Obesity and diabetes (1)

There is absolutely no doubt in my mind that adipocytes can become insulin resistant. The most convincing paper I've come across is this one

Basal lipolysis, not the degree of insulin resistance, differentiates large from small isolated adipocytes in high-fat fed mice

They took adipose tissue from a group of mice which had been made insulin resistant, and obese, by feeding a high coconut fat/sucrose (ie Surwit-like) diet and extracted a supply of adipocytes. Whether these cells were large or small, provided they had been exposed to Surwit-derived conditions for eight weeks, they were all equally insulin resistant. Big ones and little ones. Size made no difference. Insulin resistance is real but not associated with adipocyte distention.

What they also found was that size of adipocytes was very closely and positively associated with basal lipolysis, that is with the rate of lipolysis in the absence of insulin or sympathomimetic agents.

This is not a new finding. From 1972:

Effect of cell size on lipolysis and antilipolytic action of insulin in human fat cells

I like this paper. I have certain biases, one of the strongest of which is that I like papers in which you are given the concentration of glucose which is used in their cell culture medium. Here they happen to have used 1mmol/l, which might rightly be considered a little low, but at least they tell you. Unlike many papers.

Basal lipolysis correlated well with cell diameter. If basal lipolysis is related to the function of lipid droplet surface proteins this is completely plausible and almost predictable. Here's their graph:

The ability to suppress basal lipolysis using insulin appears to be completely determined by the conditions you use to incubate your cells, higher glucose appears to make insulin more effective on suppressing basal lipolysis, but that's an aside. This current study used a glucose concentration of 1mmol/l and showed absolutely no effect of insulin on basal lipolysis. In fact, as you increase the concentration of insulin from zero through high physiological to gross pharmacological the rate of basal lipolysis actually increases. Like this:

If anyone thinks this might represent insulin induced insulin resistance I might be tempted to agree, though the significance to anything physiological of exposure to 100,000microU/ml of insulin seems somewhat dubious.

They did find that physiological insulin exposure suppressed sympathomimetic induced lipolysis, an effect blunted by a grossly pharmacological overdose of insulin. Again, something confirmatory to my biases:

The take home message is that insulin is not particularly effective at suppressing basal lipolysis and that basal lipolysis increases with adipocyte cell size.

We have certain inter related processes here. Insulin facilitates lipid storage in adipocytes and we know that this function is both normally self limiting via ROS generation and is augmented pathologically by the oxidation of polyunsaturated fatty acids, leading to increased adipocyte size.

As adipocyte size increases the separate process facilitating basal lipolysis progressively increases, which cannot be suppressed by hyperinsulinaemia, certainly not completely.

Above a certain size it becomes almost impossible to suppress free fatty acid release from adipocytes using insulin. Under these circumstances there is a continuous supply of free fatty acids, despite the presence of insulin and a copious supply of post prandial glucose.

At a certain point the processes of augmented lipid storage and increasing basal lipolysis will come in to something approaching equilibrium.

The size of adipocytes at this point will be determined by the level of insulin being generated by the diet, the degree of augmentation of that insulin signalling by linoleic acid and whatever factors influence the rate of rise of basal lipolysis with increasing adipocyte size (currently unclear).

That's assuming a pancreas of steel which can crank out insulin at adequate levels to control glycaemia to non diabetic levels despite an increasingly un-suppressible fatty acid supply.

This will be relatively easy, provided adipocytes remain insulin sensitive. We know from 

Diet fat composition alters membrane phospholipid composition, insulin binding, and glucose metabolism in adipocytes from control and diabetic animals

that it is perfectly possible to have insulin sensitive adipocytes, adipocyte distention and systemic insulin resistance without those adipocytes becoming insulin resistant themselves. Under these circumstances the is ample scope for further weight gain. Provided the pancreas can hypersecrete insulin, glycaemia can stay fairly well controlled as weight increases.

Whatever causes adipocytes to change from insulin sensitive, as in this last paper, to insulin resistant, as in the first paper, will markedly increase the demand for insulin to maintain normoglycaemia. If the pancreas cannot meet this demand or beta cells start to undergo apoptosis secondary to exposure to elevated glucose and free fatty acids in combination, progression to DMT2 occurs where insulin secretion can no longer control glycaemia, let alone FFAs.

With the onset of DMT2 weight gain will stall. It is perfectly possible to facilitate the process of further weight gain (and associated increased basal lipolysis) by continuing to squeeze more insulin out of the pancreas using a sulphonyl urea drug or by the injection of exogenous insulin. Both approaches appear to be favourites with diabetologists once they've started with metformin.

To summarise: Excess insulin sensitivity from linoleic acid, combined with elevated insulin secretion, expands adipocytes. Expanded adipocytes increase basal lipolysis, which is difficult to suppress. With increased basal lipolysis fat oxidation, whole body, increases and induces the normal physiological insulin resistance which occurs via ROS/Protons mechanism. Eventually reduced pancreatic function leads to diabetes primarily via the inability to secrete enough insulin to normalise glucose levels while FFAs are elevated.

There's more to this.

Peter