Saturday Morning Research Review – October 8, 2016

Beta cells work harder in response to high-fat diet before they increase mass or divide

by Adam Burrack, PhD

It has been a long-standing question in the beta cell biology field how beta cells respond to metabolic stress – or high demand for insulin production. The answer to this question is directly relevant to the long, slow, run-up to type 2 diabetes onset (why do beta cells die?), but also has implications in type 1 diabetes. In short, if we want to prevent destruction of an islet transplant in a type 1 diabetic subject – or prevent type 2 diabetes onset – it’s worth knowing precisely why the beta cells are dying. The two basic options for beta cell response to very high insulin demand are: (1) each beta cell works much harder, significantly increasing its own insulin production, and (2) sensing an increase in demand, beta cells proliferate – and then work at the same level of insulin output. The implications for beta cell are the following: (1) if each beta cell works harder, they could literally work themselves to death, or (2) adult beta cells are somehow sensitive to death during the process of cell division – or adult beta cells don’t proliferate early enough in response to demand, subjecting themselves to too much metabolic demand.

A paper recently published in the journal Diabetes by a group studying type 2 diabetes demonstrates the power of islet transplantation into the anterior chamber of the eye and imaging beta cell biology in real time. As a model of type 2 diabetes onset, this group used a high-fat diet to study this question. The key innovation in this paper was the use of islet transplantation into the anterior chamber of the eye and real-time live imaging of beta cell mass and calcium signaling to quantify beta cell response to a high-fat diet over relatively long experiments using mice (4 weeks, up to 18 weeks). This transplantation technique is the only current method to track beta cell biology in live mice, in real time, over months of time. The high-fat diet resulted in massive weight gain and impaired fasting blood sugar levels. The primary article was accompanied by a thorough executive level summary. Primary results of the study were as follows.

First, glucose tolerance continued to get worse over time on the high-fat diet. Related and in addition, the result of a 2-hour glucose tolerance test – a measure of how quickly insulin is produced in response to a glucose challenge – continued to deteriorate over time on a high-fat diet. Combined, these results suggest the mice had reached a pre-diabetic state by 17 weeks on the high-fat diet. Second, islet volume had doubled by 16 weeks on the high-fat diet, but increased gradually. Using fluorescently-labeled beta cells, the authors observed that individual beta cells did not increase in size. The vasculature adapted to this by expanding vessel diameter and “lengthening the vascular network”. Third, the authors calculated a “beta cell functional index” – by dividing insulin stimulation by the increase in beta cell mass. This calculation demonstrated a strong and marked increase in the function of individual beta cells – which was maintained as beta cells subsequently proliferated in response to high-fat diet feeding. Fourth, beta cells in high-fat diet fed mice showed higher baseline levels of calcium signaling. Calcium signaling is a key step of beta cell secretion of secretory granules containing insulin. The authors speculate this is related to the increase in baseline glucose levels in high-fat diet mice. The authors then relate this change to a specific signaling pathway within beta cells. Fifth, and really interesting when thinking about translating these results to type 2 diabetes in the clinic, a mere 2 weeks back onto a normal diet reversed many of these changes in beta cell biology. In particular, fasting glucose level and glucose tolerance returned to normal, stimulated insulin responses returned to normal, and islet mass ceased its increase. Lastly and most importantly, beta cell functional index and the calcium flux returned to normal-diet levels.

These results have several clinical implications. Essentially, the first response of beta cells work harder in response to very high metabolic demand, rather than proliferating. This answers a long-standing open question in beta cell biology and why beta cells die prior to onset of type 2 diabetes. Beta cell function adapted much more quickly than beta cell mass – beta cells worked harder on an individual basis well before they proliferated.

In other words, simply adding more islets will not fix dysfunction in the presence of a high-fat diet: the high-fat diet itself led to beta cell dysfunction, and encouragingly, beta cell function normalized after as little as 2 weeks on a normal diet. It is tempting to speculate that athletes are subject to these same limitations on beta cell function: it is my opinion that diet is always relevant to beta cell function and blood sugar level homeostasis, regardless of aerobic conditioning or pharmacologic intervention.

Posted in beta cells, Research Review.