📘 The differences of T1 diabetes versus other types of diabetes

Type 1 diabetes mellitus and T2 diabetes are two different diseases that have in common the increase of blood glucose. T1 diabetes appears through autoimmune destruction of the beta cells in the endocrine pancreas, which leads to almost total lack of insulin. The disease appears mostly in children, adolescents and young adults, frequently in people with 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 treatment with insulin is mandatory from diagnosis [1].

T2 diabetes represents approximately 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, but the fact that the pancreas does not manage to produce enough insulin and at the right time to overcome this resistance. In other words, the problem is that we have a deficit of insulin secretion, which however is not complete as in T1 diabetes. T2 diabetes does not include the autoimmunity from T1 diabetes, appears mostly in adults after 40 years, frequently in the context of excess weight and sedentary lifestyle, has slow evolution and can be asymptomatic for years (sometimes over 10 years). Treatment starts with lifestyle change and oral medications such as metformin, and insulin becomes necessary very late in its evolution [1].

The question of which type is more severe does not have a simple answer, because both forms of diabetes can lead to serious complications. Chronic hyperglycemia, regardless of type, affects in time the eyes, kidneys, nerves, heart and blood vessels. The risk of complications depends more on the duration of the disease and on the quality of glycemic control, compared to the type of diabetes itself.

There are however important differences. T1 diabetes requires insulin throughout life and involves constant risk of hypoglycemia and diabetic ketoacidosis, which is a potentially fatal acute complication. T2 diabetes evolves slowly, frequently silently and is more often associated with cardiovascular diseases, hypertension, obesity and chronic complications, which can sometimes appear even before diagnosis. In short, T1 diabetes has greater acute risks, and T2 diabetes has more important chronic risks. Data from a recent meta-analysis show a life expectancy lower in T1 diabetes (approximately 65 years for men, 68 years for women) compared to T2 diabetes (74 years for men, 80 years for women), but the typically younger age at onset in T1 diabetes explains the difference. For the same age at onset, the cardiovascular risk and the impact on longevity are greater in T2 diabetes [2].

MODY diabetes (from maturity-onset diabetes of the young) is a rare form of diabetes caused by a mutation in a single gene, transmitted 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 autoantibodies specific to T1 diabetes. An important clue for suspecting this form of diabetes is the existence of several family members (parents, siblings, grandparents) with diabetes diagnosed in youth, in consecutive generations [3].

The distinction from T1 diabetes is based on the absence of autoantibodies, good values of C-peptide even several years from diagnosis and a strong family history of diabetes over several consecutive generations. Confirmation requires genetic testing, and the correct diagnosis is very important because some forms of MODY respond well to sulfonylureas, and the form with mutation in the glucokinase gene is surprising in that it does not require treatment. Many patients with MODY are misdiagnosed as having T1 diabetes and unnecessarily receive insulin for years, although they could be treated much more simply and effectively [3].

Neonatal diabetes is defined by the appearance of hyperglycemia in the first six months of life and almost always has a genetic cause (in over 80% of cases). Autoimmune T1 diabetes appears extremely rarely before six months (practically almost never) because the immune system is not yet mature enough to initiate the destruction of beta cells. Thus, the practical rule is that any diabetes diagnosed under six months of life must be considered neonatal diabetes, not T1 diabetes [4].

Any child diagnosed with diabetes under six months must be tested genetically, regardless of the current age at which the investigation is done (even if they are now an adult). The forms of diabetes neonatal caused by mutations in K-ATP channels (KCNJ11 or ABCC8 genes) can almost always be treated much better with oral sulfonylureas instead of insulin. Neonatal diabetes can be transient (disappears after a few months) or permanent. The correct diagnosis completely changes the treatment and prognosis of the child [4].

T1 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 treatment for another disease. The main causes include diseases of the exocrine pancreas (chronic pancreatitis, pancreatic cancer, cystic fibrosis, surgical interventions on the pancreas), some medications (such as long-term corticosteroids, antipsychotics) and endocrine diseases (Cushing's syndrome, acromegaly) [5].

The distinction is made based on the clinical context and the patient's history. Unlike T1 diabetes, secondary diabetes does not present pancreatic autoantibodies, and the mechanism is not autoimmune. In pancreatic diabetes, exocrine pancreatic insufficiency (digestive problems, fatty stools) is frequently present alongside diabetes, because the pancreas is affected as a whole, both its exocrine part (which secretes enzymes for digestion) and the endocrine part (which secretes various hormones, including insulin) [5].

Pancreatic autoantibodies are the main markers of T1 diabetes, because they reflect the autoimmune process that destroys beta cells. 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 area of T1 diabetes, regardless of the patient's age or body weight [6].

Autoantibodies help separate T1 diabetes from T2 diabetes, MODY and secondary diabetes, especially in unclear situations such as a young adult with normal weight or a patient with obesity, who also has some signs suggestive of T1 diabetes. Approximately 5-10% of patients with T1 diabetes do not have detectable autoantibodies, so a negative result does not exclude completely the diagnosis. In MODY and in secondary diabetes the autoantibodies should be absent (with minor exceptions), which helps orient 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 T1 diabetes, after several years of evolution, C-peptide drops to very low or undetectable values. The reason is easy to intuit, the majority of beta cells have been destroyed. In T2 diabetes and in MODY, C-peptide usually remains 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 be preserved even in T1 diabetes (the remission phase or „honeymoon”). Values below 0.6 ng/mL after several years of disease strongly suggest T1 diabetes (the majority have below 0.1 ng/mL), and values above 1.8 ng/mL suggest T2 diabetes or MODY. Testing must be done at a distance of at least two weeks from a metabolic decompensation, because at that moment insulin production is normally temporarily suppressed and the result is not interpretable [7].

The answer is no. Although traditionally T1 diabetes was considered the disease of children and T2 diabetes the disease of adults with obesity, the reality is quite different from this perception. T1 diabetes can appear at any age, including after 60 years. On the other hand, T2 diabetes appears more and more frequently in children and adolescents, in parallel with the obesity epidemic at young ages (generally after 13 years) [8].

Using age and weight as the only criteria leads to misdiagnoses in up to 40% of cases. A young adult with obesity may actually have T1 diabetes, and a child with normal weight may have monogenic diabetes. In the case of any clinical suspicion, evaluation with measurement of pancreatic autoantibodies, C-peptide, detailed family history and sometimes genetic testing is necessary. The correct treatment depends on this evaluation, because the wrong administration of some oral medications to a patient with T1 diabetes can at some point lead to the appearance of ketoacidosis [8].

Yes, reclassification of the type of diabetes is a real situation and increasingly often encountered in modern medical practice. The most common situation appears in adults initially diagnosed with T2 diabetes, who within a short interval of time (3-5 years) end up no longer responding to oral treatment and need to start insulin therapy. Subsequent testing of autoantibodies and C-peptide actually shows a T1 diabetes with slow evolution (LADA). There are sometimes adults diagnosed with T1 diabetes who, after additional testing, end up being reclassified as having MODY type diabetes [9].

The openness of physicians toward the reclassification process is important because it changes completely the therapeutic approach. For a patient with LADA, the early initiation of insulin therapy prevents the eventual appearance of ketoacidosis and protects the remaining beta cells. For a patient with MODY HNF1A or HNF4A, the transition from insulin to sulfonylureas can bring better glycemic control, without injections. Therefore, when the evolution does not correspond to the initially diagnosed type or when the response to treatment is unexpected, reevaluation of the diagnosis is useful, possibly radically changing the patient's life [9].

Gestational diabetes is defined as hyperglycemia detected for the first time in the second trimester or third of pregnancy, which is not an obvious classic diabetes. Often gestational diabetes has characteristics of T2 diabetes, with increased insulin resistance (due to pregnancy hormones). In the majority of cases, blood glucose returns to normal after birth, but the women remain at increased risk of developing T2 diabetes within the next 10 years. Evolution toward T1 diabetes after a pregnancy is rare, but possible [10].

There are situations in which an incipient T1 diabetes manifests for the first time in pregnancy, being mislabeled as gestational diabetes. Clues to a correct diagnosis of T1 diabetes include rapidly increasing insulin requirement, lack of obesity, young age and persistence of hyperglycemia after birth. Measuring pancreatic autoantibodies in women with atypical gestational diabetes can identify the autoimmune forms (T1 diabetes). In all women with gestational diabetes, retesting of blood glucose 4-12 weeks after birth is indicated, and the persistence of hyperglycemia requires additional investigations [10].

Transient hyperglycemia can appear in people without diabetes in situations of acute stress, such as severe infections, traumas, surgical interventions, myocardial infarction or during treatment with corticosteroids. Blood glucose can reach high values (over 200 mg/dL / 11.1 mmol/L), but returns to normal after the situation that triggered it is resolved. In febrile children with acute illnesses, elevated blood glucose values can appear, which disappear after recovery [11].

Differentiation from T1 diabetes is done by following the evolution and through specific tests. In T1 diabetes, pancreatic autoantibodies are present, C-peptide tends to be persistently low, and hyperglycemia persists even after the resolution of the acute cause. HbA1c elevated above 6.5% (48 mmol/mol) suggests that the higher blood glucose values have been present for several months, being in this case an already established diabetes, not just transient hyperglycemia. Any child or young adult with hyperglycemia detected incidentally, even if it initially seems transient, should be evaluated for autoantibodies, because the early identification of T1 diabetes in the incipient stage allows some interventions that can slow the evolution [11].