Amylin Analogues in the Treatment of Diabetes Mellitus: Medicinal Chemistry and Structural Basis of its Function

Amylin, (islet amyloid polypeptide) or diabetes-associated peptide is co-secreted with insulin in the islet of Langerhans of diabetic patients in approximately 1:100, amylin-insulin ratio. The soluble form of amylin, an analogue of amylin, is used as a supplement to insulin in the treatment of type 1 diabetes. Co-administration of amylin analogue with insulin to patients with type 1 diabetes induced a larger reduction in proprandial hyperglycemia, with a concomitant reduction in the level of glucagon when compared to insulin monotherapy. The actions of amylin analogues appear to be synergistic to insulin, with which it is co-released from insulin-producing beta cells after a meal. Amylin analogues such as pramlintide has been shown to significantly reduce body weight, HbA1c values and even the dosage of insulin. A moderate weight loss can also be achieved in obese patients with or without diabetes. A major side effect of some amylin analogues includes nausea and excitation of the area postrema. This review examines the medicinal chemistry of amylin and its analogues and their effects

Does Staphylococcus saprophyticus cause acute cystitis only in young females, or is there more to the story? A one-year comprehensive study done in Budapest, Hungary

Staphylococcus saprophyticus is a well-known urinary pathogen in acute cystitis in young females. We completed a retrospective overview of the distribution of urinary tract infections (UTIs) occurring in 2014, at Semmelweis University hospitals and at Heim Pál Children's Hospital. Six age-groups (ages 0-100) were examined, with the frequency of S. saprophyticus in females being: 0.1% (0-4), 0.7%, (5-15), 7.4% (16-24), 1.2% (25-39), 0.4% (40-59) and 0.1% (60-100), and S. saprophyticus being the 3rd most common pathogen in females aged 16-24. In males, S. saprophyticus was only isolated from those aged 5-15. Seasonal distribution of UTIs caused by S. saprophyticus showed that most infections occurred during the months of January, June, August and November. Antibiotic-resistance rates of amoxicillin, clindamycin, doxycycline, erythromycin, gentamicin and sulfamethoxazole- trimethoprim varied as follows: 0.9%, 32.7%, 19.6%, 34.6%, 0.9% and 0.9%, respectively. Thirty randomly selected samples were analysed by pulsed-field gelelectrophoresis, and 28 different genotypes were identified. S. saprophyticus is involved in the pathogenesis of acute cystitis not only in young females, but also in other age-groups, and in young males as well. We did not find any significant seasonal occurrence in S. saprophyticus-caused UTIs. The infective strains were genetically diverse. Antibiotic-resistance does not pose any issue as of yet. © 2016 Akadémiai Kiadó, Budapest

Glucagon Secreting Cells Responds to Insulin Secretion In vitro Using Immunocytochemistry

In the present study, pancreas of rats were dissected and transferred to HEPES buffer (25 mM, pH 7.4). The control tissue pieces were kept in culture medium for one hour and the treated tissues were kept in same medium for 30 minutes and incubated with Insulin (10 nm and 100 nm) for another half hour, then tissues were transferred to Bouin‘s fixative (overnight at 40 ° Cc), cryosectioned (15 µm at -16 0 c) and subjected to immunocytochemical labeling with antibodies against Glucagon

Orexin-1 Receptor Co-Localizes with Pancreatic Hormones in Islet Cells and Modulates the Outcome of Streptozotocin-Induced Diabetes Mellitus

Recent studies have shown that orexins play a critical role in the regulation of sleep/wake states, feeding behaviour, and reward processes. The exocrine and endocrine pancreas are involved in the regulation of food metabolism and energy balance. This function is deranged in diabetes mellitus. This study examined the pattern of distribution of orexin-1 receptor (OX1R) in the endocrine cells of the pancreas of normal and diabetic Wistar (a model of type 1 diabetes), Goto-Kakizaki (GK, a model of type 2 diabetes) rats and in orexin-deficient (OX−/−) and wild type mice. Diabetes mellitus (DM) was induced in Wistar rats and mice by streptozotocin (STZ). At different time points (12 h, 24 h, 4 weeks, 8 months and 15 months) after the induction of DM, pancreatic fragments of normal and diabetic rats were processed for immunohistochemistry and Western blotting. OX1R-immunoreactive nerves were observed in the pancreas of normal and diabetic Wistar rats. OX1R was also discernible in the pancreatic islets of normal and diabetic Wistar and GK rats, and wild type mice. OX1R co-localized with insulin (INS) and glucagon (GLU) in the pancreas of Wistar and GK rats. The number of OX1R-positive cells in the islets increased markedly (p<0.0001) after the onset of DM. The increase in the number of OX1R-positive cells is associated with a high degree of co-localization with GLU. The number of GLU- positive cells expressing OX1R was significantly (p<0.0001) higher after the onset of DM. The tissue level of OX1R protein increased with the duration of DM especially in type 1 diabetes where it co-localized with cleaved caspase 3 in islet cells. In comparison to STZ-treated wild type mice, STZ-treated OX−/− animals exhibited reduced hyperglycemia and handled glucose more efficiently in glucose tolerance test. The findings suggest an important role for the OX-OX1R pathway in STZ-induced experimental diabetes

An update of SGLT1 and SGLT2 inhibitors in early phase diabetes-type 2 clinical trials

Introduction: More than 424 million adults have diabetes mellitus (DM). This number is expected to increase to 626 million by 2045. The majority (90-95%) of people with DM has type 2-diabetes (T2DM). The continued prevalence of DM and associated complications has prompted investigators to find new therapies. One of the most recent additions to the anti-diabetic armamentarium are inhibitors of sodium-glucose co-transporters 1 and 2 (SGLT1, SGLT2). Areas covered: The authors review the status of SGLT2 inhibitors for the treatment of T2DM and place an emphasis on those agents in early phase clinical trials. Data and information were retrieved from American Diabetes Association, Diabetes UK, ClinicalTrials.gov, PubMed, and Scopus websites. The keywords used in the search were T2DM, SGLT1, SGLT2, and clinical trials. Expert opinion: The benefits of SGLT inhibitors include reductions in serum glycated hemoglobin (HbA1c), body weight, blood pressure and cardiovascular and renal events. However, SGLT inhibitors increase the risk of genitourinary tract infections, diabetic ketoacidosis, and bone fractures. The development of SGLT inhibitors with fewer side effects and as combination therapies are the key to maximizing the therapeutic effects of this important class of anti-diabetic drug

Terbufos sulfon pogoršava srčane lezije u štakora koji boluju od dijabetesa: studija subakutne toksičnosti

Organophosphorus compounds (OPCs) have a wide range of applications, from agriculture to warfare. Exposure to these brings forward a varied kind of health issues globally. Terbufos is one of the leading OPCs used worldwide. The present study investigates the cardiac effect of no observable dose of a metabolite of terbufos, terbufos-sulfone (TS), under nondiabetic and streptozotocin-induced diabetic condition. 100 nmol per rat (1/20 of LD50) was administered intraperitoneally to adult male Wister rats daily for fifteen days. The left ventricle was collected for ultrastructural changes by transmission electron microscopy. The blood samples were collected for biochemical tests including RBC acetylcholinesterase, creatinine kinase (CK), lactate dehydrogenase (LDH), cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides, ALT, AST, and GGT. The study revealed about 10 % inhibition of RBC-AChE in two weeks of TS treatment in non-diabetic rats whereas RBC-AChE activity was significantly decreased in diabetic TS treated rats. CK, LDH, and triglycerides were significantly higher in diabetic TS treated rats. Electron microscopy of the heart showed derangement and lesions of the mitochondria of cardiomyocytes in the TS treated groups. The present study concludes that a non-lethal dose of TS causes cardiac lesions which exacerbate under diabetic condition. Biochemical tests confirmed the ultrastructural changes. It is concluded that a non-lethal dose of TS may be a risk factor for a cardiovascular disease, which may be fatal under diabetic condition.Organofosforni spojevi (eng. Organophosphorous Compounds - OPCs) imaju široku primjenu, od one u poljoprivredi do one u vojne svrhe. Izlaganje takvim spojevima izaziva niz različitih zdravstvenih problema od globalnog značaja. Terbufos je jedan od vodećih OPC-a koji se koriste diljem svijeta. U ovom je istraživanju na modelu štakora bez dijabetesa sa streptozotocinom izazvanim dijabetesom ispitivan metabolit terbufos-sulfon (TS) u najvišoj dozi koja ne izaziva učinak te njezin utjecaj na srce. Odrasli mužjaci štakora soja Wistar dobivali su petnaest dana dnevnu dozu od 100 nmol štakor-1 (1/20 LD50) intraperitonealno. Transmisijskim elektronskim mikroskopom istražene su ultrastrukturne promjene lijeve klijetke. Na krvnim uzorcima provedeni su biokemijski testovi, uključujući aktivnost acetilkolinesteraze u crvenim krvnim stanicama, razinu kreatinin kinaze (CK), laktat dehidrogenaze (LDH), kolesterola, lipoproteina visoke gustoće (HDL), lipoproteina niske gustoće (LDL), triglicerida, ALT, AST i GGT. Istraživanjem je otkriveno oko 10 % inhibicije AChE-a u crvenim krvnim stanicama nakon dva tjedna izlaganja štakora bez dijabetesa TS-u, dok je u štakora s dijabetesom aktivnost AChE-a bila značajno smanjena. Razine CK, LDH i triglicerida bile su značajno više u TS tretiranim štakorima s dijabetesom. Elektronsko-mikroskopska analiza srca upućuje na narušenu strukturu i lezije u mitohondrijima u kardiomiocitima skupina štakora koji su tretirani TS-om. Zaključuje se da nesmrtonosna doza TS-a uzrokuje srčane lezije koje se pogoršavaju u prisutnosti dijabetesa. Biokemijski testovi potvrdili su ultrastrukturne promjene. Navedena doza TS-a može biti rizični čimbenik za kardiovaskularne bolesti, koje se mogu pokazati smrtonosnima uz istovremeno postojanje dijabetesa