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 insulin resistance itself, but the fact that the pancreas cannot produce enough insulin, and at the right time, to overcome that resistance. In other words, the problem is a deficit of insulin secretion, which is not complete as in type 1 diabetes. Type 2 diabetes does not involve the autoimmunity of type 1 diabetes, appears mainly in adults after the age of 40, often in the context of excess weight and a sedentary lifestyle, 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 very late in its course [1].

The question of which type is more serious has no simple answer, because both forms of diabetes can lead to serious complications. Chronic hyperglycaemia, 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 glycaemic 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 hypoglycaemia 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 (approximately 65 years for men, 68 years for women) compared with type 2 diabetes (74 years for men, 80 years for women), but the typically younger age at onset in type 1 diabetes explains the difference. 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, 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].

The distinction from type 1 diabetes rests on the absence of autoantibodies, good C-peptide values even several years after diagnosis, and a strong family history of diabetes over several consecutive generations. Confirmation requires genetic testing, and the correct diagnosis matters a great deal because some forms of MODY respond well to sulfonylureas, while the form caused by a mutation in the glucokinase gene is surprising in that it 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].

Neonatal diabetes is defined by the appearance of hyperglycaemia 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 at the time the investigation 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) and 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 (digestive problems, fatty stools) is frequently present alongside the diabetes, because the pancreas is affected as a whole, both its exocrine part (which secretes enzymes for digestion) and its endocrine part (which 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 and places the diagnosis, with great certainty, in the type 1 diabetes category, regardless of the patient's age or body weight [6].

Autoantibodies help separate type 1 diabetes from type 2 diabetes, MODY and secondary diabetes, especially in unclear situations such as 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 [6].

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 [7].

C-peptide becomes more useful especially after three years of evolution of the disease, because 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), while 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 at that moment insulin production is normally suppressed for a time and the result cannot be interpreted [7].

The answer is no. Although 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 from this perception. 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) [8].

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 [8].

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 who, within a short interval (3-5 years), end up no longer responding 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 [9].

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 glycaemic 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 and may radically change the patient's life [9].

Gestational diabetes is defined as hyperglycaemia detected for the first time in the second or third trimester of pregnancy, which is not an obvious classic diabetes. 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 [10].

There are situations in which an early type 1 diabetes shows itself for the first time during pregnancy and is wrongly labelled 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 hyperglycaemia 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 hyperglycaemia calls for further investigation [10].

Transient hyperglycaemia 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 [11].

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 hyperglycaemia 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, meaning an already established diabetes rather than mere transient hyperglycaemia. Any child or young adult with hyperglycaemia found incidentally, even if it initially seems transient, should be assessed for autoantibodies, because early identification of type 1 diabetes at the incipient stage allows some interventions that can slow its evolution [11].