the sodium - glucose cotransporter-2 ( sglt-2 ) inhibitors are a novel class of glucose - lowering drugs which act by inhibiting the reabsorption of filtered glucose from the kidneys .
this effect is mediated by inhibition of sglt-2 co - transporters , which are expressed in the proximal renal tubule . while their predominant mode of action is renal , sglt-2 inhibitors appear to have effects on other parts of the glucose homeostatic system as well .
clinical data suggest an improvement in beta - cell function , perhaps mediated by reversal of glucotoxicity , and a reduction of insulin resistance , with sglt-2 inhibition .
recent data , from studies performed with sglt-2 inhibitors , have demonstrated a fall in insulin to glucagon ratio upon acute exposure to these drugs ; the change is the ratio is contributed to increase in the glucagon and fall in the insulin level concentration .
this change persists , though to an attenuated degree , even after 28 days of sglt-2 inhibitor administration . in 1966 , the bihormonal hypothesis , proposed by unger , clearly highlighted the important role of glucagon in the pathophysiology of diabetes .
developments in this field , however , were overshadowed by insulin - centric research , though a few experts did highlight its significance .
the inclusion of the alpha cell in de fronzo 's infamous ominous octet , coupled with advancement in therapeutics such as glucagon receptor antagonists , and bihormonal bionic ( two hormone ) artificial pancreas devices , has brought glucagon back to the center stage of diabetes research .
while type 1 diabetes subjects manifest an exaggerated glucagon response to arginine , mediated by severe intra - islet deficiency of insulin , persons with type 2 diabetes may have alpha - cell resistance to insulin , which prevents insulin ( whether endogenous or exogenous ) from suppressing glucagon release in response to arginine .
the insulin glucagon ratio ( igr ) was a relatively frequently cited index in the literature from the 1970s and 1980s .
igr was assessed in various conditions , including nonglycemic states like burns and starvation , and dysglycemic syndromes including type 2 diabetes and gestational diabetes mellitus .
insulin glucagon ratio can be used as an index of anabolism , insulin is the most potent anabolic hormone in the body , and a high igr reflects its action , as opposed to that of glucagon , which has glycogenolytic or catabolic activity in the liver .
, this may be because of the development of more accurate indices and parameters which measure insulin sensitivity / resistance .
the challenges posed by recent understanding of sglt-2 inhibition , however , have created interest in this index .
there is , however , an associated rise in endogenous glucose production , noted both after acute and chronic administration of sglt-2 inhibitor , which attenuates the glucose - lowering efficacy of the drug .
group suggest that this paradoxical response is a manifestation of an adaptive physiological response to loss of calories in the urine .
we discuss the utility of the igr in current diabetes management , and suggest three hypotheses in addition to those put forward by bonner et al . and ferrannini et al . , to explain the effect of sglt-2 inhibition on the index .
though no firm conclusions can be drawn from current data , available knowledge opens up exciting vistas for further research .
recently , the presence of sglt-2 receptors in the alpha cell has been reported by bonner et al .
the authors suggest that sglt-2 expression in alpha cells , when down - regulated , is associated with an increase in the expression of sglt 1 and glucagon genes , as well as genes related to hepatic gluconeogenesis .
the same research team reports that sglt 1 and 2 gene expression is lower in islets of type 2 diabetes as compared to normal subjects .
similar results are obtained when slcsa-2 gene is knocked out , or when it is inhibited with dapagliflozin .
this may explain the paradoxical increase in plasma glucagon and hepatic glucose production noted with sglt-2 inhibition .
the workers who have reported a fall in igr upon exposure to sglt-2 inhibitor , propose correction of hyperglycemia , and alleviation of  glucotoxicity  upon the alpha cell ( mediated perhaps by paracrine effects ) , as a mechanism for the relative hyper - glucagonemia .
sodium - glucose cotransporter 2 inhibition leads to lowering of plasma glucose , which in turn brings counter - regulatory processes into motion .
the first line of defense against hypoglycemia is a reduction in insulin levels , while the second line is an increase in glucagon , mediated by intra - islet sensing of glucose .
the third line of defense , an increase in epinephrine release , is mediated by peripheral and central nervous system sensing . though plasma glucose concentrations with sglt-2 inhibition do not fall to hypoglycemic levels , or to levels which are thought to stimulate glucagon secretion ( 70 mg / dl ) , it is possible that relatively low intra - islet glucose concentrations or low intra - islet insulin release , have a paracrine effect upon the alpha cells .
sglt-2 inhibitors may increase the alpha cell 's glucose sensitivity through receptor - dependent , or through receptor - independent modes of action .
the latter may be a mechanism of action distinct from the alpha cell sglt-2 receptor - based pathway suggested by bonner et al .
the lowered igr suggests a catabolic state , or more accurately , mimicry of calorie restriction .
this may be construed as a beneficial action , designed to correct the  maladaptive anabolism  noted in obese type 2 diabetes .
the lowering of igr with sglt-2 inhibitors may explain or may be a corollary of , weight loss noted with these drugs . after 4 weeks , chronic treatment with sglt-2 inhibitors total glucose disposal was reduced due to prolonged reductions in insulin and glucose with maintained energy expenditure .
the enzyme carnitine palmitoyl transferase 1 ( cpt 1 ) acts as a gateway to the mitochondria to help allocate free fatty acids ( ffas ) to either of two pathways : -oxidation , or conversion to triacylglycerol .
it is possible that sglt-2 inhibition may stimulate cpt 1 , perhaps by suppressing malonyl coenzyme a ( coa ) ( a potent inhibitor of cpt 1 ) , and diverts ffas to -oxidation , instead of fat deposition .
this enzyme has been identified at the site of action of other classes of oral anti - diabetic drugs and will be discussed further . in preclinical animal models ,
as sglt-2 inhibitor treatment is known to increase plasma ffa levels , further research is warranted on effect of ffa on alpha cell with the use of sglt-2 inhibitors .
recent data which describe a reduction in igr after sglt-2 inhibitor empagliflozin treatment administration uses  estimated prehepatic igr  calculated from plasma concentrations of insulin and glucagon .
it is possible that concentrations of the hormones and their gradient may differ if estimated through portal vein sampling .
recently , the presence of sglt-2 receptors in the alpha cell has been reported by bonner et al .
the authors suggest that sglt-2 expression in alpha cells , when down - regulated , is associated with an increase in the expression of sglt 1 and glucagon genes , as well as genes related to hepatic gluconeogenesis .
the same research team reports that sglt 1 and 2 gene expression is lower in islets of type 2 diabetes as compared to normal subjects .
similar results are obtained when slcsa-2 gene is knocked out , or when it is inhibited with dapagliflozin .
this may explain the paradoxical increase in plasma glucagon and hepatic glucose production noted with sglt-2 inhibition .
the workers who have reported a fall in igr upon exposure to sglt-2 inhibitor , propose correction of hyperglycemia , and alleviation of  glucotoxicity  upon the alpha cell ( mediated perhaps by paracrine effects ) , as a mechanism for the relative hyper - glucagonemia .
sodium - glucose cotransporter 2 inhibition leads to lowering of plasma glucose , which in turn brings counter - regulatory processes into motion .
the first line of defense against hypoglycemia is a reduction in insulin levels , while the second line is an increase in glucagon , mediated by intra - islet sensing of glucose .
the third line of defense , an increase in epinephrine release , is mediated by peripheral and central nervous system sensing . though plasma glucose concentrations with sglt-2 inhibition do not fall to hypoglycemic levels , or to levels which are thought to stimulate glucagon secretion ( 70 mg / dl ) , it is possible that relatively low intra - islet glucose concentrations or low intra - islet insulin release , have a paracrine effect upon the alpha cells .
sglt-2 inhibitors may increase the alpha cell 's glucose sensitivity through receptor - dependent , or through receptor - independent modes of action .
the latter may be a mechanism of action distinct from the alpha cell sglt-2 receptor - based pathway suggested by bonner et al .
the lowered igr suggests a catabolic state , or more accurately , mimicry of calorie restriction .
this may be construed as a beneficial action , designed to correct the  maladaptive anabolism  noted in obese type 2 diabetes .
the lowering of igr with sglt-2 inhibitors may explain or may be a corollary of , weight loss noted with these drugs . after 4 weeks , chronic treatment with sglt-2 inhibitors total glucose disposal was reduced due to prolonged reductions in insulin and glucose with maintained energy expenditure . the enzyme carnitine palmitoyl transferase 1 ( cpt 1 ) acts as a gateway to the mitochondria to help allocate free fatty acids ( ffas ) to either of two pathways : -oxidation , or conversion to triacylglycerol .
it is possible that sglt-2 inhibition may stimulate cpt 1 , perhaps by suppressing malonyl coenzyme a ( coa ) ( a potent inhibitor of cpt 1 ) , and diverts ffas to -oxidation , instead of fat deposition .
this enzyme has been identified at the site of action of other classes of oral anti - diabetic drugs and will be discussed further . in preclinical animal models ,
as sglt-2 inhibitor treatment is known to increase plasma ffa levels , further research is warranted on effect of ffa on alpha cell with the use of sglt-2 inhibitors .
recent data which describe a reduction in igr after sglt-2 inhibitor empagliflozin treatment administration uses  estimated prehepatic igr  calculated from plasma concentrations of insulin and glucagon .
it is possible that concentrations of the hormones and their gradient may differ if estimated through portal vein sampling .
sodium - glucose cotransporter-2 inhibitors can be compared and contrasted with existing classes of glucose - lowering drug .
glibenclamide has been shown to inhibit the cpt 1 gateway , thus diverting substrate toward the triacylglycerol production .
metformin , on the other hand , activates the cpt 1 gateway . by inactivating acetyl coa carboxylase , which catalyzes the biosynthesis of malonyl coa
this molecule acts as a substrate for de novo fatty acid biosynthesis and inhibits cpt 1 .
lower malonyl coa production allows the cpt 1 pathway to divert ffa to the -oxidative pathway .
it is possible that sglt-2 inhibitors act in a manner similar to that of metformin in addition to weight loss due to calories lost in the urine .
it must be mentioned here that metformin is a calorie restriction mimetic , with geroprotective effects .
whether , currently available sglt-2 inhibitors share similar properties remains the focus of future research . at the same time
, it is prudent to clarify that the cpt 1 enzyme is not a homogenous entity .
it has multiple isoforms , expressed in different organs , and much needs to be learnt about its biology .
another similarity of sglt-2 inhibitors with metformin is that they are able to achieve incretin enhancement without causing hyperinsulinemia .
this property contrasts with that of incretin - based therapies such as dipeptidyl peptidase 4 inhibitors and glucagon - like peptide-1 analogs .
it supports a multifaceted effect of sglt-2 inhibitors , beyond inhibition of co - transporter in proximal renal tubule and proposes that these drugs will be able to shift the body milieu from maladaptive anabolism in type 2 diabetes to adaptive metabolism .
the igr should also be studied as a tool for research and clinical decision - making .
inclusion of plasma glucagon values or portal glucagon concentrations , in formulae or models created to measure insulin sensitivity , may improve their utility .
 the sodium - glucose cotransporter 2 ( sglt-2 ) inhibitors are a novel class of glucose - lowering drugs which act by inhibiting the reabsorption of filtered glucose from the kidneys . 
 their effect on insulin and glucagon levels has recently been studied but is not fully explained . 
 this communication proposes various hypotheses : a direct effect of sglt-2 inhibition on the alpha cell receptors , a paracrine or intra - islet mediated effect on alpha cell sensitivity to glucose , and a calorie restriction mimetic action , to explain the impact of these drugs on the insulin glucagon ratio . 