Glicazide or Insulin

[Bluetit1802]

Hi. Neither insulin nor the typical diabetes tablets such as Glic or Glip cause weight gain but the carbs you eat may do if you eat too many. The meds enable the body to metabolise the carbs which it couldn't do otherwise.

Too much circulating insulin does cause weight gain - insulin is the fat carrying hormone. Just enough insulin probably doesn't, I don't know. It is the high levels of insulin that is thought to be a cause of obesity many years before glucose levels become a problem, and of course worsening insulin resistance.

 

[tim2000s]

I've had LADA for a couple of years now and I've had all the tests. The progression to insulin is inevitable as the beta cells stop working.

To squeeze the beta cells with glicazide or not is the question. What is the benefit of protecting the few remaining producing cells? Prolonging the honeymoon phase?

And yes I'll be discussing this with a professional too.

My view is that you should look to preserve what beta cell function you have remaining, as you are undergoing an autoimmune attack on them.

Much of the autoimmune response seems to be linked to the precursor to insulin, proinsulin, that is created in the beta cells prior to insulin. Most of the therapies that have been looked at for curing T1/T1.5 seem to require beta cells in the body to encourage them to multiply.

As a result, it seems daft to take a drug that will encourage your immune system to destroy what you have by causing the generation of even more proinsulin, when you can protect them by using exogenous insulin, which should reduce the amount of insulin that the body will produce.

Obviously, it's up to you, but in my view, treating LADA like Type 2 is the wrong way to go, and you should try and preserve what beta cells you have! http://www.diabettech.com/diabetes/...t-more-prevalent-form-of-autoimmune-diabetes/

 

[michita]

Does anyone actually have a proper study report that confirms sulphonylureal drugs kill beta cells or lead to progressive loss of insulin secretion? I have done a load of searches on this subject, and all I can find is forum discussion and blogger spiel and some very biassed reporting in the press. There has certainly been folklore discussion on this matter, but there seems to be no study that actually confirms it. I can find the likes of Bernstein, Mercola, and Jenny Ruhl expounding this hypothesis, but none of them actully refer to evidential proof of the assertions. It seems that the hypothesis relies on the assumption that the drugs force or squeeze more insulin out of the pancreas so must be making the cells work harder thus depeleting their lifespan. But there are many other things that damage and destroy these cells. This is what I found

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900074/

1. Zhang et al. Second-Line Agents for Glycemic Control for Type 2 Diabetes: Are Newer Agents Better? Diabetes Care 2014;37:1338–1345

https://www.ncbi.nlm.nih.gov/pubmed/1425152

I suspect that until recently the progression of T2D towards insulin therpy being necessary was something that was inevitable and so a scapegoat had to be discovered to hang the blame on. This is the 'T2D is a progressive disease' mantra, which many of us here can now challenge.

The recent discoveries into the effect of NAFLD on insulin resistance show that this is a major stress on the pancreas, and now that it seems to be potentially reversible, then this may remove the progessive march of T2D towards self destruction (according to the media and Panorama).

To me NAFLD is far more harmful than my drugs, and hyperglycemia is also potentially fatal, so using glic to fight both these conditions makes sense to me, and in the absence of proof otherwise, I am content to continue using them.

Have you seen this one ?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811444/

For example in Japan normal practice for Lada is to start insulin treatment straight away. In uk, some or most ? HCPs think its better for the patient if beta cells are destroyed completely by taking SU drugs (easier to manage). When I was diagnosed 2 years ago I did a lots of Internet search on this topic. l asked for insulin but they didn't want to give it to me. I had very difficult time getting insulin prescribed. I was told not to research on Internet...

 

[Oldvatr]

Have you seen this one ?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811444/

For example in Japan normal practice for Lada is to start insulin treatment straight away. In uk, some or most ? HCPs think its better for the patient if beta cells are destroyed completely by taking SU drugs (easier to manage). When I was diagnosed 2 years ago I did a lots of Internet search on this topic. l asked for insulin but they didn't want to give it to me. I had very difficult time getting insulin prescribed. I was told not to research on Internet...

That is an interesting report, and very relevant to this discussion, One thing that stands out in my mind is that one problem noted with the sulfonylurea therapy is that it was difficult to get good metabolic control in any of the RCT trials. This harks back to the early days with the stage 1 sulfanyls that a were not very effective anyway, and secondly were not as good as exogenous insulin for bgl control. So given that beta cells are damaged by high levels of glucose, then their findings are not so surprising. Indeed the particular drug used in the RCT trials is known to be not as effective as Metformin. However there does seem to be an adverse effect on the autoimmune problem that is particular to LADA.

The other problem that the RCT trials do not consider is that the standard advice for diabetics has been (and remains) Eat lots of carbs, especially starchy foods, and reduce fats. So it is not surprising that the insulin therapy was more successful when compared to the oral drug being used. It remains to be seen what would happen if these tests were repeated now with a suitable lifestyle change (i,e, LC diet) also in place. Unfortunately that will not happen in the immediate future and is irrelevant to today's discussion.

 

[Oldvatr]

That is an interesting report, and very relevant to this discussion, One thing that stands out in my mind is that one problem noted with the sulfonylurea therapy is that it was difficult to get good metabolic control in any of the RCT trials. This harks back to the early days with the stage 1 sulfanyls that a were not very effective anyway, and secondly were not as good as exogenous insulin for bgl control. So given that beta cells are damaged by high levels of glucose, then their findings are not so surprising. Indeed the particular drug used in the RCT trials is known to be not as effective as Metformin. However there does seem to be an adverse effect on the autoimmune problem that is particular to LADA.

The other problem that the RCT trials do not consider is that the standard advice for diabetics has been (and remains) Eat lots of carbs, especially starchy foods, and reduce fats. So it is not surprising that the insulin therapy was more successful when compared to the oral drug being used. It remains to be seen what would happen if these tests were repeated now with a suitable lifestyle change (i,e, LC diet) also in place. Unfortunately that will not happen in the immediate future and is irrelevant to today's discussion.

To follow on, I have studied the report again in more detail, and the place in the report where it declares unambiguously that using SU drugs to pump the pancreas leads to early beta cell death and worsens the auto immune problem makes reference to a further study that actually says nothing of the sort. In fact the referenced report says aggressive combination therapy of SU with a Thiazidolone leads to protection for the beta cells in T2D. So I wonder again about the claims that SU drugs lead to beta cell burnout, apart from the expected mortality due purely to poor glycemic control. The linked report does not IMHO provide any proof towards that important statement.

 

[kokhongw]

Does anyone actually have a proper study report that confirms sulphonylureal drugs kill beta cells or lead to progressive loss of insulin secretion?

This 2009 paper by RA Defronzo has a section explaining what leads him to conclude in his abstract...
http://diabetes.diabetesjournals.org/content/58/4/773

Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of β-cell function.

Here is a snippet:
Sulfonylureas and metformin.
Professor Robert Turner, in the UK Prospective Diabetes Study (UKPDS), was the first to conclusively show that sulfonylureas had no protective effect on the β-cell in newly diagnosed type 2 diabetic patients over the 15-year study duration (36). After an initial drop in the A1C, sulfonylurea-treated patients experienced a progressive deterioration in glycemic control that paralleled the rise in A1C in the conventionally treated group (Fig. 15). Moreover, in the UKPDS sulfonylureas were shown not to have a significant protective effect against atherosclerotic cardiovascular complications (34), and some studies even have suggested that sulfonylureas may accelerate the atherogenic process (276,277). Similarly, metformin-treated patients in the UKPDS, after an initial decline in A1C, secondary to the biguanide's inhibitory effect on HGP, also experienced a progressive deterioration in glycemic control (Fig. 15) (278). Using HOMA-β, Professors Holman and Turner showed that the relentless rise in A1C observed with both sulfonylureas and metformin resulted from a progressive decline in β-cell function and that by 3 years ∼50% of diabetic patients required an additional pharmacological agent to maintain the A1C <7.0% (279–284). Although there is some in vitro evidence that metformin may improve β-cell function and prevent β-cell apoptosis (285,286), the in vivo data from the UKPDS fail to support any role for metformin in the preservation of β-cell function. However, metformin was shown to reduce macrovascular events in UKPDS (278), although by today's standards the number of diabetic subjects in the metformin arm (n = 342) would be considered inadequate to justify any conclusions about cardiovascular protection.

 

[kokhongw]

Other than sulfonylureas, there are many other contributory factors for beta cells death...
Mechanisms of β-Cell Death in Type 2 Diabetes
http://diabetes.diabetesjournals.org/content/54/suppl_2/S108
Abstract
A decrease in the number of functional insulin-producing β-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in β-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of β-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K+ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-κB, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of β-cell secretory function and cell turnover. Thus, the mechanisms regulating β-cell proliferation, apoptosis, and function are inseparable processes.

 

[Jenny15]

Hi. Neither insulin nor the typical diabetes tablets such as Glic or Glip cause weight gain but the carbs you eat may do if you eat too many. The meds enable the body to metabolise the carbs which it couldn't do otherwise.

That's my understanding too. I plan to be more careful about what I eat now that I'm on insulin. Perhaps I am misunderstanding what I've read about Glic and Glip, in that while both *can* reduce BG and *can* lead to increased weight if you increase intake, people tend to get more bang for their buck from insulin. I have a hunch that on some oral meds the risk of weight gain might outweigh the potential BG lowering benefit? I am much more confident that insulin will be more effective in helping lower my BG.

 

[Jenny15]

Other than sulfonylureas, there are many other contributory factors for beta cells death...
Mechanisms of β-Cell Death in Type 2 Diabetes
http://diabetes.diabetesjournals.org/content/54/suppl_2/S108
Abstract
A decrease in the number of functional insulin-producing β-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in β-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of β-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K+ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-κB, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of β-cell secretory function and cell turnover. Thus, the mechanisms regulating β-cell proliferation, apoptosis, and function are inseparable processes.

that looks like good info but in my befuddled state with high BG and possible Lantus side effects I'd love it if someone could translate it into plain English

 

[Jenny15]

I have only ever taken Metformin and I hope to come off it eventually because I don't think the benefits are worth it, But I will ask my doctor and nurse.

Just an update to this - I've read info at this forum today about what Metformin does in the body and I think I will stay on it even though I am now on insulin. Because it does other things that insulin doesn't do, which are helpful, such as reducing the glucose output of the liver and many other things.

Probably if I had asked my nurse or doctor they would have explained the same. Handy to know it now.

 

[Oldvatr]

Other than sulfonylureas, there are many other contributory factors for beta cells death...
Mechanisms of β-Cell Death in Type 2 Diabetes
http://diabetes.diabetesjournals.org/content/54/suppl_2/S108
Abstract
A decrease in the number of functional insulin-producing β-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in β-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of β-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K+ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-κB, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of β-cell secretory function and cell turnover. Thus, the mechanisms regulating β-cell proliferation, apoptosis, and function are inseparable processes.

Thank you. Looking at the dates of this research then it is before the recent moves to tackle T2D such as diet and lifestyle changes, and also before the market release of the latest SU drugs, that have improved glycemic control for us. The reports you link to are not actual proof as to cause of the decrease in beta cell function, and merely document the effects of the then current treatment regimes.

In fact NICE themselves have published a meta analysis of 10 RCT trials that show that not one SU drug on the market at the time had any significant effect on reducing BGL levels and were less effective in this task than Metformin. I repeat this is not necessarily the case for todays PWD who have better tools available to deal with high bgl levels such as eat to meter, LC diets, avoiding processed foods. etc. The Gliclazide drug referred to by the OP is of the same family as the older SU drugs, but not of the same class, Add to that the obvious problem with these trials in that the diet being used is based on Eatwell#1 then it is clear that the participants on oral meds would not be able to achieve good bgl control so the [beta cell] mortality due to hyperglycemia is NOT eliminated as a significant causal effect, IMO the value of these older studies reflect a methadology failure and are no longer Gold Standard evidence.

I think the hypothesis remains unproven, I do accept that even today the use of lifestyle improvement is only applicable to a few PWD who are proactive, and that the general class of PWD remain in the older treatment regimes, and will still unfortunately 'progress' to negative outcome. My own experience with Gliclazide so far has been positive and my beta cell function has improved, not reduced, due to my current lifestyle, I have been using Glic for about 6 years now, with 4 years at maximum dose and very high bgl levels in the 30's (mmol/l, that is). So I was experiencing the classic progression as described in those reports, but I have stepped back from that brink and significantly reduced my Glic dose from 320mg to 40 mg a day.

At the end of the day, a DX of LADA does involve treatment with insulin an inevitable matter so we are at best discussing a temporary stopgap measure. I think that if there is an adverse effect from SU then it will not make any significant difference to that outcome in the timescale, but may be a QOL choice for the OP to make.

 

[Daibell]

That's my understanding too. I plan to be more careful about what I eat now that I'm on insulin. Perhaps I am misunderstanding what I've read about Glic and Glip, in that while both *can* reduce BG and *can* lead to increased weight if you increase intake, people tend to get more bang for their buck from insulin. I have a hunch that on some oral meds the risk of weight gain might outweigh the potential BG lowering benefit? I am much more confident that insulin will be more effective in helping lower my BG.

I still think with Glic weight gain is thru having too many carbs. I was on full dose (320mg) Glic for at least 5 years and it had no effect on my weight; probably as I had too few beta cells left. Insulin for me was a miracle cure.

 

[Daibell]

Too much circulating insulin does cause weight gain - insulin is the fat carrying hormone. Just enough insulin probably doesn't, I don't know. It is the high levels of insulin that is thought to be a cause of obesity many years before glucose levels become a problem, and of course worsening insulin resistance.

You may be right although I have not come across that before

 

[Kailee56]

I’m very early LADA and currently just on diet. Yes, some of us are diagnosed this early thanks to my stubbornness and my new Endo. Besides +antibodies, my labs show me to be very insulin sensitive with low insulin production, so a DT2 approach is not altogether appropriate.

My vote for me, when the time comes, will be insulin as soon as needed combined with a low carb diet.

Insulin, because it is thought that asking my pancreas to make less insulin may preserve some beta cells. A lot of the research around DT1 seems to be about ways to stop the autoimmune system attack and then encourage beta cell proliferation. That would be kind of worthless if I had no beta cells left. Having some insulin production will also extend the honeymoon period, so I will need less supplemental insulin.
Low carb because I don’t need to further stress my pancreas by asking it to produce a ton of insulin. It’s already under attack. With that thought in mind, I have found that my response to carbs can be wacky, erratic, and very difficult to predict. So, limiting my carbs makes it easier to keep my glucose where I want it. Not perfect, mainly because I’m not perfect, but more predictable.

The flip side argument is that if I destroy all my beta cells, managing insulin may be easier.

These are just my thoughts

 

[Jenny15]

I’m very early LADA and currently just on diet. Yes, some of us are diagnosed this early thanks to my stubbornness and my new Endo. Besides +antibodies, my labs show me to be very insulin sensitive with low insulin production, so a DT2 approach is not altogether appropriate.

My vote for me, when the time comes, will be insulin as soon as needed combined with a low carb diet.

Insulin, because it is thought that asking my pancreas to make less insulin may preserve some beta cells. A lot of the research around DT1 seems to be about ways to stop the autoimmune system attack and then encourage beta cell proliferation. That would be kind of worthless if I had no beta cells left. Having some insulin production will also extend the honeymoon period, so I will need less supplemental insulin.
Low carb because I don’t need to further stress my pancreas by asking it to produce a ton of insulin. It’s already under attack. With that thought in mind, I have found that my response to carbs can be wacky, erratic, and very difficult to predict. So, limiting my carbs makes it easier to keep my glucose where I want it. Not perfect, mainly because I’m not perfect, but more predictable.

The flip side argument is that if I destroy all my beta cells, managing insulin may be easier.

These are just my thoughts

Well, my opinion agrees with your opinion on all points. If you haven't been reading Blood Sugar 101 then you will find the website agrees, too. There's a link in my signature if you need it.

I'm more likely to be T2 than end up being LADA, but one never knows. The approach you describe can work well for either, IMO.

Keep up the good work and good luck.

 

[Kailee56]

Well, my opinion agrees with your opinion on all points. If you haven't been reading Blood Sugar 101 then you will find the website agrees, too. There's a link in my signature if you need it.

I'm more likely to be T2 than end up being LADA, but one never knows. The approach you describe can work well for either, IMO.

Keep up the good work and good luck.

Yeah . Jenny Ruhl’s Blood Sugar 101 and Dr Bernstein’s Diabetes Solution have been my foundations. They make sense and are both written by people who live successfully with Diabetes.

 

[SimonCrox]

Does anyone actually have a proper study report that confirms sulphonylureal drugs kill beta cells or lead to progressive loss of insulin secretion? I have done a load of searches on this subject, and all I can find is forum discussion and blogger spiel and some very biassed reporting in the press. There has certainly been folklore discussion on this matter, but there seems to be no study that actually confirms it. I can find the likes of Bernstein, Mercola, and Jenny Ruhl expounding this hypothesis, but none of them actully refer to evidential proof of the assertions. It seems that the hypothesis relies on the assumption that the drugs force or squeeze more insulin out of the pancreas so must be making the cells work harder thus depeleting their lifespan. But there are many other things that damage and destroy these cells. This is what I found

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900074/

1. Zhang et al. Second-Line Agents for Glycemic Control for Type 2 Diabetes: Are Newer Agents Better? Diabetes Care 2014;37:1338–1345

https://www.ncbi.nlm.nih.gov/pubmed/1425152

I suspect that until recently the progression of T2D towards insulin therpy being necessary was something that was inevitable and so a scapegoat had to be discovered to hang the blame on. This is the 'T2D is a progressive disease' mantra, which many of us here can now challenge.

The recent discoveries into the effect of NAFLD on insulin resistance show that this is a major stress on the pancreas, and now that it seems to be potentially reversible, then this may remove the progessive march of T2D towards self destruction (according to the media and Panorama).

To me NAFLD is far more harmful than my drugs, and hyperglycemia is also potentially fatal, so using glic to fight both these conditions makes sense to me, and in the absence of proof otherwise, I am content to continue using them.

Regarding the effect of different tablets on beta cells, the best I can think of is ADOPT; this compared the time to tablet failure of sulphonylurea, metformin and rosiglitazone; rosi lasted longest and the sulphonylurea the shortest; we presume that this was the SU flogging the beta cells, but I do not think that measures of beta cell function wer performed.

https://www.nejm.org/doi/full/10.1056/nejmoa066224

Folk are all individuals, so one should health care professional should know the drugs so can discuss with patient and make teh best choice; sulphonylureas worked in UKPDS and have helped a lot of folk over the years; there are better agents now, but if working fine shows a good choice

I agree that we used to believe in progression of T2DM to insulin, but this was in the time that a lot of folk were being left on tablets for several years with awful control instead of add in insulin; I think that progression is still likely, but with aggressive dieting and/or GLP-1 RAs, it is not inevitable.

I agree about the NAFLD - a dangerous problem; it is likely that one inital problem with T2DM is insulin resistance, particularly in the liver, and this insulin resistance leads to a bit of fat in the liver (NASH) which can lead to problematic faty liver (NAFLD) which can lead to real problems for liver and blood vessels. Pioglitazone decreases insulin resistance and improves the fatty liver, GLP-1 RAs help insulin resistance a bit and help fatty liver, but lifestyle of diet, weight loss and exercise which decrease the insulin resistance are possibly the most effective.

Best wishes