How type 1 diabetes differs from other types of diabetes

Type 1 diabetes and type 2 diabetes are two different diseases that share one feature: a rise in blood glucose. Type 1 diabetes develops through autoimmune destruction of the beta cells in the endocrine pancreas, which leads to an almost total lack of insulin. The disease appears mostly in children, adolescents and young adults, frequently in people of normal weight or similar to that of the general population. The onset is usually sudden, with thirst, frequent urination, weight loss and sometimes ketoacidosis, and insulin treatment is mandatory from diagnosis [1].

Type 2 diabetes accounts for roughly 90% of all diabetes cases and has a different mechanism. Insulin is still secreted (dysfunctionally), but the body does not use it efficiently, developing what is called insulin resistance. The real problem is not only insulin resistance itself, but also the fact that the pancreas does not produce enough insulin, and at the right time, to overcome that resistance. In other words, a deficit of insulin secretion is present in type 2 diabetes as well, but it is not complete as in type 1 diabetes. Type 2 diabetes does not involve the autoimmunity of type 1 diabetes. It appears mainly in adults after the age of 40, often in the context of excess weight and a sedentary lifestyle. It evolves slowly and can be asymptomatic for years (sometimes more than 10). Treatment begins with lifestyle change and oral medications such as metformin, and insulin becomes necessary only later in the course of the disease, although some patients need it from the moment of diagnosis, as the figure below shows [1].

The question of which type is more serious has no simple answer, because both forms of diabetes can lead to serious complications. Chronic hyperglycemia, whatever the type, harms the eyes, kidneys, nerves, heart and blood vessels over time. The risk of complications depends more on how long you have had the disease and on the quality of glycemic control than on the type of diabetes itself.

There are, however, important differences. Type 1 diabetes requires insulin for life and involves a constant risk of hypoglycemia and of diabetic ketoacidosis, a potentially fatal acute complication. Type 2 diabetes evolves slowly, frequently silently, and is more often associated with cardiovascular disease, hypertension, obesity and chronic complications, which can sometimes appear even before diagnosis. In short, type 1 diabetes carries greater acute risks, and type 2 diabetes carries more important chronic risks. Data from a recent meta-analysis show a lower life expectancy in type 1 diabetes than in type 2 diabetes. In type 1 diabetes it is approximately 65 years for men and 68 years for women. In type 2 diabetes it is 74 years for men and 80 years for women. The difference is explained, however, by the typically younger age at onset in type 1 diabetes. For the same age at onset, the cardiovascular risk and the impact on longevity are greater in type 2 diabetes [2].

MODY (maturity-onset diabetes of the young) is a rare form of diabetes caused by a mutation in a single gene. It is passed from parent to child with a probability of 50%. It usually appears before the age of 25, without severe symptoms at onset, without ketoacidosis and without the autoantibodies specific to type 1 diabetes. An important clue for suspecting this form of diabetes is the presence of several family members (parents, siblings, grandparents) with diabetes diagnosed at a young age, across consecutive generations [3].

Three findings separate MODY from type 1 diabetes: absent autoantibodies, good C-peptide values even several years after diagnosis, and diabetes in several consecutive generations of the family. Confirmation requires genetic testing. The correct diagnosis matters a great deal, because some forms of MODY respond well to sulfonylureas. The form caused by a mutation in the glucokinase gene is surprising in that, outside pregnancy, it usually needs no treatment at all. Many patients with MODY are misdiagnosed with type 1 diabetes and receive insulin needlessly for years, when they could be treated far more simply and effectively [3]. Insulin must not, however, be stopped on your own: the treatment is changed only after genetic confirmation, together with your doctor.

Neonatal diabetes is defined by the appearance of hyperglycemia in the first six months of life and almost always has a genetic cause (in more than 80% of cases). Autoimmune type 1 diabetes appears extremely rarely before six months (in practice, almost never), because the immune system is not yet mature enough to begin destroying the beta cells. The practical rule is therefore that any diabetes diagnosed under six months of life should be considered neonatal diabetes, not type 1 diabetes [4].

Any child diagnosed with diabetes under six months should undergo genetic testing, whatever their age when the test is finally done, even if they are now an adult. Forms of neonatal diabetes caused by mutations in the K-ATP channels (the KCNJ11 or ABCC8 genes) can almost always be treated far better with oral sulfonylureas instead of insulin. Neonatal diabetes can be transient (resolving after a few months) or permanent. The correct diagnosis completely changes the child's treatment and prognosis [4].

Type 1 diabetes is a primary autoimmune disease in which the immune system mistakenly attacks the beta cells in the pancreas. Secondary diabetes has an exact, well-defined cause, most often another disease or a treatment for another disease. The main causes include:

• diseases of the exocrine pancreas — chronic pancreatitis, pancreatic cancer, cystic fibrosis, surgery on the pancreas;
• some medications — such as long-term corticosteroids and antipsychotics;
• endocrine diseases — Cushing's syndrome, acromegaly [5].

The distinction is made on the basis of the clinical context and the patient's history. Unlike type 1 diabetes, secondary diabetes does not show pancreatic autoantibodies, and the mechanism is not autoimmune. In pancreatic diabetes, exocrine pancreatic insufficiency is frequently present alongside the diabetes. It means digestive problems and fatty stools. The reason is that the pancreas is affected as a whole, both its exocrine part and its endocrine part. The exocrine part secretes enzymes for digestion, while the endocrine part secretes various hormones, including insulin [5].

Pancreatic autoantibodies are the main markers of type 1 diabetes, because they reflect the autoimmune process that destroys the beta cells. The usual tests measure anti-GAD (glutamic acid decarboxylase), anti-IA-2 (tyrosine phosphatase 2), anti-insulin and anti-ZnT8 (zinc transporter 8) antibodies. The presence of one or more autoantibodies confirms the autoimmune origin of the disease. It places the diagnosis in the type 1 diabetes category with great certainty, regardless of the patient's age or body weight.

Autoantibodies help separate type 1 diabetes from type 2 diabetes, MODY and secondary diabetes. They are most useful in unclear situations. Examples include a young adult of normal weight, or a patient with obesity who also shows some signs suggestive of type 1 diabetes. Approximately 5-10% of people with type 1 diabetes have no detectable autoantibodies, so a negative result does not completely rule out the diagnosis. In MODY and in secondary diabetes the autoantibodies should be absent (with minor exceptions), which helps direct the diagnosis toward genetic testing or the search for another cause.

C-peptide is a molecule produced in the pancreas together with insulin, in equal amounts. Measuring it shows how much insulin your pancreas still produces. In type 1 diabetes, after several years of evolution, C-peptide falls to very low or undetectable values. The reason is easy to grasp: the majority of the beta cells have been destroyed. In type 2 diabetes and in MODY, C-peptide usually stays within normal limits for several years [6].

C-peptide becomes more useful especially after three years of evolution of the disease. Immediately after diagnosis it can still be preserved even in type 1 diabetes (the remission phase, or "honeymoon"). Values below 0.6 ng/mL after several years of disease strongly suggest type 1 diabetes (most patients are below 0.1 ng/mL). The 0.6 ng/mL threshold, equivalent to 0.2 nmol/L, has a sensitivity (the proportion of patients with type 1 diabetes correctly identified) of approximately 93% after three years of disease. Values above 1.8 ng/mL suggest type 2 diabetes or MODY. Testing should be done at least two weeks away from a metabolic decompensation, because during a decompensation insulin production falls temporarily and the result cannot be interpreted [6].

The answer is no. Type 1 diabetes was traditionally seen as the disease of children, and type 2 diabetes as the disease of adults with obesity. The reality is quite different. Type 1 diabetes can appear at any age, including after 60. On the other hand, type 2 diabetes appears more and more frequently in children and adolescents, alongside the epidemic of obesity at young ages (generally after the age of 13) [7]. Using age and weight as the only criteria leads to misdiagnoses in up to 40% of cases.

A young adult with obesity may in fact have type 1 diabetes, and a child of normal weight may have monogenic diabetes. Whenever there is clinical suspicion, evaluation is needed with measurement of pancreatic autoantibodies, C-peptide, a detailed family history and sometimes genetic testing. The correct treatment depends on this evaluation, because wrongly giving oral medications to a patient with type 1 diabetes can, at some point, lead to ketoacidosis [7]. If vomiting, difficulty breathing or drowsiness appear, go to the emergency room straight away.

Yes, reclassification of the type of diabetes is a real situation, encountered more and more often in modern medical practice. The most common situation arises in adults initially diagnosed with type 2 diabetes. Within a short interval (3-5 years), they no longer respond to oral treatment and need to start insulin therapy. Later testing of the autoantibodies and C-peptide in fact reveals a slowly progressing type 1 diabetes (LADA). There are also, at times, adults diagnosed with type 1 diabetes who, after additional testing, are reclassified as having MODY-type diabetes [8].

An openness among doctors toward the process of reclassification matters, because it completely changes the therapeutic approach. For a patient with LADA, early initiation of insulin therapy prevents the eventual appearance of ketoacidosis and protects the remaining beta cells. For a patient with HNF1A or HNF4A MODY, switching from insulin to sulfonylureas can bring better glycemic control, without injections. So, when the course does not match the type initially diagnosed, or when the response to treatment is unexpected, reassessing the diagnosis is worthwhile. It may radically change the patient's life [8].

Gestational diabetes is defined as hyperglycemia detected for the first time in the second or third trimester of pregnancy, with values that do not reach the thresholds used to diagnose diabetes outside pregnancy. If those thresholds are reached, it is most likely diabetes that was already present before the pregnancy and has only now been discovered. Often gestational diabetes has the characteristics of type 2 diabetes, with increased insulin resistance (due to pregnancy hormones). In most cases, blood glucose returns to normal after birth, but the women remain at increased risk of developing type 2 diabetes within the next 10 years. Evolution toward type 1 diabetes after a pregnancy is rare, but possible [9].

There are situations in which an early type 1 diabetes shows itself for the first time during pregnancy and is wrongly labeled gestational diabetes. Clues to a correct diagnosis of type 1 diabetes include a rapidly rising insulin requirement, the absence of obesity, a young age and the persistence of hyperglycemia after birth. Measuring pancreatic autoantibodies in women with atypical gestational diabetes can identify the autoimmune forms (type 1 diabetes). In all women with gestational diabetes, retesting blood glucose 4-12 weeks after birth is advised, and persistence of hyperglycemia calls for further investigation [9].

Transient hyperglycemia can appear in people without diabetes during acute stress, such as severe infections, trauma, surgery, a heart attack, or treatment with corticosteroids. Blood glucose can reach high values (over 200 mg/dL / 11.1 mmol/L), but returns to normal once the situation that triggered it resolves. In feverish children with acute illnesses, raised blood glucose values can appear and then disappear after recovery [10].

Telling it apart from type 1 diabetes is done by following the course and through specific tests. In type 1 diabetes, pancreatic autoantibodies are present, C-peptide tends to be persistently low, and the hyperglycemia persists even after the acute cause has resolved. An HbA1c raised above 6.5% (48 mmol/mol) suggests that the higher blood glucose values have been present for several months. That means an already established diabetes, not merely transient hyperglycemia. Any child or young adult with hyperglycemia found incidentally should be assessed for autoantibodies, even if it initially seems transient. Early identification of type 1 diabetes at the incipient stage allows some interventions that can slow its evolution [10].