This is my first clinical blog from the IDF Congress

Introduction

Session on Pathogenesis of type 2 diabetes: Which is the predominant culprit?

1.  The beta-cell J. Leahy (USA)

The speaker presented data from the Pima indians who have a very high prevalence of type 2 diabetes.  In persons with normal glucose tolerance at the onset, followed for over 5 years about 1/3d developed type 2 diabetes.  When those who developed diabetes were compared to those who did not, it was clear that those who developed diabetes were secreting less insulin at the onset of the study and insulin secretion steadily decreased as they progressed from normal to IGT to frank diabetes.  Those who did not progress, did have insulin resistance, but compensated by appropriately increasing their insulin secretion.  This brings up the question as to what defines a "susceptible" beta cell, that is, why do some beta cells fail and others compensate?  First, it might be genetic.  Over 50 genes have been defined as associated with type 2 diabetes.  While most are related to beta-cell function, a surprising number are related to incretin function.  Second, it might be related to intrauterine or neonatal malnutrition.  Both have been shown to predispose to obesity and type 2 diabetes later in life.  Finally, beta-cells are susceptible to damage by their homeostatic environment.  Fatty acid infusion, for example, acutely impairs insulin secretion.

Comment:  the presenter made an excellent case that in the final analysis, whatever the sequence of events, the beta cell must fail in order for diabetes to develop.

2.  The liver A. Gastaldeli (Italy)

The liver contributes glucose in the fasting state in order to maintain CNS functioning.  In obesity the proportion of glucose released by the liver via glycogenlysis and gluconeogenesis are normal.  However, as diabetes develops, more substraight in the form of free fatty acids and glycerol are delivered to the liver and gluconeogenesis increases.  Simultaneously the liver is presented with more lipids, lipid content of the liver increases and hepatic resistance to insulin develops.  The liver is unable to clear the lipids presented to it and skeletal muscle begins to accumulate triglycerides resulting in peripheral insulin resistance.

Comment:  Rather than being a primary actor, it is more likely that the liver is reacting normally to an abnormal environment resulting in a fatty liver and hepatic insulin resistance.  In any case, both the liver and the peripheral tissues become insulin resistant in the course of the development of type 2 diabetes.

3.  The brain G. Morton (USA)

The brain controls energy homeostasis both by sensing nutrient signals, eg. free fatty acids and adiposity signals eg. insulin or leptin.  The hypothalamus senses nutrient and hormonal environment and adjusts food intake accordingly.  Thus, if the hypothalamus sees a leptin deficiency,  it sends signals that increases appetite and food intake.   This is most dramatically demonstrated in ob/ob mice, which can not make leptin.  They become morbidly obese; an obesity that can be reversed by exogensis leptin.   Different diets can affect the sensitivity of the hypothalamus to leptin and insulin.  As an example high fat diets decrease leptin action.

Comment: I am not sure I have done this excellent presentation justice.  While the data on the regulation of food intake is necessarily derived from experimental animals, the clinical observations regarding the effects of altering the composition of diets on obesity rates suggest that our diets are contributing to changes in the brain's sensing our nutritional state, which may underlie the increases in food  intake observed with Western dietary habits.  I expect a wave of new pharmacologic agents based upon hormones known to regulate food intake and their analogues in the next few years.

4.  Fat and skeletal muscle M. Brady (USA)

Peripheral insulin resistance in fat and muscle results in increased free fatty acid release by adipocytes and increased insulin secretion by the beta cell.  As the process continues, liver becomes insulin resistant and the beta cell becomes exhausted resulting in IGT and eventual diabetes.  In in vivo studies in man the infusion of lipids decreases glucose clearance.  Although the speaker was focusing on peripheral tissues, he cited observations that suggest that the brain may be an active participant in insulin resistance.  In studies in normal college students, sleep deprivation was observed to produce insulin resistance.  When over four nights students got either 4.5 or 8.5 hours of sleep, they demonstrated insulin resistance in the period following the sleep deprivation.  

Comment: This is a very interesting observation given that sleep apnea is relatively common in obesity.

Although we associate obesity with insulin resistance, it has been observed for years that acute changes in nutrition results in correction of insulin resistance before significant weight loss.  In elegant studies, patients who were scheduled for bariatric surgery were studied two weeks prior to and two weeks following bariatric surgery, at a time when significant weight loss had not yet occurred.  They observed significant improvements in insulin resistance comparing the first to the second study.

Comment:  This observation supports that insulin resistance results from both steady state changes in peripheral tissues and the acute nutritional and hormonal state of the individual.  

Concluding comments

These presentations emphasize the complex nature of the series of events underlying the development of diabetes.  The most reasonable take home message is that type 2 diabetes can result from a number of pathways, but in the final analysis, insulin resistance results from fat being deposited in the liver and skeletal muscle and in the case of susceptible beta cells glucose tolerance deteriorates.

(*My attendance to the IDF is sponsored by the ADA, a member organization.)