SGLT-1 & SGLT-2
SGLT-1 and SGLT-2 inhibitors block glucose uptake in the gut and glucose re-uptake in the renal tubule respectively. In rats phlorizin is a potent SGLT-1 inhibitor, but is a very potent SGLT-2 inhibitor. Thus either by reducing glucose acquisition or increasing glucose excretion the plasma glucose can be reduced and this has been demonstrated in rats. In humans the role of the SGLT receptor has been established through observation of familial renal glycosuria. Side effects in clinical practice can include diarrhea in SGLT-1 inhibition if CHO is eaten. Thus research is focusing on SGLT-2 inhibitors which are currently in phase 3 trials with limited side effects reported in the present session
Bile Acid Sequestrants (BAS)
Bile acids act as signaling molecules in the gut through the FXR receptor, which acts to reduce bile acid synthesis, thus creating a negative feedback loop. If a sequestrant is added this increases synthesis and as this utilizes LDL cholesterol it reduces LDL-c. In studying the effects on LDL-c it became clear that there is an effect on glucose homeostasis that improves glycaemia. This effect may be mediated via the activation of TGR-5 receptors in the gut due to stimulation by the sequestered bile acids in the gut. In turn activated TGR-5 receptors increase native GLP-1 secretion. It has been shown that the glucose effect is due to an almost complete suppression of glycogenolysis and that BAS reduces glucose independent of FXR. Initial lab work in rats has suggested that bile acids bound to BAS activate TGR-5 that increases GLP-1 release. Thus it appears that the effect of BAS is mediated via GLP-1. The addition of exendin9 (a GLP-1 inhibitor) completely removes the reduction of glycogenolysis that occurs with BAS, whereas exendin-4 (a GLP-1 agonist) mimics the BAS effect. BAS also appears to reduce insulin levels and improve insulin resistance although the mechanisms are not clear.
Selective PPAR Agonists
PPAR receptor family are steroid hormone nuclear receptors. Adverse effects of PPAR agonists include increased CV risk – rosiglitazone, bladder cancer – pioglitazone and increased bone turnover. Alteration of the drug moiety allows an uncoupling of the effects of the PPAR agonists and results in a class of PPAR modulators . Selective PPAR modulators (SPARM’s) are the result.
Agents may have more impact on the PPAR alpha versus PPAR gamma receptor with the present PPAR gamma agonists having limited PPAR alpha effect. However it has been established that Troglitazone (the first licensed PPAR gamma agonist) has equal effects on both alpha and gamma receptors. There are several alpha/gamma agonists under development with Aleglitazar being most developed. It is not known whether there may be problems with weight gain, or bone fracture with these newer agents. The ALECARDIO study in Acute coronary Syndrome suggest that there is probably limited cardiovascular risk with Aleglitazar however. There is emerging evidence that the fat content of the diet may also be important in modulating the effect of gamma agonists with high fat diet resulting in phosphorylation of the gamma receptor and thus an alteration in PPAR activation.
A few unknown areas persist. For example pioglitazone has a number of active metabolites one of which may cause bladder cancer, and CVD concerns persist. It is not yet clear whether any of these issues may also affect the SPARM’s. It is also not clear whether the known side effects are related to the Thiazolidinediones (TZD) and not PPAR activation per-se. Thus the potential for non-TZD SPARM’s to add significant benefit in diabetes remains of interest despite current concerns about side effects with rosiglitazone and pioglitazone.
Next Generation
(Fatty Acid Elongases, 11 Beta HSD-1 inhibitors, GPRs) and some others
There are 100+ target agents being pursued for diabetes management at the present time.
Elongase-6 – This is an enzyme present in the liver. Expression is increased wherever there is increased lipogenesis. Thus it may be over-expressed in consumption of fatty foods. In animal models there was a small reduction in weight with an increased deposition of shorter chain fatty acids in liver in treated animals. There was also a change in insulin secretion with reduced insulin secretion but reduced area under curve for glucose in the same animals suggesting an effect on insulin resistance.
11 Beta HSD-1 - This is one of the enzymes involved in the steroidogenesis pathway, and it is thought that the deposition of omental fat in central obesity increases cortisone to cortisol conversion by 11 Beta HSD-1 activation in metabolically active fat. This in turn will lead to insulin resistance through a cushingoid effect. Inhibition of this enzyme reduced fasting glucose, and there is some evidence that the effect is greatest in those with most central obesity.
G-protein Coupled Receptors – There are a host of G-protein Coupled receptors which mediate signaling in the beta cells. One study of the GPR activator shows reduced HbA1c in animals. In a phase 2 clinical trial in DM2 there was a dose dependent decrease in plasma glucose and 2 hour glucose in OGTT without any augmentation of insulin secretion. A late breaking abstract at the ADA suggests that patients who received a GPR for 12 weeks showed changes in glucose metabolism.
GLP-1 receptor activators – these drugs in animals induce GLP-1 receptor activation in a similar way to that seen with GLP-1 analogues. In patients a dose dependent reduction in OGTT stimulated glucose rise was shown.
Joint GLP-1 and GIP receptor agonists – There is evidence that combined stimulation of GLP-1 and GIP receptors is synergistic in glucose lowering. Agents are in development that offer the potential of combined GLP-1 and GIP agonism.
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