Type 1 Diabetes

Etiology

T1D results from the autoimmune destruction of the β-cells in Langerhans pancreatic islets, ultimately leading to absolute insulin deficiency.[5] This disease manifests in genetically susceptible individuals in whom the autoimmune process is triggered by one or more environmental factors, resulting in immune-mediated β-cell destruction. The loss of β-cell function progresses gradually over months to years, during which time the affected individual remains asymptomatic. Symptomatic hyperglycemia develops when a significant amount of β-cell dysfunction occurs.

Genetic Associations of Type 1 Diabetes

The exact etiology of T1D remains unknown. However, a genetic predisposition is strongly associated with specific human leukocyte antigen (HLA) alleles DR and DQ. HLA genes have been reported to account for approximately 40% of the familial aggregation of T1D. The HLA class II DRB1, -DQA1, -DQB1 genotypes confer the strongest genetic risk factors for T1D.[6] Specifically, HLA DR4-DQ8 and DR3-DQ2 have been reported to be present in about 90% of children with T1D.

The lifetime risk of developing T1D is significantly increased in close relatives of a patient with T1D. However, most cases occur in patients without any family history of T1D or other autoimmune disease. This association is more pronounced in youth-onset than adult-onset T1D.[7] Multiple other genes also contribute to heritability.[8] Screening of family members must be considered, especially first-degree relatives of individuals with T1D, to identify people who may be at risk. 

Environmental Risk Factors

Environmental factors are generally believed to trigger autoimmune β-cell destruction in genetically susceptible people. Some studies have found an increased T1D risk related to infection with Coxsackie virus, enteroviruses, cytomegalovirus, rubella virus, influenza B, mumps virus, and more recently, SARS-CoV-2 (COVID-19).[9][10][11] Other environmental factors that may increase risk include pregnancy and perinatal conditions, childhood vaccination, and dietary factors such as cow's milk and cereal exposure. Research to better understand the exact role of these environmental agents in the etiology of T1D is ongoing.

Autoimmunity

Besides genetic and environmental factors, several T1D-related autoantibodies target pancreatic β-cell autoantigens, leading to immune-mediated β-cell destruction. Autoantibody targets include antigens in the islet cell cytoplasm (ICA), insulin (IAA), glutamic acid decarboxylase isoform 65 (GAD65), insulinoma antigen 2/islet tyrosine phosphatase 2 (IA-2), and zinc transporter isoform 8 (ZnT8). IAAs are primarily detected in children.[12] GAD65 is the most common autoantibody detected in adults.[13] Testing for autoantibodies to pancreatic β-cell autoantigens is important in confirming the diagnosis and distinguishing T1D from other forms of diabetes, mainly type 2 diabetes (T2D). The greater the number of detectable antibodies and the higher their titers, the greater the risk of developing T1D. 

Epidemiology

T1D is one of the most frequent chronic diseases in children, but the disease can affect any age group. Childhood-onset T1D tends to present with more severe clinical presentations, including symptomatic severe hyperglycemia or diabetic ketoacidosis (DKA). In adults, new-onset T1D may be misdiagnosed as T2D, but youth-onset T1D is more common than adult-onset T1D. Although autoimmune disease tends to be more commonly seen in women, T1D appears to be slightly more common in men.[14]

T1D incidence and prevalence have steadily increased, now representing approximately 5% to 10% of people with diabetes. A systematic review and meta-analysis reported that the worldwide prevalence of T1D was 9.5%, with an incidence of 15 per 100,000 people.[15] Worldwide, T1D's geographic incidence varies considerably. 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 incidence is reportedly the lowest. 

Pathophysiology

The natural history and development of T1D in genetically susceptible individuals occur in 3 stages. Stage 1, the preclinical stage, is characterized by the onset of autoimmune β-cell destruction and insulitis caused by immune-mediated destruction. This stage is asymptomatic and characterized by normal fasting glucose, normal glucose tolerance, and the presence of at least 2 pancreatic autoantibodies. In Stage 2, a significant amount of β-cell dysfunction has already occurred, leading to dysglycemia. The diagnostic criteria include the presence of pancreatic autoantibodies with impaired fasting glucose (fasting glucose 100-125 mg/dL), impaired glucose tolerance (2-hour post-75 g glucose load glucose 140-199 mg/dL), or a glycated hemoglobin (HbA1c) level of 5.7% to 6.4%. Individuals remain asymptomatic.

Stage 3 is characterized by the clinical onset of disease where individuals present with symptomatic hyperglycemia. The diagnostic criteria include diabetes, defined by hyperglycemia (random glucose ≥200 mg/dL) with clinical symptoms, fasting glucose of at least 126 mg/dL, blood glucose level of at least 200 mg/dL 2 hours after ingesting 75 g of glucose during an oral glucose tolerance test, or HbA1c greater than or equal to 6.5%. T1D classically presents with symptomatic hyperglycemia, especially in children. Individuals with classic new-onset T1D usually present with symptoms of polydipsia, polyuria, polyphagia, unintentional weight loss, fatigue, and weakness. Life-threatening DKA can develop if T1D is not evaluated and treated promptly.

DKA is characterized by hyperglycemia, ketonuria, and electrolyte disturbances that lead to metabolic acidosis. Besides polyuria, polydipsia, and unintentional weight loss, patients in DKA may present with fruity-smelling breath, lethargy, and, in severe cases, even coma. Early detection and initiation of treatment, including intravenous fluids, insulin, potassium, and careful monitoring, is important. Most patients require admission to an intensive care unit for management and monitoring. The incidence of DKA in children ranges anywhere between 15% and 70%.[16]

The onset of symptoms in adults is more variable than in younger patients, and DKA is less common. Patients are often misdiagnosed with T2D and later found to be insulin-dependent. T1D can be difficult to distinguish from T2D. Screening for T1D antibodies and family history are important in confirming the diagnosis.

GAD65 should be the initial antibody tested when T1D in adults is suspected. IA2 or ZNT8 should be measured if GAD65 testing is negative or unavailable. C-peptide levels may also be used to determine β-cell function and the degree of insulin dependency when the diagnosis is still unclear. In patients with T1D, fasting insulin and C-peptide levels are inappropriately low when the concomitant plasma glucose concentration is elevated. By contrast, elevated fasting insulin and C-peptide levels suggest T2DM.

History and Physical

After the initial diagnosis and medical stabilization, successful management of T1D involves improving glycemic control, preventing long-term complications and sequelae of hyperglycemia, and T1D education while maintaining normal growth and development in children and improving quality of life. Initial diabetes education provided by an interprofessional care team is essential for the patient and family to acquire the knowledge needed to manage this chronic disease. Clinicians need to reinforce that multiple factors impact glycemic control and involve the patient or family in a comprehensive treatment plan that emphasizes a healthy lifestyle, which can improve disease outcomes. 

At the initial outpatient visit, obtaining a complete medical, psychosocial, and family history, including pregnancy and contraception history, is essential. History of prior diabetes education, monitoring of blood glucose and ketones, administration of insulin, and recognition and treatment of hypoglycemia should be obtained. Particular attention should be paid to the date of diagnosis, prior treatment received, knowledge of sick day rules, and history of acute complications (severe hypoglycemia or DKA) and chronic complications (eg, skin disorders, dental problems, diabetic retinopathy, diabetic neuropathy, kidney disease, cardiovascular disease, peripheral arterial disease, stroke, foot ulcers, and foot amputations).

Since people with T1D have an increased risk of developing other autoimmune disorders, including autoimmune thyroid pathology and celiac disease, the clinician should also screen for these conditions during clinical evaluation. Several measures are available for psychosocial screening, such as the Patient Health Questionnaire (PHQ-2/PHQ-9) for Depression and Generalized Anxiety Disorder (GAD-7). Diabetes distress and social determinants of health should be assessed. Eating disorders are common in individuals with type 1 diabetes, particularly young women. Thus, patients should be examined for this problem. Early cognitive decline is also common in adults. Therefore, cognitive testing should be considered when impairment is suspected.

A complete physical examination is also performed. A diabetes foot examination must be included to detect early peripheral neuropathy signs, foot deformities, pre-ulcerative lesions, ulcerations, calluses, and onychomycosis. Testing vibratory and protective sensations is also essential. Abnormal testing with a 10-g monofilament exam suggests an increased risk of ulceration. The skin should be examined, especially at insulin injection or infusion sites. If lipodystrophy is evident, patients should be educated on the importance of varying insulin injections or infusion sites.  

Evaluation

Patients with T1D can present with classic symptoms of new-onset diabetes, such as polyuria, polydipsia, lethargy, and weight loss. These individuals may also present more acutely with DKA. Other clinical manifestations include acute visual disturbances, perineal candidiasis, or, in some adults, an initial misdiagnosis of T2D before correctly identifying T1D.

Diabetes may be diagnosed using plasma glucose criteria, such as fasting plasma glucose or postprandial glucose during a 75-g oral glucose tolerance test (OGTT), or based on HbA1c levels. Diagnostic criteria for diabetes include the following:

• Fasting plasma glucose of at least 126 mg/dL on more than 1 occasion
• Random plasma glucose of at least 200 mg/dL with classic symptoms of hyperglycemia
• Plasma glucose of at least 200 mg/dL measured 2 hours after a 75-g OGTT
• HbA1C level of at least 6.5%[17]

In the absence of unequivocal hyperglycemia, the diagnosis is confirmed based on 2 abnormal test results. Once the diagnosis of diabetes is confirmed, distinguishing between T1D and other forms of diabetes, mainly T2D, is critical. These conditions may be differentiated based on clinical presentation and laboratory studies, including testing for T1D pancreatic autoantibodies and stimulated C-peptide levels, with the latter measuring pancreatic β-cell function. T1D pancreatic antibodies include ICA, IAA, GAD65, IA-2, and ZnT8. Most patients with T1D have 1 or more positive T1D antibodies at the time of diagnosis. 

Evaluating glycemic control by checking HbA1c levels is recommended every 3 months during each follow-up visit. Other laboratory tests that should be conducted, if not performed within the past year, include a lipid profile, serum creatinine, spot urinary albumin-to-creatinine ratio, liver function tests, thyroid-stimulating hormone, complete blood count with platelets, and serum potassium—especially if the patient is also taking an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or diuretic. Since people with T1D are at an increased risk of developing other autoimmune diseases, such as autoimmune thyroid conditions, celiac disease, primary adrenal insufficiency, and rheumatoid arthritis, screening for autoimmune disorders should be considered when clinically appropriate.[18]

Treatment / Management

Individuals with T1D require lifelong insulin replacement, regular blood glucose monitoring, and adjustments in diet and lifestyle to achieve optimal glycemic control. Glycemic targets should be personalized based on each patient's health status and coexisting conditions, guiding treatment strategies. According to the ADA, optimal HbA1c levels should be reached to minimize the risk of microvascular and macrovascular complications while preventing hypoglycemia. For most patients, an HbA1c goal of less than or equal to 7% is recommended, though older individuals or those with multiple health issues may benefit from more relaxed HbA1c targets. 

Insulin Replacement 

The goal in T1D management is physiologic replacement of insulin, either by administering multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion via an insulin pump. MDI or "basal-bolus" insulin therapy includes basal long-acting insulin (administered once or twice a day) and prandial or mealtime insulin using short-acting or rapid-acting insulin multiple times a day before meals. Continuous subcutaneous insulin infusion includes administering a rapid- or short-acting insulin continuously via an insulin pump with additional boluses initiated on the pump for prandial coverage at mealtimes. 

Multiple daily injections

Various insulin types may be used for insulin injection therapy.[19] The choice of basal and prandial insulin for MDI usually depends on patient preference, insurance coverage, availability, and cost. Long-acting insulin is preferred for basal insulin injection therapy, often given once a day (U-100 and U-300 glargine, degludec) or 1 to 2 times daily (detemir and U-100 glargine).

Glargine does not have a pronounced peak and lasts 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. Intermediate insulin, eg, neutral protamine Hagedorn or neutral protamine lispro, is the least expensive basal insulin but is more likely to cause hypoglycemia. Intermediate insulin's action onset is 1 to 2 hours. Peak action is at 2 to 8 hours, and duration is 12 to 24 hours. This insulin form is usually given before breakfast and bedtime. When MDI is used, the patient should inject rapid-acting insulin with each meal for hyperglycemia correction and a daily long-acting basal insulin. 

For prandial or mealtime coverage, options include rapid-acting insulin, ultra-rapid-acting insulin, and short-acting regular insulin. This type of insulin is usually administered within 10 to 15 minutes before meals. Rapid-acting insulin (lispro, aspart, glulisine) generally has an onset of 12 to 30 minutes, peaks in 1 to 3 hours, and has a duration of action of 3 to 6 hours. Ultra-rapid-acting lispro or aspart has a slightly quicker onset and somewhat shorter duration. Short-acting insulin (regular insulin) has an onset of 30 minutes to 1 hour, peaks in 2 to 4 hours, and has a duration of 5 to 8 hours. MDI regimens must be titrated to target a blood glucose range of, usually, 79 to 180 mg/dL while minimizing the risk of hypoglycemia (<70 mg/dL) and hyperglycemia (>180 mg/dL). 

Continuous subcutaneous insulin infusion

Continuous subcutaneous insulin infusion (CSII) or insulin pump therapy administers a continuous infusion of insulin, usually a rapid-acting insulin, to replace the basal insulin requirement. Besides basal insulin, mealtime insulin boluses are administered via the pump for prandial coverage. The insulin pump consists of the pump itself, a reservoir or cannula for holding insulin, insulin tubing, and a cannula or needle inserted subcutaneously. Advances in diabetes technology have led to newer insulin pumps that connect to continuous glucose monitors (CGMs) and enable automated insulin delivery to target optimal glycemic control.

Several types of insulin pumps are available. Sensor-augmented insulin pumps function independently from CGMs. Predictive low-glucose suspend insulin pumps are programmed to halt insulin delivery when blood glucose drops to a prespecified low threshold. Automated insulin delivery or hybrid closed-loop systems integrate an insulin pump with a connected CGM to automatically adjust insulin delivery based on CGM values and maintain blood glucose within the target range. Do-it-yourself automated insulin delivery systems are also known as "looping."

Blood Glucose Monitoring 

Monitoring blood glucose is an integral part of T1D management. Monitoring can be accomplished through capillary blood sampling with a glucose meter or CGM systems that provide real-time glucose data via a sensor and reader or smartphone app.

Glucose meter

Patients using a blood glucose meter should check their blood sugar levels at least 4 times a day, including before meals and at bedtime. Numerous blood glucose meters are available on the market, and the choice of meter often depends on cost or insurance coverage.

Continuous glucose monitors

CGMs have now become the standard of care in diabetes management. These devices are especially important in T1D management, as patients have an increased risk of frequent and severe hypoglycemia and hypoglycemia unawareness. Real-time CGM devices measure glucose every few minutes and automatically transmit glucose data to a receiver or phone application device. The device can also alarm when hypoglycemia or hyperglycemia triggers are met. CGMs collect real-time blood glucose data and trends, allowing patients to anticipate blood glucose levels for the next 30 to 60 minutes and adjust treatment decisions accordingly. Intermittent or flash-type glucose monitoring devices are also available. These devices require patients to periodically scan their sensors with a reader or phone application to obtain blood glucose readings.

Diabetes Education and Self-Management 

Optimal T1D management includes intensive education on diet, lifestyle, insulin management, and blood glucose monitoring. Treatment regimens and goals are often complex, requiring patients to receive ongoing education and self-management support to achieve these goals. Patients must understand the interaction between insulin, diet, physical activity, and daily activities on their blood glucose levels. They also need to appreciate the importance of adhering to their insulin regimen and monitoring blood glucose. Education should also cover ketone monitoring, sick day rules, detection and early treatment of hypoglycemia, and screening for diabetes complications. When appropriate, the patient’s family and caregivers should also be educated to provide adequate support.

Nutrition education, including carbohydrate estimation and counting, is important in diabetes management. Carbohydrate counting is often essential for patients to achieve optimal mealtime blood glucose targets and to accurately estimate prandial insulin needs. Carbohydrate estimation helps reduce the risk of hypoglycemia. For example, patients may have an increased risk of postprandial hypoglycemia if they consume a low-carbohydrate meal but administer the full amount of mealtime insulin without adjusting for the actual carbohydrate content. Patients should consult with a dietitian when possible to learn carbohydrate counting and be instructed to use an insulin-to-carbohydrate ratio (grams of carbohydrate covered by 1 unit of insulin) for mealtime dosing. If carbohydrate counting is not feasible, maintaining a carbohydrate-consistent diet may be the best alternative. Besides dietary education, incorporating physical activity is important for people living with T1D. Physical activity is encouraged for its beneficial effects on insulin sensitivity and overall health, but it requires careful management to avoid glucose fluctuations.

Hypoglycemia 

Hypoglycemia is the most frequent adverse effect of insulin therapy. Educating people living with T1D and their partners about the signs and symptoms of hypoglycemia is crucial. Symptoms include sweating, rapid heartbeat, lightheadedness, confusion, hunger, visual changes, and tremors. Symptoms of hypoglycemia typically occur when blood glucose levels drop below 70 mg/dL, known as level 1 hypoglycemia. Level 2 hypoglycemia occurs when blood glucose levels fall below 54 mg/dL and is usually associated with cognitive impairment and altered consciousness. Level 3 hypoglycemia involves a hypoglycemic episode that requires assistance from another person for resuscitation.

Recurrent hypoglycemic episodes, particularly in individuals with a longer duration of T1D, can lead to hypoglycemia unawareness. This condition occurs when individuals experience hypoglycemia symptoms at progressively lower glucose thresholds, likely due to reduced sympathoadrenal responses or autonomic failure. Hypoglycemia not only impacts the quality of life in people living with T1D but also increases the risk of cardiovascular events and mortality. In older adults or frail individuals, hypoglycemia can heighten the risk of falls, cognitive impairment, dementia, and fractures.

Patients must be educated about the signs and symptoms of hypoglycemia, the blood glucose thresholds for treatment, and the use of glucagon for severe hypoglycemia unresponsive to conventional treatments. Individuals at risk for recurrent and severe hypoglycemia benefit from using a CGM, which can alert them to treat hypoglycemia promptly. Hypoglycemia treatment generally involves consuming 15 to 20 grams of glucose orally if blood glucose levels fall below 70 mg/dL. Blood glucose should be rechecked 15 minutes later, with additional carbohydrates administered if necessary. Once blood glucose levels have normalized, a snack should be provided to prevent recurrence. Glucagon should be prescribed for emergency use in cases of severe hypoglycemia when the individual cannot consume carbohydrates orally.

Follow-up and Ongoing Care

Following the initial evaluation and diabetes visit, the diabetes care team should continue to provide T1D education and support while assessing the patient's insulin regimen and blood glucose control. Regular visits with the endocrinologist, diabetes educator, nurse practitioner, dietitian, and, if necessary, mental health professionals ensure comprehensive education and care aimed at maintaining optimal glycemic control. At each follow-up visit, key aspects of glycemic control, insulin management, the interaction between diet and exercise, and the treatment regimen should be reinforced. The patient's blood glucose data, whether from a glucose monitoring device or CGM, should be reviewed in detail with the patient.

For patients using an insulin pump or automated insulin delivery device, data from the device should be downloaded and discussed when appropriate. Adjustments to the patient's treatment regimen should be reviewed and reinforced as needed. Additionally, the clinician should screen for diabetes complications and comorbidities at follow-up visits and arrange referrals to specialists if necessary. Effective ongoing T1D management should also involve evaluating overall health status and engaging in shared decision-making to set treatment goals.

Differential Diagnosis

T1D must be distinguished from similar conditions based on the patient's clinical presentation, history, and laboratory studies. These conditions include type 2 diabetes, monogenic diabetes, diseases affecting exocrine pancreas function (cystic fibrosis-related diabetes, chronic pancreatitis0, posttransplantation diabetes mellitus, steroid-induced diabetes, and psychogenic polydipsia.

Prognosis

T1D is a challenging condition to manage and can lead to complications that can shorten life expectancy. However, morbidity and mortality associated with the disease have improved with advances in insulin therapy and diabetes technology, improvement in glycemic control, and control of metabolic risk factors such as hypertension and hyperlipidemia. Timely screening for microvascular and macrovascular complications and strict glycemic control at disease onset have reduced rates of serious diabetes-related complications. Mortality rates have declined, though people with T1D have 2- to 5-fold higher mortality than those without diabetes. This issue is discussed further in other sections.[20]

Complications

Complications secondary to T1D can be classified into acute and chronic conditions. Acute complications include hypoglycemia and DKA. The most serious chronic complications include nephropathy, peripheral and autonomic neuropathy, retinopathy, heart disease (including coronary artery disease, heart failure, and cardiomyopathy), peripheral arterial disease, cerebrovascular disease (including stroke and transient ischemic attack), and diabetic foot infections.