Islets in type 1 diabetes

Knowledge about the role of beta cell damage in the evolution of type 1 diabetes has been obtained from three main sources: post mortem examination of the pancreases of those who died after developing diabetes, studies in animal models of type 1 diabetes such as the NOD mouse, and functional studies in humans before and after the onset of type 1 diabetes. All three approaches have important limitations. Few (if any) autopsy specimens have been obtained before disease onset, although a major initiative has been launched to remedy this gap. Pancreas specimens obtained from people who died shortly after disease onset show lymphocytic infiltration ('insulitis') in younger individuals, whereas specimens from those with longer duration of disease show progressive loss of beta cells staining for insulin, whereas other islet cell types are preserved. Apparently functional beta cells may nonetheless survive for years or decades following clinical onset. Animal studies have mainly been used to characterise the development of insulitis preceding diabetes, although this differs in some respects from the insulitis seen in humans. Functional changes in insulin secretion are described in a separate section.

Morphological Changes

Although there were sporadic reports of lymphocytic infiltration of the islets ("insulitis") in the early part of the 20th century, the concept was not well established until the work of Willy Gepts in the 1960s. The pattern of infiltration is variable, transient, and generally more marked in younger individuals, and is discussed in more detail in the section on Insulitis.

Long-term changes in the islets include the pattern of pseudo-atrophic change, in which many islets show scanty or absent staining for insulin, with preservation of glucagon-containing alpha cells. These changes may vary from one part of the pancreas to another, and a lobular pattern has been defined. One striking feature is that apparently healthy insulin-staining beta cells may persist in some parts of the pancreas, while being virtually absent elsewhere[1]. Remarkably, such islets may be found even after 50 years of type 1 diabetes[2]

Animal Studies

Studies in the non-obese diabetic NOD mouse consistently show insulitis, with a pattern that differs from humans in that the lymphocytes accumulate around the perimeter of the islet in the early stages of disease, and that loss of beta cells rapidly follows subsequent invasion of the islets themselves. As noted above, this differs from the human pancreas in type 1 diabetes, and does not explain long term persistence of apparently functional beta cells.

Functional studies

The introduction of assays for C-peptide in type 1 diabetes allowed a residual insulin secretion to be measured despite the presence of exogenous insulin in the circulation, and revealed the presence of measurable amounts of endogenous insulin in the circulation of around 15% of people with long-term diabetes[3]. Introduction of more sensitive assays later showed that residual insulin secretion can be detected in the majority of longer term people with type 1 diabetes, and that many of these show augmented secretion in response to a mixed meal, indicating functionality[4]

Implications

The observation of selective beta cell loss in the islets is consistent with an autoimmune attack, but it has until recently seemed puzzling that evidence of active autoimmunity (islet autoantibodies and activated T lymphocytes) should persist for so long after diagnosis when, according to the traditional view, the immune system should have eliminated all the target cells. The observation of persistent beta cell, albeit in tiny quantities, helps to explain persistent activation of immune effector cells.

Whilst explaining chronic autoimmunity, the observation of beta cell persistence requires explanation. The alternatives are either that the residual cells are in some way invisible to the immune system or resistant to immune attack, or - alternatively - that the pancreas retains the ability to generate new beta cells[5]. The latter possibility has aroused considerable interest, in that it suggests that this experiment of nature might provide a route to future reversal of type 1 diabetes.

While microsecretion of insulin in itself seems unlikely to offer functional benefit, there are undoubted benefits associated with persistence of higher levels of C-peptide following diagnosis, both in terms of protection from vascular complications and a reduced risk of hypoglycaemia: preservation of beta cell function following diagnosis remains a major goal of therapy.

References

  1. ^ Foulis AK et al. The histopathology of the pancreas in type 1 diabetes mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia 1986;3:159-65

  2. ^ Keenan HA et al. Residual insulin production and pancreatic beta cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes 2010;59:2846-53

  3. ^ Madsbad S et al. Prevalence of residual beta-cell function in insulin-dependent diabetics in relation to age at onset and duration of diabetes. Diabetes 1978;27 Suppl 1:262-4

  4. ^ Oram RA et al. The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have function beta cells. Diabetologia 2013 Oct 12 (Epub)

  5. ^ Meier JJ et al. Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes. Diabetologia 2006;49:1838-44

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