The beta cell lesion in type 2 diabetes: there has to be a primary functional abnormality

Abstract

The critical role of the beta cell in the pathogenesis of type 2 diabetes is now well established. When examined in patients with type 2 diabetes and individuals at increased risk, reductions in beta cell mass and abnormalities of beta cell function can both be demonstrated. The question of whether one alone is sufficient or both are necessary for the development of hyperglycaemia has been debated. Based on human and animal studies, it appears that neither alone is sufficient. Rather, for glucose to rise to the level at which diabetes would be diagnosed, defects in beta cell mass and in beta cell function are required.

Figure 1

Hand drawn micrograph of an islet from a patient with type 2 diabetes stained with haematoxylin and eosin. Cellularity of the islet is decreased and it contains eosinophilic material termed “hyalinosis”, which we now know as amyloid. Reprinted with permission from [3].

Figure 2

Relationship of obesity and glucose tolerance with islet beta and alpha cell volume and mass based on autopsy assessments. (a) Beta cell mass (blue) is reduced in subjects with type 2 diabetes (n=25) compared to controls (n=25), while alpha cell mass (orange) is not different. Subjects with type 1 diabetes and those with amyloidosis were excluded. Data are mean ± se and from [4] with permission. (b) Beta cell volume is increased in obese (pink; n=4 controls and 6 with type 2 diabetes) compared to normal weight (white; n=7 controls and 8 with type 2 diabetes) subjects. Diabetes is associated with reduced beta cell volume in both obese and normal weight subjects. Data are mean ± sd and from [5] with permission. (c) Beta cell volume is reduced in subjects with type 2 diabetes (DM, green; n=16 normal weight and 41 obese) compared to those who do not have diabetes (ND, yellow; n=17 normal weight and 31 obese), whether subjects are normal weight of obese. Subjects with impaired fasting glucose (IFG, pink; n=19 obese) have reduced beta cell volume that is intermediate between no diabetes and diabetes. Data are mean ± se and adapted with permission from [6].

Figure 3

Differences in beta cell volume and mass in 52 subjects without (open symbols and bars) and 57 with type 2 diabetes (closed symbols and bars). (a) The volume of beta cells varies markedly in non-diabetic and diabetic subjects with a lot of overlap between the two groups. Despite this large variability, beta cell volume is greater in the pancreatic tail than body in both non-diabetic and diabetic subjects. In subjects with diabetes compared to those without, beta cell volume is reduced in both the body and tail of the pancreas. (b) Beta cell mass determined based on volume density and pancreatic weight is reduced by 35% in subjects with type 2 diabetes. Data are mean ± sd. Reproduced with permission from [12].

Figure 4

Plasma insulin concentrations before and following a 100-gram glucose load in healthy control subjects and two groups of subjects, one known to have early (“maturity onset”) type 2 diabetes and a second group in whom the duration of the diabetes was undetermined. The insulin response at 30 minutes was clearly diminished in individuals with recent onset of hyperglycaemia. Reproduced with permission from [26].

Figure 5

Incremental early insulin response (insulinogenic index) measured 30 minutes after glucose ingestion (ΔI30/ΔG30) in 240 subjects with normal glucose tolerance (NGT), 191 with impaired fasting glucose/impaired glucose tolerance (IFG/IGT) and 100 with diabetes. As glucose tolerance declined, beta cell function deteriorated. Reproduced with permission from [27].

Figure 6

Acute insulin response to intravenous glucose in subjects grouped based on their fasting glucose levels. As the fasting glucose increases, the insulin response decreases. The response is absent when fasting glucose exceeds 6.4 mmol/l. Reproduced with permission from [30].

Figure 7

Possible pathways for the development of the reduced beta cell mass and beta cell dysfunction observed in type 2 diabetes. (a) Genetic defects combined with environmental changes determine reductions in both beta cell function and mass. (b) A genetic defect in combination with environmental changes simultaneously affects both mass and function. (c) The interaction of genetic susceptibility with environmental factors results in beta cell dysfunction that in turn leads to a loss of beta cells. The effect of this combination of changes is associated with the development of hyperglycaemia.

Figure 7

Possible pathways for the development of the reduced beta cell mass and beta cell dysfunction observed in type 2 diabetes. (a) Genetic defects combined with environmental changes determine reductions in both beta cell function and mass. (b) A genetic defect in combination with environmental changes simultaneously affects both mass and function. (c) The interaction of genetic susceptibility with environmental factors results in beta cell dysfunction that in turn leads to a loss of beta cells. The effect of this combination of changes is associated with the development of hyperglycaemia.

Figure 7

Possible pathways for the development of the reduced beta cell mass and beta cell dysfunction observed in type 2 diabetes. (a) Genetic defects combined with environmental changes determine reductions in both beta cell function and mass. (b) A genetic defect in combination with environmental changes simultaneously affects both mass and function. (c) The interaction of genetic susceptibility with environmental factors results in beta cell dysfunction that in turn leads to a loss of beta cells. The effect of this combination of changes is associated with the development of hyperglycaemia.