11.Introduction

Type2 Diabetes mellitus(T2D) represents a global  health condition ,that as per the International Diabetes Federation(IDF) would influence 700 million people by 2045[1].A multidisciplinary strategy is needed for its management for avoiding along with reduction of complications. Glucose-decreasing medicines   are the crucial  agents for regulation of blood glucose amounts  . Escalated blood glucose amounts  in case of T2D get reasoned out by insulin resistance (IR),combined with a decrease in βcells function.In case of certain patients of   T2D it is the dominance of IR,while in others decreased insulin liberation is the basic impairment .Lot of  modes exist  behind  βcells  failing  in addition to  reduction of    function of insulin sensitivity .Inspite of lot of factors responsible for the etiopathogenesis   of the disease there are restricted treatment  methods  along with usually not individualized  in relation to the basic etiology of hyperglycemia. Significantly T2D represents a systemic syndrome  influencing practically all the tissues in the body ,with the disease being correlated with a lot of diseases that include cardiovascular  disease (CVD),Kidney disease, non alcoholic fatty liver disease(NAFLD), Alzheimers disease, in addition to   different cancers.Till date neither of the glucose decreasing –agents   have   made any main influence on end organ protection. Nevertheless  recent studies have demonstrated that Sodium –glucose  cotransporter 2(SGLT2) inhibitors, in addition to  glucagon like peptide 1(GLP-1)-1 receptor agonist(GLP-1RA), decrease the risk of CVD, illustrating end organ protection,that is further than just glycaemic regulation.Here the classification of T2D,brief etiopathogenesis,actions of variety of medication groups on insulin sensitivity along with βcells function,with the objective to give more individualized  treatment strategies.Earlier we had reviewed extensively on the etiopathogenesis,management of obesity in addition to its complications like DM, in addition to   etiopathogenesis of T1Dalong with their treatment modes in details in addition to their complications like CVD ,DN,neuropathy and retinopathy,HF,NAFLD,NASH[2-25].Here we further considered to present  how we  individualized treatment modalities can be done  with the idea of utilization of classification of DM as per the different metabolic phenotypes and decide how we can use individualized treatment modalities for treatment of Type2  Diabetes mellitus(T2D)patients.

2.1 Etiopathogenesis of Diabetes mellitus

Type2  Diabetes mellitus(T2D) represents a disease which implicates a lot of metabolic impairments  that possess properties of hyperglycemia that  occurs secondary to pancreatic βcells    failing in addition to  insulin sensitivity reduction.The risk factors for generation of T2D are obesity  along with insulin resistance (IR). Nevertheless, maximum obese as well as  people with IR never generate T2D,that gets reasoned by robust genetic constituents correlated with T2D.De Fronzo in 1988[26] had revealed that generation from dysfunctional glucose tolerance to T2D  is basically secondary to reduction of βcells function as well as  not associated  with  changed insulin modulated glucose uptake ,while IR is usually existing prior to hyperglycemia,with an escalation of HbA1c takes place. Nevertheless,it needs to be understood that  therapy of IR would decrease the βcells   load in addition to  alleviate hyperglycemia.The risk of generation of T2D   gets robustly inherited, with detailing of lot of genetic correlations [27].Maximum of the genetic correlations have been attributed towards   βcells function in addition to   occasional correlated with  IR[27],despite this might be secondary to no correct measures present for us in large cohorts.

In T2D,    βcells failure  has been correlated with  24-65%loss of βcell  mass, along with  a  50-97% deletion of insulin liberation ability  of βcells[28]. Pancreatic βcells   ,to start with are able to tackle the IR in peripheral  tissues  by greater generation of insulin,resulting in supraphysiological insulin amounts.Gradually βcells failure   results  causing escalated post prandial  along with fasting glucose  amounts,despite persistent  hyperinsulinemia. Modes correlated with βcells failure   are, IR, glucotoxicity, lipotoxicity, βcells senescence [29],dedifferentiation[30], as well as   /or apoptosis[31].First degree relatives of  patients with  type2Diabetes possess dysfunctional insulin liberation, with lesser  regular pulsatile nature of insulin liberation[32].These alterations in insulin pulsatile liberation might result in down regulation of  insulin function in addition to   points to  a crosstalk among dysfunctional  βcells action  in addition to    deterioration of IR[33].Thus it has to be clarified  if  insulin resistance occurs prior to  β  cells failure    in all the subjects  generating T2D.

The  other main point in the generation of T2D is the generation of  whole body in addition to  peripheral   insulin resistance (IR),that occurs over a point of time slowly .Since skeletal muscle,that represents the biggest organ of body ,takes up 85% of the postprandial glucose uptake , skeletal muscle IR  ,aids in the generation of       hyperglycemia[34].In case of       skeletal muscle,the     properties of     IR are decreased     intracellular     insulin induced   glucose uptake   in addition to   handling   secondary to decreased   insulin   stimulated GLUT4 getting transferred to the cell membrane followed by  glycogen  generation   subsequently(figure1)[35,reviewed in 36].

Legend for Figure 1

Courtesy ref no-36-Action of insulin in the postprandial state in healthy and type 2 diabetes conditions. Increasing blood glucose will lead to the secretion of insulin. Insulin stimulates glucose uptake in skeletal muscle and white adipose tissue and suppresses lipolysis in white adipose tissue, leading to a reduction in circulatory free fatty acid (FFA) levels. In the liver, insulin and reduced adipose lipolysis suppresses hepatic glucose production (HGP) via a combination of reductions in gluconeogenesis and glycogenolysis and stimulation of glycogen storage. The combined action of glucose uptake and reduction in HGP contributes to plasma glucose control. In type 2 diabetes, glucose-induced insulin secretion is not sufficient due to reduced β-cell function and insulin-stimulated glucose uptake in muscle and white adipose tissue (WAT) as well as insulin-stimulated suppression of HGP is blunted. Insulin resistance in WAT also leads to blunted suppression of lipolysis by insulin, producing higher FFA levels that subsequently negatively affect skeletal muscle and HGP. FFA, free fatty acids; HGP, hepatic glucose production.

Besides    skeletal muscle,liver   IR causes    escalated basal endogenous  glucose   generation  (EGP)   along with    reduction of   insulin suppression of   EGP,that aids in the   greater plasma   glucose amounts  (figure1)[31].  

Adipose tissue(AT)   insulin resistance  aids in hyperglycemia by  glucose uptake   reduction,despite   AT  glucose uptake   is usually believed  to be comparatively less in humans [37]. Nevertheless,  AT  IR further results in decreased hampering of lipolysis by  insulin that can lead to escalated free fatty acids(FFA)  amounts in blood    (figure1)[38]. Greater circulating    FFA can aid in    skeletal muscle  IR.Moreover greater    lipolysis rates further result in  greater glycerol,that are believed to   have a significant   part in  gluconeogenesis     along with  EGP[39].Fig1 illustrates the  postprandial  insulin effects in T2D.

2.2Mode of   generation of  βcells failure,   insulin resistance,  along with type2 Diabetes       

There exists a robust     correlation among type2 Diabetes mellitus in addition to   obesity,with   about 90%  of all  T2D patients being  overweight or   obese.Fat mass expansion  makes sure that storage  escalated    nutrient/energy occurs  ; nevertheless,when     AT expansion  capacity becomes restricted or impaired[40], an  escalation of circulating    FFA in addition to  enhancement  FFA uptake by liver  as well as     skeletal muscle  can take place, where competition with  glucose   can cause substrate oxidation, that as per Randle cycle can aid in insulin resistance[41].Besides that FFA can further collect in non adipose tissue, along with ectopic fat collection has been demonstrated to be a key factor  for the generation of IR in the liver as well as    skeletal muscle,basically secondary to  meddling  by diacylglycerol, in addition to   ceramides (of the rest) with the insulin  signaling pathway[42].Further  enhancement  of FFA uptake is also correlated with Oxidative stress( OS), inflammation  as well as   cell demise.Lipotoxicity   can take place in a variety of  tissues  like skeletal muscle, liver   ,heart,arteries,pancreas that produces separate phenotypes or end organ injury  in patients secondary to  which organs are implicated  maximum .In case of muscle,fat collection intervenes  with the insulin  initiated GLUT4 getting translocated,whereas in liver non alcoholic fatty liver (NAFL) is correlated with hepatic insulin resistance in addition to  escalated generation of very low density lipoprotein(VLDL)- triglycerides(TG),  which aid in the generation of  atherosclerotic dyslipidaemia[43].Further hepatic insulin resistance generation  can also be secondary to  pulsatile  insulin getting administered in the hepatic portal vein  along with finally in hepatocytes[33].This posit points that deranged insulin administeration as is seen in T2D,might result in impairment  of hepatic metabolism  or selective IR via FoxO1,aiding in collection of lipids[44]. Selective IR is a pathological condition where insulin doesn’t  cause reduction of HGP,yet insulin activation of denovo lipogenesis  through stimulation of SREBP-1c  does not get implicated as well as  further escalated secondary to  correlated hyperinsulinemia  resulting in ,more fat collection [45].In case of  Pancreas  βcells  getting exposed to  chronic   escalated amounts of FFA result in endoplasmic reticulum (ER) stress in addition to  mitochondrial impairment,that can lead to cell injury as well as  ultimate dysfunctional insulin liberation[46].

Chronic hyperglycemia, has further been demonstrated to have toxic actions  on βcells as well as other tissues,for which the term glucotoxicity  was coined. Glucotoxicity aids in βcells failure in addition to  decreased  insulin sensitivity in the liver through variety of events,like ER  stress, mitochondrial impairment, Oxidative stress , along with inflammation  [47]. Additionally,with Chronic hyperglycemia,glycogen storage occurring in βcells has been ,illustrated to be correlated with apoptosis[48].If Glucotoxicity influences skeletal muscle insulin sensitivity is still debatable  and needs more exploration[35].

Besides obesity ,age is another factor that decides the generation ofT2D,that has long been believed to be a disease correlated with  exaggerated ageing.Wijsman etal.[49], documented  that familial longevity had the properties of escalated insulin sensitivity in contrast to   a group possessing  similar age, sex in addition to   body make up.With age  decrement of physical activity  along with muscle mass is usually seen ,that is factors that directly aid  in the generation of skeletal muscle insulin resistance. Additionally,ageing is usually correlated with  an  escalation of fat mass which might aid in generation of lipotoxicity along with IR. Cellular stress reactions can result in a state where cellular Senescence possessing the properties of cell cycle arrest , apoptosis resistance, in addition to  Senescence- associated secretory phenotype(SASP),that has a negative impact  on organ functions .That insulin resistance exaggerated βcells Senescence in human islets(Aguayo –Mazzucalo) was demonstrated.Further more in mouse models  of type1 Diabetes,it got   illustrated that deletion of Senescent cells  stopped immune modulated βcells     break down  as well as  avoided Diabetes[50].Hence both enhancement of insulin sensitivity along with escalated apoptosis of Senescent  isletcells could result in enhancement of   βcells functions.

The Baltimore  Longitudinal study of ageing demonstrated that  a reduction of   insulin liberation  occurs with age based on body mass index( BMI)  in addition to  Adipose tissue spread[51].This might reason out why the Prevalence  of T2D is correlated with escalated age in the population.

Maximum insulin resistant people do not generate T2D along with genetic  constituents  might reason out  why certain insulin resistant people generate T2D. GWAS (genome wide association studies ) have isolated a SNP which are correlated with  function   of βcells.Of the certain variants are present over 40 loci  as well as  can escalate the risk of  T2D .Despite greater than 400gene variants have been correlated with   the existence of T2D,the presently isolated variants have only  accounted for 10% of genetic influence  for the chances of generation of T2D[52]. As compared to that maturity onset Diabetes in the young  is monogenic Diabetes,accounting for2-5% of Diabetes patients[53].

3.Diabetes Classification

An International work group generated a new Classification which included type1Diabetes mellitus(T1D), T2D in addition to  Gestational Diabetes mellitus(GDM)[54] in 1979.They further added an impaired tolerance test (IGT) group:people who did not meet the criteria for DM but had an escalated fasting  as well as      2h postprandial  glucose amounts.This Classification got reviewed in 1997 as well as       broke in 2i) impaired fasting  glucose(IFG) in addition to  ii) IGT[55].

Over 40 yr Subsequent to this Classification system  was initially advised ,insight into Diabetes pathophysiology has become further complicated . Nevertheless,still just 2 main Classifications T1D as well as      T2D.With the challenge now for more individualized medicine approach ,a further refinement of Classification system   would be aid in generation of innovative drugs  that correct the basic aetiology  of the syndrome in addition to   prescription of the best medicine currently prevalent for avoiding propagation of disease along with end organ injury .

In 2018 ,Ahlqvist etal.[56]pointed a new Classification system   of adult onset Diabetes,that at minimum takes into account ,the heterogeneous  phenotype of T2D.In the sub group Classification, adult onset Diabetes is further sub Classified into5 sub groups or clusters  with  utilization of 6 quite common parameters that can be easily acquired from the clinical scenario;namely i)BMI,ii) HbA1ciii) glutamic acid decarboxylase antibodies(GADA)iv) homeostasis model  assessment 2(HOMA2)to evaluate βcell function(HOMA2B) along with insulin resistance(HOMA2IR) depending on the   fastingglucose as well as C peptide amounts.Data driven non supervised cluster evaluation  was performed utilizing large Swedish as well as      Finnish cohorts that included all new incidents of adult onset Diabetes. Data driven non supervised cluster evaluation   made the conclusions that 5 novel sub groups for newly diagnosed adult onset Diabetes depending on the variables defined earlier;i)severe autoimmune Diabetes (SAID),ii) severe insulin deficient Diabetes(SIDD)iii) severe insulin resistance  Diabetes(SIRD)iv)Mild obesity related Diabetes (MOD),V)mild age - related Diabetes(MARD)(Figure2). SIDD in addition to  SIDD had the properties of earlier onset – Diabetes,having a lesser BMI in relative terms,bad regulationin metabolic terms(greater HbA1c), along with insulin  deficiency(based on low HOMA2B index). The variation among SAID in addition to  SIDD is the existence of GADA  in SAID but not in SIDD. SAID possesses an overlap with T1D as well as     latent autoimmune Diabetes in adults(LADA). LADA has genetic properties akin to T1D,but in a clinical scenario ,they usually possess characteristics akin to T2D patients  ,thus usually get diagnosed as T2D.With the application of similar cluster evaluation   in an independent  German cohort  demonstrated that the patients allotted to the SIDD group  further revealed signs of autoimmunity[57].

Legend for Figure 2

Courtesy ref no-36-Visual representation of the characteristics of the subgroups as suggested by Ahlqvist et al. [56]. Severe insulin-deficient diabetes (SIDD) is characterised by a relatively low age and BMI, a high HbA1c, less marked insulin resistance, but severe β-cell insulin deficiency. Severe insulin-resistant diabetes (SIRD) is characterised by a relatively high age and BMI, a relatively low HbA1c, severe insulin resistance, but no insulin deficiency. Mild obesity-related diabetes (MOD) is characterised by a relatively low age at diagnosis, a high BMI, relatively low HbA1c, and mild insulin resistance and insulin deficiency. Mild age-related diabetes (MARD) is characterised by a high age at diagnosis, a relatively low BMI, and mild insulin resistance and insulin deficiency. More severe insulin resistance/deficiency is indicated with a larger stop sign.

SIRD posseses  the properties of a greater BMI(over weight to obese) in addition to   severe IR(based on high HOMA –IR index).In SIRD, βcells function is lesser dysfunctional   in contrast to  SAID in addition to  that  SIDD(greater HOMA2B index) as well as      HbA1c amounts are lesser.Both SIRD in addition to SIDD were earlier diagnosed  as   T2D although are  markedly separate  types of robust T2D. MOD along with MARD have the propertiesof  mild insulin deficiency(HOMA2B index greater than SAID in addition to  SIDD).The variationamong MOD along with MARD is dependent on age at the time of diagnosis  as well as      BMI;MODhas the  properties of greater BMI(obesity),whereas MARD possessing greater age at the time of diagnosis  .Hence SAID is made up of patients  which are presently diagnosed as T1D or LADA,whereas in the rest 4 clusters get diagnosed as T2D.

The propagation of disease as well as  risk of end organ injury  appear to be separated by sub groups, SAID in addition to  SIDD possessing greater HbA1c at baseline  in addition to   during follow up in contrast to   rest of sub groups  also correlated with  an escalated risk of ketoacidosis [56,57]. SIRD has a correlation  with  a great prevalence of non alcoholic fatty liver disease(NAFLD), along with  fibrosis at diagnosis[56,57] in addition to  Diabetic Kidney Disease(DKD) as well as       end stage renal Disease(ESRD)[56],but on rectification for baseline Kidney function,no variation among separate  sub groups[58] .That is patients with SIRD generate end organ injury before they get diagnosed with Diabetes.Conversely neuropathy as well as  retinopathy  are more commonly correlated with the SIDD group[56,57].The sub groups also vary  by the early treatment prescribed in the cohort at the time of diagnosis.As far as the SAIDgroup is concerned 42-76% were receiving insulin therapy as well as     29-44% of SIDD patients were receiving insulin therapy[56,57].

4.Present treatment Approaches

Despite T2D being a   heterogenous syndrome as pointed by huge inter person variations with regards to insulin resistance, βcells function  ,along with autoimmunity ,the present treatment approaches basically concentrate on reduction of glucose in addition to  HbA1c for avoidance of end organ injury  .Since Atherosclerotic cardiovascular  disease (ASCVD)still continues  to be the commonest cause of morbidity as well as     mortality in T2D patients, the guidelines are very implicit with regards  the degree to which  the various medicines have exhibited reduction in risk of CV processes.Other  end organ diseases  correlated with T2D like Chronic Kidney Disease(CKD), NAFLD, neuropathy as well as      retinopathy   are further more significant to take into account  when decision of proper treatment for patients  with T2D are decided. Nevertheless, currently ,anticipation of  disease propagation  or risk of end organ injury  in persons with T2D is not fully clear.Thus for it to be more efficacious in addition to   cost beneficial it would be more advantageous if  more precise ways of anticipating risks  for treatment of patients  with greater aggression,  in those that possess a greater risk in contrast to   those with lesser risk.

Subsequent to initial  guidelines with regards to lifestyle modifications, weight reduction, along with  escalated physical activity , patients current situation remain the reference points for the choice of an antihyperglycemic agent .Thus the guidelines mostly take into account  patients   chances of generation of CV processes,weight as well as      chances of hypoglycemia when trying to select the antihyperglycemic  agent.

Other factors on which decision is based  remain the cost of medicine in addition to   possessing proven effectiveness.Hence the latest guidelines of theAmerican  Diabetes Association(ADA) along with European Association For the Study of Diabetes(EASD) of 2020,metformin still occupies the first line therapy having the knowledge of its specific profiles  when evaluation for cost benefit  along with tolerance [59,60].The mode of action of metformin on glucose regulation has not been totally worked out ,with both liver as well as      intestine  having been pointed as the major target tissues;though its mechanistic role has been extensively reviewed[61]Yet,large proportion of patients won’t have the capacity  to reach the treatment targets  by consumption of metformin alone,thus ultimately need the adding of a second  line therapy .

Second line therapy  choice  will be based  on the patients having generated ASCVD, CKD,or heart failure(HF).In case still these have not developed as yet,one makes the opinion  that is dependent on the risk of side effects like  hypoglycemia, weight gain,cost as well as      what  patients choice  is. Nevertheless,little proof  exists to be able to guide the 2^nd line therapy or for that matter even 3^rd line for attaining glucose  homeostasis.

The novel Classification system for Diabetes pointed by Ahlqvist etal.[56], demonstrated the heterogeneity of T2D, concentrating on various factors  that are IR, βcell impairment.This new Classification can aid in generation of new ,more individualized strategy  by evaluation of the association with antihyperglycemic agent as well as      their actions on the  mode of action  of T2D etiology.With this  Classification,it might also be that patients at greater risk receive more combative treatment at diagnosis  for avoidance of  end organ diseases  correlated with the   sub groups of Diabetes.Currently 5 separate classes of 2^nd line antihyperglycemic agents that have been advocated by ADA in addition to  EASD;i)DPP-4 inhibitors, glucagon like peptide 1(GLP-1)-RA, Sodium –glucose  cotransporter 2(SGLT2) inhibitors ,Sulfonylureas,thiazolidenediones.These  medicines have been used with success at commercial  in view of their capacity  to enhance glucosehomeostasis,cause reduction of HbA1c , nevertheless possess different  in addition to   inadequately found modes of action for  enhancement of glucosehomeostasis in separate methods.This offers a way out for  utilization of individualized  therapy approach .Thus idea of review is to get insight  into the posited working mode of the presently   written medicine treatment strategy for the 2^nd line antihyperglycemic agents along with the data  present  on the actions of these treatment agents on βcells function along with insulin sensitivity.

There has been asuggestion that  probable treatment approaches  for the novel  SIDD, SIRD, MOD along with MARD sub groups, that at present are made up of the largest sub groups of T2D,since these groups might improve  from separate medicines. Significantly ,very minimal results are available  for making the correct decision for the patients based on their metabolic phenotypes.Thus these are certain posit generating suggestions although cant be considered in the form of recommendations .For SAID groups not detailed  as this entails T1D as well as  LADA ,which is a heterogenous group needing insulin treatment.Sulphonylureas also not detailed as their actions on βcells function along with insulin sensitivity are well developed. Sulphonylureas do not possess any action on insulin sensitivity,but to start with will enhance insulin function. Subsequent to 1-2 yrs of treatment HbA1c amounts will escalate,pointing to a deterioration  of βcells function[62]. Nevertheless,  it needs to be appreciated that Sulphonylureas have been demonstrated in cases of MARD[58], illustrating that Sulphonylureas still have a place in long term therapy of this T2Dsubgroup.Insulin also not detailed –extensively  reviewed ,with guidelines on when to as well as  under  which situations  insulin is beneficial over rest of the second line therapy   agents[59].Medicines  which cause enhancement glucoseuptake amounts including insulin treatment ,aid the rest of βcells   by    compensation for insulin  needs by rectification of hyperglycemia .The beta cell rest  is too detailed to be discussed here ,but it  suffices  to say that at  present no clinical proof  that any medicines  changes  the propagation of Disease  with regards to beta cellfunction enhancement  but for acute actions [63]. Nevertheless, it  needs to be  addressed that utilization of insulin  in T2D  patients posseses certain disadvantages  like the chances of   enhancing the risk of weight escalation ,that might result in IR, in addition to  treatment with insulin  in T2D patients might enhance  the risk of CVS complications[64].

Here we consider Second line therapy  for T2D patients on basis of specifically  utilization of human trials utilizing hyperinsulinemic clamps or mixed meal tests ,if feasible ,since these approaches are considered the gold standard ways for evaluation of beta cellfunction along with insulin sensitivity.

4.1Sodium –glucose  cotransporter 2(SGLT2) inhibitors

SGLT2   inhibitors represent an innovative  kind of  agents resulting in  glucose reduction by action on SGLT2,that gets expressed  in the first segment of  the proximal tubules  in the Kidneys. SGLT2 results in about 90% reabsorption of   glucose from the Kidneys. Inhibiton of SGLT2 causes urinary excretion of 60-80g glucose daily ,with the precise amounts based on the plasma   glucose amounts in addition to  ) enhanced glomerular  filtration rate(GFR),resulting in decrease of HbA1c of 0.6-0.9% as well as       FBG by 1.1-1.9mmol/l in contrast to   placebo [65].The mode by which SGLT2   inhibitors cause glucose reduction is quite simple as well as      direct ,by enhancement of urinary loss of glucose,a mode  that is independent of insulin action[65].Both  glucose along with energy elimination  initiates adaptive reactions  which might aid in the advantageous actions  on of these agents. SGLT2   inhibitors are correlated with body weight reduction[65],lesser blood pressure(BP), in addition to  positive outcomes of CVdeath,HF along with propagationof CKD[52-54,rev by us  23-25CV,HF].

4,1aSGLT2   inhibitors  in addition to beta cell   function

Glucose deletion  via urine might  enhance  beta cell function through reduction in glucotoxicity along with  decrease in escalated insulin liberation secondary to  reduction in glucose  amounts[67].Despite SGLT2   inhibitors   cant target the beta cells by direct action,their     actions on beta cell   function have been extensively evaluated in variety of human intervention studies.Both Al-Jobori in addition to  Merovci et al.  documented a 2 fold enhancement of beta cell   function that is determined in the form of escalated insulin liberation/ insulin resistance  index (also Known  as  the deposition index);i.e the alteration of C peptide amounts divided by the alteration of  glucose  amounts(Δ C peptide /Δ glucose  ) divided by insulin resistance) following 2wk of SGLT2   inhibitors  treatment in  T2D patients[68,69].Akin to that Forst etal., demonstrated 2 independent  studies  of escalated beta cell   function as evaluated by enhancement of area under curve for insulin, C peptide/pro insulin ratio  at the time of hyperglycemic clamp following 30 days of treatment with SGLT2   inhibitors   in T2D patients receiving co treatment with metformin[70].

Various studies illustrated that treatment with utilization of SGLT2   inhibitors  enhances  beta cell   glucose sensitivity. Ferranini etal.[71], documented that 25%  enhancement in  beta cell  glucose sensitivity following just  48h of SGLT2   treatment in patients with  T2D in treatment-naïve  along  with and metformin pretreated  . Subsequent to 14 days of therapy , escalated beta cell  glucose sensitivity were maintained.Three separate studies demonstrated in patients with  T2D in treatment-naïve or received diet advice , metformin, Sulphonylureas,or a combination of metformin,as well as Sulphonylureas documented that beta cell  glucose sensitivity escalated following   48h along with  14days of SGLT2   treatment[68,72].

The propagation of Diabetes is basically secondary to  reduction in beta cell function.This implies that long term actions of enhancement of beta cell function can get observed since no propagation in the worsening of HbA1c amounts.The actions of SGLT2   inhibitors   were proven in a meta-analysis that included 38 studies of ≥24weeks period that was performed by Zaccardi etal.[65],.On average they revealed  a HbA1c decrease of 0.6-0.9%.On concentration  on studies possessing a long period (≥104wks)with ameasurement of  HbA1c SGLT2   inhibition generated  a maintained decrease of 0.30-1.22%[73].

4.1b.SGLT2   inhibitors   along with  insulin sensitivity

Inhibition of SGLT2 can  result in enhancement of insulin   sensitivity through a decrease of plasma glucose in addition to  decreased weight of 1.5-2kg has been illustrated in patients on SGLT2 inhibitors   [65,74].In the following detailing ,glucose reduction through urine  might result in activation of lipid oxidation for compensation  in humans ,that could influence the arrangement of escalated fat mass in addition to   reduction of ectopic fat stores ,that have a robust association with the generation of IR[67].

Various studies evaluated  the actions of Inhibition of SGLT2  on peripheral insulin sensitivity[71,75,76]. Ferranini et al.[71], documented a reduction in total glucose disposal  that was rectified for urinary glucose  excretion following acute SGLT2 inhibitors    delivery ,that got maintained following 14d  of treatment of patients with T2D  that were treatment-naïve or received metformin. Nevertheless, although the reduction in glucose disposal  mainly secondary to  non- oxidative glucose disposal  , peripheral insulin sensitivity,that was evaluated  by the ratio of the glucose metabolic  clearance rate to the mean plasma  glucose amounts at the time of a mixed meal test   enhanced markedly following acute delivery ,but the escalation did not achieve statistical significance  following 14d of therapy. Merovci et al.[75],observed akin outcomes with the utilization of  hyperinsulinemic  euhyperglycaemic clamps  for evaluation of insulin sensitivity.14 days of SGLT2 Inhibitors delivery escalated insulin  modulated  whole body glucose disposal  rectified for urinary glucose elimination from 4.3±0.4to5.0±0.4mg/kg/min ,that was a significant enhancement in contrast to  baseline as well as  placebo(4.0±0.5 to4.3±0.64mg/kg/min) in patients with  type2 Diabetes mellitus treated  with metformin or combination of metformin along with   sulfonylureas.Akin to that following  12wks of a SGLT2  inhibitor treatment, peripheral insulin sensitivity estimated  at the time of hyperinsulinemic  euhyperglycaemic clamps   enhanced in contrast to  placeboin patients with    T2D   that received co treatmenwith metformin or combination of metformin or a insulin secretagogue[76].Outcomes akin to this  were observed  in rest of studies.Hence in patients with    T2D   that received co treatment with metformin, sulfonylureas, dipeptidyl peptidase -IV inhibitorson (DPPIV) inhibitors or combination of metformin with   sulfonylureas, peripheral insulin sensitivity escalated by about 16-36% in contrast to   baseline as well as  placebo following SGLT2  inhibitor delivery [69,77].Conversely Latva Rasku etal.[78],did not observe any enhancement following   8wks of a SGLT2  inhibitor treatment  on insulin sensitivity(estimated in the form of whole body   insulin activated M Values)or skeletal muscle glucose uptake in patients with    T2D   that received co treatmenwith metformin or combination of metformin with DPPIV inhibitors. Latva Rasku etal.[78], pointed thatrobust insulin resistance in the patients taking part might reason out why a relatively lesser insulin  infusion  rate(40Mu/m²/min)could not pick up an alteration in  M Values).Despite  significant reduction in   liver fat amounts occurred(proton density fat fraction :3.7%)this decrease in hepatic fat  did not enhance insulin sensitivity(as estimated in the form  of repression of EGP)or escalated  glucose uptake by the liver .

On the other hand variation of studies documented an enhancement of EGP following SGLT2  inhibitor treatment  [71,75-77,79].The hepatic in addition to   probably renal glucose generation makes a compensation for about 50% of glucose eliminated in urine in patients of T2D,thus blunting the reduction in  plasma glucose amounts[75].The precise mode  resulting in this  compensatory enhancement   of EGP is not well understood .It has been pointed that reduction in insulin: glucagon ratioor ANS – modulated mode might be implicated . Alatrach etal.[80], documented that insulin along with glucagon amounts Under glucose clamp situations (avoidance of a reduction in glucose amounts)did not vary among subjects receiving SGLT2  inhibitors or placebo.This is against the significant part of the insulin: glucagon ratio in modulation the escalation of EGP following SGLT2  inhibitor hampering . Solls –Herrera  along with  Daniele et al[81,82]posited that renal autonomic nervous system(ANS) afferents have a significance  for enhancement of EGP following SGLT2  inhibition.They evaluated  the actions of SGLT2  inhibition on EGP in Kidney transplant patients with either both residual native Kidneys  in place or a bilateral  nephrectomy .An enhancement  of EGP following SGLT2  inhibitor  delivery  took place in both groups.Whereas the enhancement of EGP in  their native Kidneys   could be compared  by other studies,the enhancement  of EGP got blunted in those  patients with a bilateral  nephrectomy. This observation pointed that the part of Kidneys as well as /or ANS  in EGP following SGLT2  inhibition continues to be not clear.

SGLT2  inhibition has been demonstrated to alter substrate oxidation  that might be beneficial  with regards to insulin sensitivity.Hence a reduction in   glucose Oxidation along with  enhancement of lipid oxidation in addition to   ketone  generation has   got documented[77,83]that could aid in enhancement beta cell function along with  insulin sensitivity by decreasing ectopic fat as well as  mitigation of lipotoxicity. Nevertheless, escalated fatty acids Oxidation is correlated with  enhanced adipose tissue lipolysis along with  escalated fatty acids flux  which would result in reduction of  glucose uptake in skeletal muscle,resulting  in reduced skeletal muscle insulin modulated glucose uptake in skeletal muscle. Nevertheless, minimal insight  is there with regards to alteration in potentially deleterious intracellular lipids,with the maximum proof that ectopic fat reduction in liver [78,84],visceral fat[85],epicardial fat[86], subsequent to  treatment with SGLT2  inhibitor.

Thus concluding that SGLT2  inhibitors  in a modest ,albeit significant enhancement of beta cell function in addition to  beta cell glucose sensitivity.Long time studies pointed that maintainance of glucosereducing action following a minimum of 2 yr  of therapy .No washout studies  have got performed as far as we know  to evaluate  if enhancement of beta cell function gets maintained following omitting of SGLT2  inhibitors.As far as insulin sensitivity is concerned ,various research groups have documented escalated insulin sensitivity,but the degree of enhancement was not much .It is posited that advantageous actions of SGLT2  inhibitors therapy  is basically secondary to  reduction in glucotoxicity. Nevertheless, Clinical trials evaluating along with  insulin sensitivity over longer time duration  are minimal.It is possible that treatment for over3-4mths might demonstrate separate outcome.Like data point that following 3-4mths,energy decreases get compensated by escalated food intake  which could reason out why body weight reduction doesn’t occur following this period of time [87].The results present on beta cell function along with  insulin sensitivity in addition to   the knowledge that SGLT2  inhibitors   act independent  of insulin pointed that SGLT2  inhibitor therapy might be advantageous in all 4 posited novel subgroup of T2D.The first study  to evaluate the effectiveness of SGLT2  inhibitors  in addition to  glucagon like peptide  receptor agonists in patients with SIDD as well as  SIRD  has initiated enrollment.( Clinical trials.govIdentifier:NCT04451837)

4.2.Glucagon like peptide1  receptor agonists

Glucagon like peptide  (GLP-1) represents a hormone, generated by the L cells of the intestine in reaction to food consumption,specifically in meals possessing a great amount of fat along with  carbohydrate. GLP-1 delivery enhances glucose amounts via separate modes that includes glucose based insulin liberation,decrease food consumption, reduction in body weight in addition to  decreased amounts of glucagon. Glucagon like peptide1  receptor agonists(GLP-1RA)decrease HbA1c by  a range varying from 0.5-1.5%[88].

4.2a.GLP-1RA along with  beta cell function

Of the anticipated mechanistic modes of GLP-1RA is through a direct effect on βcells. Βcells themselves  show expression of GLP-1 receptors . GLP-1 receptors belong to Gprotein Coupled Receptor(GPCR) ,with their activation causing an enhancement of cAMP in addition to  protein kinase A(PKA) action that facilitates   insulin liberation  from βcells[89]. The LIBRA trial evaluated beta cell function in patients in whom type2 Diabetes mellitus  diagnosis had been  made recently,who received insulin treatment for 4 wks prior to getting randomized  with either a GLP-1RA or placebo  for48 wks along with  observed that  enhancement  of  beta cell function   occurred as estimated by insulin liberation sensitivity index 2 in the active group[90].In another  randomized controlled trial performed in    patients with  T2D   in contrast to   actions of a short acting GLP-1RA  vs placebo  for3yrs  as well as   found  beta cell function    escalated  as   estimated by  the Mari  model ,an approach that evaluates beta cell function  from results  received at the time of an oral glucose tolerance test ( OGTT)[91].

Anholm  etal.[92], observed that 12 wks of  metformin with a GLP-1RA   resulted in a significant  enhancement  of beta cell function  as evaluated  by  the disposition index  in contrast to   a  metformin or  placebo  group in a a randomized,double blind crossover trial [92].An additional randomized controlled trial   GLP-1RA  with metformin or metformin along with   lifestyle interventions  on  beta cell function   in  patients in whom  type2 Diabetes mellitus  diagnosis had been made recently,it was observed that Liraglutide  escalated beta cell function    that was expressed ,in the form of beta cell insulin liberation at the time of an OGTT in contrast to    a control group within a 15mths time duration[93].The positive action of both short as well as   long acting GLP-1RA    on beta cell function have been illustrated in variety of randomized Clinical trials .

In animal models of  Diabetes,it has been documented that   treatment with GLP-1RA   escalates the  beta cell function ,basically via proliferation as well as   differentiation [94]. Nevertheless, if GLP-1RA    escalates the functional beta cell mass  in human beings in not known as yet.The outcome of washout studies[90,91] , illustrated no long lasting  actions on the  beta cell function, hence pointed that no  action on functional beta cell mass   in addition to   the actions observed on beta cell function appeared to be acute.

4.2b.GLP-1RA    as well as  insulin sensitivity

The acute actions of short acting GLP-1RA   was evaluated by Gastaldelli etal.[95],on the hepatic in addition to  AT insulin sensitivity that was determined  in the form of glucose as well as  glycerol tracer kinetics following a 13 C enriched glucose load .This study was performed in patients withT2D along with   persons having IGT.They observed that acute treatment with GLP-1RA   escalated hepatic in addition to  AT insulin sensitivity in contrast to   placebo  .The continued action of GLP-1RA  on insulin sensitivity was  evaluated by Zander et al.[96].They examined the actions of continued s/cinfusion of GLP-1RA   vs saline infusion with the utilization of  a portable pump for6wks in patients withT2D as well as  observed that insulin sensitivity as estimated byhyperglycemic   euglycemic clamps enhanced by 77%. Nevertheless, this action on insulin sensitivity might have been overdetermined since the study did not get   randomized or blinded.The enhancement of insulin sensitivity was correlated with a reduction in fasting  plasma glucose along with FFA amounts that could have aided  in this action . The action  of GLP-1RA   as well as  metformin vis a vis metformin as well as  placebo   by Anholm etal.[97], on insulin sensitivity in obese as well as  overweight patients who  that presented with newly diagnosed   type2 Diabetes and coronary   artery disease. Evaluation of insulin sensitivity was performed  with the utilization of ISI  composite ,an estimation of whole body  insulin sensitivity, derived from a formula which combines results derived from OGTT in addition to  results derived from fasting  plasma glucose as well as  insulin[98]. GLP-1RA   as well as  metformin escalated beta cell function   as  determined by the disposition index by 40% in contrast to   metformin as well as  placebo, nevertheless insulin sensitivity was not significantly separate among the groups[97].

The actions of GLP-1RA    on hepatic insulin sensitivity was analysed by Armstrong etal.[99],as estimated by repression of EGP, following 12wks  of GLP-1RA     therapy vis a vis placebo  in individuals with non alcoholic steatohepatitis( NASH).A hyperglycemic   euglycemic clamps utilization was done prior to as well as  following treatment,it was observed  that GLP-1RA    caused reduction of EGP in contrast to placebo    (-9.3vs -2.5%). GLP-1RA ,further caused   significant reduction of body weight  in the intervention group in contrast to placebo.The actions of GLP-1RAon hepatic fat   amounts  was as estimated by magnetic resonance spectroscopy(MRS) by Dutour et al.[100],in obese  patients with T2D. Subsequent to 26wks of therapy ,they observed   a significant decrease in hepatic fat   amounts   in the intervention group in contrast to placebo.(-23.8%vs +12.5%).This decrease in fat   in the liver  had a greater association with body weight reduction.

Actually the actions of GLP-1RA  on   body weight might offer the reason for the  advantageous actions  on  liver as well as  peripheral  insulin sensitivity  which have been seen .A meta-analysis which included 25 trials for contrasting GLP-1RA   with placebo ,insulin or other glucose suppressing agents  observed that GLP-1RA   resulted in a  significant decrease in body weight[101].The outcomes documented a mean variationof -2.9kg body weight reduction in the  intervention group  in contrast to   a control group.Akin to that Davies etal.[102], documented the long term actions on body weight following 56 wks of therapy in contrast to   placebo in overweight as well as  obese individuals with T2D in addition to  documented significantly greater body weight reduction in the  intervention group  in contrast to   a placebo  group.Other probable reasons for the action on insulin sensitivity might be a correlation  that has been observed in  animal models  among   GLP-1RA treatment  along with  reduction in inflammation[103]. Lynchetal.[104]On evaluation of the correlation among GLP-1RA treatment    as well as  invariant natural killer cells (NKT) Cells in human along with   mice AT , Lynchetal.[104],found that   GLP-1RAresulted in activation of iNKT Cells. Intriguingly, activation of iNKT Cells can result in decrease in body weight.Hence GLP-1RAmay result  in partial weight reduction in addition to cause   enhancement of insulin sensitivity by  action on the immune  system.

Thus concluding that GLP-1RA escalates beta cell function at the time of treatment, although this action does not last following omitting these agents[105].The action of GLP-1RA treatment  on glucose regulation appears to majorly depend on  the capacity  to escalate insulin liberation with the aid of enhancement of insulin sensitivity through weight reduction in addition to  immunomodulation actions . Nevertheless, a restricted knowledge on alterations in insulin sensitivity following GLP-1RAdelivery exist.

Present guidelines prove that GLP-1RA is a Second line therapyin obese patients having a diagnosis of cardiovascular  disease (CVD).It is pointed by Veelen etal.[36], that GLP-1RA treatment  might further be the treatment of choice  for the obese subgroups that were detailed by Ahlqvist etal.[56],that includes SIRD ,MOD in addition to  SIDD.In view of the nausea to start with GLP-1RA might not be that advantageous for the MARD group,in view of age of onset along with   lesser  risk of Diabetes- correlated end organ injury .

4.3Dipeptidyl Peptidase -4 (DPP-4) Inhibitors

Dipeptidyl Peptidase -4 (DPP-4)  Inhibitors represent a class of glucose reducing agents which hamper the enzyme DPP-4.Expression of this enzyme  occurs on the cell surface  like adipocytes, liver, Kidney along with   small intestine in addition to  glucose reduction they cause reduction of peptide activities ,like that of GLP-1, glucose dependent insulinotropic poly peptide(GIP). DPP-4 Inhibitors  possess the characteristics of competitively hampering ,besides a great affinity  towards DPP-4. DPP-4 Inhibitors  decrease HbA1c varying from a range of 0.5-1%[106].

4.3a.Beta cell function   as well as   DPP-4 Inhibitors 

The actions of DPP-4 Inhibitors   on glucose metabolism is believed  to be  basically by the enhancement of incretins accessibility  like GLP-1 as well as  GIP,that are implicated  for escalated insulin liberation along with  reduction of glucagon liberation following a meal [107].The action on beta cell function   got proven in prior studies.In a meta-analysis that included 23 a  randomized, placebo  controlled studies correlated DPP-4 Inhibitor   treatment with a significant enhancement in HOMA-B, in contrast to  placebo[108].On  utilization of DPP-4 Inhibitors as add on    treatment,a significant enhancement in HOMA-B,was observed. HOMA-B,basically estimates  the insulin liberation,with only limited studies having estimated  the action of DPP-4 Inhibitors on beta cell function    with the utilization of golden standard approaches.

In case of animal models of  obesity ,therapy with DPP-4 Inhibitors for 11 mths  had a greater  correlation  with Beta cell function,as estimated by  the oral disposition index, received at the time of an OGTT,but not   correlated with an  escalation of   βcell mass in contrast to   controls[109].In human beings on   evaluation of the actions  of DPP-4 Inhibitors  along with metformin  in contrast to   metformin along with   placebo,on the liberation ability of   βcells, Derosaet al.[110], illustrated that  by utilization of euglycaemic -hyperinsulinemic  as well as  -   hyperglycaemic    clamp in combination with following arginine activation,they observed escalated Beta cell function,which when it was  expressed  in the form of  disposition index  following 12 mths of DPP-4 Inhibitor   treatment(from 163.8±37.9 to 214.2±48.4nmol/lxμmol/kg) in contrast to   controls(from 163.6±37.7 to 279.5±56.9nmol/lxμmol/kg).

Despite the actions  of DPP-4 Inhibitors   are basically believed to be through enhancement of incretin amounts, Aulinger etal.[111], evaluated the actions  of DPP-4 Inhibitors on  glucosehomeostasis in patients with T2D following blockade of GLP-1 action via utilization of GLP-1 Receptor antagonist . Intriguingly, they observed significant actions  of DPP-4 Inhibitors   on insulin liberation at the time of an OGTT inspite of GLP-1 Receptor blockade.In non diabetic individuals Yanagimachi etal.[112],determinedthe   incretin amounts, following DPP-4 Inhibitors delivery at the time of an OGTT and they observed DPP-4 Inhibitors delivery,besides resulting in enhancement of GLP-1,further escalated the amounts of boioactive GIP.

4.3bInsulin sensitivity as well as  DPP-4 Inhibitors

The actions  of DPP-4 Inhibitors  on insulin sensitivity have got evaluated in animal models.Like Pospisiliketal.[113], observed an enhancement in insulin modulated glucose uptake in muscle tissue along with  escalated insulin sensitivity  as estimated   through the Matsuda index following treatment with DPP-4 Inhibitors in contrast to   controls.Hoewever,in case of humanbeings ,the actions  of DPP-4 Inhibitors   on insulin sensitivity continue to be debatable. The actions  of DPP-4 Inhibitors in the form of add on  treatment on insulin sensitivity in T2D individuals ,got evaluated by Derosa et al.[114],where they observed that following 12,18 as well as  24 mths of therapy in the treatment group in contrast to   control group, significantly reduced HOMA-IR. Nevertheless, HOMA-IR ,does not precisely determine insulin sensitivity in case of studies that are interventional.No  action  of DPP-4 Inhibitors therapy for 6mth was   observed by Parthan etal.[115], in contrast to  placebo on insulin sensitivity  as determined by hyperinsulinemic- euglycaemic clamp  in well regulated T2D individuals.These outcomes pointed that,inspite of a drop in HbA1c along with  fasting  plasma glucose  amounts,there appears to an absence of actions  of DPP-4 Inhibitors therapy on insulin sensitivity,that is in contrast  with the actions  of GLP-1RA treatment  .The  probable  reason  might be that DPP-4 Inhibitors  in various studies did not appear  to possess any significant actions on weight reduction[108,116].

Intriguingly in animal models of  obesity, enhancement of weight has been correlated with escalated DPP-4 expression  in hepatic tissues [117].In case of human  beings  action  of DPP-4 has been correlated with a greater  BMI, escalated fat proportion along with   NAFLD[118].These observations might point  that DPP-4 Inhibition might be a target to decrease hepatic fat amounts.Actually DPP-4 Inhibitors  treatments in animal models has got been correlated with benefits in hepatic steatosis[119] as well as  liver fibrosis  [120]. Nevertheless,in case of humanbeings  DPP-4 Inhibitors  treatments have not proved to be of benefit in NAFLD[121].

Thus concluding that DPP-4 Inhibitors  possess a significant action   on insulin liberation in contrast to  placebo,with possibly there major actions on  glucose regulation is through enhancement of insulin liberation   instead of possessing an actions on insulin sensitivity. DPP-4 Inhibitors  in contrast to   GLP-1RA treatment   appear to possess no actions on body weight ,hence might be less advantageous for patients for whom weight reduction causing agents might prove to be most favourable .Veelen et al. pointed that  DPP-4 Inhibitors  treatments might be the agents to or preferred  in case of SIDD ,MARD in view of  the absence of DPP-4 Inhibition on body  weight along with insulin resistance( IR).

4.4Thiazolidenedione

Thiazolidenediones alias glitazones  are insulin sensitizers.They got initially invented  by screening for hypoglycemic action in ob/ob mice [122].Later it was invented that thiazolidenediones escalated insulin sensitivity  in animals that showed  insulin resistance. In case of human beings, akin outcomes were   illustrated,since delivery of thiazolidenediones,led to glucose reduction, in addition to    insulin amounts, besides resulting in enhancement of IR along with lipid   metabolism.Usually it is agreed upon that thiazolidenediones work in the form of nuclear Peroxisome Proliferator Activated Receptor (PPAR)agonist particularly    gamma subtype (PPARγ),which is mainly expressed in White Adipose tissue(WAT),although in lesser amounts in the muscle, liver as well as   heart[123].On activation of the PPARγ transcription of the PPARγ target genes,which are basically implicated in  lipid in addition to    carbohydrate metabolism along with   immune functions [124].In view of robust side effects ,most kinds of thiazolidenediones that include troglitazone, as well as  rosiglitazone got removed from market .At present only Pioglitazone has the approval of European Medical Agency (EMA) along with   the USFDAfor treatment of T2D .Generally pioglitazone delivery  is correlated with  plasma glucose decrease of 1.2-2.0 mmol/l, HbA1c reduction of 0.9-1.3%, in addition to  enhancement of body weight of 3,6kg[125].

4.4a.Beta cell function   as well as Thiazolidenedione

The actions of Pioglitazone on beta cell function    got proved  in a meta-analysis[126].With the utilization of monotherapy HOMA-B, escalated  by 16%in contrast to the baseline.On combinationof Pioglitazone with    metformin or Sitagliptin, a little albeit significant enhancement of 9.8 as well as  11.8% in HOMA-B respectively was found in T2D patients. Nevertheless,despite HOMA-B yields certain knowledge with regards to actions of Pioglitazone on beta cell function,trialswhere  utilization of the gold standard for evaluation of     beta cell function ,the    disposition index,are restricted.As far as we know just 2 trials disposition index  demonstrated the beta cell function in T2D patients. Gastaldelli etal.[127], along with  Tripathy etal.[128],documented enhancement of beta cell function with the utilization of disposition index following Pioglitazone delivery for 4 as well as  6mths, respectively.It is not known the method by which pioglitazone causes enhancement of beta cell function,but there might be direct (expression of PPARγ in Pancreatic islet cells [129])or in direct  actions associated  with significant enhancement of insulin sensitivity by  pioglitazone  .

During a longer time duration  as determined by the PROactive trial with a mean follow up of 34.5mths , pioglitazone proved to be more efficacious  in resulting in HbA1c   amounts reduction in contrast to placebo in case of   patients who got treatment with metformin or sulfonylurea.The HbA1c   amounts reduction occurred at a fast pace  as well as  remained maintained over the total time duration[130], pointing  that   the   longer time duration  of pioglitazone action on beta cell function conservation.

4.4bInsulin sensitivity as well as Thiazolidenedione

The actions of thiazolidenediones,on insulin sensitivity in    case of human beings  has been exhaustively evaluated . Natali  as well as  Ferranini[131] conducted a systematic review marked 23 papers  which determined the actions of thiazolidenediones, on peripheral glucose disposal by utilization of  hyperinsulinemic  clamps as well as /or EGP with the utilization of  glucose tracer evaluation in T2D patients. On combination of data evaluation there was documentation of enhancement in  range  variation of 31-36% along with  19-33% in peripheral in addition to  hepatic insulin sensitivity, respectively  , following thiazolidenediones delivery in contrast to   baseline or placebo. Nevertheless, in this systematic review,besides inclusion of pioglitazone, troglitazone, as well as  rosiglitazone were included .As far as pioglitazone is concerned ,various research groups illustrated a statistically significant enhancement inperipheral[131-133], hepatic[127,134], along with  AT insulin sensitivity[134,135] in T2D patients.

Since PPARγ is mainly expressed in AT,it is pointed that enhancement in peripheral in addition to  hepatic insulin sensitivity, along with beta cell function are indirect as well as  predominantly evoked by a reduction in fatty acids  efflux from adipose tissue,that  escalates insulin  modulated   glucose uptake as well as  decreasing lipotoxicity.That pioglitazone induced PPARγ activation,  results in reduction of plasma amounts of triglycerides as well as  FFA, is well understood[136].In view of greater FFA amounts are correlated with ectopic fat collection  in addition to  insulin resistance, reduction of FFA amounts carries a  significant part in enhancement of insulin sensitivity. Actually pioglitazone  delivery is correlated with rearrangement of    adipose tissue that causes a reduction in ectopic as well as  lipid collection ,but escalated subcutaneous AT . Promrat et al.[137],were the 1^st group that documented the actions of Pioglitazone delivery on hepatic lipid amounts in non diabetic patients with non alcoholic steatohepatitis.In this particular trial , significant  reduction of the hepatic lipid amounts was demonstrated, from 47.5% to 22.8 % following 48 wks  of  Pioglitazone delivery, nevertheless the total body fat percentage escalated from 35.8% to37.6%.The insulin sensitivity index as evaluated  by  a repititively  sampled iv GTT escalated.The actions of pioglitazone  vs metformin  delivery for 10wks  on  insulin sensitivity along with  intramyocellular lipid amounts(IMCL)in patients with IGT was performed by Rasouli et al.[133].They documented a significant reduction of the IMCL following pioglitazone in contrast to   metformin as well as   baseline. The reduction of the IMCL amounts was associated  with an enhancement in insulin sensitivity,as estimated through an iv  glucose tolerance test ( GTT),with a rearrangement of visceral fat towards s/c  fat stores.Akin outcomes  were documented later  in  patients with pre Diabetes as well as  T2D that were simultaneously  treated  with diet advice,hypocaloric diets , metformin or insulin resulted in a reduction of the hepatic lipid amounts[134,138,139], IMCL[138], as well as myocardial[139] lipid amounts, in addition to  escalated s/c  fat[134,138,139].Although a reduction in  ectopc fat occurs , treatment results in escalated body weight, secondary to   greater caloric consumption in the patients treated with pioglitazone[140].

Notably all studies were  consistent on the pioglitazone’s action on metabolic adaptations . Phielixetal.[135], documented enhancement in AT insulin sensitivity but didn’t observe enhancement in peripheral or hepatic insulin sensitivity   inspite of a reduction in hepatic lipid amounts following 12wks of pioglitazone’s treatment in non obese patients with T2D. Van der Meer et al.[141], documented reduction in hepatic lipid amounts yet no alterations in  intra myocardial  lipid  amounts or  myocardial FA  oxidation  following 24wks  of pioglitazone  delivery  in patients with T2D. Bajpeyi et al.[132], documented a significant switch  from IMCL towards extramyocellular lipid (ECML)in the gastroscnemius,tibialis anterior  as well as  soleus muscle‘s with a chances  towards a reduction in hepatic lipid amounts following 12wks of pioglitazone  delivery in patients with T2D.These alterations were associated with  an enhancement in peripheral insulin sensitivity muscle  metabolic flexibity(Δrespiratory quotient)estimated at the time of insulin infusion(80mu/min/m²) in contrast to   the fasted state  of a of hyperinsulinemic -euglycaemic – clamp.Substrate oxidation  during fasting in addition to mitochondrial function that was evaluated in the  form of resting  ATP turnover along with the maximum   ATP generation rate  by 31P-MRS was not influenced by pioglitazone.

Hence concluding ,that pioglitazone  is efficacious in resulting in reduction of peripheral,AT in addition to  hepatic insulin resistance basically via mitigation of lipotoxicity by decreasing ectopic lipid  getting stored.Further pioglitazone also manages to induce HbA1c reduction over long duration of time,that points that there is enhancement in beta cell function. Nevertheless, these actions donot remain maintained following pioglitazone  omission[142]. Pioglitazone might work to be a robust treatment for a restricted group of patients in whom overcoming IR in addition to  NAFLD treatment  are much more  significant in contrast to    the side effects of weight gain,osteoporosis[143] along with   water retention, escalated risk of heart failure(HF)[144].Thus it was posited by Veelen etal.[36  ],that pioglitazone  might be advantageous treatment for SIDD  as well as  SIRD , in addition to  it needs to be  prevented in MOD as well as  MARD  in view of adverse actions.

5.Conclusions

Type2 Diabetes mellitus represents a heterogenous disease , possessing a complicated  metabolic disturbances  resulting in hyperglycemia  in addition to  beta cell function Impairment.Various second line   therapy choices are present currently; nevertheless,selecting the maximum appropriate  choice of anti diabetic agents  might be a tough job.The classication system provided by Ahlqvist etal.[56],yields a broad spectrum of the disease  which aids in getting greater insight  in the basic metabolic etiology of  T2D.

Depending on the  documented actions  of the presently existing antidiabetic agents on  beta cell function, insulin sensitivity along with  metabolism,certain medicines might be more appropriate  for the treatment of a subgroup of patients with T2D. Metformin continues to be the first –line therapy for glucose regulation of patients with T2D along with   probably works as a first –line therapy for patients in all 4 T2D subgroups. Metformin might prove to be enough  in form of monotherapy in milder disease,that basically includes  some with MARD as well as MOD. Nevertheless, for the subgroup of patients presenting with robust insulin deficiency(SIDD) it is concluded  that they might have  advantageous actions  from the present second–line therapy for T2D.As the SIDD group is correlated with   a lesser BMI ,no particular  antidiabetic agents are considered superior over others for these patients that needs rectification of weight.

Those patients belonging to the category of  robust or severe insulin resistance(SIRD),that present with greater BMI in addition to  the existence of greater BMI along with  greater chances of coexistence of NAFLD,might have preference of treatments  which result in weight reduction in addition to   cause enhancement of insulin sensitivity.For these such groups of agents are SGLT2  inhibitors in view of their potentially resulting in escalated insulin sensitivity, as well as  clinically significant reductions of body weight .It is still not clear if GLP-1RA treatment would prove to be advantageous in this group in view of restricted Clinical trials that have evaluated insulin sensitivity. Nevertheless,since GLP-1RA cause reduction of weight in addition to   hepatic lipid amounts,they might be promising  for SIRD.Further  pioglitazone treatment is also efficacious  for escalated insulin sensitivity in addition to   NAFLD reduction. Nevertheless, it needs to be thought of only when no other treatment modalities are available ,in view of the proven weight increments in addition to   other side actions that are correlated with  pioglitazone  delivery .In this group apparently DPP-4 Inhibitors do not seem to have any therapeutic part  in view of no proven actions  on insulin sensitivity, decrease in weight, or NAFLD reduction.

The patients belonging to the  mild –obesity – associated Diabetes(MOD) possessing the properties of moderate IR along with  little deficiency of insulin,but a greater BMI.They might just need metformin monotherapy,however in case glucose  amounts remain uncontrolled ,for them SGLT2  inhibitors as well as  GLP-1RA treatment might give benefits,since both groups result in significant weight reduction.In this groups it is preferable to prevent use of pioglitazone in view of the associated side effects of weight gain.

As far as patients belonging to the mild age –related Diabetes(MARD) possess the properties of moderate IR in addition to  little deficiency of insulin, greater age  on diagnosis  as well as  lower chances of end organ injury, sulfonylurea along with  DPP-4 Inhibitors might be the best modalities  as add  on therapies to metformin,in case metformin alone can’t control the hyperglycemia. Nevertheless, SGLT2  inhibitors as well as  GLP-1RA treatment might also be the modality for MARD patients having proven end organ damage  like cardiovascular  disease (CVD) in addition to    decreased kidney function.As the population here are older ,the final decision have to be made by precision as well as  considering adverse effects of every medicine  needs to be taken into account .

For  managing to perform successful T2D treatment,here we took into account that significant percentage of patients would need extra medicines,besides llifestyle modifications along with  metformin therapy.The subgroups addressed by Ahlqvist etal.[56], in addition to   the accepted metabolic  actions on beta cell function along with  insulin sensitivity of the separate  classes of antidiabetic medicines might aid in giving a more individualized type of   treatment for T2D patients  depending on the major root causes of hyperglycemia   in each person as addressesd above. Nevertheless, the  ultimate therapy  decision in every T2D person needs to account for other parameters that are  correlated  with Diabetes.Like in the existence of CVD, SGLT2  inhibitors or GLP-1RA treatment might be the accepted choice, without accounting for their correlated  subgroups.Other parameters  like existence of Diabetic  Kidney Disease(DKD),the significance  of weight reduction combined  with llifestyle modifications,age of the patient, patient’s choice in addition to probable asdverse actions need to be accounted for.

We understand that Ahlqvist etal.[56], trying to cluster sub subgroups   considering  the metabolic phenotype  of T2D might not turn out to be the ultimate Diabetes classification,with greater evaluations are required.Mofreover at present  no intervention trials  that  exhibit scientific  proof that points that which particular antidiabetic medicines is the most efficacious for  patients on the basis of their metabolic  phenotype.Hence the  advice detailed here are just the posit development  as well as  should not be considered to be recommendations.For proving the most proper treatment,subsequent trials  are required  in Diabetes subgroups to  give a scientific basis for generation of individualized  medicine for treatment of large as well as   variable populations  of T2D patients.