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Editorial Insight into Newer Anti-diabetic Treatment

(BIRDEM Med J 2019; 9(1): 1-6)

Introduction threshold of glucose absorption in renal tubules Diabetes is a disease for great research. Before discovery resulting in increased glucose excretion in urine of by Benting and Best diabetes was like cancer causing reduction of blood glucose.4.GLP-1 agonist: of present days. Improves pancreatic beta cell function,Inhibits Diabetes mellitus is an entity of considerable morbidity glucagon secretion from alpha cell in the presence comprising a spectrum of multisystem dysfunctions of higher plasma glucose. Lowered glucagon happen stemming from the combination of insulin resistance to decreases hepatic glucose production. These group and inadequate insulin secretion. Management of of drugs also reduces hunger and energy intake in diabetes, akin to a tightrope walk, requires a brain.5.DPP4 inhibitor increases insulin availability comprehensive understanding of various factors such in circulation,decease glucagon secretion in as over-all clinical picture, adverse effect profile, the circulation in glucose dependent manner.Blocks complex of inter-play of drugs, etc. More than two-thirds degradation of native GLP 1 and GPI resuling in of people with will eventually require increased half-lives of GPI and GLP-1. more than one oral agent, with or without insulin. There 2. The Dirty Dozen of Diabetes (8+4): addition of four is a perpetually increasing newer range of antidiabetic well-known hormones were proposed to the list of drugs targeting novel aspects of diabetes which warrant players in diabetes etiology to bring the number to adequate awareness by the treating clinicians 12. Multiple pathophysiological factors has been implicated All four hormones have adequate biochemical, in the etiology of diabetes mellitus. This knowledge have epidemiological, observational or clinical support to paved the ways of drug discovery. merit inclusion in the list of the Dirty Dozen of Diabetes.

The ominus octate: 1. Insulin: both it’s deficiency and Catecholamines Including Dopamine(no.9). resistance is responsible for diabetes mellitus The ninth player beyond the Ominous Octet is the 2. Glucagon the antagonist of insulin remain unoffended catecholamine family. Dopamine, is the catecholamine to cause diabetes mellitus. 3.Glucose absorption with highest concentration in the brain,”. The dopamine threshold in the renal tubules is decreased which c causes modulator drug is used for the increased reabsorption of glucose so increases blood management of type 2 diabetes. Stress is linked with the glucose . 4. Lipid:increased fat/fatty acid increases onset of and with poor control in diabetes. glucose resistanse to cause diabetes 5. Liver produces Judicial use of timed release bromocriptine helps in abundant glucose in situation of insulin deficiency resetting the sustained hyperdopaminergic tone that is 6. Decreased muscle utilization also affects glucose characteristic of many type 2 diabetes patients. homeostasis. 7. Impairment of incretin effect imparts Vitamin D(no 10) acting as an immuno-modulatory impairs insulin availability which causes hormone, it decreases pro-inflammatory cytokines, hyperglycemia.8.Neurotransitter defect in brain in day increases anti-inflammatory cytokines, reduces by day is being recognized as an etiology of diabetes autoimmune insulitis and protects against type 1 diabetes mellitus in children exposed to high doses of vitamin D in utero or Discovery of anti-diabetic agents has so far been in infancy. In adults, vitamin D is linked with both insulin occured addressing these etiological factors. secretion and insulin sensitivity, and there is a strong 1. Sulphonureas: Increases insulin secretion and also2. body of evidence, which justifies its inclusion in the decreases glucagon 3.SGLT 2 inhibitors increases Diabetes Dirty Dozen. Birdem Medical Journal Vol. 9, No. 1, January 2019

Low vitamin D levels are associated with a higher target and initiate pharmacotherapy based on A1C. prevalence of metabolic syndrome, diabetes, obesity, Initiate with monotherapy if A1c less than 9,dual therapy hypertension, coronary artery disease and stroke. if A1c equal to or mor than 9.If A1C is equal to or greater Renin–Angiotensin System(11):Vitamin D deficiency than or equal to 10,blood glucose e their equal to or and obesity are associated with stimulation of RAS greater than 300mg/dl,or patient is markedly activity. Randomized controlled trials reveal a lower symptomatic consider combination injection therapy. incidence of new-onset diabetes in patients prescribed How to select a dual therapy:If patient has angiotensin -converting enzyme inhibitors and atherosclerovascular(ASCVD) disease viz Iscemic heart angiotensin receptor blockers. Because of this, and their disease,TIA or Stroke add agent proven to reduce major nephro-protective and cardio-protective effects, these cardiovascular events and/or cardiovascular morbidity. molecules have become drugs of first choice in How to individualize:SGLT 2 inhibitor specially hypertension associated with diabetes. The future holds empagliflozine and has proven evidence promise for RAS-based intervention in diabetes care. that they reduce cardiac and cerebral events.But they RAS, therefore, should justifiably be included as part have limitataion in use in renal failure cases.Since 2008 of the Dirty Dozen.. FDA does not approve drugfor marketing until and TESTOSTERONE(NO 12):The fourth hormone, which should unless they have proven evidence of cardiovascular be added to the list of diabetes players to complete the safety. This drugs have proven safety. So if eGFR Dirty Dozen, is testosterone.In diabetes, low levels of support this drugs should be used in (ASCVD) patients. FSH may cause lower androgen synthesis through local Similar evidence based drug is ,it has no cytokines and may lose its capacity to do so in diabetes. eGFR limitation.Even if there is no ACSVD or eGVR Studies have shown that low testosterone precedes the limitation they have compelling indications in onset of diabetes, and androgen deprivation therapy overweight patients.Liraglutadie has beneficial effect exacerbates insulin resistance/worsens glycemia in on blood glucose,overweight,systolic hypertension all prostate cancer patients. Hypogonadism in men with renders ii most suitable for in patients with metabolic diabetes”condition affects much more than sexuality. syndrome.When other things are not barrier patient Low testosterone levels should certainly be treated, preference and cost should be taken into aiming for high-normal values, but equally certainly consideration..Sulphonylureas still the drug of should not be over-treated. preference in these cases. should not be used Treacherous thirteen -12+1 (iron included):we need to in renal failure,.DPP4 inhibitors (gliptins can cause, utilize every preventive and therapeutic strategy pancreatitis specially in presence of available to us in order to halt the diabetes pandemic. hyprtryglyceridemia. Thyroid nodule should be Each of the known pathogenetic mechanisms should be excluded before their use’.SGLT-2 inhibitor cause studied and assessed with an open mind for each genitourinary infection. individual patient in order to achieve the best possible Evolution of drug use in diabetes treatment:Record outcomes. shows a big evolution in discovery antidiabetic drugs.In How to decide drug treatment of diabetes:Tablet:Blood 1996 Glimipride and Metiglinide came into the market. glucose:< 16 mmol/L.HbA1C :7-9%.To follow an Rapid acting analog also came into the algorithm: To start with pluslifestyle change. market in same year. It was 1999 when the Glitziness Address the comorbidities and never forget the patient and was introduced preference. Insulin:High blood glucose with severe .Rosiglitazone was subsequently withdrown from symptom.Secondary failure.HbA1C > 9.Renal market due to it’s non favorable Cardiovascular profile. failure.Hepatic failure.Diabetic emergency.Non diabetic The long acting analog Glargine was introduced in tha emergency.Pregnancy.Acetonuria same year.Biasp, the mixed insulin and combination Anti-hyperglycemic therapy in adults with T2DM how metformin and glitazone came into the market in 2001 to initiate: at diagnosis Initiate lifestyle management and 2002 respectively.,,sexgliptin and metformin(if no obvious contraindication)set A1c and came over the years 2008-11.Liraglutide

2 Editorial was introduced in 2010. Subsequent years were for g-agonists () influence free fatty acid gliptins and glutides.SGLT 2 inhibitors canagliflozen flux and reduce insulin resistance and blood glucose came in 2013,Empagliflozine,dapaglifloine and orher levels. The PPAR a/g dual agonism addresses both gliflozines in next year having proven their insulin resistance and key aspects of the dyslipidemia cardiovascular safety. (LX 4211), an oral that contribute to the high risk of cardiovascular disease SGLT1 and SGLT2 combined inhibitor for adult type-1 (CVD) in diabetics. diabetes is in process of approval to be marketed.. , a new balanced dual PPAR a/g agonist, Drugs in pipeline:GRP 119,GRP 90 like GLP1 agonist reduces hyperglycemia and improves the levels of decrease gastric emptying ,suppression of food intake HbA1C, HDL-C, LDL, and triglycerides with minimal thus glucose availability. They increase insulin PPAR-related adverse effects.In in vitromodels, availability and decrease glucagon .The first one in aleglitazar strongly decreased the multiple aspects of phase 1 trial while the second one in phase 3 trial. the inflamed phenotype of human adipocyte/ Extended action GLP-1 agonists- (HSA)-GLP-1 hybrid macrophage co-culture system compared to pioglitazone protein with half life of about a week and is found to and suggesting its contribution to prevent display resistance to DPP IV. It has shown consistent progression of adipose dysfunction and insulin efficacy in type 2 diabetics. , another resistance, and increased cardiovascular risk. Although analogue, exerts insulinotropic action in vitro and in a similar molecule showed efficacy as an vivo, retains the glucoincretin property of human GLP- add-on therapy for poorly controlled diabetics, excess 1, is fully resistant to DPP IV cleavage and has an incidence of death, major adverse cardiovascular events extended in vitro plasma half-life Upcoming GLP-1 (MI, stroke, TIA), and were noted with it agonists:Variuos companies are on the way to introduce and hence withdrawn. GLP1 agonist with extended action profile(one SGLT 1 & 2 inhibitor (oral type 1 DM)-Sotagliflozin, week,one month). dual SGLT-inhibitor currently is in Phase 3 studies.The Glucokinase activators: Glucokinase activator increase FDA New Drug Application for Sotagliflozin is based glucose utilization is in phase 2 trial Glucokinase on data from the inTandem clinical trial program which activators (GKAs) stimulate insulin biosynthesis and includes three Phase 3 clinical trials assessing the safety secretion and augment glucose metabolism and related and efficacy of Sotagliflozin in approximately 3,000 processes in other glucokinase-expressing cells via adults with inadequately controlled type 1 diabetes. The GKA-mediated increase in the affinity of glucokinase safety and efficacy data have not yet been evaluated by for glucose and its maximal catalytic rate.. GKAs any regulatory authority. The target FDA action date mediate their antidiabetic effects via generalized under the Prescription Drug User Fee Act (PDUFA) is enhancement of b-cell function and through fasting anticipated to be March 22, 2019. restricted changes in glucose turnover. Piragliatin, a Drugs in in research:(drugs to come into the market): GKA, has shown an acute glucose-lowering action in The target therapy patients with mild type 2 diabetes. An experimental GKA 1. PTP 1B (Protein Tyrosine Phosphatase 1B) acts as a molecule ZYGK1 showed promising efficacy in negative regulator for both insulin and leptin signaling. controlling both fasting and non-fasting blood glucose. Inhibition of PTP 1B could address both Diabetes and The side effects although rare of GKAs are Obesity. Traditional therapeutics cannot specifically hypoglycemia, fatty liver, and hyperlipidemia. target PTP 1B.Anti sense based oligonucleotides inhibit Dual PPAR (Peroxisome proliferator-activated receptor the expression and activity of PTP 1B gene without gamm) agonists:Dual ppar a/g receptor agonist affecting other highly related Tyrosine Phosphatases. hyperglycemia dyslipidemia atherosclerosis, but the Protein tyrosin phosphatase inhibitor-new side effect like fluid retention, bone fracture, bladder thiozolidindiones, dual ppar a/g antagonist,vanadyl cancer are more. Inhibition of PPAR a-agonists thiamine hydrochloride complex and several other () lowers plasma triglycerides and VLDL synthetic and natural antagionists 2. The cannabinoid particles and increases HDL while PPAR receptor inhibitors-rimonobant is in market since 1994,

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3. GSK3 (glycogen synthase kinase inhibitor has shown various cell types .Increased GSK3 has been reported to increase the rate of beta cell replication by 2-3 fold. in type II diabetics and obese animal models. 4. Acetyl coA carboxylase 1&2 inhibitors(ND-630)- Inhibitors of GSK3 have been demonstrated to have anti- reduces hepatic steatosis,improves insulin sensitivity diabetic effects in test tubes and animal and modulates dyslipidemias. 5. Glucagon receptor model.Overexpression and overactivity of GSK-3 in the antagonists. 6. The intranasal monthly GLP1 agonist muscle of rodent models of obesityand type 2 diabetic for diabetes and neurodegenerative disorders 7. humans are associated with an impaired ability Fibroblast growth factor 21 (FGF21) is a novel of insulin to activate glucose disposal and glycogen metabolic regulator produced primarily by the liver that synthase. exerts potent antidiabetic and lipid-lowering effects in animal models of obesity and type 2 diabetes mellitus.. Increased hypothalamic GSK3b signaling contributes Experimental studies have shown marked improvements to deleterious effects of leptindeficiency and exacerbates in diabetes compensation and dyslipidemia after FGF21 high-fat diet-induced weight gain and glucose administration in diabetic mice and primates. intolerance. Since obesity is pandemic and diabetes is endemic in present world.an agent addressing both the Monoclonal antibodies metabolic disorder is worthy research. To induce immune tolerance via monoclonal antibodies Newer targets:1. uncOCN: undercarboxylated form of has been tried as a way to prevent and effectively treat Osteocalcin (uncOCN) : seems to have positive effects diabetes. Otelixizumab, an anti-CD3 monoclonal on the metabolic syndrome, including improvement of antibody, is known to stimulate C-peptide levels and insulin resistance, b-cell function and reduce insulin requirement in type 1 diabetes. Similarly dyslipidemia.2.INDY Gene (‘I’m not dead yet’):Its studies with teplizumab are also reassuring. Other deletion mimics aspects of dietary restriction and monoclonal antibodies such as anti-CD20, anti-CTGF, protects again adiposity and insulin resistance in anti-IL-1b, have shown promising results and are yet to mice3.VEGF-B Blocker. 4. 2H10ABHD6- a/g be approved. hydrolase domain-6: breaks down monoacylglycerol Dopamine-2 receptor agonist and thus negatively controls insulin release. Inhibition Timed bromocriptine (centrally-acting dopamine D2 may help in treating diabetes.5.FFAR3: b cell short- receptor agonist) is believed to act on circadian neuronal chain fatty acid receptors.Newer drugs:Glargine U-300: activities within the hypothalamus to reset abnormally Three-fold more concentrated formulation of elevated hypothalamic drive for increased plasma GlargineReduced volume (1/3) and reduced surface area glucose, triglyceride, and free fatty acid levels in fasting (1/2) of subcutaneous depotSlower and more constant and postprandial states in insulin-resistant patients. rate of absorption Gla-300 provided sustained glycemic control with a lower risk of hypoglycemia compared Chromium (Cr) may reduce myocellular lipids and with Gla-100 enhance insulin sensitivity in subjects with type 2 DAPD: A Knowledgebase for Diabetes Associated diabetes mellitus independent of its effects on weight Proteins. or hepatic glucose production.[41] Clinical response to Cr is more likely in insulin-resistant type 2 diabetics Recent advancements in genomics and proteomics with elevated fasting glucose and A1C levels provide a solid foundation for understanding the pathogenesis of diabetes. Proteomics of diabetes Proxyfan, a central histamine H3 receptor ligand, is associated pathways help to identify the most potent shown to significantly improve glucose excursion by target for the management of diabetes. .. Thus, a web increasing plasma insulin levels via a glucose- source “Diabetes Associated Proteins Database independent mechanism (DAPD)” has been developed to link the diabetes Obesity and Type 2 Diabetes associated genes, pathways and proteins using PHP, Glycogen synthase kinase-3 (GSK-3) has important MySQL. The current version of DAPD has been built roles in the regulation of glycogen synthesis, protein with proteins associated with different types of diabetes. synthesis, gene transcription, and cell differentiation in In addition, DAPD has been linked to external sources

4 Editorial to gain the access to more participatory proteins and Lower post-prandial glucose. Shorter duration of action. their pathway network. DAPD will reduce the time and Less late prandial hypoglycaemia. Less biologic it is expected to pave the way for the discovery of novel variability. Fewer glycaemic fluctuations. The action anti-diabetic leads using computational drug designing profiles of modern , while an improvement on for diabetes management. human insulin, do not accurately mimic the physiological release of endogenous insulin. Therefore, Available injections: the aim of future insulins is to more closely mimic the Insulins:Rapid acting: Glulisine, Aspart, Lispro.Short end genous response. We need ultra fast inulin to cover acting: .Intermediate acting: NPH.Long postprandial peak of blood glucose.Our aim is true basal acting (basal): Glargine,, Detemer.Ultra-long acting to have twenty four hours flat profile,premix shouold (true basal)-degludeg have prandial peak only. GLP-1 analogues: Exenatine, , Insulin delivery system:The refill pen is the cheapest at Liraglutide..Best option is early insulin overcoming the present. Monitring also have been changed.The inertia of doctor and physicians. We now have evidence continuous glucose monitoring (CGM) gives the exact for action of insulin beyond glycemic control. These ideas of fluctuation.Cnontinuous subcutaneous insulin actions beyond glycemic control are 1. Improves beta- infusion(CSII)-the open and closed loop pump makes cell function(reduces glucotoxicity & Lipotoxicity) 2. the delivery comfortable and ease to use costly Reverses insulin resistance 3.Beneficial effects on lipids system.The exubra and afrezza are inhalation insulin. and 4. Improves Quality of Life Starts to work immediately after inhala tion, peaks in Insulin evolution:Since discovery of insulin by Best and about 12mins, and wanes off by 3 hrs. Oral Insulin his teacher Banting treatment of diabetes mellitus has Delivery Systems undergoing lot of clinical Trials. undergone a revolutionary change.Thomsone the first Smart insulin : Smart insulins is something beyond diabetic victim treated with insulin has given the diabetic CGM,CSII. It is defined as a pharmaceutical preparation patients the light of insulin blessing.since 1922 which contains a 1. Inbuilt sensor mechanism to assess manufacturer has brought into the market different ambient hyperglycaemia, and 2. Ensures release of brands of insulin.Initially it was crude(animal) bovine insulin based upon this information. The patch contain and porcine insulin.In 1977 the breakthrough came with glucose responsive vesicles (GRV)-containing Micro mass production of insulin using recombinant Needle MN-array patch (smart insulin patch) for in vivo technology ,the human insulin.1990 was the year of insulin delivery triggered by a hyperglycemic state to introduction of analog insulin.All the effort of release combines the nanotechnology of tiny pyramid- discovering insulin with profile of human shaped microneedles with pancreatic cells that detect physiology.The tremendous improvement was in insulin glucose levels. The needles in the patch—each 800 delivery system micrometers long and thinner than a human hair— penetrate only the top layer of skin, making it painless. Eras in the history of therapeutic insulin-100 years of The duration of action of these nano-networks is 10 days lessons:Insulin has proved to be a difficult molecule to in type 1 mice, and has been noted to last up to 14 days isolate, to purify, and to understand.The major in some animal subjects.It works only when glucose is consequence is that we still give it subcutaneously, as higher,donot release in normoglycemic state no risk for 90 years ago, and we still have no small molecule hypoglycemia. Scientists worldwide are working on analogues.Technologically, the major advances have administering smart insulin in different forms, such as been in manufacturing technology, allowing the capsules and patches. But the research is in its infancy - production of rapid-acting and long-acting insulin in many cases, human testing of smart insulin is not analogues delivered by easy to use pen-injectors. scheduled for several years. Potential advantages of even faster-acting insulin Bionic Pancreas (not closed loop insulin pump only) analogues:Earlier onset and peak of biologic activity. is dual-chambered. It has

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– Two separate pumps for delivering both insulin Conclusion and glucagon, There is rapid and accelerated progress in the – A continuous glucose monitor (CGM) antidiabetics drug-development front that runs parallel to our ever evolving comprehension of the – A control algorithm built into an iPhone app. pathophysiology of diabetes. Clinicians need to be The bionic pancreas system includes a continuous abreast of this plethora of newer antidiabetic drugs glucose monitor and a smart phone app that wirelessly coming up, their efficacy, adverse effect profile and stand in diabetes management that empowers them to connects with insulin and glucagon pumps better manage diabetes. The bi hormonal “bionic pancreas” continues to perform http://www.easdvirtualmeeting.org/resources/isis-ptp- well in clinical trials and could reach the US market by 1brx-a-novel-ptp-1b-antisense-inhibitorimproves- 2022. hba1c-and-body-weight-in-patients-with-type-2- diabetes-on-metforminsulphonylurea-3.

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