Case Studies

Diagnosing LADA in Adults with "Brittle Diabetes"

A 52-year-old male presents with “brittle diabetes.” He was diagnosed three years ago with type 2 diabetes (T2DM). His A1C was 10.6% at that time. He was started on metformin and titrated up to 500 mg at breakfast and lunch and 1,000 mg at dinner. The patient is 6’0” and 161 lbs. with a BMI 21.8; BP of 128/82, and pulse of 69. Blood tests show his current A1C as 8.7%, triglycerides as 131 mg/dl, HDL as 53 mg/dl, and LDL as 97 mg/dl. Is T2DM the correct diagnosis for this patient?A 52-year-old male presents with “brittle diabetes.” He was diagnosed three years ago with type 2 diabetes (T2DM). At the time of diagnosis, he had problems with fatigue, vision changes, the “polys” and a recent 15 lb. weight loss. His A1C was 10.6% at that time. He was started on metformin and titrated up to 500 mg at breakfast and lunch and 1,000 mg at dinner. He is still taking metformin on that schedule, plus acetylsalicylic acid (ASA) to prevent cardiovascular disease.

The patient reports that he monitors his FSG, and most mornings his glucose is 100-130 mg/dl, but he spikes to >200 mg/dl with all meals, especially if he eats “things with carbs.” He is frustrated that his glucose is not better all of the time despite his efforts. He says he is eating a restrictive diet and controlling portion size.

He has a history of asthma for which he still uses a beta agonist inhaler as needed, and an inguinal hernia. He does not use tobacco, alcohol, or recreational drugs. He has never had pancreatitis. He does not have a family history of diabetes. However, heart disease is present in both parents, and one sibling has autoimmune thyroid problems. 

Physical exam is otherwise normal. The patient is 6’0” and 161 lbs. with a BMI 21.8; BP of 128/82, and pulse of 69. Blood tests show his current A1C as 8.7%, total cholesterol as 172 mg/dl, triglycerides as 131 mg/dl, HDL as 53 mg/dl, and LDL as 97 mg/dl.

This case brings up a number of issues and may not be as atypical as it might first appear:

·         Is T2DM the correct diagnosis for this patient?

·         What tests should be ordered to determine the correct diagnosis?

·         What is the best treatment option for this patient?

 

Is T2DM the Correct Diagnosis for This Patient?

As we all know diabetes, especially T2DM, has become an epidemic. About 1 in 10 Americans have diabetes, a ratio projected to be as high as 1 in 3 by the year 2050.[i] Because 90% of all diabetes cases are T2DM, it would be reasonable to assume that an adult with a new onset of diabetes mellitus like this patient has T2DM. However, approximately 10% of people initially diagnosed with T2DM turn out have another form of diabetes.[ii]

When someone presents in middle age and without the typical type 2 phenotype, the astute clinician should consider other diagnoses, including a secondary cause of beta cell failure. First, and most importantly, if a person presents with new onset insulin deficiency above over the age of 50—especially when they present with the “polys,” weight loss, and steatorrhea—the primary concern should be pancreatic insufficiency either from pancreatitis or a pancreatic tumor. In this scenario, the person would be started on insulin and should have the pancreas imaged and hormonally tested. This is particularly true if there are no antibodies that may indicate type 1 diabetes.

In the case of this patient, who has not yet been tested for antibodies, there is also the possibility that he may have a variant form of diabetes. For one thing, he has characteristics suggesting what Paul Zimmet first described as adult onset type 1 diabetes, in which patients did not have an immediate need for insulin.[iii] The condition has been termed latent autoimmune diabetes of the adult (LADA), slowly progressive type 1 DM, or type 1.5 diabetes. For this case, we will use the term LADA. Although thought to be an autoimmune disease like type 1 diabetes, LADA also shares certain characteristics with T2DM: it is diagnosed typically in middle aged adults, and most people will have a delay from time of first diabetes diagnosis and need for insulin. .

Spiros Fourlanos developed a screening tool to help identify people with LADA. The clinical criteria used were: 1. Age <50; 2. acute symptoms (polys); 3. BMI <25; 4.  Personal history of autoimmune disease; and 5. Family history of autoimmune disease.  If a person has two or more of these features there is a 90% sensitivity and 71% specificity for identifying LADA. If one or no factors are present, the negative predictive value of these features is 99%.[iv]  This patient, of course, has four of these criteria, if you consider that he was diagnosed at age 49, making LADA a distinct possibility.

What Tests Should Be Ordered to Differentiate T2DM from Other Conditions?

From his history, physical examination, and recent laboratory results, it appears that the patient in this case could have either LADA or secondary diabetes (stemming from some external disorder—not autoimmunity as in type 1 diabetes or long-standing insulin resistance as in type 2 diabetes). The key features that would make you consider these alternatives are the patient’s normal BMI, intolerance to carbohydrates, and limited response to medication only “three” years into diagnosis. Next steps might therefore involve conducting imaging studies, reviewing the lipid panel, and checking for the presence or absence of insulin producing capacity (insulin and c-peptide levels) and auto-antibodies that are markers of type 1 diabetes.

Imaging of the pancreas and pancreatic enzymes are useful to help determine if there is a secondary cause for diabetes. In this patient’s case, you complete a CAT scan of the abdomen, and it is normal with no evidence of pancreatic tumors, infiltration, or pancreatitis.

Measures of beta cell function such as c-peptide. The c-peptide is released when the prohormone precursor proinsulin is cleaved into insulin and c-peptide. Since c-peptide levels generally reflect insulin levels and are easier to assess than insulin itself, they can be used as a measure of endogenous insulin release, which normally decreases in response to falling glucose levels. C-peptide levels should be measured in conjunction with glucose measurement.  A low or non-detectable c-peptide in the face of a normal glucose is indicative of insulin insufficiency. This test is most useful if the glucose is in the normal range, since chronic hyperglycemia can also suppress endogenous insulin production from “glucotoxicity” rather than the presumed autoimmunity associated with LADA. This patient has a fasting c-peptide is 0.8 ng/mL, which is low normal for a concurrent glucose of 144 mg/dl.  

Lipid panel: Many people with LADA will have normal lipid panels given that their underlying pathophysiology is not insulin resistance. Most people with type 2 diabetes will have diabetic dyslipidemia characterized by high total cholesterol, low HDL-C, and high triglycerides.  The absence of dyslipidemia in this patient is an additional factor that should make you question the type 2 diabetes diagnosis.

Markers of auto-immunity: Auto-antibodies associated with type 1 diabetes include glutamic acid decarboxylase antibodies (GAD), islet cell antibodies, and insulin antibodies.  GAD antibodies are the most likely of these to be positive in LADA. In this patient, tests for islet cell antibodies come back normal at <1:4, and insulin antibodies are absent. However, glutamic acid decarboxylase autoantibodies (GAD) come back positive at 53.9 U/mL (<1.1 nmol/L).]

What is the Best Treatment Option for This Patient?

This gentleman initially presented with T2DM and was started on therapeutic lifestyle changes and metformin, but he only had a short term response to treatment. Despite a normal initial weight, he lost a few pounds purposefully by cutting back on calories and significantly restricting carbohydrates. He has been monitoring his glucose and feels that the fasting readings are close to target but has trouble getting post-meal glucose readings to goal.  All of these factors, coupled with your recent laboratory findings (including the absence of diabetic dyslipidemia, positive auto-antibodies, and insufficient insulin production measured by a low c-peptide) and the patient’s family history of autoimmune disease, suggest that he is more likely to have a form of adult-onset slowly progressive type 1 diabetes (LADA) than T2DM.

Your next treatment option will need to address the patient’s post-prandial hyperglycemia in light of his new diagnosis. Prior to this change in diagnosis his treatment was focused on improving insulin resistance by reducing hepatic glucose production. In LADA, however, the primary problem to be addressed is insulin deficiency caused by failing beta cells rather than insulin resistance. This requires a very different educational and treatment approach.

With the assumption that this patient has LADA, insulin should be a primary treatment consideration, as it would be in typical Type 1 diabetes. There is evidence to show that earlier use of insulin can provide more stable and lasting control for LADA.[v]  At a minimum, this patient needs meal time insulin replacement. Alternatively, he could use both basal and bolus insulin as a physiologic insulin replacement. Titrated in small increments, the insulin would cover the time from reduced insulin production to no insulin production. This approach would require diabetes education about the disease process and treatments, particularly with respect to the identification and treatment of hypoglycemia.

Disease education in fact, is essential for this patient, even if he already completed diabetes education for T2DM. Given his new diagnosis, he will not only need to learn about hypoglycemia but will also need instruction in insulin administration and titration and in carbohydrate consistency or “carb counting.”  Because abstaining from carbohydrates is not realistic over the long term without contributing to other nutritional deficiencies, he will need to learn how to help make insulin match his carbohydrate intake to keep his glucose under better control. Re-introduction of a well-balanced diet and providing treatment to try to concurrently minimize glucose excursions is a priority.

If the person refused to go on insulin until absolutely necessary (which is becoming much less common) you might consider using a combination of metformin plus a DPP-4 inhibitor, a GLP-1 receptor agonist (GLP-1 RA), a thiazolidinedione (TZD), or an amylin mimetic.  The DPP-4 or TZD would be a once daily tablet. The GLP-1 RA would require an injection that would be administered twice daily, once daily, or once weekly. The amylin mimetic would require injections with each meal.

All of these treatments are temporary solutions as eventually the person will require full insulin replacement. In fact, even as temporary measures, all of these considerations are problematic, given the dearth of evidence supporting the use of these agents and other oral agents to improve glucose control in LADA. Sulfonylureas in particular should not be used because—while these secretagogues clearly can address post-prandial hyperglycemia—the use of these medications in LADA may contribute to faster beta cell decline.[vi] There is also no evidence to guide the use of incretin-based agents in this patient. Both DPP-4 inhibitors and GLP-1 RAs do address post-prandial hyperglycemia but do not address the core defect in LADA, which is autoimmune-mediated beta cell destruction, despite some early evidence that the incretin-based agents may contribute to beta cell preservation in people with type 2 diabetes. Nor is there enough evidence to support the use of thiazolidinediones (TZDs) in treating a patient with LADA. Although TZDs are the most potent medications addressing insulin resistance on the market and may preserve beta cell function,[vii] these benefits were most clearly seen in the diabetes prevention trials and the ADOPT trail with respect to patients with T2DM.

 

REFERENCES

1.       Centers for Disease Control and Prevention. 2011 National Diabetes Fact Sheet. Atlanta: CDC, 2011. Accessed May 14, 2014. http://www.cdc.gov/diabetes/pubs/factsheet11.htm?loc=diabetes-statistics.

2.       Harris MI, Robbins DC. Prevalence of adult onset IDDM in the U.S. population. Diabetes Care 1994. 1337-1340.

3.       Zimmet PZ. The pathogenesis and prevention of diabetes in adults: Genes, autoimmunity, and demography. Diabetes Care 1995;18:1050-1064.

4.       Fourlanos S, Perry C, Stein MS, et al. A clinical screening tool identifies autoimmune diabetes in adults. Diabetes Care 2006. 29:970-975.

5.       Maruyama T, Tanaka S, Shimada A et al. Insulin intervention in slowly progressive insulin dependent (type 1) diabetes mellitus. J Clin Endocrin Metab 2008;93:21.

6.       Maruyama T, Tanaka S, Shimada A et al. Insulin intervention in slowly progressive insulin dependent (type 1) diabetes mellitus. J Clin Endocrin Metab 2008;93:21.

7.       Harrison LB, Adams-Huet B, Raskin P, Lingvay I.  Beta-cell function after 3.5 years of intensive diabetes therapy. Diabetes Care 2012. 35;7:1406-1412.

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“My very first experience wearing the fit, it was actually stunning and I have in fact in no way informed <director>James Wan] this specific, ” Momoa stated. “I wear it, I actually didn’t have a very hand mirror, and We turn out of clothing and I be able to see his deal with. He has constantly very enthusiastic and reveals immediately. https://tvhds.com/aquaman/ However the absolute happiness — this individual looked like a youngster — this individual beamed, ‘I made it happen. ’ Having been extremely happy, and this individual did not need to state something, I could find it on his deal with. ”

Regarding Momoa, movie director James Wan, and fellow cast members Amber Heard and Patrick Wilson, who joined them from <a href=https://123moviefull.com/aquaman/>Watch Aquaman Online Free</a> press junket on Saturday, December 1 within New York Metropolis, Aquaman is all about stretching which childlike ponder of viewing a popular superhero become more active to a whole movie. With zero, it’s not merely concerning wax mannequins — however eerily comparable they are (“I can fault anything that goes wrong onto it! ” Momoa exclaimed). Momoa, Wan, Heard, and Wilson talked about the individual and mythic elements that travelled into Aquaman, and the very long highway to getting this to be able to the big screen.

Here are a few of the splashiest items all of us learned about the making of <a href=https://123moviefull.com/aquamanfull/>Aquaman Full Movie</a> in advance of the film’s release on December 21, 2018.

Jason Momoa Received Through His very own Life to try out Aquaman
Being given birth to inside Hawaii and brought up inside Grand rapids, Momoa is aware something special about being ripped among two realms. The half-Hawaiian, half-Caucasian actor may have been any bold casting selection with was revealed that he was enjoying the typically blonde-haired, blue-eyed <a href=https://fullmoviehds.com/Aquaman-full-movie/>Aquaman Full Movie</a> inside 2014, but the casting could not are already much more perfect:

“The cool problem is, is simply to be able to relate with a person who is genuinely <of> 2 diverse civilizations. Every of those civilizations do not know about the other one. People inside The hawaiian islands definitely do not know everything with New jersey and Iowans certainly don’t know about Hawaii so that was something I can illustrate. ”

https://netflixhds.com/aquaman2018/: The some other point that actually allowed me to out there had been brought up by a single parent, ” Momoa added. “I merely had just me and my mommy my expereince of living, ” relating their situation we were young to be able to Arthur Curry and becoming elevated by just one father (played by Temuera Morrison). The two Momoa and Morrison are of Hawaiian descent, that aggregates an additional coating of ethnical specificity in order to Momoa’s casting.

“Coming from the Polynesian of the islands there’s so many drinking water gods we certainly have, and a great deal folklore, and a lot mythology around exactly how the islands came to exist: Kanaloa, Tangaroa, and Maui, ” Momoa observed, adding:

“With <a href=https://fullmoviefree.net/aquaman/>Aquaman Full Movie</a> there’s <a>Poseidon-like figure] and We be able to enjoy which, and honestly be the 1st mixed-race superhero. Within 2018, it’s such as, “Really? Can there be not one? ” And that’s an enormous respect. And perform it truly near who We are and just about all of their flaws. Really dont need to be Terme conseillé, do not assess me. We be able to perform this in such a way where he has divided in between those a couple of realms. ”

<a href=https://fullhds.com/aquamanfreeonline/>Watch Aquaman Online Free</a> Had A few of the Most difficult Stunts with regard to Both Stars and Stunt Clubs Stories of large-scale production for superhero movies are some thing we will utilized to ability to hear, but Aquaman has been in another degree, the superstars described. “Just how big the range of this particular movie was, that required numerous clubs and members and folks, ” Heard explained. “Sometimes we would take the lunch time tent and notice four or five enhances of oneself. https://3xhds.com/aquaman-fullmovie/ I did so perform the butt off…but I’m thankful to the stop group, I will not have been in a position to take action without one. ”

However Wilson included that even for the stunt team, Aquaman must have been a difficult film. That is saying some thing to get a team of specialists who focus on superhero films for any residing.

<a href=https://123moviehds.c>Aquaman Full Movie</a>: “We had stop guys, saying, ‘Wow, I have never experienced several various sorts of departments in a single day. ’ And you also know whenever your stop group — that will by the approach really does superhero films to get a residing — you realize whenever they’re expressing that, which youre in uncharted lakes and rivers, reduce the jua.

“I consider we were all that way, ” Wilson additional. “Jason’s carried out tricks his entire professional profession and you understand —

“Hardest to date, ” Momoa interjected.

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But for Heard, filming <a href=https://tvhds.com/aquaman/>Watch Aquaman Online Free</a> got at least one benefit. “It had been the most covered upward I have have you ever been inside a arranged, ” the lady raved, talking about the girl body-covering vivid green wetsuit. “He’s the one particular who is partially nude all the time! ” she directed in order to Momoa. It is correct — hanging in wiring while shirtless is not comfy.

Most of the Under the sea Displays Have been Photo “Dry regarding Wet”
You can’t have got Aquaman without having water — it is actually in the subject. Yet that offered an original obstacle with regard to Wan, who to handle the element that most filmmakers would prevent. https://netflixhds.com/aquaman-fullmovie/ “You listen to it all the moment from filmmakers which make movies together with h2o. It may be not the many pleasurable point, it may be uncomfortable and it merely slows down the filmmaking process, ” Wan said. His or her solution: capturing almost everything “dry for damp, ” which usually this individual discussed:

“The paradox is, any kind of of the items that is actually totally immersed under the sea, that was really chance ‘dry for damp. ’ That’s literally what it feels like, in which utilize the method ‘dry regarding wet’ in which shoot, as the stars thought, in these rigs which replicate going swimming, suspended and all that. Yet we all do take water as nicely. I don’t believe you may make a good <a href=https://fullhds.com/aquaman-fullmovie/>Aquaman Online</a> and not have anybody get wet. And also once again the irony will be, whenever we will in fact above the drinking water, when we’re dried, that is when I need to drench the stars non-stop. Whenever that they are actually away of water, honestly, that is whenever they are still dripping wet moist. But when they are underwater the paradox will be folks in fact appear dry and so that is why we photo it with no h2o. ”

But this does not mean that <a href=https://filmhds.com/aquamanfullmovie/>Aquaman Online Free</a> didn’t possess big, pricey sequences that will demonstrated a pain regarding each cast and team. You’ve noticed that, or maybe meme’d that. It’s the splashy submarine series. A fresh series that be expensive of our blood, perspiration, and tears, Wan mentioned:

“I would admit the biggest water arranged that individuals experienced in the film has been the sub series at the begin of the film. That has been a massive setpiece that we developed the boat more than a h2o tank that we immersed once more, and once again, and once again. Like we would enjoy the scene, we may submerge that, and we might take it out there of the h2o tank. We would blow-dry it down, and we would carry out consider 2. It was a significant mind-numbing method, and the new little of annoying. ”

https://xxxhds.com/aquaman-2018/: The Majority of the Film Has been Worn out Post “I do not consider I have personally actually observed the film…where so much is done in publish, ” Wilson stated. Momoa hasn’t actually noticed the done film but, that Wilson said mostly been around in Wan’s use the entirety of generation. It took a little time for Wan and his or her enhancing crew — including five-time collaborator Kirk M. Morri with Kelvin McIlwain and Oscar winner Charles Gibson as overall enhancements superiors — over the 12 months to finish post-production.

Wilson said during filming, that many of what the famous actors have got to see was limited by concept art:

<a href=https://123moviefull.com/aquaman-fullmovie/>Aquaman Online</a>: “You notice this all pre-vis and exactly what seems like a little video gaming. And after that you observe the art work. Yet truly it is all in that guy’s head over there, therefore really that is that which was awesome, is to notice just what he was carrying out for the earlier yr. ”

“You really see it with regard to the very first time, ” Heard additional. That’s the reason why Momoa has anxiously waited to look at <a href=https://fullmoviefree.net/aquaman2018/>Aquaman Online</a> regarding the first time:

“I’m holding out to see it along with our youngsters. It’s the first-time I can manage to watch items along with our youngsters regarding the first time. As well as Im will be really psychological and affected, and to maintain their palms — the 10-year-old and an 11-year-old boy — it is going to become a really cool moment. ”

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