Type 1 and type 2 diabetes (T1D and T2D) both present with hyperglycemia and have similar chronic complications.
On the other hand, they are largely phenotypically and genotypically distinct. The key clinical differences are that T1D is insulin dependent whereas, in contrast, T2D patients are rarely insulin dependent. We’ve learned over time that these differences result from different biological causes.
T1D patients demonstrate autoimmunity with positive autoantibodies to beta-cell antigens. The presence of these autoantibodies suggests autoimmune destruction of beta cells in genetically susceptible people – primarily with genes in the HLA domains. Since concordance rates between monozygotic twins is only about 50%, it suggests that the genes don’t automatically doom one to developing T1D, but rather makes one susceptible to environmental triggers that turn on the immune system to attack the beta-cell, decreasing beta-cell function, then beta-cell mass – frequently causing ablation of insulin production. Most T1D patients develop the disease in their youth, which can be thought of as ‘relatively fast destruction of beta cells’.
However, some phenotypically similar patients, who generally present in clinics thin, with no family history of T2D, antibody positive, with rapid deterioration to ketosis-prone and requiring insulin immediately do not exhibit the disease until they are significantly older, usually >25 or 30 years old. These patients seem to have slower destruction of beta cells than typical T1D types of patients and are frequently referred to as late onset or adult onset T1D.
T2D is typically characterized by insulin resistance – usually related to obesity, but has also been associated with suppressed AM dopa surge in the suprachiasmic nucleus, abnormal gut biome, undue stress hormone exposure and relative insulin deficiency. A fraction of T2D patients are not obese by US criteria, as is the case in many/most Asian countries. These non-obese patients appear to have greater insulin resistance at lower BMI’s, suggesting that T2D in these patients is due to a different entity(ies). It could be inferred that, in these non-obese T2D patients, the disease is caused by a different set of genes(s) altogether and perhaps these patients are storing more visceral fat at lower BMIs than is usually seen.
About 2/3 of insulin resistant individuals, obese or not, do not progress to diabetes. In these patients, their beta-cells continue to function adequately (may even have an increase in relative beta-cell mass) and are able to maintain normal glucose control by matching insulin resistance with increasing insulin production. However about a third of these insulin resistant individuals have a reduced beta-cell mass, and develop diabetes. This is an early process occurring in patients with pre-diabetes and leads to our terminology that there is only 1 CORE DEFECT in all diabetes, genetically predisposed abnormal beta-cells, but in those with typical T2D their dysfunction is usually precipitated by insulin resistance.
Thus T2D develops, in most, when there is a failure of the beta-cell to adequately compensate with the increased insulin demands engendered by insulin resistance. There is clearly a genetic predisposition to beta-cell failure, as many loci have been identified, among them TCF7L2, which confers the greatest risk of developing T2D. However, in clinical practice, it is not standard to try to identify a genetic abnormality, and environmental factors — poor diet, sedentary lifestyle — predominate as the obvious clinical underlying etiology as well as dictate the most common treatments for individuals with T2D. Multiple mechanisms for impaired beta-cell function in T2D have been espoused, including glucotoxicity, lipotoxicity, accumulation of pancreatic amyloid, and inflammatory destruction of beta cells. These patients traditionally presented over the age of 40, but, with the epidemic in obese in our population, we can now see it in pre-teens. Usually there is a slow progression over many years, requiring more medications, finally needing insulin for good glycemic control, but NOT insulin-requiring to prevent ketogenesis and death.
However, there is another type of diabetes that is much less understood than T1D and T2D, where patients are generally overweight but not obese, have a family history of T2D, have been found to quickly develop a REQUIREMENT for insulin or develop DKA, and seem to frequently have islet cell antibodies. These patients seem to have a rapid destruction of beta-cells compared to typical T2D patients.
The classification (in one sense), and the therapeutic problem, has been these two similar, but different phenotypes have been lumped together into the terminology-classification = Latent Autoimmune Diabetes of Adults (LADA).
a. T1D-like, but who do not present until they are significantly older (>25 or 30 years old), seem to have slower destruction of beta cells than typical T1D types of patients, and
b. T2D-like, but who are found to quickly develop (<6 years) a REQUIREMENT for insulin or develop DKA, and seem to frequently have islet cell antibodies.
It has also been designated by different authors imprecisely including the terms type 1.5 diabetes, slowly progressive insulin-dependent diabetes mellitus, latent type 1 diabetes, youth-onset diabetes of maturity, latent-onset type 1 diabetes, and antibody-positive non–insulin-dependent diabetes.
Controversy exists as to whether LADA is a distinct entity, or whether, indeed, some patients are T1D and have slow destruction of their beta cells or, some are T2D patients with fast-destruction of their beta-cells. This confusion arises as LADA exhibits features of both T1D and T2D, with patients generally expressing islet-cell antibodies and then developing insulin-dependence at older ages.
LADA may account for up to 12% of all cases of diabetes. This would indicate that the number of LADA patients is actually greater than the number of T1D patients. It is therefore crucial to properly define these patients and in turn bring about better suited therapeutic interventions.
At least 60 loci have now been uncovered for T1D and T2D apiece. Some studies have pointed to a possible genetic similarity between T1D and T2D. However, to date, none of the genes identified for either of these disorders have concretely shown an association with both T1D and T2D. Our own focus, working with Dr. Struan Grant, who discovered variation in the TCF7L2 gene playing a key role in conferring T2D, has been funded to do a ‘Genome Wide Association Study’ (GWAS) of patients classified as ‘LADA’ to see if there is/are distinct genes causing this disease and to determine to what extent ‘LADA’ shares genetic similarities with T1D and T2D.
We have some encouraging results and hope to present them at an upcoming meeting. In the meantime, our study is currently ongoing and actively recruiting patients. For more information on this study and if you are interested in participating, please contact Vanessa Guy at 215-590-6815. Additional information can also be found at http://clinicaltrials.gov/ct2/show/NCT01793974?
We are proud to count Dr. Stanley Schwartz as one of our Diabetes In Control Advisory Board members.
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