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

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

Mechanisms of COVID-19-induced heart failure: a short review

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected more than 23 million people globally resulting in the death of over 800,000 subjects. It has inflicted severe public health and economic hardships across the world. In addition to acute respiratory distress syndrome, respiratory failure, sepsis, and acute kidney injury, COVID-19 also causes heart failure (HF). COVID-19-induced HF is manifested via different mechanisms, including, but not limited to, (1) virus-induced infiltration of inflammatory cells, which could impair the function of the heart; (2) pro-inflammatory cytokines (monocyte chemoattractant protein-1, interleukin-1β; interleukin-6; tumor necrosis factor-α) that could cause necrosis and death of the myocardium; (3) endothelial injury coupled with micro-thrombosis which could damage the endocardium; and (4) acute respiratory distress syndrome and respiratory failure that could lead to heart failure due to severe hypoxia. It is concluded that the etiology of COVID-19-induced HF is multifactorial and mitigation of the development of HF in patients with COVID-19 will require different approaches such as social distancing, drug therapy, and the urgent development of a vaccine to eradicate the disease

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

Antagonism of histamine H3 receptors alleviates pentylenetetrazole-induced kindling and associated memory deficits by mitigating oxidative stress, central neurotransmitters, and c-Fos protein expression in rats

Histamine H3 receptors (H3Rs) are involved in several neuropsychiatric diseases including epilepsy. Therefore, the e ects of H3R antagonist E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) were evaluated on the course of kindling development, kindling-induced memory deficit, oxidative stress levels (glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)), various brain neurotransmitters (histamine (HA), acetylcholine (ACh), -aminobutyric acid (GABA)), and glutamate (GLU), acetylcholine esterase (AChE) activity, and c-Fos protein expression in pentylenetetrazole (PTZ, 40 mg/kg) kindled rats. E177 (5 and 10 mg/kg, i.p.) significantly decreased seizure score, increased step-through latency (STL) time in inhibitory avoidance paradigm, and decreased transfer latency time (TLT) in elevated plus maze (all P < 0.05). Moreover, E177 mitigated oxidative stress by significantly increasing GSH, CAT, and SOD, and decreasing the abnormal level of MDA (all P < 0.05). Furthermore, E177 attenuated elevated levels of hippocampal AChE, GLU, and c-Fos protein expression, whereas the decreased hippocampal levels of HA and ACh were modulated in PTZ-kindled animals (all P < 0.05). The findings suggest the potential of H3R antagonist E177 as adjuvant to antiepileptic drugs with an added advantage of preventing cognitive impairment, highlighting the H3Rs as a potential target for the therapeutic management of epilepsy with accompanied memory deficits

A pilot study: effect of irisin on trabecular bone in a streptozotocin-induced animal model of type 1 diabetic osteopathy utilizing a micro-CT

Background. Osteoporosis is a significant co-morbidity of type 1 diabetes mellitus (DM1) 41 leading to increased fracture risk. Exercise-induced hormone 'irisin' in low dosage has been 42 shown to have a beneficial effect on bone metabolism by increasing osteoblast differentiation 43 and reducing osteoclast maturation, and inhibiting apoptosis and inflammation. We investigated 44 the role of irisin in treating diabetic osteopathy by observing its effect on trabecular bone. 45 Methods. DM1 was induced by intraperitoneal injection of streptozotocin 60 mg/kg body 46 weight. Irisin in low dosage (5 μg twice a week for 6 weeks I/P) was injected into half of the 47 control and 4-week diabetic male Wistar rats. Animals were sacrificed six months after induction 48 of diabetes. The trabecular bone in the femoral head and neck was analyzed using a micro-CT 49 technique. Bone turnover markers were measured using ELISA, Western blot, and RT-PCR 50 techniques. 51 Results. It was found that DM1 deteriorates the trabecular bone microstructure by increasing 52 trabecular separation (Tb-Sp) and decreasing trabecular thickness (Tb-Th), bone volume fraction 53 (BV/TV), and bone mineral density (BMD). Irisin treatment positively affects bone quality by 54 increasing trabecular number p < 0.05 and improves the BMD, Tb-Sp, and BV/TV by 21-28%. 55 The deterioration in bone microarchitecture is mainly attributed to decreased bone formation 56 observed as low osteocalcin and high sclerostin levels in diabetic bone samples p < 0.001. The 57 irisin treatment significantly suppressed the serum and bone sclerostin levels p < 0.001, 58 increased the serum CTX1 levels p < 0.05, and also showed non-significant improvement in 59 osteocalcin levels. 60 Conclusions. This is the first pilot study to our knowledge that shows that a low dose of irisin 61 marginally improves the trabecular bone in DM1 and is an effective peptide in reducing 62 sclerostin levels

Hyperglycemia-induced cardiac contractile dysfunction in the diabetic heart

The development of a diabetic cardiomyopathy is a multifactorial process, and evidence is accumulating that defects in intracellular free calcium concentration [Ca2+]i or its homeostasis are related to impaired mechanical performance of the diabetic heart leading to a reduction in contractile dysfunction. Defects in ryanodine receptor, reduced activity of the sarcoplasmic reticulum calcium pump (SERCA) and, along with reduced activity of the sodium-calcium exchanger (NCX) and alterations in myofilament, collectively cause a calcium imbalance within the diabetic cardiomyocytes. This in turn is characterized by cytosolic calcium overloading or elevated diastolic calcium leading to heart failure. Numerous studies have been performed to identify the cellular, subcellular, and molecular derangements in diabetes-induced cardiomyopathy (DCM), but the precise mechanism(s) is still unknown. This review focuses on the mechanism behind DCM, the onset of contractile dysfunction, and the associated changes with special emphasis on hyperglycemia, mitochondrial dysfunction in the diabetic heart. Further, management strategies, including treatment and emerging therapeutic modalities, are discussed