The islets in type 2 diabetes

In the early days of the 20th century the islets in what we now call type 2 diabetes looked reasonably normal when viewed through the microscope, and it was not until the end of the century that it was fully appreciated that beta cell mass is depleted in type 2 diabetes relative to body mass.

Historical Aspects

In the early days of the 20th century the islets in what we now call type 2 diabetes looked reasonably normal when viewed through the microscope, apart from a hyaline (glassy) background which now known to be due to deposition of IAPP. This apparent normality gave rise to the notion of that late-onset diabetes originated outside the pancreas, and was probably due to oversecretion of growth hormone.

By the 1960s glucagon staining techniques and radioimmunoassay became available, showing that type 2 diabetes was characterized by glucagon excess as well as reduced insulin action, and leading to the bihormonal hypothesis. See History of glucagon

For much of the remainder of the century the dominant concept was that type 2 diabetes was primarily due to insulin resistance, leading secondarily to increased insulin secretion and progressive exhaustion of the beta cell. The pancreatic islets were considered to contain normal numbers of beta cells, until more sophisticated studies using controls matched for body weight (obese individuals have more beta cells) showed that beta cell deficiency is characteristic of type 2 diabetes; indeed, it seems likely that the condition cannot develop in a person with healthy insulin secretory capacity.

There is morphological evidence of a reduction in beta cell mass relative to body mass in type 2 diabetes, with a more severe (~50%) functional deficit, as judged by HOMA measurement in The United Kingdom Prospective Diabetes Study [UKPDS][1]. Other functional deficits include loss of pulsatile insulin secretion and of first phase insulin responses to intravenous insulin, with a delayed and exaggerated second phase response. Insulin secretory defects in type 2 diabetes are considered further under the Pathophysiology of type 2 DM.

Why do beta cells fail?

Some animal species, such as the wild-type rat or dog do not developed diabetes in response to overfeeding and obesity because they have the capacity to increase their beta cell mass many-fold in response to increased demand. Humans are limited in their ability to do this, with a capacity of perhaps ~50%[2]. Limited beta cell regenerative capacity, plus other factors underlying the ability to maintain and replenish beta cells may underlie human susceptibility to diabetes.

Genetic factors

Many of the genes associated with type 2 diabetes influence aspects of healthy beta cell function.Those most strongly associated are TCF7L2 in Western populations and KCNQ1 in Asian populations. TCF7L2 is associated with reduced insulin secretion and increased hepatic glucose production. Other important genes include SLC30A8, a zinc transporter involved with crystallisation of insulin and peroxisome proliferator-activated receptor (PPAR)γ, a receptor that controls the expression of several genes. The FTO gene increases diabetes susceptibility indirectly by contributing to weight gain. Overall this pattern is consistent with the concept of beta cell dysfunction as the underlying problem in type 2 diabetes.

What is the initial beta cell defect?

The absence of a single predominant gene defect in type 2 diabetes further underlines the heterogeneity of the condition and reinforces the concept of multiple small "hits". The notion of an initial lesion remains elusive, but likely mechanisms involved in the onset of beta cell dysfunction include mitochondrial dysfunction, oxidative stress, ER stress, dysfunctional triglyceride/FFA (TG/FFA) cycling, and glucolipotoxicity. Once hyperglycemia has become established, additional processes come to bear including islet inflammation, O-linked glycosylation, and amyloid deposition.

References

  1. ^ UKPDS 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. Diabetes 1995;44:1249-58

  2. ^ Prentki M, Nolan CJ. Islet beta cell failure in type 2 diabetes. J Clin Invest 2006; 116:1802-12

Comments

Nobody has commented on this article

Commenting is only available for registered Diapedia users. Please log in or register first.