One of the most sexually dimorphic aspects of metabolic regulation is the bidirectional modulation of glucose homeostasis by testosterone in male and females. Severe testosterone deficiency predisposes men to type 2 diabetes (T2D), while in contrast, androgen excess predisposes women to hyperglycemia. The role of androgen deficiency and excess in promoting visceral obesity and insulin resistance in men and women respectively is well established. However, although it is established that hyperglycemia requires β cell dysfunction to develop, the role of testosterone in β cell function is less understood. This review discusses recent evidence that the androgen receptor (AR) is present in male and female β cells. In males, testosterone action on AR in β cells enhances glucose-stimulated insulin secretion by potentiating the insulinotropic action of glucagon-like peptide-1. In females, excess testosterone action via AR in β cells promotes insulin hypersecretion leading to oxidative injury, which in turn predisposes to T2D.
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- Abstract: Diabetes x
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- Abstract: Glucagon x
- Abstract: IGF* x
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Weiwei Xu, Jamie Morford, and Franck Mauvais-Jarvis
VA Gault, PR Flatt, P Harriott, MH Mooney, CJ Bailey, and FP O'Harte
The therapeutic potential of glucagon-like peptide-1 (GLP-1) in improving glycaemic control in diabetes has been widely studied, but the potential beneficial effects of glucose-dependent insulinotropic polypeptide (GIP) have until recently been almost overlooked. One of the major problems, however, in exploiting either GIP or GLP-1 as potential therapeutic agents is their short duration of action, due to enzymatic degradation in vivo by dipeptidylpeptidase IV (DPP IV). Therefore, this study examined the plasma stability, biological activity and antidiabetic potential of two novel NH2-terminal Ala2-substituted analogues of GIP, containing glycine (Gly) or serine (Ser). Following incubation in plasma, (Ser2)GIP had a reduced hydrolysis rate compared with native GIP, while (Gly2)GIP was completely stable. In Chinese hamster lung fibroblasts stably transfected with the human GIP receptor, GIP, (Gly2)GIP and (Ser2)GIP stimulated cAMP production with EC(50) values of 18.2, 14.9 and 15.0 nM respectively. In the pancreatic BRIN-BD11 beta-cell line, (Gly2)GIP and (Ser2)GIP (10(-8) M) evoked significant increases (1.2- and 1.5-fold respectively; P<0.01 to P<0.001) in insulinotropic activity compared with GIP. In obese diabetic ob/ob mice, both analogues significantly lowered (P<0.001) the glycaemic excursion in response to i.p. glucose. This enhanced glucose-lowering ability was coupled to a significantly raised (P<0.01) and more protracted insulin response compared with GIP. These data indicate that substitution of the penultimate Ala2 in GIP by Gly or Ser confers resistance to plasma DPP IV degradation, resulting in enhanced biological activity, therefore raising the possibility of their use in the treatment of type 2 diabetes.
S. J. Winder, S. D. Wheatley, and I. A. Forsyth
Sucrose density centrifugation was used to prepare a partially purified membrane fraction from the mammary glands of non-pregnant, pregnant and lactating sheep. The binding of125 I-labelled insulin-like growth factor-I (IGF-I) was dependent on membrane protein concentration, pH, time and temperature. The binding showed the characteristics of a type-1 IGF receptor, being displaced by IGF-I (median effective dose (ED50) 0·55 nmol/l), less effectively by IGF-II (ED50 8·8 nmol/l) and least effectively by insulin. Glucagon, ovine prolactin and ovine placental lactogen could not displace binding. A molecular weight of 135 000 was determined by affinity cross-linking using disuccinimidyl suberate; this was consistent with the reported size of the type-1 receptor α-subunit. Scatchard analysis was used to determine binding affinity and numbers of IGF-I-binding sites. A single class of high-affinity binding sites was found in all physiological states. In non-pregnant sheep and sheep at days 40, 75 and 110–120 of pregnancy and at term, the binding affinity was similar (apparent dissociation constant (K d) 2·73 ±0·31 nmol/l, n = 22). In lactating sheep (weeks 1, 4 and 10), the binding affinity was significantly (P = 0·02) higher (K d 0·77± 0·06 nmol/l n = 9). Binding capacity was similar in non-pregnant and pregnant sheep (1005 ± 113 fmol/mg, n = 19), but fell by parturition and remained low in lactation (570±52 fmol/mg membrane protein, n = 12). The results suggest that the mammary growth of pregnancy is not regulated at the level of the type-1 IGF receptor.
Journal of Endocrinology (1993) 136, 297–304
D. R. NAIK and C. J. DOMINIC
Seven morphologically and tinctorially distinct types of cell (types 1–) have been distinguished in the pars anterior of the pituitary gland of the musk shrew (Suncus murinus L.). On the basis of their responses to various experimental stimuli, these cell types were correlated with the secretion of various trophic hormones. Type 1 cells exhibited conspicuous changes after thyroidectomy or inactivation of the thyroid gland and hence appeared to be the source of TSH. Types 2 and 3 cells responded to gonadectomy and administration of androgens, which suggests that they were associated with gonadotrophin secretion. The granules of the type 2, but not the type 3 cells could be extracted with 10% trichloroacetic acid, which may indicate that type 2 and 3 cells secrete FSH and LH respectively. After the administration of either reserpine or oestrogen, the type 4 cells underwent hypertrophy and hyperplasia, which suggests that they were the likely source of prolactin. Type 6 cells, which are distinguishable from type 4 cells by their thinly dispersed erythrosinophilic granulation, showed conspicuous changes after unilateral adrenalectomy, administration of metyrapone or exposure to stress and may therefore be responsible for secretion of ACTH. Type 5 cells tinctorially resembled the somatotrophic cells of other mammalian species and did not respond to any of the experimental treatments used in the present study. It is therefore possible that these cells have a somatotrophic function. The possible significance of type 7 cells has been discussed previously.
C. L. FOSTER, E. CAMERON, and B. A. YOUNG
The ultrastructure of the adenohypophysis of the rabbit, after treatment with propylthiouracil, is described. All cells in the zona tuberalis and pars distalis proper, with the exception of the prolactin producing (type 1) and stellate cells (type 5), were affected. However, the only ones which presented some evidence of sequential changes were the type 4 cells. These became markedly degranulated and sometimes showed vesiculation of the cisternae of the granular endoplasmic reticulum, similar to that observed in the 'thyroidectomy' cells in some other species. Although changes occurred in the somatotrophs (type 2) and in the gonadotrophs (type 3) the evidence suggests that it is the type 4 cells which have a thyrotrophic function.
Alison J Forhead, Juanita K Jellyman, Katherine Gillham, Janelle W Ward, Dominique Blache, and Abigail L Fowden
The actions of angiotensin II on type 1 (AT1) and type 2 (AT2) receptor subtypes are important for normal kidney development before birth. This study investigated the effect of AT1 receptor antagonism on renal growth and growth regulators in fetal sheep during late gestation. From 125 days of gestation (term 145±2 days), chronically catheterised sheep fetuses were infused intravenously for 5 days with either an AT1-specific receptor antagonist (GR138950, 2–4 mg/kg per day, n=5) or saline (0.9% NaCl, n=5). Blockade of the AT1 receptor decreased arterial blood oxygenation and pH and increased blood pCO2, haemoglobin and lactate, and plasma cortisol and IGF-II. Blood glucose and plasma thyroid hormones and IGF-I were unchanged between the treatment groups. On the 5th day of infusion, the kidneys of the GR-treated fetuses were lighter than those of the control fetuses, both in absolute and relative terms, and were smaller in transverse cross-sectional width and cortical thickness. In the GR-infused fetuses, renal AT2 receptor protein concentration and glomerular density were significantly greater than in the saline-infused fetuses. Blockade of the AT1 receptor had no effect on relative cortical thickness, fractional or mean glomerular volumes, or renal protein levels of the AT1 receptor, IGF type 1 receptor, insulin receptor or protein kinase C ζ. Therefore, in the ovine fetus, AT1 receptor antagonism causes increased renal protein expression of the AT2 receptor subtype, which, combined with inhibition of AT1 receptor activity, may be partly responsible for growth retardation of the developing kidney.
Maaike M Roefs, Françoise Carlotti, Katherine Jones, Hannah Wills, Alexander Hamilton, Michael Verschoor, Joanna M Williams Durkin, Laura Garcia-Perez, Melissa F Brereton, Laura McCulloch, Marten A Engelse, Paul R V Johnson, Barbara C Hansen, Kevin Docherty, Eelco J P de Koning, and Anne Clark
Type 2 diabetes (T2DM) is associated with pancreatic islet dysfunction. Loss of β-cell identity has been implicated via dedifferentiation or conversion to other pancreatic endocrine cell types. How these transitions contribute to the onset and progression of T2DM in vivo is unknown. The aims of this study were to determine the degree of epithelial-to-mesenchymal transition occurring in α and β cells in vivo and to relate this to diabetes-associated (patho)physiological conditions. The proportion of islet cells expressing the mesenchymal marker vimentin was determined by immunohistochemistry and quantitative morphometry in specimens of pancreas from human donors with T2DM (n = 28) and without diabetes (ND, n = 38) and in non-human primates at different stages of the diabetic syndrome: normoglycaemic (ND, n = 4), obese, hyperinsulinaemic (HI, n = 4) and hyperglycaemic (DM, n = 8). Vimentin co-localised more frequently with glucagon (α-cells) than with insulin (β-cells) in the human ND group (1.43% total α-cells, 0.98% total β-cells, median; P < 0.05); these proportions were higher in T2DM than ND (median 4.53% α-, 2.53% β-cells; P < 0.05). Vimentin-positive β-cells were not apoptotic, had reduced expression of Nkx6.1 and Pdx1, and were not associated with islet amyloidosis or with bihormonal expression (insulin + glucagon). In non-human primates, vimentin-positive β-cell proportion was larger in the diabetic than the ND group (6.85 vs 0.50%, medians respectively, P < 0.05), but was similar in ND and HI groups. In conclusion, islet cell expression of vimentin indicates a degree of plasticity and dedifferentiation with potential loss of cellular identity in diabetes. This could contribute to α- and β-cell dysfunction in T2DM.
G Üçkaya, P Delagrange, A Chavanieu, G Grassy, M-F Berthault, A Ktorza, E Cerasi, G Leibowitz, and N Kaiser
Glucagon-like peptide 1 (GLP-1) analogues are considered potential drugs for type 2 diabetes. We studied the effect of a novel GLP-1 analogue, S 23521 ([a8-des R36] GLP-1-[7–37]-NH2), on the metabolic state and β-cell function, proliferation and survival in the Psammomys obesus model of diet-induced type 2 diabetes. Animals with marked hyperglycaemia after 6 days of high-energy diet were given twice-daily s.c. injection of 100 μg/kg S 23521 for 15 days. Food intake was significantly decreased in S 23251-treated P. obesus; however, there was no significant difference in body weight from controls. Progressive worsening of hyperglycaemia was noted in controls, as opposed to maintenance of pre-treatment glucose levels in the S 23521 group. Prevention of diabetes progression was associated with reduced mortality. In addition, the treated group had higher serum insulin, insulinogenic index and leptin, whereas plasma triglyceride and non-esterified fatty acid levels were decreased. S 23521 had pronounced effect on pancreatic insulin, which was 5-fold higher than the markedly depleted insulin reserve of control animals. Immunohistochemical analysis showed islet degranulation with disrupted morphology in untreated animals, whereas islets from S 23521-treated animals appeared intact and filled with insulin; β-cell apoptosis was approximately 70% reduced, without a change in β-cell proliferation. S 23521 treatment resulted in a 2-fold increase in relative β-cell volume. Overall, S 23521 prevented the progression of diabetes in P. obesus with marked improvement of the metabolic profile, including increased pancreatic insulin reserve, β-cell viability and mass. These effects are probably due to actions of S 23521 both directly on islets and via reduced food intake, and emphasize the feasibility of preventing blood glucose deterioration over time in type 2 diabetes.
Hongbin Liu, Anthony E Dear, Lotte B Knudsen, and Richard W Simpson
Glucagon-like peptide-1 (GLP-1) administration attenuates endothelial cell dysfunction in diabetic patients and inhibits tumour necrosis factor α (TNF)-mediated plasminogen activator inhibitor type-1 (PAI-1) induction in human vascular endothelial cells. The short half-life of GLP-1 mediated via degradation by the enzyme dipeptidyl peptidase 4 mandates the clinical use of long-acting GLP-1 analogues. The effects of a long-acting GLP-1 analogue on PAI-1 and vascular adhesion molecule expression in vascular endothelial cells are unknown. In this report, we demonstrate for the first time that the treatment with liraglutide, a long-acting GLP-1 analogue, inhibited TNF or hyperglycaemia-mediated induction of PAI-1, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 mRNA and protein expression in a human vascular endothelial cell line. In addition, treatment attenuated TNF- or hyperglycaemia-mediated induction of the orphan nuclear receptor Nur77 mRNA expression. Taken together, these observations indicate that liraglutide inhibits TNF- or glucose-mediated induction of PAI-1 and vascular adhesion molecule expression, and this effect may involve the modulation of NUR77. These effects suggest that liraglutide may potentially improve the endothelial cell dysfunction associated with premature atherosclerosis identified in type 2 diabetic patients.
Jun-ichi Eiki, Kaori Saeki, Norihiro Nagano, Tomoharu Iino, Mari Yonemoto, Yoko Takayenoki-Iino, Satoru Ito, Teruyuki Nishimura, Yoshiyuki Sato, Makoto Bamba, Hitomi Watanabe, Kaori Sasaki, Sumika Ohyama, Akio Kanatani, Toshio Nagase, and Toshihiko Yada
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates insulin secretion in a glucose-dependent manner. Selective GLP-1 secretagogue would be one of the potential therapeutic targets for type 2 diabetes. Here, we describe a newly identified small molecule compound (compound A) that stimulates secretion of GLP-1 in murine enteroendocrine cell lines, STC-1 and GLUTag cells, and in primary cultured fetal rat intestinal cells (FRIC). The underlying mechanism by which compound A stimulated GLP-1 secretion was also examined. Compound A stimulated GLP-1 secretion from STC-1 cells in a concentration-dependent manner, and also from GLUTag cells and FRIC. The action of compound A was selective against other tested endocrine functions such as secretion of insulin from rat islets, growth hormone from rat pituitary gland cells, and norepinephrine from rat PC-12 cells. In STC-1 cells, the compound A-stimulated GLP-1 secretion was neither due to cyclic AMP production nor to Ca2+ release from intracellular stores, but to extracellular Ca2+ influx. The response was inhibited by the presence of either L-type Ca2+ channel blockers or K+ ionophore. Perforated-patch clamp study revealed that compound A induces membrane depolarization. These results suggest that neither Gαs- nor Gαq-coupled signaling account for the mechanism of action, but depolarization-coupled Ca2+ influx from extracellular space is the primary cause for the GLP-1 secretion stimulated by compound A. Identifying a specific target molecule for compound A will reveal a selective regulatory pathway that leads to depolarization-mediated GLP-1 secretion.