Efficacy and safety of liraglutide, a once-daily human glucagon-like peptide-1 receptor agonist, in African-American people with Type 2 diabetes: a meta-analysis of sub-population data from seven phase III trials.

AIM: To evaluate the efficacy and safety of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide in African-American people with Type 2 diabetes. METHODS: Analyses were performed on patient-level data from individuals self-defined as African-American or non-African-American in seven phase III studies. Endpoints included change in HbA1c level, fasting plasma glucose level and body weight from baseline, proportion of patients reaching HbA1c target [< 53 mmol/mol (< 7.0%)], and incidence of hypoglycaemia and nausea. Analyses used data obtained after 26 weeks. Within-population comparisons of liraglutide were performed vs placebo for African-American and non-African-American patient groups. In addition, between-population comparisons with non-African-American patients were performed for each treatment. RESULTS: In African-American patients (n = 225), HbA1c was significantly reduced at 26 weeks with liraglutide 1.2 and 1.8 mg (-11 and -14 mmol/mol, respectively compared with placebo; P < 0.0001). There were also significant reductions in fasting plasma glucose (-2.4 and -3.1 mmol/l, respectively, compared with placebo; P < 0.0001). Statistically significant reductions in body weight were observed with 1.8 mg liraglutide (-2.1 kg compared with placebo; P = 0.0056), but not with 1.2 mg liraglutide (-0.26 kg; P = 0.7307). The P value for interaction between treatment and race was significant for body weight (P = 0.0355). The incidence of non-severe hypoglycaemia with liraglutide was low (11-15% of patients), and < 25% of patients receiving liraglutide experienced nausea. CONCLUSIONS: This meta-analysis suggests that liraglutide is well tolerated and efficacious for treatment of Type 2 diabetes in African-American patients, with an efficacy that was shown not to differ from that observed in non-African-American patients over 26 weeks.

Functional expression of NOD2 in freshly isolated human peripheral blood γδ T cells.

γδ T cells play an important role in anti-infective immunity. The major subset of human γδ T cells selectively recognizes phosphorylated bacterial metabolites of the isoprenoid biosynthesis pathway, so-called phosphoantigens. The activation of γδ T cells is modulated by functionally expressed innate immune receptors, notably Toll-like receptor 2 and 3. It was also reported that in vitro expanded γδ T cells respond to muramyl dipeptide (MDP), the minimal peptidoglycan motif activating the nucleotide-binding oligomerization domain containing 2 (NOD2) receptor, although it is unknown whether ex vivo isolated human γδ T cells express functional NOD2. Here, we report that freshly isolated, highly purified peripheral blood γδ T cells express NOD2 mRNA and detectable amounts of NOD2 protein. The biologically active MDP L-D isomer but not the inactive D-D isomer augmented the interferon-γ (IFN-γ) secretion in phosphoantigen-stimulated peripheral blood mononuclear cells. Moreover, a moderate but reproducible and statistically significant increase in IFN-γ secretion was also observed when highly purified peripheral blood γδ T cells were activated by T cell receptor cross-linking in the presence of MDP. Taken together, our results indicate that in addition to the T cell receptor and Toll-like receptors, circulating human γδ T cells express NOD2 as a third class of pattern recognition receptor for sensing bacterial products.

An oxidation resistant radioligand for corticotropin-releasing factor receptors.

The methionine residues in Tyr-corticotropin-releasing factor (CRF) and Tyr-sauvagine radioligands are subject to oxidation, which renders them biologically inactive. Therefore [Tyr(0,) Gln(1,) Leu(17)]sauvagine (YQLS), in which the methionine was replaced with leucine was synthesized and labeled with (125)Iodine using chloramine-T. Mass spectroscopy revealed that chloramine-T-treatment did not oxidize YQLS. (125)I-YQLS bound with high affinity to cells expressing the murine CRF receptor 1 (CRFR1), CRF receptor 2 (CRFR2), and the mouse brain regions known to express both CRF receptors. (125)I-YQLS chemically cross-linked to CRFR1. In conclusion, (125)I-YQLS is oxidation-resistant, high affinity radioligand that can be chemically cross-linked to the CRF receptors.

Juxtamembrane region of the amino terminus of the corticotropin releasing factor receptor type 1 is important for ligand interaction.

The functional properties of the amino terminus (NT) of the corticotropin releasing factor (CRF) receptor type 1 (R1) were studied by use of murine (m) CRFR1 and rat (r) parathyroid hormone (PTH)/parathyroid hormone-related peptide receptor (PTH1R) chimeras. The chimeric receptor CXP, in which the NT of mCRFR1 was annealed to the TMs of PTH1R, and the reciprocal hybrid, PXC, bound radiolabeled analogues of sauvagine and PTH(3--34), respectively. Neither hybrid bound radiolabeled CRF or PTH(1--34). CRF and PTH(1--34) weakly stimulated intracellular cAMP accumulation in COS-7 cells transfected with PXC and CXP, respectively. Thus the NT is required for ligand binding and the TMs are required for agonist-stimulated cAMP accumulation. Replacing individual intercysteine segments of PXC with their mCRFR1 counterparts did not rescue CRF or sauvagine radioligand binding or stimulation of cAMP accumulation. Replacement of residues 1--31 of mCRFR1 with their PTH1R counterparts resulted in a chimeric receptor, PEC, which had normal CRFR1 functional properties. In addition, a series of chimeras (F1PEC--F6PEC) were generated by replacement of the NT intercysteine residues of PEC with their PTH1R counterparts. Only F1PEC, F2PEC, and F3PEC showed detectable CRF and sauvagine radioligand binding. All of the PEC chimeras except F5PEC increased cAMP accumulation. These data indicate that the Cys(68)(-)Glu(109) domain is important for binding and that the Cys(87)(-)Cys(102) region plays an important role in CRFR1 activation.

Medical therapy for gonadotroph and thyrotroph tumors.

Gonadotroph adenomas, a common type of pituitary tumor, are not associated with syndromes of hormonal hypersecretion and thus present as pituitary macroadenomas with mass effects, or as incidentally discovered pituitary masses. When indicated, primary therapy is neurosurgery, but there may be a limited role for medical therapy in patients with residual disease. Thyrotroph adenomas are rare neoplasms that present with hyperthyroidism and local mass effects. Medical therapy may be effective in controlling tumor growth and in achieving euthyroidism, when surgery or radiation, or both, do not control the tumor.

Hypercalcemia in a woman with hypoparathyroidism associated with increased parathyroid hormone-related protein during lactation.

OBJECTIVE: To report a case of postpartum hypercalcemia in a woman with hypoparathyroidism associated with increased serum concentrations of parathyroid hormone-related protein (PTHrP) during lactation. METHODS: The clinical and laboratory data for our patient and the related literature are reviewed. RESULTS: A 35-year-old woman with long-standing surgical hypoparathyroidism treated with dihydrotachysterol and calcium carbonate gave birth to a healthy boy at 40 weeks of gestation and began lactating normally. Two and a half weeks later, hypercalcemia developed in association with nausea, vomiting, and myalgias. Subsequently, an increased serum PTHrP concentration was noted. After saline diuresis and corticosteroid therapy to correct the hypercalcemia, a normal serum calcium level was maintained without vitamin D preparations or calcium supplements until the 12th postpartum week, when hypocalcemia reappeared. The serum PTHrP level was no longer increased, and treatment with calcitriol and calcium carbonate was resumed. Subsequent serum calcium concentrations have been normal. CONCLUSION: This case suggests that PTHrP stimulation of the parathyroid hormone-PTHrP receptor during lactation may compensate for the absence of parathyroid hormone in lactating women with hypoparathyroidism and that treatment with pharmacologic doses of vitamin D preparations during the postpartum period may result in hypercalcemia.

The use of anti-aging hormones. Melatonin, growth hormone, testosterone, and dehydroepiandrosterone: consumer enthusiasm for unproven therapies.

Since ancient times, humans have been concerned with developing and preserving youthful vigor. Today, there is enough understanding of the aging process to attempt to delay it. This review considers four popular and easily obtainable anti-aging hormones: melatonin, growth hormone, testosterone, and dehydroepiandrosterone (DHEA). Many of the benefits of using these hormones, which are promoted in the lay literature, are based on animal studies and weak associations. This review critically examines the scientific literature. At this time, there is insufficient evidence to recommend these hormones as therapies for aging, and there are potential risks from their use. The information provided here will help physicians discuss the use of these hormones with inquiring patients.