- ACRONYMS AND DEFINITIONS
- A1C - Hemoglobin A1C
- ADA - American Diabetes Association
- CrCl - Creatinine clearance
- DKA - Diabetic ketoacidosis
- OGTT - Oral glucose tolerance test
- HLA - Human leukocyte antigen
- LADA - Latent autoimmune diabetes in adults
- T1DM - Type one diabetes mellitus
- T2DM - Type two diabetes mellitus
- ULN - Upper limit of normal
- EPIDEMIOLOGY
- The incidence of T1DM varies by geography. The lowest rates are seen in China and South America (<1 case/100,000 per year), and the highest occur in Europe, Canada, and New Zealand (>20 cases/100,000 per year). Males and females are affected equally, and Whites are affected more than other races.
- In the U.S., the overall incidence is between 10 - 20 cases/100,000 per year with the following breakdown by age:
- 0 - 4 years: 14.3 cases/100,000 per year
- 5 - 9 years: 22.1 cases/100,000 per year
- 10 - 14 years: 25.9 cases/100,000 per year
- 15 - 19 years: 13.1 cases/100,000 per year [27]
- PATHOLOGY
- Type 1 diabetes, also called insulin-dependent diabetes mellitus (IDDM) and juvenile-onset diabetes, accounts for 5 - 10% of diabetes cases, and T2DM makes up the rest. T1DM occurs when insulin-producing beta cells in the pancreas are destroyed over time by autoimmune antibodies (see antibodies in T1DM). Insulin production typically ceases in childhood or adolescence, with an average age of onset of 13 years.
- A small subset of patients with T1DM have no autoimmune antibodies, and these cases are referred to as "idiopathic type 1 diabetes" or "type 1 diabetes with unknown cause." Affected patients are typically of African or Asian descent with a very strong family history of diabetes. The disease course can be highly variable, with some patients experiencing intermittent episodes of DKA and fluctuating insulin requirements.
- Type 1 diabetes can also develop in adulthood. See latent autoimmune diabetes in adults for more. [2,28]
- RISK FACTORS
- Family history
- Family history is the strongest known risk factor for developing T1DM, with 10 - 15% of affected individuals having a family member with the disease
| Lifetime risk of T1DM for a person with an affected family member | |
|---|---|
| Lifetime risk in the general population is 0.4% | |
| Relative with T1DM | Lifetime risk for patient |
| Identical twin | > 70% |
| Both parents | 10 - 25% |
| Father | 6 - 9% |
| Sibling | 6 - 7% |
| Mother | 1 - 4% |
- Genetic association
- A number of genes have been identified that increase the risk of T1DM. HLA haplotypes DQB1 and DRB1 are associated with islet cell antibody development (see T1DM antibodies), the most common cause of T1DM. Monogenic (single gene) defects that impair beta cell function are less common (< 5%) and divided into two groups: neonatal diabetes and maturity-onset diabetes of the young (MODY). Neonatal diabetes is marked by diabetes within the first 6 months of life, and MODY presents as mild hyperglycemia before the age of 25 with normal insulin sensitivity. Identifying patients with monogenic defects is important because it has treatment implications. ADA recommendations for monogenetic testing are provided below. See NIH monogenic diabetes webpage for more.
- Monogenetic testing is indicated in the following patients:
- Diabetes diagnosed within the first 6 months of life (with occasional cases presenting later, mostly INS and ABCC8 mutations)
- Diabetes without typical features of type 1 or type 2 diabetes (negative diabetes-associated autoantibodies, no obesity, lacking other metabolic features, especially with strong family history of diabetes)
- Stable, mild fasting hyperglycemia (100 – 150 mg/dL [5.5–8.5 mmol/L]), stable A1C between 5.6% and 7.6% (between 38 and 60 mmol/mol), especially if no obesity [28]
- Other risk factors
- Observational studies that have looked for other T1DM risk factors (e.g. geography, infant diet, vaccines, viral infections) have had mixed results, and no clear association has been established
- SCREENING
- Overview
- T1DM typically presents with an abrupt onset of symptomatic hyperglycemia (e.g. polydipsia, polyuria, polyphagia. weight loss), and 40 - 60% of patients will be in DKA. There is no universal T1DM screening recommendation for the general population. Screening relatives of affected individuals for autoimmune antibodies is the most logical approach, and ADA recommendations are provided below.
- Screening recommendations for type 2 diabetes are covered here - ADA T2DM screening recommendations
- ADA T1DM screening recommendations
- Screening for presymptomatic type 1 diabetes using screening tests that detect autoantibodies to insulin, glutamic acid decarboxylase (GAD), islet antigen 2 (IA-2), or zinc transporter 8 is currently recommended in the setting of a research study or can be considered an option for first-degree family members of a proband with type 1 diabetes.
- Development of and persistence of multiple islet autoantibodies is a risk factor for clinical diabetes and may serve as an indication for intervention in the setting of a clinical trial or screening for stage 2 type 1 diabetes [28]
- SYMPTOMS
- Classic symptoms
- Patients with T1DM often present with sudden worsening of the symptoms below, whereas in T2DM, symptoms may be lacking or mild for many years
- Classic symptoms of T1DM include:
- Increased urination (polyuria)
- Increased thirst (polydipsia)
- Weight loss
- Increased hunger and visual changes may also be present but are less frequent
- Diabetic ketoacidosis (DKA)
- In the U.S., approximately 25% of type 1 diabetics present with DKA. DKA occurs when a lack of insulin prevents the body from utilizing glucose for energy, causing it to metabolize fatty acids instead. A byproduct of fatty acid metabolism is ketone bodies, which are acidic and lower blood pH (ketoacidosis). Ketoacidosis-induced electrolyte and pH imbalances can be fatal. See high anion gap metabolic acidosis for more.
- Symptoms of DKA include:
- Increased urination (polyuria)
- Increased thirst (polydipsia)
- Weight loss
- Dehydration
- Deep or rapid breathing - a natural reaction that expels carbon dioxide and helps raise blood pH
- Nausea and vomiting
- Lethargy progressing to coma in severe cases [3]
- DIAGNOSIS
- Overview
- Diagnostic criteria for T1DM are the same as T2DM (see blood sugar values below). Disease presentation and patient characteristics can help distinguish between the two.
- Factors that are associated with a higher likelihood of T1DM
- Presentation in childhood or adolescence - almost all diabetes before age 10 is T1DM
- Diabetic ketoacidosis
- Classic symptoms are present
- Symptom onset is abrupt
- Patient is normal weight or underweight
- Blood sugar values
- Blood sugar values can be used to diagnose T1DM and prediabetes using one of the three methods below
- Fasting blood sugar
- A fasting blood sugar is defined as no caloric intake for 8 hours prior to testing
- Diabetes: ≥ 126 mg/dl
- Prediabetes: 100 - 125 mg/dl
- Two-hour oral glucose tolerance test (2-hour OGTT)
- During a 2-hour OGTT, the patient consumes a 75 gram load of glucose solution and a blood sugar is drawn 2 hours later
- Diabetes: ≥ 200 mg/dl
- Prediabetes: 140 - 199 mg/dl
- Random blood sugar
- A random blood sugar (drawn without regard to last calorie intake) of ≥ 200 mg/dl when classic symptoms of diabetes are present (e.g. weight loss, polyuria, polydipsia) is diagnostic for diabetes. Random blood sugars are not used to diagnose prediabetes. [29]
- Hemoglobin A1C test
- The hemoglobin A1C test can be used to diagnose T1DM and prediabetes; however, it is less sensitive than a fasting glucose level, as one-third of patients with an A1C < 6.5% will have a fasting glucose ≥ 126. The lower sensitivity appears to be more of an issue in adolescents than adults (see hemoglobin A1C for more). [29]
- Diabetes: A1C ≥ 6.5%
- Prediabetes: A1C 5.7 - 6.4%
- Stages of T1DM
- Three stages of T1DM (see below) have been described that are now being used as study inclusion criteria and indications for Tzield®
| T1DM Stages |
|---|
|
Stage 1
|
|
Stage 2
|
|
Stage 3
|
- Insulin, Proinsulin, and C-peptide
- Beta cells produce insulin in several steps (see insulin production illustration)
- Insulin levels can help determine if patients with early T1DM still make insulin. However, they do not distinguish between endogenous and exogenous insulin, so they are not useful in patients receiving insulin injections.
- C-peptide is a byproduct formed when proinsulin is cleaved to insulin. Unlike insulin levels, it is not affected by exogenous insulin, so it can be used to measure insulin production in patients receiving insulin. It can also be used to evaluate for factitious hypoglycemia, a condition where people inject themselves with insulin to cause low blood sugars so that they appear sick.
- Proinsulin is an insulin precursor found in beta cells. Normally, only 1 - 3% of proinsulin is secreted into the circulation. Elevated levels can be a sign of insulinoma, a rare cancer of beta cells. Proinsulin levels are not helpful in evaluating diabetes. [4,29]
- Genetic and antibody testing
- The ADA recommends genetic testing in certain patients with atypical features (see genetic association)
- Antibody testing may be appropriate for screening or staging of T1DM (see T1DM antibodies)
- T1DM AUTOIMMUNE ANTIBODIES
- Antibody types
- Most patients with T1DM have autoimmune antibodies that lead to the destruction of pancreatic beta cells. The hormone-producing cells of the pancreas are collectively referred to as islet cells, and beta cells are the subtype that produces insulin. Other subtypes include alpha (glucagon), delta (somatostatin), and epsilon (ghrelin). Pancreatic autoimmune antibodies include the following:
- Islet cell cytoplasmic autoantibodies (ICA) - ICAs are antibodies to various antigens in islet cells. ICAs are present in up to 90% of patients with newly-diagnosed T1DM.
- Glutamic acid decarboxylase (GAD) 65 antibodies - GAD is an enzyme in beta cells. GAD65 antibodies are present in up to 80% of type 1 diabetics at the time of diagnosis.
- Islet cell antibody IA-2 - also referred to as islet cell autoantigen 512 (ICA-512), insulinoma-associated-2 autoantibodies (IA-2A), and tyrosine phosphatase-related islet antigen-2. Islet cell antibody IA-2 is present in 60% of type 1 diabetics.
- Insulin autoantibodies (IAA) - IAA are antibodies to insulin present in 90% of type 1 diabetics under the age of 5 and 70% of those older than 5. IAA testing is not informative in patients who have been treated with exogenous insulin, which often elicits similar antibodies, turning the test positive. [29]
- Zinc transporter 8 antibodies (ZnT8Ab) - ZnT8Ab are antibodies to zinc transporter 8, a cation efflux transporter on the surface of islet cells. The test has a sensitivity of 65% and a specificity of > 98% for T1DM. [22]
- NOTE: Islet cell antibody IA-2, GAD65 antibody, and insulin antibody (IAA) are sometimes collectively referred to as islet cell antibodies, and some labs offer screening tests that detect these 3 antibodies combined.
- Diabetes risk
- Type one diabetes: 85 - 90% of patients with T1DM have autoimmune antibodies. The presence of more than one antibody type is associated with a > 90% lifetime risk for T1DM. In one study, normoglycemic children (median age 3.1 years) with ≥ 2 autoimmune antibodies had a 3-year cumulative risk of T1DM of 24.9%. [PMID 31990315]
- Type two diabetes: 10 - 15% of Caucasian adults with T2DM have islet cell autoantibodies, particularly GAD65A (see latent autoimmune diabetes in adults)
- Individuals without diabetes: 1 - 2% of healthy individuals have one type of antibody and are at low risk for developing T1DM [4]
- ADA recommendations
- Screening for presymptomatic type 1 diabetes using screening tests that detect autoantibodies to insulin, glutamic acid decarboxylase (GAD), islet antigen 2 (IA-2), or zinc transporter 8 is currently recommended in the setting of a research study or can be considered an option for first-degree family members of a proband with type 1 diabetes.
- Development of and persistence of multiple islet autoantibodies is a risk factor for clinical diabetes and may serve as an indication for intervention in the setting of a clinical trial or screening for stage 2 type 1 diabetes [28]
- TREATMENT RECOMMENDATIONS
- ADA recommendations
- Other related pages
- Exercise and insulin - review of dosing insulin around exercise
- Diabetic diet - review of diabetic diet
- Carbohydrate counting - review of carbohydrate counting
- Glycemic index - review of the glycemic index
- TEPLIZUMAB (TZIELD®)
- Overview
- In 2022, the FDA approved teplizumab (Tzield®) for the prevention of T1DM in pediatric patients 8 years and older with stage 2 type 1 diabetes. Teplizumab is a monoclonal antibody that binds CD3 antigen on T lymphocytes, activating signaling that reduces their affinity for pancreatic beta cells.
- Effectiveness
- The effects of teplizumab on T1DM prevention were evaluated in a placebo-controlled trial that enrolled 76 subjects (median age 14 years) with ≥ 2 autoantibodies, dysglycemia (FBS 110 - 125 or 2-hour OGTT 140 - 199), and a relative with T1DM. Patients were randomized to a 14-day infusion of teplizumab or saline. During follow-up, the median time to T1DM diagnosis was 48.4 months in the teplizumab group and 24.4 months in the placebo group. The annual rate of diabetes diagnosis was 14.9% and 35.9%, respectively. [PMID 31180194]
- Side effects / Precautions
- Acute Epstein-Barr virus (EBV) or cytomegalovirus (CMV) infection - teplizumab is not recommended in patients with acute EBV or CMV infection.
- Lymphopenia - in its pivotal trial, teplizumab caused lymphopenia in up to 73% of patients. The average lymphocyte nadir occurred on day 5 of treatment and returned to normal in most patients by day 45. Teplizumab is not recommended in patients with a lymphocyte count less than 1000/mcl.
- Rash - in trials, 48% of teplizumab-treated patients developed a rash. Most rashes were mild and resolved without treatment.
- Cytokine release syndrome (CRS) - in trials, CRS occurred in 5% of teplizumab-treated patients, typically within the first 5 days of treatment. Symptoms of CRS include fever, nausea, fatigue, headache, myalgia, arthralgia, and elevations of ALT, AST, and total bilirubin. Monitor liver enzymes during treatment and stop or hold teplizumab for severe symptoms, including ALT/AST > 5 X ULN or bilirubin > 3 X ULN.
- Infections - in trials, serious infections occurred in 3.5% of teplizumab-treated patients and 2% of control patients. Do not give to patients with active or chronic infections.
- Hypersensitivity reactions - Hypersensitivity reactions, including serum sickness, angioedema, urticaria, rash, and bronchospasm, have been reported in patients receiving teplizumab. Premedication with an NSAID or acetaminophen, an antihistamine, and an antiemetic during the first 5 days of dosing is recommended.
- Vaccinations - the safety of teplizumab with live-attenuated vaccines has not been studied. Inactivated or mRNA vaccinations are not recommended within the 2 weeks prior to teplizumab treatment, during treatment, or 6 weeks after completion of treatment. Live-attenuated vaccinations are not recommended within the 8 weeks prior to teplizumab treatment, during treatment, or up to 52 weeks after treatment.
- Dosing
- Teplizumab is not recommended in patients with any of the following:
- Lymphocyte count less than 1,000/mcL
- Hemoglobin less than 10 g/dL
- Platelet count less than 150,000/mcL
- Absolute neutrophil count less than 1,500/mcL
- Elevated ALT or AST greater than 2 X ULN or bilirubin greater than 1.5 X ULN
- Laboratory or clinical evidence of acute infection with Epstein-Barr virus (EBV) or cytomegalovirus (CMV)
- Active serious infection or chronic active infection other than localized skin infections
- Administer teplizumab by IV infusion over 14 days using the following schedule:
- Day 1: 65 mcg/m2
- Day 2: 125 mcg/m2
- Day 3: 250 mcg/m2
- Day 4: 500 mcg/m2
- Days 5 through 14: 1,030 mcg/m2
- See body surface area calculator
- Missed doses
- If a planned teplizumab infusion is missed, resume dosing by administering all remaining doses on consecutive days to complete the 14-day treatment course [33]
- THYROID DISEASE AND CELIAC DISEASE SCREENING
- Overview
- Type 1 diabetics are at greater risk for other autoimmune disorders, particularly hypothyroidism and celiac disease. Hypothyroidism is seen in 10% of type 1 diabetics, and celiac disease is diagnosed in 3 - 16%. ADA recommendations for screening are provided below.
- ADA screening recommendations for celiac disease and hypothyroidism
- Adults
- Screen for thyroid disease soon after diagnosis
- Screen for celiac disease in the presence of gastrointestinal symptoms, signs, or laboratory manifestations suggestive of celiac disease
- Children
- Check a TSH at diagnosis and every 1 - 2 years thereafter. Consider testing for antithyroid peroxidase and antithyroglobulin antibodies soon after diagnosis. (see thyroid labs for more)
- Screen children with type 1 diabetes for celiac disease by measuring IgA tissue transglutaminase (tTG) antibodies, with documentation of normal total serum IgA levels, soon after the diagnosis of diabetes, or IgG to tTG and deamidated gliadin antibodies if IgA deficient. Repeat screening within 2 years of diabetes diagnosis and then again after 5 years and as indicated (see celiac disease labs for more). [26]
- LATENT AUTOIMMUNE DIABETES IN ADULTS (LADA)
- Physiology
- Most patients with T1DM stop producing insulin in childhood. A small subset of patients, however, continue to have functioning beta cells for many years, and insulin production does not cease until adulthood. This condition is sometimes referred to as latent autoimmune diabetes in adults (LADA). LADA patients are often diagnosed with T2DM, which eventually becomes unresponsive to non-insulin therapies.
- Incidence
- The incidence of LADA is not well-defined, but islet cell antibodies are found in 25% of type 2 diabetics younger than 35 and 10% of those 40 - 75. [32]
- Signs of LADA
- LADA can be challenging to diagnose because it develops gradually, and affected patients will already be using insulin in many cases
- Signs that a patient has developed LADA may include the following:
- Patient requires a significant amount of insulin
- Blood sugar control is erratic with very high numbers and episodes of hypoglycemia
- Blood sugar control that changes abruptly
- Type 2 diabetic that develops DKA
- Diagnosis
- There are no consensus diagnostic criteria for LADA. In general, LADA may be considered when a patient with T2DM is found to have islet cell antibodies, of which GAD65A is the most common. C-peptide levels to measure insulin production may also be informative.
- Treatment
- The ADA makes no specific recommendations for LADA other than to say that it is important to accelerate insulin initiation prior to deterioration of glucose control or development of DKA. Some studies have shown that early insulin therapy may help preserve remaining beta cell function better than non-insulin agents. [28,32]
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