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.
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.