Diabetes mellitus is a metabolic condition characterized by an inability to regulate blood glucose levels. It is caused by either defects in insulin production and secretion (Type I) or defects in insulin signaling (Type II). As of 2000 at least 2.8% of the worlds population suffer from diabetes.
Type I Diabetes
Type I diabetes, previously known as insulin-dependent or juvenile diabetes, is usually due to autoimmune attack of β-islet cells in the pancreas. It can also be idiopathic and there is increasing evidence of a viral etiology. The normal function of β-islet cells is to produce insulin in response to elevated blood glucose, which in turn promotes the conversion of glucose into glycogen polymers for storage. Destruction of β-islet cells prevents insulin production and subsequently manifests as hyperglycemia.
Genetic susceptibility genes for type I diabetes have been identified and include IDDM1, which codes for a MCH II complex that is displayed on the surface of β-islet cells. Certain polymorphisms of this gene result in the display of improper antigens on the surface of β-cells, leading to their targeting for destruction by T-cells.
Type II Diabetes
Type II diabetes, previously known as non-insulin-dependent or obesity-related diabetes, is characterized by insulin resistance and a loss of insulin sensitivity. Insulin levels may be increased (hyperinsulinemia) or decreased (hypoinsulinemia). Other factors that contribute include decreased activity of glucose transporters, increased hepatic glucose production and delayed β-cell sensitivity to hyperglycemia. The etiology of type II diabetes is unknown, but it is associated with obesity (particularly central obesity), sedentary lifestyle, high sugar diet, total body irradiation (a cancer treatment), hypertension and increasing age.
First line treatment for type I diabetes is insulin replacement therapy. Type II diabetes is initially treated by attempts to maintain glycemic control with diet modifications. Pharmacological interventions, such as metformin, are used later. Diabetic complications are prevalent and uncontrolled so there is intense interest in developing pharmacological agents that allow better management of this condition. Novel antidiabetic treatments include fibroblast growth factor-21 analogs, renal sodium-glucose transporter inhibitors, free fatty acid receptor ligands, dipeptidyl peptidase IV (DPP-IV) inhibitors and more.
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A highly potent and selective SGLT2 inhibitor with IC50 of 4.4, 3.7 and 2.0 nM for hSGLT2, rSGLT2 and mSGLT2, respectively; displays >100-fold selectivity over SGLT1; improves glycemic control and beta-cell function in rodent models of T2DM, and reduces body weight gain in rodent models of obesity.
A PARP inhibitor and an inducer of HSF-1/HSP72 (cotreatment with heat) in vtiro; has no effect on HSP90 levels, markedly increases the phosphorylation of HSF1 and expression of HSF1 and HSP72 in adipocytes and muscle cells; protects against obesity-induced insulin resistance and orally active; alleviates ventilation-induced diaphragm dysfunction associated with HSP72 induction and PARP-1 inhibition.
A potent, orally bioavailable Glucokinase (GK) activator with EC50 of 60 nM; increases the affinity of GK for glucose by 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models; lowers glucose excursion in an ob/ob mouse model of diabetes.
RX 871024 is a imidazoline compound that stimulate insulin release by inhibition of ATP-dependent K+ channels and inducing of Ca2+ mobilization in mouse pancreatic beta-cells; blocks ATP-dependent K+ channels and membrane depolarization, and activates voltage-dependent Ca2+ channels.
MK-8722 is a potent, selective, allosteric pan-AMPK activator with EC50 of 1-60 nM for all 12 mammalian AMPK isoforms; exhibits higher affinity for β1-containing (1-6 nM) versus β2-containing (15-63 nM) pAMPK complexes; increases glucose uptake into skeletal muscle in vitro and in vivo, but induces cardiac hypertrophy.
DS-6930b (DS-6930 calcium salt) is the calcium salt of DS-6930, which is a novel potent, selective PPARγ agonist with EC50 of 41 nM, Emax-68%; significantly recruits several cofactors, such as RIP140 and PGC1, in cofactor recruitment assays; demonstrateshigh PPARγ agonist potency with robust plasma glucose reduction, maintains diminished PPARγ-related adverse effects upon toxicological evaluation in vivo, and demonstrated no hepatotoxicity.
DS-6930 (DS 6930, DS6930) is a novel potent, selective PPARγ agonist with EC50 of 41 nM, Emax-68%; significantly recruits several cofactors, such as RIP140 and PGC1, in cofactor recruitment assays; demonstrateshigh PPARγ agonist potency with robust plasma glucose reduction, maintains diminished PPARγ-related adverse effects upon toxicological evaluation in vivo, and demonstrated no hepatotoxicity.
BMS-823778 free base
BMS-823778 (BMS823778) is an orally available, potent and selective inhibitor of 11βHSD-1 with IC50 of 2.3 nM, displays >10,000-fold selectivity over 11βHSD-2; exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50=0.6mg/Kg) and in diet-induced obese (DIO) mice (ED50=34 mg/Kg), also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50=5.2 mg/Kg).
Chiglitazar (CS-038, CS038) is a potent, dual PPARα/γ dual agonist with EC50 of 1.2, 0.08, 1.7 uM for PPARα, PPARγ and PPARδ, respectively; inhibited alanine gluconeogenesis, lowered the hepatic glycogen level in MSG obese rats. Like rosiglitazone, chiglitazar promoted the differentiation of adipocytes and decreased the maximal diameter of adipocytes; Chiglitazar reduced plasma triglyceride, total cholesterol (TCHO), nonesterified fatty acids (NEFA) and low density lipoprotein-cholesterol levels; lowered hepatic triglyceride and TCHO contents; decreased muscular NEFA level. Unlike rosiglitazone, chiglitazar showed significant increase of mRNA expression of PPARα, CPT1, BIFEZ, ACO and CYP4A10 in the liver of MSG obese rats.
Dorzagliatin (HMS-5552, HMS5552) is a novel potent, fourth-generation glucokinase (GK) activator; exerts its antidiabetic effect by inhibiting insulin resistance and increasing insulin sensitivity, significantly increased GK expression; effectively improves GK activity and insulin resistance by targeting both the liver and pancreas in rat T2DM models.
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