Insulin-producing β-cells are the predominant endocrine cell type in pancreatic islets, comprising 50 – 80% of islet cells [1 – 3]. Studies with autoptic samples, organ donor specimens, and surgical cases have found that β-cell mass in the human pancreas may vary from 0.6 to 2.1 g, with β-cell volume and area (relative to the pancreatic tissue) ranging from 1.1 – 2.6% and 0.6 – 1.6%, respectively [4 – 15]. Islet insulin content has been reported to be 100 – 500 μU per islet [16 – 20], but some islets may contain more than 1000 μU insulin . As islet number in adult subjects also varies widely (0.5 – 4 million per pancreas) , pancreatic insulin content, as measured in a few studies, shows a marked intersubject variability (up to 10-fold) [7,17].
Functionally, β-cells are the most sophisticated of endocrine cells. Insulin must be supplied to body tissues in amounts, time-dynamics and flexibility able to maintain plasma glucose within a narrow concentration interval on a minute-by-minute basis [22–25]. In fact, insulin secretion must cope with acute (meals, exercise, stressful events) and long-term (body weight gain or loss, aging, pregnancy) changes. Whereas the amount of insulin released daily has been reported to range ∼20–70 U (mainly depending on body weight) [26,27], capturing the multifaceted features of insulin secretion in vivo is a difficult task [28–30]. However, the recent use of human islets isolated from the pancreas of organ donors has allowed the direct study of β-cell insulin release under different conditions, showing that several of the insulin secretion properties observed in vivo (dynamics, oscillatory pattern, metabolic and/or pharmacologic perturbations) can be reproduced ex vivo [18,31 – 37]. In this chapter, we will summarize available knowledge on the quantitative and functional differences between nondiabetic and T2DM β-cells, showing that β-cell loss and changes in β-cell secretory phenotype could have a different impact on the onset and progression of type 2 diabetes (T2DM).
?-Cell mass in type 2 diabetes
Although quantification of β-cells in the human pancreas is a difficult task, morphometric analyses have been per- formed by several authors to assess β-cell mass (when the weight of pancreas specimens was available), volume (usually assuming that the islets are spherical), and/or area (insulin-positive proportions in the islets or the pancreatic tissue) [4 – 7,9,10,12 – 15,38 – 46]. The amount of β-cells has been usually (although not always) reported to be significantly reduced in the pancreata of patients with T2DM; Table 24.1 summarizes most of the available data. Early work reported that total islet number was 30 – 50% lower in histology samples from type 2 diabetic subjects as compared to nondiabetic individuals [38,39]. A reduction of total islet volume in diabetic versus nondiabetic pancreata was also shown [40,41], which became more marked when accounting for the presence of amyloid . In the following years, although a few authors were not able to find major differences in β-cell amount in diabetic compared to nondiabetic pancreas specimens [42–44], several studies consistently showed that β-cell quantity is reduced in T2DM. Clark and colleagues reported a 24% reduction in β-cell area in their series of type 2 diabetic pancreas samples , and islet β-cell volume and total β-cell mass were found to be significantly lower (∼30%) in specimens from Japanese type 2 diabetic patients than in samples from nondiabetic individuals . Similarly, a study conducted in Korea with pancreatic samples from organ donors or following surgical removal found that β-cell volume was approximately 25% reduced in T2DM . Pancreatic autoptic samples from type 2 diabetic patients, subjects with impaired fasting glycemia, and nondiabetic individuals have also been studied (the groups were subdivided into lean or obese based on BMI) . Obese subjects with IFG or diabetes had a 40–60% reduction in β-cell volume in comparison to BMI-matched, nondiabetic cases. In the nonobese group, diabetes was associated with 41% reduction of β-cell volume. In a more recent study , the authors analyzed autoptic samples from 57 type 2 diabetic and 52 nondiabetic European subjects, confirming that β-cell mass is lower (35% on average) in the diabetic cases (Figure 24.1). Similarly, when a comparison was made of pancreata obtained from lean and obese (BMI > 27 kg m−2 ) diabetic and nondiabetic cadaveric donors , it was found that β-cell volume and mass were reduced by approximately 35% in the obese type 2 diabetic cases; however, β-cell amount in lean donors was unaffected by the presence of diabetes . Additional information from later studies indicates that β-cell loss in T2DM may preferentially involve larger islets (in particular when located in the head of the pancreas) [10,13], confirms the potential role of amyloid deposition  and the presence of β-cell reduction in prediabetes , and suggests that the use of incretins may be associated with changes in β-cell amount .
Interestingly, however, a study carried out with the combined use of light and electron microscopy  suggested that the loss of β-cells in T2DM as assessed by insulin staining may be overestimated because of degranulation. In summary, the amount of β-cells appears to be reduced in human T2DM, especially in patients with long-standing disease ; further work is needed to more precisely quantify the prevalence, time-course and circumstances of β-cell loss.