LADA -- Slow Onset Type 1 Diabetes with Some Type 2 Features

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Graphic from Juvenile autoimmune diabetes: A pathogenic role for maternal antibodies? Matthias von Herrath1 & Jean-Francois Bach2 Nature Medicine 8, 331 - 333 (2002)

What is LADA

Latent Autoimmune Diabetes of Adults (LADA) is a slow developing form of autoimmune diabetes found in people over 35 years old which is often misdiagnosed as Type 2.

The reason for this misdiagnosis is that by age 35 many people in the general population are slightly overweight or may have developed some insulin resistance or other signs of the metabolic syndrome which doctors associate with Type 2 diabetes.

In addition, evidence is emerging that suggests that LADA, though it is an autoimmune disease, is not quite the same as Type 1 diabetes, and, in fact, has a genetic profile that includes genes also found in people who develop Type 2 diabetes.

This was made clear in a study published in February of 2008 that reports that people diagnosed with LADA had variations in the HLA autoimmunity genes similar to those found in people with Type 1 diabetes but that many of them also had variations of the TCF7L2 gene that has been associated with Type 2 diabetes.

Genetic Similarities Between LADA, Type 1 and Type 2 Diabetes Camilla Cervin et al, Diabetes DOI: 10.2337/db07-0299

This led the researchers to conclude that
LADA shares genetic features with both type 1 (HLA, INS VNTR, and PTPN22) and type 2 (TCF7L2) diabetes, which justifies considering LADA as an admixture of the two major types of diabetes.
This finding was confirmed by a second study published in November of 2008 which found that young people with Diabetes who were negative for GAD Antibodies had higher levels of a common Type 2 gene than their peers who were positive for these antibodies, but that in older people diagnosed with LADA the frequency of a common Type 2 gene was the same as it was in people of that age who were not positive for GAD antibodies. This led the authors to conclude:
Common variants in the TCF7L2 gene help to differentiate young but not middle-aged GADA-positive and GADA-negative diabetic patients, suggesting that young GADA-negative patients have type 2 diabetes and that middle-aged GADA-positive patients are different from their young GADA-positive counterparts and share genetic features with type 2 diabetes.
Common variants in the TCF7L2 gene help to differentiate autoimmune from non-autoimmune diabetes in young (15–34 years) but not in middle-aged (40–59 years) diabetic patients E. Bakhtadze et. al. Diabetologia. DOI 10.1007/s00125-008-1161-2

How LADA Is Treated

Treatment for LADA is different from treatment for Type 2 diabetes because the primary problem is insulin deficiency caused by failing beta cells rather than insulin resistance. This means that the oral drugs given to people with Type 2 diabetes often will have very little impact on the blood sugar of a person with LADA. In addition, over a period of 3-5 years, most people with LADA become fully insulin dependent and may develop Diabetic Ketoacidosis (DKA) without insulin--which is a life-threatening condition.

Because people with LADA often have mildly elevated blood sugar at first diagnosis, there is some debate about whether they should be started immediately on insulin.

It was thought in the past that starting insulin treatment as early as possible might stop the autoimmune attack associated with LADA. But recent research investigating whether the use of early insulin can slow the development of classic Type 1 diabetes suggests it does not:

Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial. Näntö-Salonen K et al.Lancet. 2008 Nov 15;372(9651):1746-55. Epub 2008 Sep 22.

Still, there is a lot of evidence that starting insulin early in Type 2 can make control much easier in the future--and since LADA combines genetic feature of both Type 1 and Type 2 diabetes, it is possible that some of the benefit seen in Type 2 may extend to people with LADA.

For now, there seems to be no compelling reason for a person with LADA NOT to start insulin early.

Also, several of the oral drugs used to treat Type 2 diabetes stimulate the beta cells to produce insulin, and because LADA involves an autoimmune attack which is stimulated by the production of insulin at the beta cells, stimulating insulin production by the beta cells with drugs may increase the ferocity of the attack, killing more beta cells.

So it is very important to get a correct diagnosis so you can avoid the drugs that stimulate insulin production by the beta cells. These drugs include the sulfonylureas like Amaryl and Glipizide and may also include the incretin drugs, Byetta and Januvia because they also stimulate insulin production by the beta cells.

Indicators that You May Have LADA

1.A family history of Type 1 diabetes. There is a genetic tendency towards developing autoimmune diabetes, so if you have a close family member who has autoimmune diabetes, it is more likely that you have that same genetic make up and the same tendency towards developing autoimmune diabetes.

2. The Presence of Other Autoimmune Conditions If you already have been diagnosed with another autoimmune condition, like Rheumatoid Arthritis or some Thyroid diseases, it is more likely that your diabetes is also caused by an autoimmune response.

3. Normal or Near Normal Weight Although there are, indeed, other forms of Type 2 diabetes that strike people of normal weight as well as non-autoimmune genetic forms of diabetes that are also misdiagnosed as Type 2 diabetes, most thin people who are incorrectly diagnosed with Type 2 diabetes turn out to have LADA.

So LADA should always be tested for in a thin or normal weight "Type 2," especially if blood sugars are extremely high at diagnosis.

However, LADA is usually not a concern for normal weight people diagnosed with the mild blood sugar irregularity diagnosed as "prediabetes" unless they have a family history of Type 1 diabetes or other autoimmune conditions.

4. Failure to Respond to Oral Drugs People with LADA often see swift deterioration in their blood sugars in the months after a Type 2 diagnosis. If your blood sugars are getting worse, not better, despite taking oral drugs and cutting back on carbohydrates, a combination which is usually effective in Type 2 diabetes, you should demand that your doctor test you for LADA or send you to an Endocrinologist who will do this.

How to Test for LADA

The most common test for LADA is one that looks for GAD (glutamic acid decarboxylase) antibodies. However, a small number of people with autoimmune diabetes will not have GAD antibodies, but they will have islet cell antibodies and/or tyrosine phosphatase antibodies. So a lack of GAD antibodies does not entirely rule out LADA. Another issue is that very early on in the disease process there may be no detectable antibodies, but over time they may emerge.

The other important test for LADA is the fasting C-peptide test. A very low C-peptide result suggests that the beta cells have stopped making insulin, possibly because they are dead. People with Type 2 diabetes often test with normal or high levels of C-peptide. So a low C-peptide level is suggestive of LADA, though it should be confirmed with antibody tests.

What To Do If You Think You Have LADA

If you have LADA, you'd do best to get treated by an endocrinologist who specializes in treating Type 1 diabetes as you will need an up-to-date insulin regimen and the kind of diabetes education Type 1s get which will help you learn how to use insulin to get more normal numbers.

It is important to note that people with LADA have the same risk of damaging their organs by running higher than normal blood sugar as do people with other forms of diabetes. This means that it is essential that, no matter what your doctor tells you, you learn What Is a Normal Blood Sugar and strive to achieve Healthy Blood Sugar Targets.

If your doctor, no matter what their specialty might be, tells you that a 7.0% A1c is excellent control, please read Research Connecting Blood Sugar Level with Organ Damage. The best blood sugar level for a person with insulin-dependent diabetes is the lowest level they can achieve without experiencing hypos--with hypos being defined as blood sugars under 70 mg/dl.

Free Antibody Testing Available from TrailNet

An organization called Type 1 Diabetes TrialNet is sponsoring several studies which offer those with relatives diagnosed with Type 1 the opportunity to get free antibody testing. Those who have already tested positive for the antibodies can be enrolled in studies involving experimental treatments intended to delay the destruction of beta cells.

To be eligible for the screening test you must meet one of the following criteria:
  • 1 to 45 years of age and have a brother, sister, child, or parent with type 1 diabetes

  • 1 to 20 years of age and have a cousin, aunt, uncle, niece, nephew, half sibling, or grandparent with type 1 diabetes
More information about the TrialNet screening and studies can be found at:
Type 1 Diabetes TrialNet: Information for Study Participants

Are There Dietary Interventions For LADA?

Unlike the case with Type 2 diabetes, it is usually not possible to reverse or control LADA with carbohydrate restriction alone. That said, it is much easier to make insulin work when you are eating a lower carbohydrate diet than it is with a high carbohydrate diet. To learn more about how lowering carbs allows you to fine tune your blood sugar control and avoid dangerous hypos and soaring post-meal blood sugars, read Dr. Bernstein's Diabetes Solution: The Complete Guide to Achieving Normal Blood Sugars. Though many people with LADA are able to eat higher amounts of carbohydrate than those that Dr. Bernstein recommends, the principles he explains hold true for all people with diabetes and reading this book will give you a much better idea of how to use insulin effectively.

References

Latent autoimmune diabetes of adulthood: Unique features that distinguish it from types 1 and 2 Fadi Nabhan, MD; Mary Ann Emanuele, MD; Nicholas Emanuele, MD. Postgraduate Medicine Vol 117, No 3, Mar 2005.

Genetic Similarities Between Latent Autoimmune Diabetes in Adults, Type 1 Diabetes, and Type 2 Diabetes. Camilla Cervin et. al. Diabetes 57:1433-1437, 2008

Autoimmune Diabetes Not Requiring Insulin at Diagnosis (Latent Autoimmune Diabetes of the Adult) Definition, characterization, and potential prevention Paolo Pozzilli, Umberto Di Mario, Diabetes Care 24:1460-1467, 2001.

 

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