1. The relationship between polycystic ovary syndrome, glucose tolerance status and serum preptin level
Bei Xu,Hanwang Zhang,Rui Wang,Zhiqin Bu,Jie Meng,Kakei Kuok Reprod Biol Endocrinol . 2012 Feb 6;10:10. doi: 10.1186/1477-7827-10-10.
Background:Polycystic ovary syndrome (PCOS) is linked to obesity, impaired glucose tolerance and diabetes. Recently, studies have found that preptin enhances insulin secretion in rats and might play a role in the pathogenesis of diabetes and PCOS in humans. The aim of this study was to evaluate the relationship between PCOS, glucose tolerance status, and serum preptin level.Methods:This study was conducted in a university-affiliated hospital from October 2010 to August 2011. Anthropometric parameters, sex hormone concentrations, blood pressure, lipid profiles, fasting glucose and insulin, 2-h blood glucose after glucose overloaded (2hOGTT), glycosylated haemoglobin (HbA1c), homeostasis model assessment-insulin resistance index (HOMA-IR), and serum preptin of the samples were analyzed.Results:Sixty-three PCOS patients, including 33 women with normal glucose tolerance (NGT) and 30 women with impaired glucose tolerance (IGT), and 63 patients without PCOS, including 35 women with NGT and 28 women with IGT were recruited in this study. For patients with and without PCOS, women with IGT had higher serum preptin levels compared with women with NGT. Preptin levels in PCOS patients were higher compared with patients without PCOS, but the difference was not significant. Fasting serum preptin levels correlated positively with TG, SBP, DBP, FBG, 2hOGTT, and HOMA-IR in simple regression analysis of the pooled data. While in multiple stepwise regression analysis, preptin levels were independently related with glucose tolerance, but not with PCOS.Conclusions:Irrespective of PCOS status, women with IGT had higher serum preptin levels compared with women with NGT. Preptin levels are related with glucose tolerance status, but not with PCOS status.
2. Preptin derived from proinsulin-like growth factor II (proIGF-II) is secreted from pancreatic islet beta-cells and enhances insulin secretion
G J Cooper,A R Phillips,C M Buchanan Biochem J . 2001 Dec 1;360(Pt 2):431-9. doi: 10.1042/0264-6021:3600431.
Pancreatic islet beta-cells secrete the hormones insulin, amylin and pancreastatin. To search for further beta-cell hormones, we purified peptides from secretory granules isolated from cultured murine beta TC6-F7 beta-cells. We identified a 34-amino-acid peptide (3948 Da), corresponding to Asp(69)-Leu(102) of the proinsulin-like growth factor II E-peptide, which we have termed 'preptin'. Preptin, is present in islet beta-cells and undergoes glucose-mediated co-secretion with insulin. Synthetic preptin increases insulin secretion from glucose-stimulated beta TC6-F7 cells in a concentration-dependent and saturable manner. Preptin infusion into the isolated, perfused rat pancreas increases the second phase of glucose-mediated insulin secretion by 30%, while anti-preptin immunoglobulin infusion decreases the first and second phases of insulin secretion by 29 and 26% respectively. These findings suggest that preptin is a physiological amplifier of glucose-mediated insulin secretion.
3. Swim therapy-induced tissue specific metabolic responses in male rats
Amira Moustafa,Ahmed Hamed Arisha Life Sci . 2020 Dec 1;262:118516. doi: 10.1016/j.lfs.2020.118516.
Swim therapy in the form of moderate physical activity has general health benefits. Regular exercise prevents the progression of chronic diseases affecting the different bodily systems. The metabolic alterations associated with following such lifestyle remain not fully understood. The aim of the present study was to elucidate the metabolic changes following prolonged swim therapy. Twenty-four Sprague Dawley rats were divided into sedentary and exercise groups. Our results revealed that regular exercise significantly increased the serum levels of growth hormone (GH), glucagon and corticosterone. A reduction in the circulating levels of irisin and insulin hormones, and glucose were noticed alongside with an upregulation in the mRNA expression levels of FNDC5, PGC-1α, GLUT-4 and preptin receptors with downregulation in the expression of Enho gene in the heart of exercised rats. Liver of the exercised rats showed elevation in the transcriptional levels of Enho gene, PPARα, and preptin with reduction in the transcriptional levels of preptin receptors. Exercise induced an increase in the pancreatic mRNA of Enho gene, preptin and preptin receptors, and a reduction in FNDC5, PPARα and PGC-1α. An elevation in the gastrocnemius muscle PGC-1α mRNA expression and a decline in the soleus muscle Enho mRNA were found. Exercise diminishes the activities of SOD, CAT and GPx in the gastrocnemius muscle, liver and pancreas. Myogenin expression increased in all examined skeletal muscles. This study takes into account the complex crosstalk between different signaling pathways in skeletal muscles, heart, liver and pancreas as well as the metabolic alterations in response to regular exercise.
4. Structure activity relationship study on the peptide hormone preptin, a novel bone-anabolic agent for the treatment of osteoporosis
Young-Eun Park,Maureen Watson,Renata Kowalczyk,Zaid Amso,Margaret A Brimble,Karen E Callon,Jillian Cornish,David S Musson Org Biomol Chem . 2016 Oct 21;14(39):9225-9238. doi: 10.1039/c6ob01455k.
Preptin is a 34-residue pancreatic hormone shown to be anabolic to bone in vitro and in vivo. The bone activity of preptin resides within the (1-16) N-terminal fragment. Due to its peptidic nature, the truncated fragment of preptin is enzymatically unstable; however it provides an attractive framework for the creation of stable analogues using various peptidomimetic techniques. An alanine scan of preptin (1-16) was undertaken which showed that substitution of Ser at position 3 or Pro at position 14 did not inhibit the proliferative activity of preptin in primary rat osteoblasts (bone-forming cells). Importantly, Ser-3 to Ala substitution also showed a significant activity on osteoblast differentiation in vitro and increased the formation of mineralised bone matrix. Additional modifications with non-proteinogenic amino acids at position 3 improved the stability in liver microsomes, but diminished the osteoblast proliferative activity. In addition, to provide greater structural diversity, a series of macrocyclic preptin (1-16) analogues was synthesised using head-to-tail and head-to-side chain macrolactamisation as well as ring-closing metathesis. However, a detrimental effect on osteoblast activity was observed upon macrocyclisation.
5. Preptin, another peptide product of the pancreatic beta-cell, is osteogenic in vitro and in vivo
K E Callon,U Bava,V A Chan,X Xu,I R Reid,M Watson,J M Lin,C M Buchanan,G J S Cooper,D Naot,A B Grey,J Cornish Am J Physiol Endocrinol Metab . 2007 Jan;292(1):E117-22. doi: 10.1152/ajpendo.00642.2005.
Several hormones that regulate nutritional status also impact on bone metabolism. Preptin is a recently isolated 34-amino acid peptide hormone that is cosecreted with insulin and amylin from the pancreatic beta-cells. Preptin corresponds to Asp(69)-Leu(102) of pro-IGF-II. Increased circulating levels of a pro-IGF-II peptide complexed with IGF-binding protein-2 have been implicated in the high bone mass phenotype observed in patients with chronic hepatitis C infection. We have assessed preptin's activities on bone. Preptin dose-dependently stimulated the proliferation (cell number and DNA synthesis) of primary fetal rat osteoblasts and osteoblast-like cell lines at periphysiological concentrations (>10(-11) M). In addition, thymidine incorporation was stimulated in murine neonatal calvarial organ culture, likely reflecting the proliferation of cells from the osteoblast lineage. Preptin did not affect bone resorption in this model. Preptin induced phosphorylation of p42/p44 MAP kinases in osteoblastic cells in a dose-dependent manner (10(-8)-10(-10) M), and its proliferative effects on primary osteoblasts were blocked by MAP kinase kinase inhibitors. Preptin also reduced osteoblast apoptosis induced by serum deprivation, reducing the number of apoptotic cells by >20%. In vivo administration of preptin increased bone area and mineralizing surface in adult mice. These data demonstrate that preptin, which is cosecreted from the pancreatic beta-cell with amylin and insulin, is anabolic to bone and may contribute to the preservation of bone mass observed in hyperinsulinemic states such as obesity.
6. Synthesis of truncated analogues of preptin-(1-16), and investigation of their ability to stimulate osteoblast proliferation
Maureen Watson,Young-Eun Park,Sung H Yang,Renata Kowalczyk,Margaret A Brimble,Karen E Callon,Jillian Cornish Bioorg Med Chem . 2014 Jul 15;22(14):3565-72. doi: 10.1016/j.bmc.2014.05.026.
Preptin, a 34-amino acid residue peptide hormone is co-secreted with insulin from the β-pancreatic cells and is active in fuel metabolism. We have previously established that a shorter fragment of preptin, namely preptin-(1-16), stimulates bone growth by proliferation and increasing the survival rate of osteoblasts. This was demonstrated in both in vitro and in vivo models. These findings suggest that preptin-(1-16) could play an important role in the anabolic therapy of osteoporosis. However, due to the large size of the peptide it is not an ideal therapeutic agent. The aim of this study was to identify the shortest preptin analogue that retains or even increases the bone anabolic activity as compared to the parent preptin-(1-16) peptide. Truncations were made in a methodical manner from both the N-terminus and the C-terminus of the peptide, and the effect of these deletions on the resulting biological activity was assessed. In order to improve the enzymatic stability of the shortest yet active analogue identified, ruthenium-catalysed ring closing metathesis was used to generate a macrocyclic peptide using allylglycine residues as handles for ring formation. We have successfully identified a short 8-amino acid preptin (1-8) fragment that retains an anabolic effect on the proliferation of primary rat osteoblasts and enhances bone nodule formation. Preptin (1-8) is a useful lead compound for the development of orally active therapeutics for the treatment of osteoporosis.
7. Characterization of preptin-induced insulin secretion in pancreatic β-cells
Kai-Chun Cheng,Ying-Xiao Li,Ikuo Kato,Miharu Ushikai,Yuki Sato,Akio Inui,Akihiro Asakawa,Juei-Tang Cheng J Endocrinol . 2012 Oct;215(1):43-9. doi: 10.1530/JOE-12-0176.
We aimed to characterize the effects of preptin on insulin secretion at the single-cell level, as well as the mechanisms underlying these changes, with respect to regulation by intracellular Ca(2+) [Ca(2+)](i) mobilization. This study assessed the effect of preptin on insulin secretion and investigated the link between preptin and the phospholipase C (PLC)/protein kinase C (PKC) pathway at the cellular level using fura-2 pentakis(acetoxymethyl) ester-loaded insulin-producing cells (Min 6 cells). Our results demonstrate that preptin promotes insulin secretion in a concentration-dependent manner. Using a PLC inhibitor (chelerythrine) or a PKC inhibitor (U73122) resulted in a concentration-dependent decrease in insulin secretion. Also, preptin mixed with IGF2 receptor (IGF2R) antibodies suppressed insulin secretion in a dose-dependent manner, which indicates that activation of IGF2R is mediated probably because preptin is a type of proIGF2. In addition, preptin stimulated insulin secretion to a similar level as did glibenclamide. The activation of PKC/PLC by preptin stimulation is highly relevant to the potential mechanisms for increase in insulin secretion. Our results provide new insight into the insulin secretion of preptin, a secreted proIGF2-derived peptide that can induce greater efficacy of signal transduction resulting from PLC and PKC activation through the IGF2R.
8. Preptin analogues: chemical synthesis, secondary structure and biological studies
Vijayalekshmi Sarojini,Zhenzhen Peng,Aiko Cefre,Christina M Buchanan Chem Biol Drug Des . 2013 Oct;82(4):429-37. doi: 10.1111/cbdd.12168.
Peptide hormones that modulate insulin secretion have been recognized to have therapeutic potential, with peptides such as amylin (pramlintide acetate, Symlin) and exendin-4 (exenatide, Byetta) now commercially available. Preptin is a peptide that has been shown to increase insulin secretion in vitro and in vivo. Here, we describe the first chemical synthesis and analysis of a short series of preptin analogues based on the rat preptin sequence. Phe 21 in the preptin sequence was substituted with the non-protein amino acids D-Phe, D-Hphe, 3-aminobenzoic acid and 1-aminocyclooctane-1-carboxylic acid, which rendered the preptin analogues resistant to chymotryptic protease hydrolysis at this position. Substitution of Phe 21 with these non-protein amino acids did not abrogate the insulin secretory effect of preptin, with analogues showing a similar dose-dependent effect on insulin secretion from βTC6-F7 mouse β-cells in both the presence and absence of glucose as unmodified rat preptin. Further studies on the stability of the preptin analogues and their effect on insulin secretion are in progress.
9. The effect of thyroid dysfunction and treatment on adropin, asprosin and preptin levels in rats
Saltuk Bugra Baltaci,Rasim Mogulkoc,Dervis Dasdelen,Abdullah Sivrikaya,Abdulkerim Kasim Baltaci Horm Mol Biol Clin Investig . 2020 Dec 14;42(1):37-42. doi: 10.1515/hmbci-2020-0058.
Objectives:Thyroid hormones have important roles in normal development and energy regulating mechanisms as well as signaling mechanisms that affect energy consumption through central and peripheral pathways. The aim of this study was to determine the effects of thyroid dysfunction on adropin, asprosin and preptin levels in rat.Methods:The study was performed on the 38 male Wistar-albino rats. Experiment groups were designed as follows. 1-Control, 2-Hypothyroidism; To induce hypothyroidism PTU was applied by intraperitoneal as 10 mg/kg/day for 2 weeks. 3-Hypothyroidism + Thyroxine; Previously animals were made with hypothyroidism by 1 week PTU application and then 1 week l-thyroxine was given by intraperitoneal as 1.5 mg/kg/day. 4-Hyperthyroidism; Rats were made with hyperthyroidism by 3 weeks l-thyroxine (0.3 mg/kg/day). 5-Hyperthyroidism + PTU; Animals were made hyperthyroisim by l-thyroxine as groups 4, then 1 week PTU was applied to treatment of hiperthyrodism. At the end of supplementation animals were sacrificed and blood samples were collected for FT3, FT4, adropin, asprosin, preptin analysis.Results:FT3 ve FT4 levels were reduced significantly in hypothyroidism while increased in hyperthyroidism (p<0.001). Hipothyrodism led to reduces adropin, asprosin and preptin levels. And also hyperthyroidism reduced adropin and preptin levels (p<0.001).Conclusions:The results of study show that experimental hypothyroidism and hyperthyroidism lead to significantly change to adropin, asprosin and preptin levels. However, correction of thyroid function caused to normals levels in asprosin and preptin.
10. Is Preptin a New Bone Metabolism Parameter in Hemodialysis Patients?
Małgorzata Kałużna,Marek Ruchała,Katarzyna Ziemnicka,Krzysztof Pawlaczyk,Krzysztof Hoppe,Magdalena Czlapka-Matyasik,Andrzej Oko,Aisha Yusuf Ibrahim,Krzysztof Schwermer,Elżbieta Wrotkowska Life (Basel) . 2021 Apr 12;11(4):341. doi: 10.3390/life11040341.
Background:Preptin is a bone-anabolic pancreatic peptide hormone. Its role in bone metabolism has been studied in rats and in patients with diabetes, but its levels and significance in bone metabolism in hemodialyzed (HD) patients is unknown.Methods:The relationships between preptin and anthropometric and biochemical parameters related to bone metabolism were studied in 73 patients on chronic hemodialysis (48 males, 25 females; mean age of 57 years; HD vintage of 69.7 months). Of these subjects, 36 patients had diabetes or impaired glucose tolerance (DM/IGT), and 37 patients had normal glucose tolerance (NGT). Dual-energy X-ray absorptiometry of the femoral neck and lumbar spine were also performed.Results:No differences were observed in preptin levels between DM/IGT and NGT HD patients. Preptin was positively correlated with HD vintage (r = 0.312,p= 0.007). Negative correlations between preptin and bone mineral density (BMD), T-score, and Z-score in the lumbar spine (L2-L4) were observed (r = -0.319,p= 0.009; r = -0.341,p= 0.005; r = -0.375,p= 0.002). Preptin was positively correlated with parathormone (PTH) levels (r = 0.379,p< 0.001) and osteocalcin levels (r = 0.262,p= 0.027).Conclusions:The results indicate that preptin may reflect on bone and mineral metabolism disturbances seen in HD patients. The significant correlation of preptin with PTH and osteocalcin suggests that preptin may be important in indirect measurement of bone turnover in HD patients.
