The Problem

It is time that the full scope of Type 1 diabetes is acknowledged, which includes millions of adults who are too frequently misdiagnosed as having Type 2 diabetes, an altogether different disease.

Saturday, June 20, 2020

How Does Type 1 Diabetes Develop? T1D Etiopathogenesis

Often, I hear people say that a certain event caused them to develop Type 1 diabetes, such as an accident, a stressful time in their lives, or pregnancy, but in fact the actual disease process begins far before such an event, perhaps years before. Another misconception that I hear often is that the autoantibodies destroy the pancreatic beta cells, but it is actually killer T cells. Type 1 diabetes is characterized by immune-mediated destruction of pancreatic beta cells in genetically predisposed individuals, which results in severe insulin deficiency and the need for exogenous insulin to sustain life.  In Type 1 autoimmune diabetes, the healthy insulin-producing beta cells of the pancreas are destroyed by T-cells of the immune system, which mistake the beta cells as “foreign” and attack them. Here are the sequential steps in the development of Type 1 diabetes:

Step 1: Genetic Predisposition
People genetically predisposed to Type 1 diabetes have either HLA-DR3-DQ2 or HLA-DR4-DQ8 haplotypes, or both [Footnote 1].  Some HLA epitopes protect against the development of Type 1 diabetes; the presence of resistance HLA epitopes has been correlated with a later age of onset (adult-onset Type 1 diabetes) [Footnote 2].

Step 2: Immune Activation/Environmental Trigger
It is still not known what triggers the immune-mediated destruction of the beta cells, but it is related to environmental factors that are still poorly defined [Footnote 3]. Type 1 diabetes was first described in detail in about 100 C.E. by Aretaeus of Cappadocia [Footnote 4], so whatever the environmental factors are, they have been present for thousands of years.

Step 3: Immune Response/Development of Autoantibodies
During the immune activation and immune response involved in Type 1 diabetes, the immune system mistakenly attacks beta cells in the pancreas and destroys them over time, ultimately resulting in insulin deficiency. This process leads to the production of islet-specific autoantibodies (GAD, ICA, IA-2, IAA, and ZnT8); the autoantibodies are not pathogenic, but they represent biomarkers of the pathogenesis [Footnote 5].  Or put another way, diabetes autoantibodies are proteins that mark insulin-producing beta cells for destruction, but the autoantibodies are not believed to be directly pathological.

Step 4: Triggering Event
The triggering event is any event that stresses the body, such as illness, accident, or even pregnancy.  The stressful event means that the body requires additional insulin for proper functioning, but the ongoing destruction of the beta cells means that insufficient insulin is secreted in response to the stressor. This event is a tipping point or “the straw that broke the camel’s back,” but it is not causal.

Step 5: Development of Overt Type 1 Diabetes
Type 1 Diabetes TrialNet has identified three stages of progression in Type 1 diabetes. In stage 1, a person tests positive for autoantibodies, blood sugar levels remain normal, and the individual is asymptomatic. In Stage 2, individuals are autoantibody positive, there is a loss of beta cells, blood sugar levels are abnormal, and typically there are no symptoms. In stage 3, Type 1 diabetes symptoms are present due to significant beta cell loss. Common symptoms include increased thirst and urination, extreme hunger, unexplained rapid weight loss, blurred vision, and extreme fatigue. Exogenous insulin is necessary to sustain life. Note that in adults with slowly progressive Type 1 diabetes, symptoms may be far milder, which often leads to adults with new-onset T1D being misdiagnosed as having Type 2 diabetes (an altogether different disease).

Footnote 1: The majority of studies of HLA association with Type 1 diabetes have used Caucasian subjects.

Footnote 2:  Multiple HLA Epitopes Contribute to Type 1 Diabetes Susceptibility.  CL Roark et al. Diabetes 2014 Jan; 63(1): 323-331.

Footnote 3:  American Diabetes Association (ADA) Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2020. Diabetes Care 2020; 43 (Suppl 1): S14-S31.

Footnote 4: Aretaeus of Cappadocia, “Diabetes is a remarkable affliction, not very frequent among men… The course is the common one, namely, the kidneys and the bladder; for the patients never stop making water, but the flow is incessant, as if from the opening of aqueducts… The nature of the disease, then, is chronic, and it takes a long period to form; but the patient is short-lived, if the constitution of the disease be completely established; for the melting is rapid, the death speedy. Moreover, life is disgusting and painful; thirst, unquenchable; excessive drinking, which, however, is disproportionate to the large quantity of urine, for more urine is passed; and one cannot stop them either from drinking or making water. Or if for a time they abstain from drinking, their mouth becomes parched and their body dry; the viscera seems as if scorched up; they are affected with nausea, restlessness, and a burning thirst; and at no distant term they expire. They thirst, as if scorched up with fire … But if it increases still more, the heat is small indeed, but pungent, and seated in the intestines; the abdomen is shriveled, the veins protuberant, and there is general emaciation, when the quantity of urine and the thirst have already increased; and when, at the same time, the sensation appears at the extremity of the member, the patients immediately make water. Hence, the disease appears to me to have got the name diabetes as if from the Greek word διαβήτης (which signifies a siphon), because the fluid does not remain in the body, but uses the man’s body as a ladder, whereby to leave it. They survive not for long, for they pass urine with pain, and the emaciation is dreadful; nor does any great portion of the drink get into the system, and many parts of the flesh pass out along with the urine”. From Adams F (ed), 1856.The extant works of Aretaeus the Cappadocian. The Sydenham Society, London.

Footnote 5: If a single islet autoantibody or multiple islet autoantibodies are detected in a person diagnosed with diabetes (fasting blood sugar greater than 125 mg/dl), the diagnosis of Type 1 autoimmune diabetes is confirmed.

Sunday, June 7, 2020

ADA Acknowledges “Misdiagnosis is Common,” CDC Indirectly Acknowledges Undercounting of Cases of Type 1 Diabetes

Twenty-five years ago, I began my advocacy on behalf of people with adult-onset Type 1 diabetes, shortly after I was misdiagnosed at age 35.  At that time, it was the position of the American Diabetes Association (ADA) and Centers for Disease Control and Prevention (CDC) that Type 1 diabetes was a childhood disease, and the organizations did not acknowledge misdiagnosis as a problem.  Back then, doctors would become enraged when I used the term “misdiagnosis.”  Finally, more than a quarter century later, the ADA has stated that misdiagnosis is common (since Type 1 and Type 2 are altogether different diseases, yes, it is misdiagnosis).  Additionally, CDC’s National Diabetes Statistics Report 2020 indirectly references the problem of undercounting of Type 1’s and misdiagnosis, by categorizing people who self-report in surveys that they went on insulin within one year of diagnosis as having Type 1 diabetes.

These changes from leading organizations are very positive—we have come a long way, but we are not there yet.  Misdiagnosis and undercounting continue to hamper people’s access to the appropriate care and treatment of Type 1 diabetes.  But this change of position by the ADA and CDC is a fantastic step which will hopefully pave the way for people with adult-onset Type 1 diabetes to receive a correct diagnosis, appropriate care, and overall better outcomes.

In this blog I provide excerpts from ADA’s Standards of Medical Care in Diabetes 2020 and CDC’s National Diabetes Statistics Report 2020.

Here are some pearls from ADA Standards of Medical Care in Diabetes 2020 [all emphasis is mine]:

“Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical presentation and disease progression may vary considerably. Classification is important for determining therapy, but some individuals cannot be clearly classified as having type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms of type 2 diabetes occurring only in adults and type 1 diabetes only in children are no longer accurate, as both diseases occur in both age-groups. Children with type 1 diabetes typically present with the hallmark symptoms of polyuria/polydipsia, and approximately one-third present with diabetic ketoacidosis (DKA). The onset of type 1 diabetes may be more variable in adults; they may not present with the classic symptoms seen in children and may experience temporary remission from the need for insulin.

It is important for the provider to realize that classification of diabetes type is not always straightforward at presentation and that misdiagnosis is common (e.g., adults with type 1 diabetes misdiagnosed as having type 2 diabetes; individuals with maturity-onset diabetes of the young [MODY] misdiagnosed as having type 1 diabetes, etc.). Although difficulties in distinguishing diabetes type may occur in all age-groups at onset, the diagnosis becomes more obvious over time.

Characterization of the underlying pathophysiology is more developed in type 1 diabetes than in type 2 diabetes. It is now clear from studies of first-degree relatives of patients with type 1 diabetes that the persistent presence of two or more islet autoantibodies is an almost certain predictor of clinical hyperglycemia and diabetes. The rate of progression is dependent on the age at first detection of autoantibody, number of autoantibodies, autoantibody specificity, and autoantibody titer.

There is debate as to whether slowly progressive autoimmune diabetes with an adult onset should be termed latent autoimmune diabetes in adults (LADA) or whether the clinical priority is awareness that slow autoimmune β-cell destruction means there may be long duration of marginal insulin secretory capacity. For the purpose of this classification, all forms of diabetes mediated by autoimmune β-cell destruction are included under the rubric of type 1 diabetes.

Immune-mediated diabetes, previously called “insulin-dependent diabetes” or “juvenile-onset diabetes,” accounts for 5–10% [Note 1] of diabetes and is due to cellular-mediated autoimmune destruction of the pancreatic β-cells. Autoimmune markers include islet cell autoantibodies and autoantibodies to GAD (GAD65), insulin, the tyrosine phosphatases IA-2 and IA-2β, and zinc transporter 8 (ZnT8). The disease has strong HLA associations, with linkage to the DQA and DQB genes. These HLA-DR/DQ alleles can be either predisposing or protective.

The rate of β-cell destruction [in Type 1 diabetes] is quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults). Children and adolescents may present with DKA as the first manifestation of the disease. Others have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and/or DKA with infection or other stress. Adults may retain sufficient β-cell function to prevent DKA for many years; such individuals may have remission or decreased insulin needs for months or years and eventually become dependent on insulin for survival and are at risk for DKA
Although patients are not typically obese when they present with type 1 diabetes, obesity is increasingly common in the general population and there is evidence that it may also be a risk factor for type 1 diabetes. As such, obesity should not preclude the diagnosis.”

Melitta’s Note 1:  Type 1 diabetes that is correctly diagnosed accounts for 5-10% of all cases of diabetes.  However, as the Standards of Care point out, misdiagnosis is common, and in fact ~10% of people diagnosed with “Type 2” diabetes are autoantibody positive, have been misdiagnosed, and in fact have Type 1 diabetes.  Therefore, Type 1 diabetes represents more than 5-10% of all cases of diabetes.  See the CDC National Diabetes Statistics Report for additional information.

CDC National Diabetes Statistics Report 2020

“Most estimates of diabetes in this report do not differentiate between type 1 and type 2 diabetes. However, as type 2 diabetes accounts for 90% to 95% of all diabetes cases, the data presented here are more likely to be characteristic of type 2 diabetes, except as noted.

Prevalence of diagnosed diabetes:
  • 210,000 children and adolescents younger than age 20 years—or 25 per 10,000 US youths— had diagnosed diabetes. This includes 187,000 with type 1 diabetes.
  • 1.4 million adults aged 20 years or older—or 5.2% of all US adults with diagnosed diabetes—reported both having type 1 diabetes and using insulin.
  • 2.9 million adults aged 20 years or older—or 10.9% of all US adults with diagnosed diabetes—started using insulin within a year of their diagnosis

APPENDIX B of the National Diabetes Statistics Report: Detailed Methods and Data Sources: Validated methods to distinguish between types of diabetes in surveys are not available. The percentage of adults aged 20 years or older with diagnosed diabetes who self-reported type 1 diabetes plus current insulin use and the percentage of adults aged 20 years or older with diagnosed diabetes who started using insulin within a year of their diagnosis were estimated from 2017 NHIS data. To estimate the number of adults aged 20 years or older with type 1 diabetes, these percentages were then applied to the derived number of adults aged 20 years or older with diagnosed diabetes.”