The rising global rates of type 2 diabetes and obesity present a significant economic and social burden, underscoring the importance for effective and safe therapeutic options. The success of glucagon-like-peptide-1 receptor agonists in the treatment of type 2 diabetes, along with the potent glucose-lowering effects of bariatric surgery, highlight the gastrointestinal tract as a potential target for diabetes treatment. Furthermore, recent evidence suggests that the gut plays a prominent role in the ability of metformin to lower glucose levels. As such, the current review highlights some of the current and potential pathways in the gut that could be targeted to improve glucose homeostasis, such as changes in nutrient sensing, gut peptides, gut microbiota and bile acids. A better understanding of these pathways will lay the groundwork for novel gut-targeted antidiabetic therapies, some of which have already shown initial promise.
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- Abstract: Diabetes x
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Paige V Bauer and Frank A Duca
P. F. Terranova, J. Th. J. Uilenbroek, L. Saville, D. Horst, and Y. Nakamura
Preovulatory follicles from adult hamsters on the morning of pro-oestrus were used in this study. Serotonin stimulated oestradiol production by preovulatory follicles during a 5-h incubation in 1 ml Krebs–Ringer bicarbonate glucose medium containing isobutylmethylxanthine (0.1 mmol/l; IBMX) and androstenedione (1 μmol/l). The enhanced oestradiol production by serotonin was dependent on the dose of IBMX and androstenedione. Mianserin, a serotonin type-1 and serotonin type-2 receptor antagonists, prevented the serotonin-enhanced oestradiol production in a dose-dependent manner. Ketanserin, a specific serotonin type-2 receptor antagonist, was ineffective in blocking the action of serotonin, indicating that the effect of serotonin was mediated by the serotonin type-1 receptor. In the presence of androstenedione (1 μmol/l), serotonin was unable to enhance oestradiol production in isolated granulosa cells. It was also unable to enhance oestradiol production in early atretic follicles; atresia was induced experimentally by an injection of phenobarbital in order to prevent ovulation.
The data indicate that serotonin stimulates oestradiol production by hamster preovulatory follicles in vitro. The mechanism of action of serotonin involves an intact healthy follicle, a serotonin type-1 receptor and possibly cyclic AMP. The increased oestradiol secretion might be related to increased androgen production by the follicle and increased permeability (leakiness) of the follicle to androstenedione which serves as substrate for aromatization to oestradiol by the granulosa cell.
Journal of Endocrinology (1990) 125, 433–438
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.
Chun Zeng, Xin Yi, Danny Zipris, Hongli Liu, Lin Zhang, Qiaoyun Zheng, Krishnamurthy Malathi, Ge Jin, and Aimin Zhou
The cause of type 1 diabetes continues to be a focus of investigation. Studies have revealed that interferon α (IFNα) in pancreatic islets after viral infection or treatment with double-stranded RNA (dsRNA), a mimic of viral infection, is associated with the onset of type 1 diabetes. However, how IFNα contributes to the onset of type 1 diabetes is obscure. In this study, we found that 2-5A-dependent RNase L (RNase L), an IFNα-inducible enzyme that functions in the antiviral and antiproliferative activities of IFN, played an important role in dsRNA-induced onset of type 1 diabetes. Using RNase L-deficient, rat insulin promoter-B7.1 transgenic mice, which are more vulnerable to harmful environmental factors such as viral infection, we demonstrated that deficiency of RNase L in mice resulted in a significant delay of diabetes onset induced by polyinosinic:polycytidylic acid (poly I:C), a type of synthetic dsRNA, and streptozotocin, a drug which can artificially induce type 1-like diabetes in experimental animals. Immunohistochemical staining results indicated that the population of infiltrated CD8+T cells was remarkably reduced in the islets of RNase L-deficient mice, indicating that RNase L may contribute to type 1 diabetes onset through regulating immune responses. Furthermore, RNase L was responsible for the expression of certain proinflammatory genes in the pancreas under induced conditions. Our findings provide new insights into the molecular mechanism underlying β-cell destruction and may indicate novel therapeutic strategies for treatment and prevention of the disease based on the selective regulation and inhibition of RNase L.
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.
JA Shaw, MI Delday, AW Hart, HM Docherty, CA Maltin, and K Docherty
The objective of these studies was to evaluate human insulin gene expression following intramuscular plasmid injection in non-diabetic rats as a potential approach to gene therapy for diabetes mellitus avoiding the need for immunosuppression. A wild-type human preproinsulin construct and a mutant construct in which PC2/PC3 sites were engineered to form furin consensus sites were evaluated in in vitro transfections of hepatocyte (HepG2) and myoblast (C2C12/L6) cell lines, primary rat myoblasts, and dermal fibroblasts. In vivo gene transfer by percutaneous plasmid injection of soleus muscle +/- prior notexin-induced myolysis was assessed in rats. In vitro transfection of non-neuroendocrine cell lines and primary cultures with wild-type human preproinsulin resulted in secretion of predominantly unprocessed proinsulin. Employing the mutant construct, there was significant processing to mature insulin (HepG2, 95%; C2C12, 75%; L6, 65%; primary myoblasts, 48%; neonatal fibroblasts, 56%; adult fibroblasts, 87%). In rats aged 5 weeks, circulating human (pro)insulin was detected from 1 to 37 days following plasmid injection and the potential of augmenting transfection efficiency by prior notexin injection was demonstrated (wild-type processing, 87%; mutant, 90%). Relative hypoglycaemia was confirmed by HbA1C (saline, 5.5%; wild type, 5.1%; mutant, 5.1% (P<0.05)). Human (pro)insulin levels and processing (wild-type, 8%; mutant, 53%) were lower in rats aged 9 months but relative hypoglycaemia was confirmed by serum glucose at 10 days (saline, 6.4 mmol/l; wild-type, 6.0 mmol/l; mutant, 5.4 mmol/l). In conclusion, prolonged constitutive systemic secretion of bioactive human (pro)insulin has been attained in non-neuroendocrine cells in vitro and in growing and mature rats following intramuscular plasmid injection.
L van Bloemendaal, J S ten Kulve, S E la Fleur, R G Ijzerman, and M Diamant
The delivery of nutrients to the gastrointestinal tract after food ingestion activates the secretion of several gut-derived mediators, including the incretin hormone glucagon-like peptide 1 (GLP-1). GLP-1 receptor agonists (GLP-1RA), such as exenatide and liraglutide, are currently employed successfully in the treatment of patients with type 2 diabetes mellitus. GLP-1RA improve glycaemic control and stimulate satiety, leading to reductions in food intake and body weight. Besides gastric distension and peripheral vagal nerve activation, GLP-1RA induce satiety by influencing brain regions involved in the regulation of feeding, and several routes of action have been proposed. This review summarises the evidence for a physiological role of GLP-1 in the central regulation of feeding behaviour and the different routes of action involved. Also, we provide an overview of presently available data on pharmacological stimulation of GLP-1 pathways leading to alterations in CNS activity, reductions in food intake and weight loss.