while that of serum SHBG fell within the normal range by 16.8±4.0% and that of IGF1 increased by 18.4±7.7% (P<0.05). The concentration of peripheral testosterone increased from 0.4±0.1 to 1.1±0.2 nmol/l (P<0.05), without exceeding the upper normal limit. There was no change in energy expenditure and fat and carbohydrate utilization.
Hepatic exposure to unesterified testosterone by oral delivery stimulates protein anabolism by reducing protein breakdown and oxidation without inducing systemic androgen excess in women. We conclude that a small oral dose of unesterified testosterone holds promise as a simple novel treatment of protein catabolism and muscle wasting.
Anna McDonald, Rachel M Williams, Fiona M Regan, Robert K Semple and David B Dunger
Severe insulin resistance resulting from known or putative genetic defects affecting the insulin receptor or post-insulin receptor signalling represents a clinical spectrum ranging from Donohue’s and Rabson–Mendenhall syndrome, where the genetic defect is identified, through to the milder phenotype of type A insulin resistance, where a genetic defect can only be detected in around 10% of cases. Paradoxically, subjects with these conditions may present with hypoglycaemia due to mismatch of post-prandial glucose excursion and compensatory hyperinsulinaemia. Ultimately, treatment with insulin and insulin sensitisers will be unsuccessful and subjects may succumb to diabetes or its complications. Recombinant human IGF-I alone or combined with its binding protein (IGFBP-3) provides an alternative therapy as IGF-I receptor shares structural and functional homology with the insulin receptor and recombinant human insulin-like growth factor I (rhIGF-I) therapy could improve glucose disposal by signalling through the IGF-I receptor, whilst reducing the adverse effects of high insulin concentrations. There are also data which indicate that IGF-I signalling through the IGF-I receptor on the pancreatic β-cell may be important in maintaining insulin secretion. Pilot studies confirmed that rhIGF-I could reduce glucose and insulin levels in subjects with type A insulin resistance and those with Rabson–Mendenhall syndrome with sustained beneficial effects on HbA1c. Continued study has confirmed efficacy of rhIGF-I when combined with IGFBP-3 in the treatment of Donohue’s and type A insulin resistance subjects. Observations that IGF-I treatment can improve C-peptide levels in these subjects may indicate that it might be more valuable as a first line intervention to preserve β-cell function, rather than its current use as a medication of last resort in subjects where all other therapies have failed.
Ken K Ong, Francis de Zegher, Abel López-Bermejo, David B Dunger and Lourdes Ibáñez
Addition of androgen receptor (AR) blockade (flutamide) to insulin-sensitising therapy (metformin) may confer synergistic benefits in girls with hyperinsulinaemic androgen excess. We hypothesised that girls with shorter AR gene CAG repeat alleles, and thus greater receptor sensitivity, might benefit more from the addition of low-dose flutamide.
Open randomised crossover study.
In this study, 32 post-menarcheal girls (mean age 12.1 years) with a history of low birth weight and precocious pubarche were subgrouped by CAG genotype (‘short’: CAG mean length ≤20, n=14; ‘long’: CAG >20, n=18). Within each subgroup, girls were 1:1 randomised to metformin alone (850 mg/day) or in combination with flutamide (62.5 mg/day) for 12 months. To allow comparisons with no treatment, long-CAG girls randomised to flutamide–metformin, and short-CAG girls randomised to metformin alone were observed for 12 months before treatment. Body composition by absorptiometry, fasting lipid profiles and levels of insulin, glucose and androgens were measured during the first 12 months on each treatment.
In all girls, 12 months flutamide–metformin lowered body fat and improved lipid profiles when compared with no treatment. Compared with metformin alone, flutamide–metformin achieved greater reductions in the percentage of body fat and abdominal fat mass in the short-CAG subgroup (P=0.001 to P<0.0001). In contrast, in the long-CAG subgroup, flutamide–metformin produced no further improvements when compared with metformin alone.
In young post-menarcheal girls with preclinical androgen excess, low-dose flutamide–metformin improved body composition and key endocrine–metabolic abnormalities. However, only those girls with genetic markers of greater AR sensitivity may benefit from the addition of flutamide above metformin alone.
G. F. X. David, V. Puri, A. K. Dubey, C. P. Puri and T. C. Anand Kumar
Abstract. Adult female rhesus monkeys exhibiting normal ovulatory menstrual cycles were treated with progesterone nasal sprays. Animals in group A (n = 9) were treated with the solvent only (controls). Animals in groups B (n = 6), C (n = 17) and D (n = 7), respectively, were treated with a daily dose of 0.4, 2 and 10 μg of progesterone and the spraying was done between days 5–14 of the cycle. Ovulation was monitored by laparoscopy on day 20. The serum endocrine profile throughout the treated menstrual cycle was studied with respect to oestradiol and progesterone. Bioactive luteinizing hormone (bLH) was studied in blood samples taken on the day of the mid-cycle oestradiol peak, 2 days before, and 2 days after. The menstrual cycle was divided into two phases with respect to the mid-cycle oestradiol peak: phase I was taken to include day 1 of the cycle to the day of the oestradiol peak, and the remaining part of the menstrual cycle was considered to be phase II.
The serum-endocrine profile in the controls was similar to that observed in normal ovulatory menstrual cycles. However, in the progesterone-treated groups three types of menstrual cycles were discernable on the basis of the serum endocrine profile. In the type I menstrual cycle, observed only in group C (n = 10), the mid-cycle bLH peak was abolished and the progesterone levels remained low throughout the cycle. Laparoscopy revealed these to be anovulatory cycles. In the type II menstrual cycle, seen in the 3 animals of group B, 2 animals of group C, and in all the 7 animals of group D, the mid-cycle bLH peak was abolished and the progesterone levels during phase II of the cycle were significantly lower than in the controls, indicative of poor luteal function. In the type III menstrual cycle seen in the remaining monkeys, the serum endocrine profile did not differ from that seen in the controls. Thus, the present studies indicate that the intranasal administration of progesterone shows a dose-response effect with respect to the suppression of the oestradiol induced mid-cycle surge of bLH. Suppression of the mid-cycle bLH peak resulted in anovulatory cycles or ovulatory cycles with poor luteal function.
Linda Y. Johnson, Mary K. Vaughan, Russel J. Reiter, David E. Blask and P. Kevin Rudeen
Arginine vasotocin (AVT) treatment (1 μg/injection) every two hours beginning at 06.00 h on the morning preceding expected ovulation significantly inhibited ovulation in 29-day-old immature female rats treated 2 days earlier with 30 IU of PMS. Pre-ovulatory plasma surges and pituitary decreases in LH, FSH and prolactin as measured by radioimmunoassay were not eliminated by AVT treatment. However, there appeared to be an early rise in plasma FSH in these rats and the maximum plasma LH value attained during the surge period in PMS-treated rats was elevated by AVT treatment. Arginine vasotocin significantly inhibited the increase in ovarian weight which occurs in PMS-treated rats on the day preceding ovulation and uterine weights were consistently depressed in AVT-treated rats. The results of this study indicate that AVT likely inhibits PMS-induced ovulation at the level of the ovary, although the possibility cannot be ruled out that inhibition resulted from the advancement of the plasma FSH rise. These data and other studies investigating the effects of AVT on reproduction indicate that AVT is possibly capable of acting at more than one level of the hypothalamo-hypophyseal-gonadal axis.
H. Leon Bradlow, David K. Fukushima, Barnett Zumoff, Leon Hellman and T. F. Gallagher
Studies have been carried out on the metabolism of 3β-hydroxy-androst-5-en-17-one-3α-3H in two subjects. Rapid oxidation of the 3β-hydroxyl group appears to be the primary reaction occurring after the administration of dehydroepiandrosterone-3H with a substantial portion of the 3H appearing in the body water pool. Reduction to epiandrosterone does not occur to any significant extent before oxidation of the hydroxyl group. A small amount of 3H was found in androsterone and epiandrosterone indicating that some of the liberated 3H may be incorporated during the reduction of the double bond.