It appears therefore that reductions in both beta cell mass and beta cell function are present in individuals with type 2 diabetes. A critical question then arises. Does one follow the other, with one possibly even causing the other? As we cannot assess beta cell mass non-invasively, information in humans is non-existent and it is difficult to know exactly what happens in the progression from normal glucose tolerance through impaired glucose tolerance to type 2 diabetes. Thus, we have no choice but to turn to either animal models or in vitro studies, both of which clearly have limitations, in extrapolating findings to the human disease process. When considering this important question, one has to include as part of this discourse consideration of additional aspects many of the studies discussed earlier.
First, let’s consider the possibility of simple reductions in beta cell mass of the order observed in type 2 diabetes begetting beta cell dysfunction. The available evidence in animal models would suggest this simple mechanism is not likely to be operative. A 50% percent surgical reduction of pancreatic mass in dogs failed to produce changes in either fasting or arginine-stimulated insulin levels, fasting glucagon concentrations, the peak insulin response to intravenous glucose, or insulin sensitivity [16
]. In the face of this lack of change, it is not surprising that the animals did not develop hyperglycaemia. This contrasts with both type 2 diabetes and IGT where to a variable extent reduced insulin responses, excessive glucagon release and insulin resistance exist [1
]. In order to produce a state of hyperglycaemia in these dogs with a reduced number of islets, it was necessary to infuse glucose continuously for two weeks to maintain the plasma glucose level above 13.9 mmol/l [16
]. Similarly, in rats following a 60% pancreatectomy, glycaemia was not altered six weeks following surgery unless sucrose was introduced into the drinking water, and then it took three weeks with the increase in non-fasting glucose still being <1 mmol/l [50
]. In Gottingen minipigs treated with both streptozotocin and nicotinamide, a model of beta cell mass reduction in which alpha cells would not be anticipated to be reduced, mild hyperglycaemia developed but derangements in the periodicity or entrainability of insulin release could not be reproduced and all that was observed was a simple reduction in the amplitude of the pulses [51
]. These findings contrast with the derangements of continuous insulin release observed both in type 2 diabetic subjects and those at increased risk [37
]. Consequently, as simple mass reduction does not seem to beget the functional abnormalities, one has to conclude that beta cell mass has been replenished and/or beta cell function has improved.
That it is unlikely that replenishment of beta cell mass is occurring is suggested by the fact that there does not appear to even be a period of transient hyperglycaemia in the immediate days or weeks post-partial pancreatectomy, even when up to two-thirds of the pancreas has been removed [16
]. More importantly, as discussed and in keeping with this observation, six months following removal of 50% of the pancreas the size and number of islets as well as the number of beta cells was not different to that in the portion of pancreas obtained at the time of resection [16
]. Interestingly, this observation in dogs is compatible with the recent report of a lack of new beta cell formation following 50% pancreatectomy in humans [25
]. Thus, it would seem more likely that the normal beta cell is adapting functionally to the loss of a large proportion of its compatriots.
That the normal beta cell has an innate capacity to obviate the development of hyperglycaemia by enhancing its function is suggested by studies in healthy animals that have undergone a surgical reduction in islet mass. Following a 65% pancreatectomy in dogs, which reduces beta cell mass more than typically found in human type 2 diabetes, the beta cell’s sensitivity to glucose is enhanced [17
]. This adaptive change means that at physiological glucose concentrations each beta cell is releasing insulin more efficiently and thereby maintaining euglycaemia. Observations compatible with such an enhancement of beta cell sensitivity to glucose have also been made in rodent models of reduced beta cell mass [53
]. Thus, it would appear that a dysfunctional beta cell might be unable to adapt to a reduction in beta cell mass, resulting ultimately in the development of hyperglycaemia.
More recent work using genetically modified rodents strongly support the thesis that reduced beta cell mass alone is insufficient and that beta cell dysfunction is a sine qua non
if mass reduction is to result in the development of hyperglycaemia. In a mouse lacking the critical transcription factor FoxM1, proliferation of existing beta cells cannot occur; yet, despite this inability to form new beta cells, a 60% pancreatectomy does not result in a change in glucose tolerance [54
]. On the other hand, a 70% pancreatectomy in GLP-1 receptor null mice that fail to release insulin in response to GLP-1 [55
] results in the development of marked hyperglycaemia [56
]. Thus, one is left to conclude that when the remaining beta cells are functionally normal, a simple reduction in mass alone does not produce beta cell dysfunction, while when the remaining beta cells are dysfunctional, the additional insult of a reduction in beta cell mass results in the development of hyperglycaemia.
Could beta cell dysfunction then be the basis for a reduction in beta cell mass? Here again the inability to monitor possible changes in beta cell mass in situ
has required the use of in vitro
systems or examination of animal models in which pancreatic material is typically only accessible post mortem. It is clear from in vitro
work that elevations in glucose and fatty acids, either alone or together, are associated with the induction of beta cell dysfunction and the loss of s cells by apoptosis [57
]. However, these changes are not easily recapitulated in vivo
Glucose-induced changes in beta cell morphology that could be considered indicative of reduced beta cell mass have been observed. In dogs, following two months of sustained hyperglycaemia only attainable after two weeks of continuous glucose administration on a background of reduced beta cell mass, a profound reduction in the number and size of islets was found with marked depletion of insulin stores [16
]. In contrast, in rats 96 hours of hyperglycaemia produced by continuous infusion of glucose is associated with an increase in beta cell mass as a result of hypertrophy and replication, likely averting further hyperglycaemia [58
]. These findings contrast with those in hyperglycaemic humans where a compensatory generation of new beta cells does not occur [5
]. While these glucose-infused animal models are of interest, their relevance as a primary mechanism to explain human type 2 diabetes is questionable since the human condition does not typically transition rapidly from normal glucose tolerance through IGT to marked hyperglycaemia, but instead progresses over years.
While classically thought of in terms of peptide release, beta cell dysfunction could lead to beta cell loss through a mechanism(s) unrelated solely to exocytosis. Insulin is not the only unique peptide synthesized by the beta cell; the cell produces and co-releases islet amyloid polypeptide (IAPP or amylin) in parallel with insulin [59
]. Whereas the physiology of IAPP is poorly understood, its association with the loss of beta cell mass in type 2 diabetes is clearer. Normally this amyloidogenic peptide does not aggregate to form amyloid fibrils, whereas in type 2 diabetes it does so and during this process beta cell death and mass loss likely ensue [60
]. It is not clear in human type 2 diabetes what beta cell environment is permissive for IAPP aggregation to occur, but it has been suggested that impaired processing of the larger precursor proIAPP to native IAPP may be an important contributor [61
]. Further work is needed to determine the basis for IAPP aggregation and may throw light on whether this represents an instance where beta cell dysfunction may commence the process of beta cell loss.
It would appear therefore that any ability of reduced beta cell mass to beget beta cell dysfunction or beta cell dysfunction to beget reduced beta cell mass is complex. Of the two processes, current data would suggest the latter is more likely. However, the evidence is far from definitive and more work is clearly required.