A DIFFERENT DIABETES: LATENT AUTOIMMUNE DIABETES OF THE ADULT (LADA)

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WHAT IS LADA?

Latent Autoimmune Diabetes of the Adult (LADA) is a type of autoimmune diabetes which shares common features between type 1 and type 2 diabetes.It is also called Type 1.5 diabetes or slowly progressive autoimmune diabetes.The 3 common criteria for diagnosis of LADA are:
  • Adult onset:the age at diagnosis ranges from 15 to 30 years.However, nowadays Type 2 diabetes is being diagnosed in increasingly younger people.The youngest person to be diagnosed with type 2 diabetes is a three year old girl in Texas, USA.
  • Antibody positivity: Diabetes Associated Antibodies (DAA) are usually present in people with LADA.However this may not be quite so clear-cut, given that different laboratories may have different cut-off values.These DAA include antibodies to glutamic acid decarboxylase 65 (GAD 65), insulinoma-associated antigen, islet cell & zinc transporter 8. The commonest is GAD 65 antibody.Antibody levels may fluctuate and the type of positive antibody may change over a period of time.Even a transient increase in autoantibody indicates autoimmunity.
  • Insulin treatment: Arbitrary definition of LADA include a period without insulin treatment of at least six months, but the need to use insulin is usually at the discretion of the physician.

WHY DO YOU NEED TO KNOW IF YOU HAVE LADA?

  • Patients with LADA generally have worse HbA1c levels (measure of 3 month’s average blood sugar) than type 2 diabetes patients.
  • Often they are misdiagnosed as type 2 diabetes.Incorrect treatment will lead to higher loss of insulin producing beta cells of pancreas.
  • Studies have shown that patients with LADA need insulin treatment earlier than those with type 2 diabetes and therefore may need closer monitoring.
  • Patients with LADA have lower levels of C-Peptide. (Connecting peptide is a marker of insulin production by your body). C-Peptide levels influence treatment.
  • The sulphonylurea group of drugs like chlorpropamide,glyburide,glipizide etc which work by stimulating the pancreas to release more insulin, are not the right choice of drugs for people with LADA.
  • Despite greater use of insulin, patients with LADA have worse blood sugar control. Therefore there is something more that needs to be done.
  • When any one autoimmune condition is present, the chances of developing others are high. People with LADA have a higher incidence of thyroid autoimmunity. Hence it is important to screen for other diseases as well.

WHAT IS DIFFERENT ABOUT A FUNCTIONAL AND METABOLIC MEDICINE APPROACH?

In addition to testing for DAA we would look at the following:

  • Gut Health.
  • Gut dysbiosis
  • Intestinal Permeability Dysfunction (Leaky Gut)
  • Vitamin D3 levels
  • Chronic Inflammation
  • Sleep
  • Nutrient Depletion
  • Stress Response
  • Movement/Exercise
  • Test for other autoimmune conditions, particularly thyroid autoantibodies.
  • Risk for heart disease and stroke
  • Check for heart failure.

Should everybody be screened for LADA?

That will depend on your goals.I practice patient-participatory medicine. My duty as a physician is to provide you with correct information and help  you make the best decision for yourself.

You MAY BE INTERESTED IN READING:

Do you have autoimmune diabetes

Predictive Autoantibodies

Vitamin D and Autoimmunity

Ebook on Autoimmunity

REFERENCES
Gambelunghe, Giovanni, et al. "Increased risk for endocrine autoimmunity in Italian type 2 diabetic patients with GAD65 autoantibodies." Clinical endocrinology 52.5 (2000): 565-573.
Priyanka P. Brahmkshatriya, Anita A. Mehta, Banshi D. Saboo, and Ramesh K. Goyal, “Characteristics and Prevalence of Latent Autoimmune Diabetes in Adults (LADA),” ISRN Pharmacology, vol. 2012, Article ID 580202, 8 pages, 2012. doi:10.5402/2012/580202

DO YOU HAVE AUTOIMMUNE DIABETES?

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WHY DO YOU NEED TO KNOW IF YOU HAVE DIABETES AUTOIMMUNITY?

Sonia Kumar (not her real name) a 38 year old mother of two young girls, spent seven frustrating months trying to get her blood sugar under control.She was recommended escalating doses of oral anti-diabetes medications. She was even accused of cheating on her diet!But none of this helped her! It took an astute physician (not me!) to test her for diabetes autoantibodies to find out that she actually had Type 1 Diabetes!

The diagnosis was missed because people often think that Type 1 Diabetes does not develop in adults.

WHAT IS DIABETES?

Diabetes is a group of metabolic diseases with high blood sugar (hyperglycaemia) as the common feature. The high blood sugar results from defects in insulin secretion, defects in insulin action or both. About 20 years ago diabetes was classified into Insulin Dependent (IDDM) or Juvenile and Non-Insulin Dependent (NIDDM) or Adult Onset Diabetes. However, in the last several years it has become apparent that the use of insulin or age at onset could not adequately explain the disease conditions and specify the best treatment plan. Therefore, there is an opinion amongst diabetes researchers that the time has come for a new classification of the disease.

Diabetes develops because of an interaction between genes and the environment. Our genes have not changed in thousands of years,but our environment has.To a great extent this explains the dramatic increase in diabetes over recent years. Some of the influences have originated in the intrauterine environment before a person is born!

Exposure to environmental toxins like BPA have also contributed to the recent epidemic of diabetes.

Developments in the field of precision medicine, ethnicity-specific data and big data along with patient-participatory research will change the management of diabetes for the better.

TYPES OF DIABETES:

(For a medically appropriate classification please check the American Diabetes Association website for “Etiologic classification of diabetes mellitus”).

  • Type 1 Diabetes
  • Type 2 Diabetes (Commonest)
  • Gestational Diabetes (GDM/Pregnancy Diabetes)
  • Maturity Onset Diabetes of the Young (MODY)♣
  • Latent Autoimmune Diabetes of the Adult(LADA)♣
  • Drug Induced Diabetes.♣
TYPE 1 DIABETES

High blood sugar resulting from an absolute deficiency of insulin secretion. Type 1 Diabetes may be

  • Autoimmune or
  • Idiopathic.

Autoimmune Diabetes occurs when the Insulin producing cells in the pancreas are destroyed by an autoimmune process. Autoimmune markers for Type 1 Diabetes, also called Diabetes-Associated Autoantibodies (DAA) are usually present in most of these patients.

Idiopathic—In a small percentage of patients there is Insulin deficiency but no autoimmunity.

Though absolute insulin deficiency is a hallmark of Type 1 Diabetes, about 30 % of people with this condition have insulin resistance as well.

DIABETESASSOCIATED AUTOANTIBODIES (DAA):

  • Glutamic Acid Decarboxylase Autoantibodies (GAD65 or Anti-GAD)
  • Insulin Autoantibodies (IAA)
  • Insulinoma-Associated-2 Autoantibodies (IA-2A)
  • Islet Cell Cytoplasmic Autoantibodies (ICA)
  • Zinc Transporter 8 (ZnT8Ab) Autoantibodies
GESTATIONAL DIABETES (GDM or PREGNANCY DIABETES)

GDM is defined as any degree of glucose intolerance that was first recognized during pregnancy. This definition would include women who had previously undiagnosed Type 2 Diabetes and also those women who developed diabetes for the first time during pregnancy.Asian Indian women are at a very high risk for pregnancy diabetes. Therefore it is very important for them to be screened at the beginning , during mid-trimester as well as in the last trimester.

GDM raises the risk of several complications in both the mother as well the baby. Increased birth defects, increased birth weight, early (preterm) delivery are some of the risks in the babies born of mothers with GDM. The mother is at increased risk of pregnancy high blood pressure and pre-eclampsia and is at a higher risk for developing diabetes later in life. In addition, she is at increased risk for heart disease even if she does not develop diabetes later on in life!

TYPE 2 DIABETES

This is the commonest type of diabetes.Type 2 diabetes includes individuals who have insulin resistance and usually relative insulin deficiency. These individuals may not need insulin treatment to survive. However, use of insulin does not decide the type of the disease. Diabetes Associated Autoantibodies are absent in people with Type 2 Diabetes.

HOW DOES THIS AFFECT YOU?

It is important to keep in mind that adults can develop autoimmune diabetes too! British Prime Minister Theresa May, who was diagnosed with Type 1 Diabetes at age 56 and Sonia Kumar mentioned above were both initially diagnosed as Type 2 Diabetics. However both of them needed insulin therapy to control their blood sugar levels,when they were found to have Diabetes Antibodies.

Sulfonylurea (SU) drugs like chlorpropamide,glyburide,glipizide which work by stimulating the pancreas to release more insulin, are not the right drugs for these people.Use of these drugs in patients with diabetes autoimmunity have shown poor metabolic control and earlier loss of insulin producing beta cells in the pancreas.

A study in apparent long-standing type 2 diabetes found that those with Diabetes Associated Autoantibodies or with low C-peptide did not respond well to glucagon-like peptide 1 (GLP-1) agonist drugs like Liraglutide,Exenatide etc.

People with one autoimmune condition are at a higher risk for other autoimmune conditions as well. Diabetes Autoimmunity has often been associated with thyroid autoimmunity.

NUMBERS TO KNOW

If you have diabetes you obviously know your blood sugar and glycated haemoglobin (HbA1C) levels. In addition the following tests are important for the right treatment:

  • Diabetes Associated Autoantibodies (DAA)
  • C-Peptide ♣ :This  test can indicate how much insulin your body is producing.

(♣ Separate blog posts on these topics later.)

As Dr. Elliott P. Joslin, (who was the first doctor in the United States to specialize in diabetes and the founder of Joslin Diabetes Center) wrote “ . . . unless the physician takes care, he will fall into schematic ways and forget that it is the patient who comes for treatment and not the diabetes. Each is a case unto itself.” 

 

REFERENCES

Mohan V, Usha S, Uma R. Screening for gestational diabetes in India: Where do we stand? Journal of Postgraduate Medicine. 2015;61(3):151-154. doi:10.4103/0022-3859.159302.
Goueslard, Karine, et al. "Early cardiovascular events in women with a history of gestational diabetes mellitus." Cardiovascular diabetology 15.1 (2016): 15.
Leslie, R. David, et al. "Diabetes at the crossroads: relevance of disease classification to pathophysiology and treatment." Diabetologia 59.1 (2016): 13-20.
Brophy S, Davies H, Mannan S, Brunt H, Williams R. Interventions for latent autoimmune diabetes (LADA) in adults. Cochrane Database of Systematic Reviews 2011, Issue 9. Art. No.: CD006165. DOI: 10.1002/14651858.CD006165.pub3.

CIRCADIAN DISRUPTION: ARE YOUR MEALTIMES AFFECTING YOUR METABOLISM?

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Your body has an internal biological clock which decides when you sleep, eat, wake up, secrete hormones, process food and do many more functions.

The term circadian comes from the Latin word circa, meaning “approximately”, and diēm, meaning “day”. This daily rhythm is related to Earth’s rotation around its own axis which exposes all living beings to a 24-hour light-dark and temperature cycle.

Chronobiology is the science or study of the effect of time, especially rhythms, on living systems (including humans).

In the last several years many scientific studies have shown that the disruption of the circadian rhythm is related to a higher incidence of many conditions like Type 2 Diabetes, heart disease, inflammation, mood disorders, some cancers and obesity. In fact, rotating night shift–work has been called a probable carcinogen (cancer causing) by the World Health Organization. Night shift work and light at night(LAN) have been associated with a higher risk for breast cancer in women.

BASICS OF CIRCADIAN RHYTHM

Your body’s circadian rhythm is controlled by a circadian clock. The master clock is in the brain (Suprachiasmatic Nucleus SCN) and this controls all the other clocks in the other organs (peripheral clocks). Every cell in your body has this intrinsic clock and there are genes involved in the clock mechanisms. In fact, the clock is present even in cells in a petri dish in the lab!

Clocks

Fig: Central clock in the Suprachiasmatic Nucleus in the brain and peripheral clocks in different organs.Zeitgebers: Light on retina and food intake.

Although circadian rhythms are built-in and self-sustained, external cues can modulate circadian rhythms.

What are the external cues (zeitgebers) modulating your circadian rhythm?

  • Light falling on your eyes.

(Nerd Alert: Retinal melanopsin influences this. Loss of melanopsin retinal cells may be related to dysregulation of circadian rhythm in  Alzheimer’s Disease )

  • Intake of food
  • External temperature.

CHRONONUTRITION:

Chrononutrition refers to food intake in coordination with your body’s daily rhythm. This concept implies that in addition to the type of food you consume, the time of ingestion is also critical for your health and well-being.

STUDY USING A SMARTPHONE APP:

In an interesting study reported in the journal Cell Metabolism (2015), Dr. Satchidananda Panda and Shubhroz Gill used a smartphone app to track eating patterns in healthy men and women who were living regular lives (not in a lab). The smartphone app was used to take pictures of everything that they ate or drank. This was done for 3 weeks.

WHAT DID THEY FIND:

  • Most food (53.6%) was consumed after 6 PM, with less than 25% of caloric intake occurring before noon.

(My comments: Why is this important? This is related to your insulin secretion and insulin sensitivity. Lower Insulin sensitivity (IS) means higher body fat percentage and higher risk for Type 2 Diabetes and a whole host of diseases.) IS tends to be higher at breakfast than at lunch or dinner. So if most of your food intake occurs at a time of the day when you are less insulin sensitive, what can happen? You can become metabolically dysregulated and insulin resistant. This is a big problem in Asian Indians because diabetes and heart disease strikes them at least a decade before it does in the Western population. My dictum is “all Asian Indians are either pre-diabetic or diabetic until proven otherwise”)

  • Only 25% of the meals occurred after >6 hours 41 min of fasting.
  • About 90 % of people in the study ate for 14 hours 45 minutes in a day.
  • In another part of the study, 8 people who ate for more than 14 hours in a day, were asked to reduce their eating duration to 10-12 hours and to follow the same pattern during week days and weekends.

What did they find?

  • In 16 weeks of study duration the participants lost 3.27 kilograms of body weight!
  • These 8 people on the time restricted eating (TRE) program reported better sleep, better energy levels and less hunger at bedtime.
  • These people voluntarily agreed to stay on this eating pattern and they maintained their weight loss and sleep improvement and higher energy levels 1 year after they started on TRE. All this improvement from just restricting your eating from >14 hours to 10-12 hours! This is major!

Though the study did not mention testing for inflammatory markers or blood sugar and insulin, I am sure if they had measured, they would have found improvements in these biomarkers as well.

Weight loss is not a simple problem of calorie-in-calorie-out(CICO). I prefer to say fat loss because your weight includes your muscles and bones too. You don’t want to lose muscle! (More on this later).

ACTION STEPS:

  • Download and use the app (REFERENCES SECTION) and track for yourself. You will get great insight.
  • Implement Time Restricted Eating and see the difference in your health.
  • Eat an early dinner: This is a big challenge in many Asian Indian homes but try moving your dinner time by half hour every week until you have your dinner around 6:30-7 PM everyday.May be difficult to change dinner time from 9:30 PM to 6:30 PM in one day.
  • I know some of you do not reach home in time to have an early dinner. Maybe you can carry a second box of home cooked food to eat in the office or on the commute.
  • If you reach home by 7 PM, have your dinner at that time  instead of eating snacks then and save yourself from a late dinner just before you go to bed.

(Watch for post on “metabolic/social” jetlag ,later)

REFERENCES:

myCC

Picture:App myCircadianClock.

Android:https://play.google.com/store/apps/details?id=com.salk.mycircadianclock&hl=en

iTunes:https://itunes.apple.com/ca/app/mycircadianclock/id982118665?mt=8

La Morgia, Chiara, et al. “Melanopsin-expressing retinal ganglion cells: implications for human diseases.” Vision research 51.2 (2011): 296-302. La Morgia, Chiara et al.

Melanopsin Retinal Ganglion Cell Loss in Alzheimer Disease.” Annals of Neurology 79.1 (2016): 90–109. PMC. Web. 18 Aug. 2016.

Gill, Shubhroz, and Satchidananda Panda. “A smartphone app reveals erratic diurnal eating patterns in humans that can be modulated for health benefits.”Cell metabolism 22.5 (2015): 789-798.

Time for Food: The Intimate Interplay between Nutrition, Metabolism, and the Circadian Clock Asher, Gad et al. Cell, Volume 161, Issue 1, 84 – 92

Saad, Ahmed, et al. “Diurnal pattern to insulin secretion and insulin action in healthy individuals.” Diabetes 61.11 (2012): 2691-2700.