Long-term changes

Histopathologic lesions in chronic type 1 diabetes differ from those in acute disease. Insulitis is only rarely found and most islets no longer contain any insulin; these pseudoatrophic islets contain abundant glucagon-producing alpha cells, but appear shrunken due to loss of beta cells. Even so, a few beta cells are often present, even after 50 years of diabetes, and these can be found in focal clusters or scattered throughout the gland.

Insulitis is rare in chronic type 1 diabetes

In contrast to the islets in recent onset diabetes, the islets in patients with chronic disease only rarely show the characteristic inflammatory lesions that are found at the onset of the disease.While >70% of young patients with acute onset of the disease show insulitis (in 5-10% of their islets), the lesion is present in only 4% of patients one year after the diagnosis is made. The inflammation disappears together with the remaining beta cells, leaving small islets that are devoid of any insulin-positivity[1] (Fig 1).

Fig 1.  Pseudoatrophic islet from the pancreas of a patient with chronic type 1 diabetes. Alpha cells are stained in red; beta cells are stained in green but are absent.
Fig 1. Pseudoatrophic islet from the pancreas of a patient with chronic type 1 diabetes. Alpha cells are stained in red; beta cells are stained in green but are absent.

Initially it was thought that the small islets in patients with chronic type 1 diabetes were ‘atrophic’ and composed of atrophied and inactive beta cells. After the introduction of immunohistochemistry in the early seventies it was recognized that these ‘atrophic’ islets are mainly composed of glucagon-containing alpha cells and that the islets are small because of immune-mediated beta cell death. As these islets are not truly atrophic and are composed of fully functional alpha cells, they are considered to be ‘pseudo-atrophic’ [2].

Not all beta cells disappear

Not all islets in patients with chronic type 1 have lost all their beta cells. Residual beta cells can be found in many patients, even after a disease duration of fifty years. In the Joslin Medalist Study more than 67.4% of the participants had levels in the minimal (0.03-0.2 nmol/l) or sustained range (≥ 0.2 nmol/l). Higher random C-peptide was associated with lower hemoglobin A1C, older age of onset, higher frequency of HLA DR3 genotype, and responsiveness to a mixed-meal tolerance test (MMTT) [3].

Many patients with chronic type 1 diabetes therefore have remaining beta cells. In some these cells are found scattered throughout the exocrine parenchyma, in others the cells can be found in specific lobes of the pancreas where they may be prominent and in considerable quantity forming normal islet structures (fig 2)[4].

Fig 2. Islet of Langerhans from the pancreas of a patient with chronic type 1 diabetes of 19 years duration. A single lobe of the pancreas was found to contain islets rich in residual beta cells (alpha cells in red; beta cells in green).
Fig 2. Islet of Langerhans from the pancreas of a patient with chronic type 1 diabetes of 19 years duration. A single lobe of the pancreas was found to contain islets rich in residual beta cells (alpha cells in red; beta cells in green).

An important question in this context is if these residual beta cells are surviving cells that have been present for many years, perhaps even before disease onset, or if they are newly formed cells that either escape detection by the immune system or are part of a continuous cycle of neoformation and immune-mediated cell death [5].

Observations such as this have generated considerable interest, since they suggest that beta cell regeneration might still be feasible, even after many years of diabetes.

References

  1. ^ In’t Veld P, Insulitis in human type 1 diabetes: the quest for an elusive lesion. Islets 3: 131-138, 2011.

  2. ^ Gepts W and Lecompte PM, The pancreatic islets in Diabetes. Am J Med 70: 105-115, 1981.

  3. ^ Keenan HA, Sun JK, Levine J, Doria A, Aiello LP, Eisenbarth G, Bonner-Weir S, King GL. Residual insulin production and pancreatic beta cell turnover after 50 years of diabetes: Joslin Medalist study. Diabetes 2010; 59:2846-2853.

  4. ^ M Löhr and Klöppel G, Residual insulin positivity and pancreatic atrophy in relation to duration of chronic type 1 (insulin-dependent) diabetes mellitus and microangiopathy. Diabetologia 757-762, 1987.

  5. ^ Meier JJ, Bhushan A, Butler AE, Rizza RA, Butler PC. Sustained beta cell apoptosis in patients with long-standing type 1 indirect evidence for islet regeneration. Diabetologia 2221-2228, 2005.

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