Type 1 diabetes mellitus (T1DM) is an autoimmune disease that leads to the destruction of the insulin-producing pancreatic beta cells. Insulin is an essential anabolic hormone that exerts multiple effects on glucose, lipid, protein and mineral metabolism, as well as growth. Importantly, insulin allows glucose to enter muscle and adipose cells, stimulates the liver to store glucose as glycogen and synthesize fatty acids, stimulates the uptake of amino acids, inhibits the breakdown of fat in adipose tissue, and stimulates the uptake of potassium into cells. People with T1DM require life-long insulin replacement therapy. Without insulin, diabetic ketoacidosis (DKA) develops and is life-threatening.
In T1DM there is the immune destruction of the beta cells in the pancreatic islets over months or years, causing an absolute deficiency of insulin. Although the exact etiology of T1DM is still unknown, researchers believe there is a genetic predisposition, with a strong link with specific HLA (DR and DQ) alleles, especially DRB103-DQB10201 and DRB 10401-DQB10302H. Multiple other genes contribute to the heritability as well. The risk of developing T1DM with no family history is approximately 0.4%, while offspring of an affected mother is 1% to 4%, offspring of an affected father is 3% to 8%, and offspring of both affected parents is as high as 30%. In monozygotic twins, the risk of developing T1DM in the first 10 years of diagnosis of the first twin is 30%, with a lifetime risk around 65%.
The presence of circulating pancreatic autoantibodies suggests that the individual is at risk for or has developed T1DM. These antibodies include islet cell cytoplasmic antibodies (ICA), antibodies to insulin (IAA), glutamic acid decarboxylase (GAD65), insulinoma-associated 2 or protein tyrosine phosphatase antibodies (IA-2) and zinc transporter8 (ZnT8). The greater the number of detectable antibodies and the higher their titers, the greater the risk of developing T1DM.
In those at risk, it is generally believed that a virus or other environmental factors trigger the autoimmune beta-cell destruction. Some studies have found an increased development of T1DM in children born to a mother that had Coxsackievirus or another Enterovirus during pregnancy. Environmental toxins have also been postulated to play a role. The hygiene hypothesis suggests that improved sanitation relates to the increased development of autoimmune-mediated disorders. It is proposed that the reduction of childhood exposure to infectious agents leads to the lack of proper immune system development. Dietary factors have also been examined as potential triggers. In one study showed an increased development of islet autoimmunity with cow’s milk-protein consumption in study participants with low to moderate-risk HLA-DR genotypes but no significant increased risk in those with a high-risk genotype.
T1DM is one of the most frequent chronic diseases in children but can start at any age. There has been a steady increase in the incidence and prevalence of T1DM, representing approximately 5% to 10% of people with diabetes. In the United States, there are an estimated 1.24 million people with T1DM, and that number is expected to grow to 5 million by 2050. Between 2001 and 2009 there was a 21% increase in the prevalence of T1D in those 20 years of age or younger. The most common age of presentation is between the ages of 4 to 6 and in early puberty (10 to 14 years). Worldwide, there is also a considerable geographic variation in incidence. The highest reported incidences are in Finland and other Northern European nations with rates approximately 400-times greater than those seen in China and Venezuela, where there is the lowest reported incidence. In the United States, the highest rate of T1DM is seen in non-Hispanic Caucasians, affecting both females and males almost equally.
The development of T1DM occurs in 3 stages. Stage 1 is asymptomatic and characterized by normal fasting glucose, normal glucose tolerance, and the presence of greater than or equal to 2 pancreatic autoantibodies. Stage 2 diagnostic criteria include the presence of greater than or equal to 2 pancreatic autoantibodies and dysglycemia: impaired fasting glucose (glucose of 100 to 125 mg/dl) or impaired glucose tolerance (2-hour PG of 140 to 199 mg/dL) or a hemoglobin A1c between 5.7% to 6.4%. Individuals remain asymptomatic. In Stage 3 there is diabetes or hyperglycemia with clinical symptoms and 2 or more pancreatic autoantibodies.
T1DM in children classically presents with hyperglycemic symptoms, with one-third of cases presenting in DKA. The onset of symptoms can be sudden at the time of diagnosis, especially in youth. If not evaluated and treated promptly, it can become a medical emergency. Patients most commonly present hyperglycemic with polydipsia, polyuria, and polyphagia. Polyuria is secondary to osmotic diuresis, which is caused by the hyperglycemia. Young children may present with nocturnal enuresis. Polydipsia is related to hyperosmolality and dehydration from increased urination. Blurred vision is possible as glucose can cause osmotic swelling of the lens. There is also a common history of weight loss. There is increased lipolysis and ketone production with a breakdown of muscle and fat. This results in muscle wasting, polyphagia, fatigue, and weakness. Electrolyte abnormalities may also be present. If these symptoms are not recognized, patients will present in DKA requiring hospitalization and treatment with intravenous fluids, insulin, potassium and careful monitoring.
The onset of symptoms in T1DM in adults can be more variable. Diagnosis of diabetes can be made based on plasma glucose criteria or hemoglobin A1c (HbA1c) criteria. If the patient presents with acute onset of symptoms, it is preferred to use the plasma glucose level for diagnosis instead of the HbA1c, as the patient’s 2 to 3-month average glucose levels may not be abnormal. T1DM can be diagnosed with random plasma glucose greater than or equal to 200 mg/dl in a patient with classic symptoms. For diagnosis, a fasting plasma glucose greater than or equal to 126 mg/dl (fasting is nothing orally for at least 8 hours, except for water) can also be used. An oral glucose tolerance test (OGTT) is rarely performed. For the OGTT, the glucose level 2 hours after ingesting 75 g of anhydrous glucose should be greater than or equal to 200 mg/dl to diagnose diabetes. The diagnostic criteria for HbA1c are greater than or equal to 6.5%, performed in a laboratory using a method that is NGSP-certified and standardized to the DCCT assay. If the patient lacks classic symptoms of hyperglycemia or hyperglycemic crisis, it is recommended that a second test is performed to confirm the diagnosis.
In the initial outpatient visit, it is important to obtain a complete medical, surgical, social, and family history. History of prior diabetes education including monitoring of blood glucose and ketones, proper administration of insulin, recognition/treatment of hypoglycemia, education on nutrition, sick-day rules, and foot care should also be obtained. Particular attention should be paid to prior treatment, current medication, and history of acute (hypoglycemia including severe episodes and episodes of DKA) and chronic (skin disorders, dental problems, retinopathy, macular edema, neuropathy, kidney disease, cardiovascular disease, peripheral arterial disease, stroke, foot ulcers) diabetic-related complications.
Clinicians should measure height, weight, and blood pressure. The thyroid should be palpated, as patients with T1DM are at increased risk of developing autoimmune thyroid disease. The skin should be examined, especially at sites of insulin injection or infusion. If lipodystrophy is evident, they should be educated on the importance of varying injection sites. The heart, chest, and abdomen should also be examined. A foot exam is performed to examine pedal pulses, foot deformities, pre-ulcerative lesions, ulcerations, callus, and onychomycosis. It is also important to test vibratory and protective sensation with a 10-g monofilament exam to look for peripheral neuropathy. A screen for depression (for example, PHQ-2/PHQ-9) is also recommended annually.
HbA1c is recommended every 3 to 6 months. The HbA1c reflects glycemic control over the previous 2 to 3 months. There should also be a yearly lipid profile, liver function tests, spot urine albumin to creatinine ratio, serum creatinine, GFR, and TSH. These tests can be repeated more frequently if the previous results were abnormal. It is also important to remember that patients with T1DM are at an increased risk of developing other autoimmune diseases, such as autoimmune thyroid disease, primary adrenal insufficiency, celiac disease, and vitiligo. Screening for these disorders should be considered when appropriate.
All patients with T1DM require insulin therapy. Multiple, daily, insulin injections (MDI) using a basal/bolus insulin regimen or continuous subcutaneous insulin infusion through an insulin pump are the preferred treatment. The patient’s weight in kilograms is multiplied by 0.5 to 0.6 units to calculate the initial total daily insulin dose (TDD) in an adult. In general, 40% to 50% of the total daily dose comprises the patient’s long-acting insulin needs and the other half approximates the daily short-acting insulin needs, to be given before or with meals. Dosing is modified based on many factors including diet and physical activity. Adjustments can also be made based on self-monitoring of blood glucose or continuous glucose monitoring results. When possible, patients should be taught carbohydrate counting and instructed to use insulin to carbohydrate ratio that approximates the grams of carbohydrates that will be covered by one unit of insulin. If carbohydrate counting is not realistic due to poor numeracy or other reasons, a carbohydrate-consistent diet is helpful. Patients should be taught which foods contain carbohydrates and benefit from meeting with a dietician. It is also recommended to calculate a correction factor, which can be initially estimated using the formula 1800 divided by the TDD. This estimates the fall in blood glucose for every 1 unit of insulin given. This number will need to be adjusted per subsequent glucose monitoring results.
It is important to note that insulin requirements vary across the lifespan and under specific circumstances. For example, larger doses of insulin are normally required during puberty, pregnancy, when steroids are given and with the development of obesity. Individuals need less insulin when they are engaged in aerobic exercise and during the “honeymoon period.” The honeymoon period occurs soon after diagnosis when there is a temporary recovery of beta cell function.
Multiple types of insulin can be used for diabetes management. Rapid-acting insulin (lispro, aspart, glulisine) will generally have on onset in 10 to 30 minutes, peak in 30 to 90 minutes, and have a duration of 3-5 hours. Insulin aspart injection is more rapidly acting. Short-acting insulin (regular insulin) has an onset in 30 minutes to 1 hour, peak in 2 to 4 hours with a duration of 6 to 8 hours. Intermediate insulin (NPH, NPL) will have on onset in 1.5 to 4 hours, peaks around 4 to 10 hours and with a duration of 12 to 18 hours. Long-acting insulin is often given once a day (glargine, degludec) or 1 to 2 times daily (detemir). Glargine does not have a peak and will last for approximately 20 to 24 hours. U-300 glargine lasts more than 24 hours, and degludec has a longer duration of action, up to 42 hours. When MDI is used, the patient will ideally use rapid insulin with each meal and for hyperglycemic correction, and long-acting basal insulin. If using insulin pump therapy, a continuous infusion of rapid-acting insulin will be used.
Blood glucose readings should be monitored throughout the day. Patients should check their blood glucose pre-meals, 2 to 3 hours post meals (when adjusting prandial dosing), before bedtime and when they suspect hypoglycemia. It is beneficial to check a 2 am to 3 am glucose reading if the morning glucose value is high, to determine the underlying cause of hyperglycemia. It is important to educate patients about the symptoms of hypoglycemia, which include diaphoresis, tachycardia, lightheadedness, confusion, visual changes, and tremors. 15 to 20 g of glucose should be given orally for blood glucose levels below 70 mg/dl. Patient’s should then recheck their blood glucose 15 minutes later and consume a snack once the value has normalized to prevent recurrence. Glucagon should be prescribed for emergency use when patients have a severe hypoglycemic episode and are unable to consume carbohydrates by mouth.
Continuous glucose monitors (CGM) are extremely useful tools for people with T1DM. Sensors are inserted into the subcutaneous tissue and measures interstitial glucose levels which are transmitted to a receiver and displayed in real time. One can examine trends and use alarms to prevent serious hypoglycemia episodes. There are continuous glucose monitoring systems (CGMs) that transmit glucose readings every 5 minutes and can alarm the patients if readings are too high or too low, or if there is a rapid change in glucose value (thresholds set by the patient). These CGMs can communicate with insulin pumps. Readings from the certain CGM sensors can be transmitted to smartphones and can be shared with relatives, friends, or caregivers. Other sensors communicate with insulin pumps, providing hybrid artificial pancreas. Another CGM is a less expensive option that is worn for 10 days at a time. This “flash” CGM records glucose readings every 15 minutes, does not have an alarm feature, and uses a “reader” (a device the user scans over the site of sensor placement) to visualize recent glucose readings and trends. All these devices make it easier to monitor glucose values throughout the day. Users examine trends and are provided with important information to guide insulin therapy and food intake to help avoid wide glycemic variation.
In addition to insulin therapy, diet, and physical activity, individuals with T1DM should generally have an annual eye exam by an eye care specialist. Those with foot deformities, neuropathy, history of foot ulcers or peripheral arterial disease should see a podiatrist, be educated in proper foot care/footwear, and be evaluated for orthotics if necessary. Other specialists such as psychologists, nephrologists, and cardiologists may be needed as well.
More advances in T1DM management can be expected soon. “Closed loop” systems in which CGMs directly communicate with insulin pumps and automatically direct insulin infusion rates are anticipated. Research is also being conducted on islet cell transplantation. Currently, individuals who receive islet cell transplantation require immunosuppressive therapy, and many islets do not have a long lifespan. Encapsulated islets unrecognizable by the immune system would obviate the need for immunosuppressive therapy and are a promising future therapy. These and other research initiatives give hope to the increasing number of youth and adults with T1DM that a cure is in their future.