86 P. Westermark importance. Both insulin (62) and IAPP(63) are normally released in pulses. It is tempting to believe that the tightly regulated pulses are disturbed by the amyloid interposed between b-cells and capillaries and most probably interfering with the cell membrane function. Another important issue is whether formation of islet amyloid is a pathogenic event in the development of type 2 diabetes or just participating in the ﬁnal destruction of islets. This question cannot be answered presently (64). A reason why islet amyloid has been denied as a pathogenic mechanism in dia- betogenesis is that islet amyloid does not occur in all individuals with type 2 diabetes. Interestingly, in a recent study on a baboon colony, islet amyloid appeared before the development of diabetes, and the amount of amyloid correlated well with the pro- gression of the disease (65). It has not been possible to demonstrate such a direct association in human. What we call type 2 diabetes is heterogeneous in human, and most probably several different mechan- isms act in the pathogenesis. It is quite possible that, in one major subgroup of individuals, aggregation of IAPP and development of islet amyloid actually is of major importance. It is also possible that deposi- tion of islet amyloid acts in concert with other path- ogenic mechanisms. This possibility will probably not be answered until methods have been developed by which amyloid deposits can be demonstrated in vivo, e.g. by positron emission tomography (PET), or until methods to prevent islet amyloid formation or even to dissolve already formed ﬁbrils have been introduced. The b-cell mass in type 2 diabetes For a long time there was no agreement concerning the question whether there is a reduction in islet volume and b-cell mass in type 2 diabetes. In early studies, types 1 and 2 diabetes were usually not clearly separated (66,67). Several later studies have shown a modest reduction of the islet mass in type 2 diabetes compared to age-matched controls, but there has been a considerable overlap (68,69). This reduction depends mainly on a smaller b-cell mass, shown in a number of studies (64,70–72). In one study we measured the total pancreatic volume as well as islet volume in 12 subjects with type 2 diabetes and 15 age-matched controls (69). The total islet volume in non-diabetic subjects was 1.60 ± 0.16cm3 (mean ± SEM) and in diabetic indi- viduals 1.01 ± 0.12 cm3 (P < 0.01). In another study we found that the percentage of b-cells was signiﬁ- cantly lower in islets of type 2 diabetic individuals compared to non-diabetic controls (43.0% ± 22% versus 59.2% ± 1.9%; P < 0.001) (70). If we assume that the materials in these two studies, emerging from the same department, are comparable, an estimate of b-cell volume in type 2 diabetes and controls would be 0.43 ± 0.05 and 0.95 ± 0.09 cm3, respectively. In reality, the difference should be even greater since in this calculation the volume taken up by amyloid has not been taken into consideration. These data ﬁt well with a ﬁnding that the b-cell area in diabetic subjects was reduced only in amyloid-containing islets (64). Even more intriguing was the signiﬁcant difference in b-cell percentage between islets in non-diabetic subjects with amyloid and those without any deposits (70). While islets in those without any amyloid con- tained 64.6% ± 1.4% b-cells, the percentage of b-cells in islets in individuals with islet amyloid was 55.9% ± 2.5% (P < 0.01). This indicates that deposition of islet amyloid is directly associated with b-cell loss and not only a result of the diabetic state per se. Limitations of islet volume determination in human All islet volume determinations suffer from the lim- itation that they have had to be performed on autopsy material. That means that individuals with diabetes usually have had their disease for several years, while it would have been of greater interest to study the pancreas very early in the diabetic state, or preferably before diabetes had become established. This is pres- ently impossible in humans until new methods have been developed. Since the pancreas is very sensitive to autolytic changes, obscuring histological details, it should be pointed out that studies have to be per- formed on material obtained well within 24 hours after death, something that was possible in the 1970s but is completely impossible today, at least in Sweden although it seems possible in some other countries (72). There are some good animal models which should be relevant for human type 2 diabetes. Thus, Howard showed that the diabetes which develops in Macaca nigra resembles the human form (31). Islet amyloid with loss of b-cells developed before overt diabetes. A type 2-like diabetes can also be found in elderly domestic cats (34,73). Baboons may also offer a relevant model (see above). In addition, there are transgenic mouse and rat models over-expressing human IAPP in which diabetes associated with islet amyloid develops (for review, see (25)). Functional b-cell mass Even in islets ﬁlled with amyloid, there are a number of b-cells ﬁlled with secretory vesicles (24). These cells are in direct contact with amyloid ﬁbrils and show