Getting It Right for People with Adult-Onset Type 1 Diabetes

Note that I am liberally elaborating off of “Getting It Right for People with LADA,” by Ernest Maddaloni and Paolo Pozzilli (DiabetesVoice, September 2014, Volume 59, Issue 3).  Of course, LADA is the acronym for latent autoimmune diabetes in adults, or slowly progressive Type 1 diabetes.  I appreciate the authors’ advocacy for people with adult-onset Type 1 diabetes—I just took their work several steps further.

Adult-onset Type 1 diabetes can be rapid onset, with marked hyperglycemia and a high risk of diabetic ketoacidosis (DKA), or more slowly progressive (LADA).  Many medical professionals also are not aware that gestational diabetes (GDM) may be a precursor to Type 1 diabetes, not just Type 2 diabetes.  The stress of pregnancy is "the straw that broke the camel's back" and pushes a woman over into overt Type 1 diabetes (autoimmune gestational diabetes).

Type 1 diabetes/LADA is characterized by immune-mediated destruction of the beta cells of the pancreas, leading to severe insulin deficiency requiring exogenous insulin to sustain life.  Type 1 diabetes is a distinct clinical entity from Type 2 diabetes:  according to The Type 1 Diabetes Sourcebook (ADA/JDRF 2013, a reference guide for clinicians), “The pathophysiology of the two diseases [Type 1 diabetes and Type 2 diabetes] differ on a basic pathophysiologic level such that Type 1 diabetes is marked by insulinopenia while Type 2 diabetes is characterized by obesity, hyperinsulinemia, insulin resistance, and relative insulinopenia.”  In other words, the Type 1/LADA phenotype is quite far from the “metabolic syndrome phenotype” so typical of people with Type 2 diabetes. Some people with Type 1 diabetes/LADA may develop insulin resistance, but insulin resistance is not characteristic of Type 1/LADA.

Both rapid onset Type 1 diabetes in adults and LADA are often wrongly diagnosed as Type 2 diabetes, by physicians who assume that an adult with new onset diabetes must be Type 2.  Of course, physicians see a preponderance of Type 2 diabetes in their clinics.  Physicians also frequently assume that a person who is overweight must have Type 2 diabetes, but many people with adult-onset Type 1 diabetes are overweight when they are newly diagnosed. Autoantibody tests for the diabetes-associated autoantibodies (DAA, which include GAD, IA-2, IAA, and ZnT8) can be used to distinguish Type 1 autoimmune diabetes and diabetes due to other causes.  Guidelines assign all patients with DAA, including those with LADA, to Type 1 diabetes, and it is an oxymoron to write about autoantibody-positive Type 2 diabetes (Footnote 1).  The American Association of Clinical Endocrinologists (AACE), in its Clinical Practice Guidelines for Diabetes Mellitus, now states that Type 1 diabetes should be confirmed by the presence of autoantibodies (GAD, IA-2, IAA, ZnT8), to distinguish between Type 1 diabetes and Type 2 diabetes and to determine appropriate treatment.

People with adult-onset Type 1 diabetes/LADA who are misdiagnosed as having Type 2 diabetes are wrongly treated as though they have Type 2 diabetes.  Consistent evidence shows the importance, in terms of clinical outcome, of early initiation of insulin therapy in Type 1/LADA.  Thus, the early clinical recognition of people with adult-onset Type 1 diabetes, as distinct from Type 2 diabetes, is extremely important to guarantee the most suitable treatment in order to preserve beta-cell function, gain optimal metabolic control, and improve long-term outcomes.  A correct diabetes diagnosis is the cornerstone of correct therapy and a wrong diagnosis delays achievement of optimal metabolic control, frustrates patents, and increases the risk of life-changing or fatal complications.

References

Footnote 1:  Diabetes at the crossroads: relevance of disease classification to pathophysiology and treatment.  R. David Leslie, Jerry Palmer, Nanette C. Schloot, Ake Lernmark.  Diabetologia (2016) 59:13-20.

Historical References to Adult-Onset Type 1 Diabetes: How did Type 1 diabetes ever become defined as a childhood disease?

Close to 2,000 years ago, Type 1 diabetes was first described in detail by Aretaeus of Cappadocia, and Aretaeus only referred to adults acquiring the disease.  In the American Diabetes Association’s The Type 1 Diabetes Self-Care Manual (Jamie Wood, MD, and Anne Peters, MD, 2018), the authors open by stating, “Type 1 diabetes has unique features and contrary to popular belief, is not a disease only of children; it occurs at any age and in people of every race, shape, and size.”  Why then in modern times does the myth persist that Type 1 diabetes is a childhood disease, when for over 1,800 years it was documented as a disease that affected both adults and children, but primarily adults?  The consequence of the medical community believing in the myth that Type 1 diabetes is a childhood disease is that many if not most people who acquire Type 1 diabetes as adults are misdiagnosed as having Type 2 diabetes, an altogether different disease.  In fact, numerous studies, with the first study published in The Lancet in 1977, based on autoantibody testing, about 10% of people diagnosed with “Type 2” diabetes are autoantibody positive, have been misdiagnosed, and in fact have Type 1 diabetes.  That 10% represents the largest group of Type 1 autoimmune diabetes. Michael J. Haller MD, in Type 1 Diabetes Sourcebook (ADA/JDRF, 2013), says “Importantly, adults with [slowly progressive Type 1 diabetes] may represent an additional 10% of those adults incorrectly diagnosed with Type 2 diabetes."

Let’s follow the trail of history:

• The first known mention of (possible) diabetes symptoms was about 1552 B.C., when Hesy-Ra, an Egyptian physician writing in what is called the Ebers Papyrus, offered remedies for “correcting urine that is in excess.”   However, it is uncertain whether what is being described is an excessive volume of urine (polyuria) or excessively frequent urination symptomatic of an infection.  Also around this time, ancient healers noted that ants seemed to be attracted to the urine of people who had this disease.
• In about 100 C.E., Aretaeus of Cappadocia provided the first detailed description of diabetes.  Aretaeus of Cappadocia clearly described what is now called Type 1 diabetes (polyuria, polydipsia, rapid weight loss and swift death), and his descriptions were of adults.  In Principles of Diabetes Mellitus, 2^nd Edition (Leonid Poretsky, MD, Editor), the authors in Chapter 1 write:  “A medical condition producing excessive thirst, continuous urination, and severe weight loss has interested medical authors for over three millennia.  Unfortunately, until the early part of the twentieth century the prognosis for a patient with this condition was no better than it was over 3000 years ago.  Since the ancient physicians described almost exclusively cases of what is today known as Type 1 diabetes mellitus [emphasis mine], the outcome was invariably fatal.”
• Thomas Willis, in 1674, describes diabetes as “the pissing evil.”
• In an 1877 book, Diabetes Mellitus:  Its History, Chemistry, Anatomy, Pathology, Physiology, and Treatment, the author describes the first stage of diabetes (and clearly describing Type 1 diabetes) as being of a shorter duration in youth than in adults.
• Dr. Frederick Allen of the Rockefeller Institute in New York publishes his Total Dietary Regulations in the Treatment of Diabetes (1919) that introduces a therapy of strict dieting – dubbed the ‘starvation treatment’ –- as a way to manage diabetes.  Dr. Allen described both adults and children as having what is now known as Type 1 diabetes.  His “Case #1” was a 28-year-old woman with Type 1 diabetes.
• Insulin was discovered in 1921/1922, with the first human injected being a 14-year-old boy, Leonard Thompson, on January 11, 1922.  Frederick Banting’s medical school classmate, Toronto physician Joe Gilchrist who had been diagnosed with diabetes several years prior, was the first human that Dr. Banting injected with insulin, in May 1922, and Dr. Gilchrist was the “guinea pig” for experimentation on dosing and purification.  Insulin was first given to both children and adults who were dying of the disease, but the children received the most publicity.
• Elliott Joslin gave his first patient insulin in August 1922.  Elizabeth Mudge became diabetic in July of 1917, at the age of 37.  She restricted her diet, omitting sugar and starches, and was able to remain alive (barely) until Dr. Joslin started her on insulin after its discovery.  At the time of her first insulin injection, Elizabeth Mudge weighed 71 pounds and ate 900 calories per day (from Bittersweet).
• Dr. Harold Himsworth performed a study, published in The Lancet on January 18, 1936, that demonstrated how to differentiate between two types of diabetes—insulin sensitive and insulin insensitive.
• A 1958 book by one of the preeminent diabetes physicians of his day, How to Live with Diabetes, used the term “juvenile diabetes,” but stated emphatically that the disease was not confined to juveniles.  Also at the time, the authors said that about 30% of all cases of diabetes were of the insulin-deficient type.  The authors state that insulin-deficient diabetes [T1D] is about three times more common in adults than in children.  The authors noted the slower onset of insulin-deficient diabetes in adults, saying that only a small percentage of adults had the rapid-onset that is common in children.  The authors also noted that, “women may first become aware of diabetes during a pregnancy or after a stillbirth.”
• In 1969, after suffering a miscarriage, Mary Tyler Moore was diagnosed with Type 1 diabetes at the age of 33.
• In 1970, TV producer Lee Ducat founded the Juvenile Diabetes Foundation, now called JDRF, after Lee’s son developed Type 1 diabetes.  Lee was frustrated with what she saw as the limited aims of the doctor-dominated American Diabetes Association, and she decided to raise money for a cure for Type 1 diabetes.  The Juvenile Diabetes Foundation put a huge emphasis on children acquiring Type 1 diabetes, probably both because children garner much more sympathy and thus more funding, but also to differentiate Type 1 diabetes from the more common Type 2 diabetes, which many saw as a disease of older fat people that had much stigma associated with the disease [note that Type 2 diabetes is a complex disease and such generalizations are harmful]. [Note that today, JDRF is a tremendous advocate for people with adult-onset Type 1, and JDRF's funding of cure research and of technological progress, etc., is absolutely groundbreaking and game-changing.]
• In 1974, Type 1 diabetes was determined to be an autoimmune disease, as documented with the publication of two articles.
• In 1977, researchers published an article in The Lancet stating that 10% of people diagnosed with “Type 2” diabetes were autoantibody positive, and in fact had Type 1 autoimmune diabetes.  In the Lancet study, 11% of study subjects were autoantibody positive.  One conclusion of the study, “We believe that ICAb-positive diabetes controlled by oral hypoglycemic agents [O.H.A., medications for Type 2 diabetes] is an earlier stage in the same disease process (type 1 diabetes) that culminates in insulin-dependency.”
• In 1985, in The Lancet, the authors stated that “Development of IDDM (then the name for Type 1 diabetes) is by no means rare in older patients.  In many older patients the progression to insulin dependence is gradual, the diagnosis can be made in a pre-ketosis-prone stage by clinical acumen, supported by observations of low insulin or c-peptide response during a glucose tolerance test or positive islet cell antibodies.”  They also described, evidently for the first time, Type 1.5 diabetes (“When diabetes is again reclassified, we may find them [diabetic patients who are ketosis-resistant but have an inadequate insulin reserve for normal health] accommodated in a new category of Type 1-1/2 diabetes—a condition in which insulin sustains not life itself but the quality of life.”
• The term “LADA” (latent autoimmune diabetes in adults) was coined by Tuomi et al in a February 1993 article in Diabetes.  In that article, the authors state, “It further confirms that patients with LADA represent a discrete subgroup of IDDM [Type 1 diabetes] with a pathogenesis similar to that of IDDM.”  Tuomi et al defined LADA as being (1) diagnosed at age 35 or older, (2) GAD autoantibody positive, and (3) non-ketotic and non-insulin-dependent for 6 months or more.  The authors also state that people with LADA “have low body weight.”  Those that first defined LADA made no mention of relationship to obesity or insulin resistance, indeed, quite the opposite.

The first mention I found of “juvenile diabetes” was in the 1958 book How to Live with Diabetes, which said that Type 1 diabetes was three times more common in adults and children.  The 1970 advent of the Juvenile Diabetes Foundation seems to be the “change in tide” for claiming that Type 1 diabetes was a childhood disease.  Again, for 1900+ years, Type 1 diabetes was viewed as a disease that affected both adults and children, not by any means a childhood disease.

REFERENCES

Diabetes:  A Medical Odyssey.  USV Pharmaceutical Corp.  1971.

Tattersall, Robert.  2009.  Diabetes:  The Biography.

Bliss, Michael.  2007.  The Discover of Insulin.

Reudtner, Chris.  2003.  Bittersweet:  Diabetes, Insulin, and the Transformation of Illness.

Dolger, H., and B. Seeman, 1958.  How To Live With Diabetes.  W.W. Norton and Company, New York.

Irvine WJ, McCallum CJ, Gray RS, Duncan LJP (1977) Clinical and pathogenic significance of pancreatic islet cell antibodies in diabetics treated with oral hypoglycaemic agents. Lancet 1: 1025–1027.

Antibodies to Glutamic Acid Decarboxylase Reveal Latent Autoimmune Mellitus in Adults With a Non-Insulin-Dependent Onset of Disease, Tuomi et al, Diabetes February 1993.

The Lancet, October 12, 1985.  “Insulin-Dependent?”