Episode 46: Chronic Complications of Diabetes Mellitus

Welcome to MedPod, the audio podcast from the Department of Internal Medicine at AFMC. We've been continuing with our series on topics which are of relevance to undergraduate students, postgraduate residents and young specialists in field. And in the same series, today we bring with commander Sandeep Kumar, endocrinologist in the department to talk on a very important topic as far as management of a chronic disease like diabetes is concerned and that happens to be the microvascular complication. Sandeep is an alumnus of AFMC and like traditionally in medicine, you first teach your students and then you learn from them and Sandeep happens to be one of my illustrious students who is now going to teach all of us. So, welcome back Sandeep. Thank you, sir. And it is always great honor to speak in front of the doin who himself is, you know, expert in the diabetes. But sir, I will try to do justice to my audience today, sir. Right. The challenge of treating diabetes happens to be mainly to prevent its complication. And we all understand how difficult it is to ensure that patients continue to take their medications for years on end even when they have no symptoms. And one thing that keeps us going and them going with this is the fact that if they don't control their diabetes properly, they are likely to have complication. And microvascular complications happen to be a very important set of such conditions. So, how do you talk or classify these complications and how are you going to go into the topic today when you converse with the students? Yes, sir. Sir, as you have told that we have an audience who includes medical students predominantly. So, before I begin, I want to highlight here is that it is very, very important to understand all the aspects of diabetes from the medical academic point of view. And I will not be wrong if I say that diabetes is a new tuberculosis or malaria of the present times. Because we can recall that in earlier days, if you're not able to answer or manage the tuberculosis or malaria, it was taken very, very negatively by the faculty. So, everyone should, irrespective of the specialties which they take on subsequently, everyone should be able to manage and understand diabetes, malitis. And why do we say that? Because if we take the figures in India, almost every 11th person in India is a diabetic, every third family in India is having a diabetic. And not only this, these figures are going to grow very, very phenomenally in coming times. And where everyone of us need to manage or deal with the patient for diabetes. And I also want to draw attention of today's audience because when we had an earlier podcast with the diabetes, we talked about the pillars of the six pillars of the diabetes treatment. And we discussed that we need to see about coronary artery disease, heart failure, diabetic retinopathy, obesity, hypoglycemia and also to keep in concentration the cost and the symptomatology means how much emergent hyprosmotic symptoms are present or not. So, basically, what I'm trying to say here is that the diabetes treatment is not only the management of the glucose, but we also, you know, the target like cardiac diseases, you know, the nephropathy, which should be, wherever we're treating, utilizing the drugs, we should address such components as well. So, now sir, coming to the complications of the diabetes, so we can have a microvascular complication and macrovascular complications. So, among the microvascular are the diabetic retinopathy, diabetic neuropathy, diabetic nephropathy and amongst the macrovascular complication, we have coronary artery disease, cerebrovascular accidents and peripheral artery disease. So, this is how we classify the complications of diabetes. Right, so today, we shall be focusing mainly on the microvascular complications of diabetes and these happen to be very, very classical findings as far as the diabetes are concerned because macrovascular is something that also is due to other factors like hypertension or atherosclerosis, whereas microvascular is very classical of hypoglycemic damage and inflammation due to endothelial involvement. Now, what are these microvascular complications and how do you classify them? So, we need to understand, so why do we call them a microvascular complication at a cellular level? So, it is said that when the vessels of less than 10 micrometers are involved, they are called to be microvascular complication and as I've discussed, it includes retinopathy, nephropathy and your diabetic neuropathy. So, what happens, sir, because of the hyperglycemia, there is a change in the milieu at the cellular level and we all know that when the cells are exposed to the hyperglycemia for a long period because of various mechanisms, they lead to such microvascular complications. And again, I want to, you know, bring to the notice of our audience that these complications, we are mentioning them with the prefix of diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, but they are not exclusive to diabetes, malitis only, but they do occur. In even the pre-diabetes patients and these are the subgroups which are that we should be managing these people aggressively. Although the frequency of this complication is lesser in the pre-diabetes to the range of 10%, but we can have a higher prevalence of this complication to the tune of 50 to 90% in the over-diabetes malitis. Right, and because now we find diabetes in much younger population and these conditions are more as diabetes duration advances, so it is more likely that people are going to develop these complications if you do not manage diabetes well. So, what is the mechanism? How does hyperglycemia actually cause this microvascular damage? Yes, sir, you've already sensitized the audience that the microvascular, what are the very, very important characteristics of microvascular complications is that they have, they are directly proportional to the duration and degree of hyperglycemia. So, my students, I would give them, I would like to give them a mnemonic of 2D durations and degree of the hyperglycemia, which leads to it. So, the younger the onset, the more longer you live with the diabetes, the more you will see these microvascular complications. And important concept I need to tell here also that about degree, if you reduce a 1% HPA1C, the microvascular complication will reduce phenomenally. And the figures I can quote about diabetic retinopathy that with 1% reduction in your HPA1C, the retinopathy may decrease to the tune of about 35%. So, having understood that, let us understand how does this hyperglycemia or diabetes malitis lead to this microvascular complication. So, what happened is that with the chronic hyperglycemia, there is activation of the various cellular mechanism and most important of those is that there is an increased polyol flux, there is an increased diacylglycerol and protein kinase and increased hexosamine flux. And one of the most important concept which the students should remember is there is increased formation of the advanced glycosylation products. So, once these four or five mechanisms are activated, this lead to increased oxidative stress, endothelial dysfunction, increased cytokines, accumulation of the sobotol and increased expression of the various, you know, the growth factors like, you know, a vascular endothelial growth factors, etc. And this lead to the microvascular injury. And as I mentioned that most important of this, the mechanism is formation of the advanced glycosylation end products and I would like to, you know, dwell more upon this. So, what happens is that when there is increased glucose in the cellular level, this glucose combined with the various amino acids and lipids and initially this combination is a reversible, means it is a temporary. But once the cell or body or tissues is exposed to the increased duration of the glucose, this combination becomes irreversible, irreversible because of the various biochemical phenomena which happen and that phenomena is called as amadori rearrangements. And this combination with the proteins become irreversible and this lead to various disruption. And what happens is that there is endothelial dysfunction, the cross linking of the proteins is ampered, there is an increased, decreased synthesis of the nitric oxide. And there is also, you know, disruption of the extracellular matrix composition structured and as well as gene alteration which happens and this eventually leads to these various microvascular complication which we are discussing today. Right, so now going into the specific complications, let's start with diabetic retinopathy. And what makes diabetic retinopathy more sort of specific as far as diabetic complications are concerned? Yes, so we call a diabetic retinopathy as a mirror of hyperglycemia damage or a mirror of a diabetes mellitus. So it is a very, very specific complication of this diabetes mellitus. In fact, we recall all our trial, which a landmark trial which has been done and these retinopathy was basically the parameter which was used to, you know, the device of various cutoff levels. So why this is very, very specific because we can, you know, recall that in neuropathy and nephropathy can happen because of the other disorders like simple hypertension or other diseases, toxins, even nutritional deficiency which can lead to neuropathy. However, on the other side, the diabetic retinopathy is directly related to the duration and degree of hyperglycemia and it is not influenced by other conditions or various other metabolic abnormalities. That is why it is said that retinopathy is one of the most specific or a mirror of diabetes mellitus. Right, so that's why even the reduction in the risk for retinopathy is directly related to SPA, even see much better than the others. And also the fact that neuropathy and nephropathy are a sort of a diagnosis or exclusion, even in presence of diabetes, you would like to rule out other conditions before saying that this is due to diabetes. Unlike retinopathy, which is fairly specific. Now, so if you have a patient of diabetes, how do you screen for retinopathy and when do you start doing that? Yes, so this is one of the most important aspects because all the understanding and learning that we are doing, so aim is prevention not to treat and that should be the first step and obviously we treat when it develops. So it's very important to pick these at earlier stages and screening of this complication is the most important component of the holistic management of the diabetes mellitus. So let's come to type 1 diabetes. So whenever the person is diagnosed with type 1 diabetes, he should undergo the retinopathy screening within five years. And it is very important for our students to understand because when we interacted with the students, they had a concept that the type 1 diabetes should undergo the screening of retinopathy after five years of the onset. It is not after five years, it is within five years, it means that you can screen the type 1 diabetes even at the onset of the type 1 diabetes according to your decision or a clinical scenario. So having understood that and coming to the type 2 diabetes mellitus, all the type 2 diabetes should have initially dilated comprehensive eye examination by the onset of the diabetes, at the diagnosis of the type 2 diabetes mellitus. And who is doing this screening? So it doesn't mean that ophthalmologist should be doing this screening. We as a, you know, the medicine resident physicians or medical officers, they can very well do. In fact, the guidelines have recommended that even the optometrist can do the such screening with the diabetes mellitus. Now coming, how do we follow up? Once we have done the initial screening, so how do we do the follow up screening? So it is said that every, the person, if he does not have evidence of retinopathy, you can decrease the frequency as, you know, as long as one to every one to two years. But if there's any evidence of retinopathy, the person should be screened every year. And if the degree of retinopathy is advanced or more, you can, you need to do a very frequent screening also means you can even screen them every three to six months. And other concept about the screening, which we should understand is within the context of the pregnancy. And it has been seen that with the pregnancy and even with the puberty and all your retinopathy can, you know, worsen. So the, whenever the lady entering into pregnancy and she's a known diabetic, we should do the diabetic retinopathy screening. And once the pregnancy is achieved, we should screen at the onset of the pregnancy and then every trimester and according to if it is present or not, we can decide the frequency accordingly. And another concept, sir, because which we want to, I want to convey to my students today that we have, you know, retinal use of retinal photography equipments which are available. And these are FDA approved now and the guidelines or learned societies are telling us that you can screen the patient with these also. In fact, they are very good tools where it very easily you can do red site and you need not involve the ophthalmology and optometrist and in the hope itself you can do that. And I take this opportunity like a department of medicine, sir, we have recently, we also have such a fundamental camera and most of students can come and utilize its facilities and you can have a visual impression. You can understand all the normal, how the normal retina looks like and you can pick up all the abnormalities and not only that you see and find the abnormalities, but you can also take the aid of AI tools which are integrated into such systems and you can learn more about retinopathy. So, that is another new things which have come with the respect to diabetic retinopathy, sir. Right. So, they have to understand that screening begins at diagnosis for type 2 diabetes where we understand that the disease is already brewing inside the patient for few years before it is diagnosed. Whereas in type 2 diabetes, we can actually start screening the patient later, not at the diagnosis, but even up to five years one can see, but of course, like you said, depending on the situation, there are certain patients who do develop features of retinopathy even earlier than five years. So, we must keep a track of that and of course, hand-held device help us in doing population surveys as well. So, it makes it much easier for screening. Now, like treatment of retinopathy is a domain of the ophthalmologist, but it is very important for us to know at least what is the role of physician in that one and do also to be able to explain to our patient what kind of treatment is available. So, what are the modalities as far as retinopathy is concerned? Sir, it is very common misconception on ground that, you know, diabetic retinopathy is involved the ophthalmologist, but that is not the truth. So, basically, not only the eye management, diabetic retinopathy is not, the management is not only specific to the eye treatment, but there are other adjunctive things which you need to do to achieve the optimal outcome. So, coming to that, it is very important to control your blood pressure and so, BP control has to be good and there is enough scientific evidence available that the good BP control translates into the better outcome when we are with the diabetic retinopathy. And not only this, and so there are trials with respect to, you know, it has been seen that, you know, dyslipidemia also lead to worsening of the retinopathy, so good lipid control also translates into better retinopathy outcomes and out of this one drug which is important is phenophybrid and I draw attention to my audience towards a field trial and at your time you can read about this and field trial has, you know, demonstrated that phenophybrid translates into better retinopathy outcomes. And not only this, but basically it is important to have a good glycemic control which we have already discussed degree, 2D phenomenon means degree and duration of the diabetes, so and we have told, we have already discussed that 1% reduction HVA1C translate into about 35% protection from the diabetic retinopathy. So, these are simple but most important things whenever you are managing diabetes, retinopathy dealing with the person with the diabetic retinopathy. So, once we have understood this, then obviously there is an important role of thalamologist and we have various degrees of retinopathy which we can classify, we have a non-proliferative diabetic retinopathy which can be mild, moderate, severe and we can have proliferative diabetic retinopathy and macular edema. So, basically on the presence of what extent it is present, we generally in the PDR or proliferative diabetic retinopathy or late NPD, we employ like laser photo coagulation can be done which can be focal or which can be diffused pan retinal photo coagulation can be done, but also important drugs that we talked about, you know, whenever we were discussing the pathogenesis of microvascular complication, we talked about vascular endothelial growth factor. So, here the role of NTVGF drugs comes into play and these are very, very important and time tested scientifically proven modalities which are used for treatment of the diabetic retinopathy and not only this but also there is intra retinal, you know, the steroids which can be used given intra vitrile steroids which can be used in the treatment of diabetic retinopathy. So, it is the treatment is, you know, the three dimensional and not only is focused to the, you know, laser or NTVGF which generally the ophthalmologist would be doing but other parameters are very, very important to achieve good outcomes in retinopathy. Right, and if I may add, smoking cessation is a very important advice that as physicians we must give to any, anyone who comes to us but more importantly for diabetics and especially when they develop complications. Now, moving on to neuropathy, how do you screen for neuropathy and usually what are the ways in which these patients present? So, again, sir, in the type 2 diabetes, basically we screen at the diagnosis for the neuropathy and in type 1 diabetes here we screen after 5 years and generally after 5 years we start screening for diabetic neuropathy and the important thing I want to, you know, highlight here is that we understand about, you know, it is not only the peripheral neuropathy but it is also the autonomic neuropathy which we should be screening and more often, sir, we see that our students forget to screen the patient. For the autonomic neuropathy also and that also should be kept in mind and again the guidelines are same after 5 years in type 1 and at the diagnosis in type 2 diabetes and yearly we should at least do the screening follow-up for the neuropathy for the post autonomic and peripheral neuropathy. So, the students would be thinking, sir, how do we, you know, the screen for the autonomic neuropathy, let's finish our answer this question. So, basically, the first of all, we should, you know, ask the patient for any symptomatology or history should be taken about orthostatic dissonance, synchro, any crack skins in extremities and even, you know, the gastroparesis, post vandal, fullness, any sexual dysfunction, urinary incontinence and any exercise intolerance at times. This is one of the most important way how the cardiac autonomic neuropathy involves. And in the simplistic way, I want to convey that the autonomic neuropathy can involve the cardiovascular system, gastro system and GI system, which are the most important and the history with respect to these should be taken. And once this history has been taken, we can simply screen the patient in the bedside by simply checking for the resting tachycardia, orthostatic hypotension and examination for the dryness, blacking of the skin and for the autonomic neuropathy. So, once autonomic neuropathy, we have understood how do we screen for the diaptic neuropathy, per se. So, this is done very simplistic way we can do is simply we can do our inner day-to-day opiates as well as in wards. And we should check the patient for the large fiber as well as small fiber neuropathy. And this is achieved by doing the, you know, vibration for the large fiber, we do the vibration testing. And I want to, you know, emphasize here that it is 128 hertz tuning fork, and we can also check for the basically, we can do the 10 gram monofilament testing, which I would be telling my students. And for the small fibers, we can check for the pain and pin prick test, which can be done in the patient as well as we can do the ankle reflex. So ankle reflex, a tuning fork test, 128 hertz, 10 gram monofilament and the pin prick test is a four modalities, which are good enough to diagnose all the patient with a diaptic neuropathy. And my students would be wondering here that I talk about 10 gram monofilament. Most of you would not be aware, but it is very, very important. So what is 10 gram monofilament? It is also called as scenes winstrain test. And it is simply a filament or wire kind of thing, which we use. And why do we, when we have a modalities like ankle reflex and vibration, why do we do this for the large fiber testing? So the background for this is that when we do with ankle reflex, the sensitivity of this, although it's good, but specificity of the ankle reflex is low. So we may, you know, miss a few people, we may not die with few people. So now it has been seen that when we use a 10 gram monofilament, the sensitivity and specificity can reach to as high as 95 to 100 percent. So what is 10 gram monofilament? So when it was basically 10 gram monofilament, you started in the patients in the earlier days during the era of the leprosy. It was a simple horse here, which was used. And subsequently we, you know, evolved and now we have a nylon filament, which is used. And 10 gram is a force which we apply. So basically I draw, I request students to come to the enterprise and go wherever it is available. You can see videos also. So it is a wire or a filament, which is pressed, it buckles and pressure is done for one to two seconds at a specific areas. And if the patient is not able to feel, we say that that negative point is present. And generally there are a lot of protocols for testing of 10 gram monofilament. But we generally do a 10, five areas in each foot and that is a helix third head to tip of the third toe and first and third, first, third and fifth metatarsal. So if eight points, less than eight patient is able to perceive less than eight out of total 10 into feet, then we say that there is a significant deficit is there. And these by detecting neuropathy, we, you know, can also come to know about the foot, which can go on to develop ulceration and all that. That means there's a loss of protective sensation of LOPS by doing such weak mechanism. We come to know about this. And another thing about neuropathy, sir, I want to tell you here is that it is very, very commonly present in the increased frequency in the pre diabetics. And another thing is that the about 40% of the people with neuropathy may be asymptomatic. So these tests becomes very, very important to pick up subtle or the preclinical kind of neuropathy in the patients of diabetes. Right now, you mentioned a few types of neuropathy, but like you mentioned about large fibres, all fibres, autonomic, are there any other types of neuropathies as in related to diabetes? Yes, so diabetes, sir, now we had a neurology classes also. So among the neuropathy, diabetes is the most common causes and diabetes can cause any type of neuropathy. That is one message the students would understand. But if we had to further classify it, it can cause generalized kind of presentation or it can cause a focal problem. Among the generalized, it is a chronic sensory motor neuropathy, which is diabetic polyneuropathy, which is one of the most common. And we understand it is distally involved and a more normal garden variety of neuropathy. And it can cause acute sensory involvement also, or and it causes a diffuse involvement is also autonomic neuropathy. And again, I want to highlight here is our students commonly forget to, you know, screen the patients for that. And then we can have a focal limb neuropathy, cranial neuropathy, any cranial nerves can be involved. We would have seen isolated cranial nerves involvement in diabetes without any explained reason. We can have a truncal radical neuropathy. We have a co-existing chronic inflammatory demyelentic neuropathy in the diabetes. And we can also have something like a proximal motor neuropathy, which is also called the diabetic amyotropy or also known by a fancy syndrome laser. Brun's garland syndrome in the patient with the diabetes malitis. Right. Now, coming to the treatment of diabetic neuropathy, common things like sugar control, blood pressure control, lipids, we call these spoken, that applies to all microastral complications. But beyond that, for neuropathy, what do we have? Yes, sir. So once those common things, smoking, etc., is addressed, so there are various drugs which are available for treatment of the diabetic neuropathy. Like tricyclic antidepressant, anticonvulsant, substance P inhibitors, 5-hydroxy-tryptamine and non-epinephrine V-uptake inhibitors, and even a semi-synthetic opioids, even topical capsicane, these are capsicine, cream, and etc., is approved by the FDA. And all these drugs are approved and we, according to availability in our setting, we can commonly, we can use these, but there is more evidence with the use of the tricyclic antidepressant. Antidepressants and galopantinoids drugs and as well as the duloxetine, etc., which are used in the diabetic neuropathy whenever it is present. And not only the drugs, but there is also the new data which is coming up with the use of the non-pharmacological symptomatic treatment. And in fact, our students would be encountering some various physical therapies where they may be confused whether it is correct thing or not to correct thing. But I want to tell you here is there is a, not in sufficient evidence as of now with respect to the physical therapy, but yes, with a transcutaneous electrical nerve stimulation that is tense. There is some evidence that it may be helpful, but the evidence with respect to others like, pence, electrical spinal cord stimulation, magnetic field therapy, etc., even with electro acupuncture, etc., is lacking as of now. And also we must ensure that our patients are sufficient as far as vitamin B12 is concerned, especially because metformin also leads to further worsening of B12 deficiency. And the fact that alcohol patients are consuming may also contribute to neuropathy. So, at least we can ensure that part of cause of neuropathy is at risk. Now, moving on to the last of the microacetylacomplication, which is nephropathy, and we understand it's a huge problem with the commonest cause of CKD right now. So, what are the different stages of diabetic nephropathy? Yes, so it is a commonest cause of CKD and if a student visits the dialysis center, so it will be good idea that you just have observation for how many people are diabetic and undergoing a dialysis because of the kidney disease. So, it's very, very important and it's very important, that is why it is important to understand. So, we can have various stages. It has been seen that initially we can have five stages according to which the dysfunction at the kidney levels happen. And in the stage one generally it has been seen that there is a stage of renal hypertrophy or glomerular hyperfiltration happen. And in this stage there is a renal hypertrophy and glomerular hyperfiltration that causes the increase in glomerular filtration rates. And this sets in only when the blood glucose is uncontrolled, but subsequently once the sugar, but if we attend to the glucose and we control the glucose level, so the GFR then comes down to the normal. And there's another stage which generally we see after about five to ten years and it is a stage two that is a stage of apparent normalcy. So, what happens in this stage is that the GFR which was increased in the stage one comes down to the normal, comes to the normal in this stage. And this stage is very difficult to pick up the abnormalities at this stage, but the stage three is the stage where it which is one of the most important stage where you should be picking up the patient with the diabetic nephropathy. And again I want to, for the younger colleagues, we focus on the creatinine, creatinine is not a parameter or it is a very, very late stage of the renal dysfunction. We should be picking up early by checking for the albumin. So, in the stage three what happens, so even though your GFR may be normal, but here you start developing the albumin area. And it generally again is seen about five to ten years after the onset of the diabetes mellitus and there you have an albumin area to the range of 50 to 300 milligram per 24 hours. And here you can also have a slight increase in the blood pressure which can happen and at times you can simply have a lack of the nocturnal dipping of the blood pressure, etc. So, it is important stage and here if you intervene you can reverse the diabetes and why it is important because it is a reversible. So, there are various modalities which we would be discussing and at the stage three you should be picking up all the diabetic nephropathy and if you intervene with the recommended drugs or the measures you may prevent your patient to progressing to nephropathy. Then we have a stage four where there is a established nephropathy where proteinuria increases and it becomes the dipstick proteinuria or more than 300 milligram per 24 hours. And then we have a end stage which is stage five and obviously at this stage the patient go on to have requiring a renewal replacement, but also at this stage is also there are various intervention which can be done to prevent the progression, but reversion cannot be done at these stages. Right, so protein estimation in urine is a very important aspect for diagnosis like you mentioned and of course creatinine will help us but estimated GFR is a better way of actually looking at renewal function. So, what is the normal urine protein excretion? So, sir in the normal healthy individuals it has been seen that there is a one less than 150 milligram of proteins and I want to highlight the word proteins in a 24 hour spirit. So, we go back to biochemistry and it has been seen that about 20% of these is contributed by the albumin and rest is by the Tom Haas bulk protein. So, 20% of 150 is 30 and that is why less than 30 milligram of albumin in 24 hours is said to be a normal. So, this is so once so what happens in the diabetic there is there is a disruption of the glow metal basement membrane dysfunction is happen and photosytopathy happen and also there is a change in the charges of the GVM where there is a widening and increase albumin selective albuminuria happens in the patient with the diabetic nephropathy. So, once this protein area increases and it has been seen that once the protein area becomes 500 milligram proteins 500 milligram and that is also called a dipstick proteinuria that time that this contribution increases of the albumin increases from 20% to 60%. So, from the mathematically under 60% of 500 is 300 milligrams in 24 hours. So, that is how we arrived at less than 30, 30 to 300 and more than 300. So, once it is more than 300 that correspond to about stage 4 of nephropathy, but having said that it's very important with nephropathy we discussed it that this other causes of the nephropathy can happen. So, we should confirm that it is because of dipstick nephropathy there we should rule out congestive heart failure fever, urinary tract infection uncontrolled blood pressures and we should document you know persistent albuminuria means you should check it after six months and once the persistent albuminuria is present and other causes has been ruled out this patient we can say that there is established nephropathy is there. And like we normally always teach that whenever the proteinuria or renal dysfunction is way beyond the degree or duration of diabetes or there is active urinary sediment or there is hypertension or there is absence of retinopathy then we start looking for other causes of nephropathy which should not be missed just because the patient is diabetic. Now, coming to the end of this talk what are the treatment modalities as far as nephropathy is concerned. So, again since it's a microvascular so glycemic control has to be good blood pressure control has to be optimal use of angiotensin convertase enzyme ACE inhibitors or ARBs has been proven to be helpful use of statin correction of the anemia is important and once the established nephropathy is there then we should address acidosis even the inappropriate hyperparathyroidism. It should be halted in these patients so these are important measures that we can deal when we deal with the nephropathy according to the various stages of the nephropathy. But we can understand that there is a new drugs which has come up and we talk about the SGLT2 inhibitors which has been proven to be a nephroprotective and we have a Redense trial we have the trials with the empathy cogin and other drugs which has proven to be nephroprotective and that this benefit is beyond the glycemic benefit within these drugs. That is why you would have seen in the prescription that nephrologists use these drugs irrespective of the presence of antiretismalitis in the nephropathy and also there is a evidence which is coming up with the use of GLP1 analogs like we have a flu trial with the semaglutide and even there is availability of non-steroidal mineral cortical entagonist like funerinone and all which are available which can be used for the diabetic nephropathy but he has glycemic control BP control and ACE inhibitors ARBs are important tools which are available. So, the nephrologists will get involved in the management at what stage for a student to understand or a young physician when would he prefer the nephrology. So, as you have already highlighted so they can be a lot of overlap so we can wrongly tackle the patient having proteinuria or albuminuria and with the diabetes is present that we can attribute it to diabetes when it is inappropriate. So, there is when you should involve the nephrologists in appropriate proteinuria or albuminuria please seek the consult of the nephrologists because they can or presence of the active sediments then you consult a nephrologist and whenever the patient goes on to more than 300 milligram in 24 hours that is stage 4 there you should involve the nephrologist in this case. So, I think that is fairly comprehensive to address these three important microascular complications. We have covered most of the aspects and students need to remember that the basics of diabetes management are the most important key factors in preventing and reducing the progression of these complications that is glycemic control, blood pressure, lipid management and anti smoking. So, with that we conclude this podcast and we thank you very much for the time. I think the students should revise this often and come back to us with any doubts or clarifications that they require. Thank you sir. (upbeat music)