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Does pre-LADA exist?


I accept that metformin could be modestly helpful to many people who are not T2. It "tweaks" a lot of things, and a lot of tweaks could add up to a significant total effect. However, I have these two observations. 1. Isn't the increased liver dumping an aspect of IR? 2. Logically, making the body "more sensitive" to insulin means decreasing IR, because "insulin sensitivity" is the complement of "insulin resistance".

I found a 100% relevant article on liver dumping by a credentialed diabetes blogger. http://www.diabetesselfmanagement.com/blog/diabetes-metformin-and-your-liver/
"Metformin prevents the liver from dumping more glucose into the blood. Scientists used to think it worked by telling CRTC2 to cooperate with insulin (in other words, reducing insulin resistance.) But new studies have found that metformin actually works by bypassing CRTC2 and directly telling the liver cells to hold the sugar."
Right, the difference between reducing insulin resistance and bypassing it is logically important. This doesn't negate the facts and the logic that excess liver dumping is a result of insulin resistance.

Background understanding: "insulin resistance" occurs in the striated muscles (muscles other than smooth muscles), belly fat, and liver.
 
@sud5nala

While I understand your viewpoint, I have not come across any literature that directly links IR and liver dumping. Plenty of T1's and non diabetics experience liver dumps, just maybe the level is individualized. I just don't think you can say Metformin only benefits one type of diabetes. My sister in law, who has been T1 since she was 10 years old, is on Metformin, as part of her diabetes treatment. I believe that doctors prescribe it not because they know exactly why it works, but just that it works! It has many beneficial uses: weight loss, controlling symptoms of PCOS, and is recently being tested as a 'youth fountain' drug of sorts.
 
I’m in Canada and I have finally asked the right person and found out that my province doesn’t cover GAD antibody testing. Apparently if I can convince my Dr to prescribe a GAD Antibody test I could private pay $160 for a test that would be sent to the US to be run. Not sure if it’s worth it or not, especially since yes means yes (but my dr’s might not change my treatment anyway) and no means maybe.

My understanding is that with zero family history and being in my late 30’s it is unlikely that I have any of the MODYs. (?)


How I wish this were the case! However, in my experience it is actually very difficult to find out whether I have T2 or not. I have high fasting glucose, but not high fasting c-peptide. I have had some diabetes-related conditions (e.g., frozen shoulder) and several classic symptoms, but no metabolic syndrome type complications such as high BP, cholesterol/trigs/low HDL, PCOS, etc. I am thin and fit and have low BP and cholesterol, and absolutely no family history of any kind of diabetes.

Please, if it’s so easy, I would love it if you could tell me whether or not I have T2! (My doctor sure cannot…he is just waiting for it to get worse and then maybe it will be evident, I guess.)

As a previous poster suggests, the idea with metformin for me was that it might reduce my liver dumping, which I think it has done a little bit. My IFG, which was a pretty intractable problem, has improved some, and as a result so has my A1c. I still cannot tolerate many carbs, and especially starches. I just wish I knew whether this was a “honeymoon” that I need to keep an eye on or just the new way things are. And also whether or not I should consider adding other orals if metformin isn’t quite enough.
 
@Glink

I'm in Canada as well and I didn't have to pay for Antibody testing. Have you been to see an endocrinologist?
 
Hm. I saw an endo a couple times but he sent me back to my gp for management/until things get worse. I'm in BC, and was told msp doesn't cover gad testing. Will poke about a bit more.
 
Glink said:
Hm. I saw an endo a couple times but he sent me back to my gp for management/until things get worse. I'm in BC, and was told msp doesn't cover gad testing. Will poke about a bit more.
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I'm in Ontario, but I don't think the rules are that different. It was my endo that suggested the antibody testing, as she was convinced I was LADA, so maybe there needs to be reason behind it, so they can justify charging it to OHIP? Have you had insulin level testing? Your family doc can order that as part of your normal 3 month lab tests.

Have you been to a diabetes clinic? It's also something you can bring up with your diabetes nurses. They're in constant contact with your endo.

Edit: it's called OHIP in Ontario, but I'm referring to your provincial healthcare.
 
To ensure finding pancreatic autoantibodies, GADA alone isn't enough (unless perhaps you test positive for it). That's because some people have other autoantibodies but not GADA. If LADA or ordinary Type 1 are suspected, you should test for at least GADA and ZnT8A, the latter being second in prevalence. It is rare to have either IA-2A or IAA only, but it's good to test for them also because it's good to know that you are positive for multiple autoantibodies versus being positive for one.

ZnT8A is the only islet cell Ab that never occurs in Type 2 patients, according to the United States Food and Drug Administration in their press release of 2014 August 14.
 
On this Website, I can share public information and my own circumstances. I'm thin, to put it mildly. Fasting insulin is rather low, and I'm negative for those other blood tests that indicate insulin resistance. My first-phase mealtime response is defective, which can lead to me having postmeal glucose of 10.2.

As to MODY, mutations do occur spontaneously, and the chain of inheritance had to start with somebody. Besides, most of the MODY's are heterogeneous as to the mutations. Diabetic genes are not like the genetic diseases they use as examples in elementary biology, where every patient has the exact same change in the DNA. This means there are dozens of MODY 3's, etc.

You mentioned age. Although 90% of diagnoses of MODY 3 come by age 40 (I chased down the graph), specialists in MODY 3 report that there are cases that didn't get triggered until advanced age. Have you seen the tutorials on MODY at diabetesgenes.org?

Measure fasting insulin too. It's crucial for precise diagnosis, more useful than C-peptide (which is useful when it's below range). It's crucial for calculating IR. The "metabolic syndrome" is actually a checklist of IR. It is a shortening of other checklists for IR that do include plasma insulin level.

A theory of insulin resistance diabetes, T2, has accumulated since 1990 (eg, look up "ominous octet"). This theory seems to have no critics. While scientists are striving to fill gaps in knowledge, they are very confident of the IR theory as it stands. The reasons for T2 are progressive loss of beta cell activity, but also progressive insulin resistance.

Here's my reasoning: if I am negative for most or all of the supposed consequences of insulin resistance, or if they're not getting worse and worse (are not progressive), then I don't have the condition that is defined to be that these things are happening. Bad values of TG and HDL are called dyslipidaemia. Only half of hyperglycaemic people have elevated blood pressure. But if somebody has good blood pressure, and no dyslipidaemia, and scant abdominal fat, then, it would break the theory of Type 2 to call us Type 2!

High fasting insulin is evidence for IR. If fasting plasma insulin is high due to IR, but the patient is negative for all the consequences of IR, maybe the ailment just started. Or else try searching the Web for nondiabetic causes of hyperinsulinaemia and of hyperglycaemia.

If signs and symptoms seem to rule out T2, MODY, LADA, and ordinary T1, it would seem the condition must have an exceedingly rare cause, including causes not yet known to science. Neuroendocrine tumors are among the miscellaneous causes. For me, I suspect that a toxic reaction to a medication has caused my first-phase deficiency, but I'm sure there is no possibility of proving it. MODY 3 is a possibility, although for an old person like me, really remote.
 

My endo was fascinated at my weird case at first, but dismissive of the possibility of LADA/1.5. He ran a lot of tests to rule out a whole schwack of non-diabetic reasons for my high sugars and then sent me back to my GP for now. My GP is who gave me metformin, as my numbers were gradually getting worse despite my strict low carb diet, but not bad enough that the endo wanted me back.

I had a c-peptide test last fall that I guess was okay (so I was told--I'm not clear on how to interpret the "normal" results I got myself in light of simultaneous somewhat-high fasting blood glucose) but not an insulin test. Because I'm classed as merely pre-diabetic (perhaps because I immediately went very low carb and have not wavered) there is no space for me at the diabetes clinic.

My GP just says I must have some gene mutation or something. He is unlikely to send me for anything other than my quarterly standing order for FBG and HbA1C numbers to monitor (and from what he has said, it seems that many of the advanced tests are only covered if order by a specialist). If those go south, he'll send a new referral back to the endo. So I guess I'm just in a holding period until/unless things get worse. I suppose I just need to learn to live with the uncertainty and hope my GP will prescribe more test strips so I can keep an eye on things at home (the endo gave me tons but they will run out soon as I test when I feeling poorly or trying new foods).
 
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You know, there is little specific or precise in the posts. That's not a criticism, because this information touches on privacy. But it's difficult to advise. Eg, is your glucose even that high to begin with? I think the only thing that been revealed is there is IFG. What if it's barely there and there is no other dysglycaemia?

One of the MODY's is MODY 2. It is a benign, nonprogressive condition that consists of lifelong elevated FPG, in the range that has come to be designated IFG. If one has this mutation, there isn't any problem at all.

Fasting C-peptide's nice to have -- I had mine measured -- but fasting plasma insulin seems to be more useful. With fasting insulin and fasting glucose, you can get a fairly accurate measure of insulin resistance, ie, whether you are normally resistant/sensitive, or whether you are "insulin resistant". There are many indices of IR, but the one most widely used in research and clinically is the HOMA2-IR, which is calculated as insulin * glucose / [normalizing factor].

I'm surprised at the obstacles in your path to getting certain tests. In southern California, I requested GAD, insulin, C-peptide. Approved quickly by the GP, results posted online in one to two days.
 

Why is he dismissive of possible LADA/T1?

Do you have classic T2 characteristics?
 
I have no classic type 2 characteristics. No family history. Fine cholesterol, low BP, lifelong thin, no PCOS, no GD. Some family autoimmune issues.

My glucose is not that high. My FBG and H1bAc have been in the "prediabetes" range for at least a year. I've never topped 10 even postprandial, and rarely am over 7 fasting, but apparently I am "sensitive" and show diabetes symptoms at lower, prediabetic highs (the symptoms are the only reason I ever got my blood sugar tested at all--otherwise I would happily never know about all this!), so I am quite concerned with keeping my sugars good.

My story is that I got mono, felt terrible for 2 yrs, and during this time developed several "classic" diabetes symptoms that didn't go away (polydypsia, polyuria, moods, fatigue, swelling hands & feet, blurred vision on & off, chronic thrush in multiple body areas). Dr tested FBG 6 mos in and it was fine (later learned that it was .1 under the level for prediabetes, but within range). Worsened over the next year, suddenly gained 30 lbs (still "normal" BMI but more than I ever weighed before, even when pregnant), he tested again (a couple times, with OGTT and H1bAc) and it was "prediabetes." He told me not to worry about it, but hoping to finally feel better, I immediately went on a very low carb diet after reading on forums like this (while waiting to see a consultant) and everything got better. For a while. Then slowly control worsened. And I rapidly lost 35 lbs. And then saw the endo, who ruled out a lot of other things (thought there was a parathyroid tumor for a while, etc.). I also got to see a diabetes dietitian who was worse than useless, albeit a very nice person. Control was gradually worsening even on strict low-carb. I was diagnosed with frozen shoulder. My foot started going numb. Was getting close to diabetic fasting #s even while eating hardly any carbs. GP gave me metformin, and more metformin. Control got better again. 4 mo later, my H1bAc is now good but my fasting #s are starting to be erratic again and am starting to have symptoms again (night waking to urinate, swelling fingers, thrush).

Physician friends suggest that I might be LADA, but my GP does not know much about diabetes beyond the standard info about controlling type 2 by avoiding sugary drinks and sweets (mostly gross to me anyway) and exercising (I already did: biking and weight training). I don't know why the endo dismissed the idea; whether he doesn't believe in 1.5 in general or if he thought it didn't apply to me. My (and my family's) quality of life is quite affected by my highs, so by posting here I was hoping to understand whether LADA was ever caught at a prediabetes level (in which case I may be waiting for the other shoe to drop) or whether I can just assume I'm an atypical T2 (in which case I could try another oral med if things worsen further). And I guess the answer is: who knows?
 
Hi Glink

It's funny because i'm in exactly the opposite position to yourself. I have 2 autoimmune diseases and have been under an endo for about 19 years. I was fortunate enough to have a very good endo at one point who tested for many autoimmune anti bodies and I came up positive to GAD (I believe there may have been some Type 1 diabetes in my family). I have had 2 c-peptide tests and 3 GAD tests all up but since he retired and I've moved on to a different endo ... couldn't be less interested!

I find it frustrating as I'm the kind of person who believes that knowledge is power and it peeves me that I don't know if I will eventually end up with LADA. Currently my blood sugars are fine, the c-peptide tests were in normal range (in first third of range) but I test regularly to keep an eye on things. I no longer get HbAlc's done since changing endo's as they don't see a need, even though I do!. I also have a family history of Type 2.

So I understand your frustration that your doctor won't do the appropriate tests. I asked my GP to do a glucose tolerance test which I did and it was fine so at present, I am not pre-diabetic, though I have had some insulin resistance in the past.

You've clearly done the right thing by adopting a low carb diet but this can unfortunately cloud the picture from the doctor's perspective. Have you considered reverting to a higher carb diet and recording your levels and presenting them to your doctor - maybe then you will be taken more seriously.

Lesley
 
@Glink

If you can afford it, I would go ahead and do the tests. It's not exactly the same, but I was having some digestion/nausea issues a while ago, and the doctor recommended a celiac panel to rule out Celiac disease. It cost me about $150, and I don't have any kind of intolerance to gluten, but it was a big relief knowing that. This was before I tested positive for LADA, so everything was later attributed to diabetes. Ruling out one disease, let my doctors look at others they hadn't considered.
 
@tpaz, ironically my endo did test me for celiac (negative, which was not at all a surprise to me, as I've done some hardcore elmination diets before due to a bunch of food allergies and I think I'd know if gluten were an issu) and I didn't have to pay out of pocket at all for that!

I'm on the fence about the GADA testing, although I don't know if my GP will even write a referral. It might be handy if positive, but if negative that doesn't necessarily mean very much. *shrug*
 

If it's negative, then your endo needs to start looking at other autoimmune diseases or start taking it seriously that you may have T2D. I'm just saying its a good start. It's weird how sometimes many diseases can produce similar symptoms. It may be helpful for you to go see an internal medicine doctor, too.
 

So as to leave no stone unturned, I would search the Web on hyperglycemia causes nondiabetic. Repeat for each of the three polys. I know you consulted an endo, and an endo is supposed to investigate all the possibilities; but under the circumstances, I would do that literature search. On the other hand, I am wondering if the only thing "pre" about your condition is the glucose levels. Screening for the more familiar complications seems in order. There are noninvasive technologies for scanning for atherosclerosis: MRA and "calcium scan".

These are indeed rough symptoms! The previous description of intractable IFG, well, IFG and IGT in themselves are ordinary varieties of hyperglycaemia. You seem to have IGT, too, no? (And simultaneous IGT and IFG is also ordinary.)

I searched on diabetes increased infection risk. I recommend these search hits, particularly Casqueiro 2012. Thrush (as candiadiasis) is on the list of infections associated with diabetes.

I would search on antibody negative LADA. I would look for case reports by searching on case report [antibody name]. For the antibody name, I would search on both the acronym and the full name.

It's plausible to me that the mono you had, which was chronic, could have given you the current disease, via a disruption of the immune system. I know someone who was put in a psychiatric hospital in the 1970s. He said he was forcibly administered benzodiazepines for 9 months, and this made him T1. I myself two years ago had elevated A1c for 10 months because of a toxic medication that I discontinued after four days.

At the level of process modules, the causes of postprandial hyperglycemia include insulin resistance, deficiency in insulin production, secretory defect, and other. You think you don't have significant insulin resistance, and maybe except for the liver, I agree. Several researchers have noted that in IFG without IGT, the liver is insulin resistant, while the muscles are not.

The original question was, is there a recognized "pre-LADA". I haven't heard of it. But a narrower question would be: is there a recognized phase of antibody negative LADA? I would search on that. So far, I don't know how LADA can be diagnosed if the patient is negative for all four antibodies and the C-peptide level shows negative for loss of production.

It is often reported that T1 patients have all four autoantibodies, while LADA patients have just GAD. Although this may be statistically true, there are exceptions -- I've read the research reports. You would need to get tested for all four.

Don't discount MODY because of your age. MODY researchers say that it can be "triggered" later in life. 10% of diagnoses of MODY 3 come after age 40. That is vague, true, but so little is known so far. Also, almost all varieties of hyperglycaemia have a high genetic component.

This set of symptoms seems so unusual. I think the endo, instead of sending you back to your GP, should have sent you to a nationwide expert!
 
Glink said:
My glucose is not that high. My FBG and H1bAc have been in the "prediabetes" range for at least a year. I've never topped 10 even postprandial, and rarely am over 7 fasting,
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Never over 10. That's good news and bad news. When glycaemia reaches about 10, the kidneys are triggered to spill glucose into the urine. 10 mmol/l is called the "renal threshold". (In many people with MODY 3 hyperglycaemia, the renal threshold is low. This is a distinctive sign that would support a request for the expensive genetic test for MODY 3.)

I too never exceed 10. Then I read about the "ominous octet", and one member of the "octet" is the failure of the kidney spillover backup: the renal threshold rises. This was mortifying news. The only reason for never exceeding 10 is that this backup mechanism involving the kidneys works fully. In those moments, all other glycaemic control has failed.

Many of us have heard of the drug class, SGLT inhibitors. They are intended for patients whose renal threshold has risen. They force the kidneys to start spilling over at a lower glycaemia.
 
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Any ONE of these antibodies being positive will indicate LADA, so all must be done:
islet cell antigens (ICAs)
glutamic acid decarboxylase autoantibodies (GADAs)
tyrosine phosphatase proteins (IA-2s)

Also a c peptide test will indicate your insulin function or how much you have left.
 
Mitochondrial diabetes. May or may not be relevant. Hearing loss is absent in 25% of patients. Here is the OMIM entry.

Diapedia.org is an excellent information center. Its articles are written by researchers for patients.
 
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