β-Cell dysfunction vs insulin resistance in type 2 diabetes: the eternal “chicken and egg” question
OK Gang. The first of the two reviews on the changing paradigms on the etiology of type 2 diabetes. This one thanks to Craig in CT.
The idea that type 2 diabetes (T2DM) is mainly due to insulin resistance stems from the 1930s, but became dominating from the 1980s. However, evidence since the 1960s indicates that insulin response to glucose is markedly diminished from the earliest signs of glucose intolerance. Insulin pump treatment induces near-normoglycemia in T2DM with doses similar to type 1 diabetes, indicating that hyperglycemia is caused by lack of insulin, insulin resistance acting as an amplifier. Insulin secretion is genetically controlled. T2DM risk gene polymorphisms hint toward mechanisms of reduced insulin secretion in diabetes-prone subjects, in whominsulin response decreases as the number of diabetic alleles increases. I hypothesize that the genetic background of the β cell determines its adaptation capacity to increased insulin demand imposed by augmented caloric intake and insulin resistance; failure to adapt eventually leads to T2DM. Therefore, I regard the “prediabetic” β cell as a normal cell with limited adaptability, diabetes risk being entirely context-dependent (nutritional load and insulin sensitivity). Once hyperglycemia is established, β cells are exposed to continuous nutrient stimulation, with consequent oxidative and endoplasmic reticulum (ER) stresses. The result is increasing functional deficiencies and β-cell apoptosis, hence reduced β-cell mass. Some of its mechanisms are discussed. An intriguing as yet unanswered question is whether the mechanisms of β-cell deficit in the diabetic environment operate before hyperglycemia in overfed, insulin-resistant subjects. Therapeutic agents preventing β-cell oxidative and ER stress could stop the progression and perhaps initiation of T2DM.
When I first read this, it was that emphasized passage that caught my eye. The timeline was interesting as well, as it reminded me of this paper, Insulin: understanding its action in health and disease, that refers to:
... a 20 yr ‘black age’ of endocrinology (between approximately 1960 and 1980), where leading scientists—through extrapolating beyond their new discoveries—confused scientific thinking and teaching.
This is the period, BTW, from which most of a certain science journalist's understanding of endocrinology is gleaned.
When one reads studies like the one from my last post, it can be downright depressing ... does the pancreas poop out that quickly? Well, on the encouraging side, we have a plethora of evidence that it can be reversed. This is why the insulin pump comment jumped out at me. So take a look at this paper this weekend gang. I'd love to discuss it and it's implications.
Comments
It is very disturbing to learn that there may well be a huge gap between the actual mechanism of type II diabetes, and the commonly understood mechanism that guides treatment and management of the disease. But then I realized that this is very analogous to the situation with the management of coronary artery disease: we have turned treatment and prevention of CAD into treatment and prevention of elevated LDL cholesterol.
Now consider that diabetes and heart disease are 2 of the 3 great scourges of modern civilization (cancer being the third)! How can we seem to know so much about such important diseases, and yet be left fumbling in the dark to treat them appropriately?
* T2 diabetes is not a disease caused by peripheral insulin resistance, such that excessive insulin demand 'burns out' the pancreas. Peripheral insulin resistance (such that it exists) may exacerbate the problems of diabetes by increasing insulin needs, but even its role as an accelerant may be overstated. Rather it is the inability of the body to down regulate hepatic glucose production that leads to excessive glucose levels.
* In most/all (?) diabetics, the inability to downregulate hepatic glucose production is primarily due to abnormalities or insufficiencies in the ability to produce insulin. The cause and the nature of the insufficiency may vary according to the type. In classic T1, you have rapid beta cell destruction resulting from autoimmune attack, leading to a complete lack of insulin. What exactly happens in other forms is not quite as clear, but genetic abnormalities/susceptibilty seems to have a pretty clear role. Autoimmune disfunction also clearly has a role late onset T1 diabetes (e.g., LADA, MODY, etc)
* For many, if not most, classic obese/overweight T2 diabetics, it seems that the genetic susceptibility is such that the pancreas is unable to adapt adequately to conditions of overnutrition, and that in absence of chronic overnutrition, many of these people would not develop the disease. But if you happen to be a susceptible individual in a state of chronic overfeeding, then something happens within the pancreas that triggers a death spiral for beta cells. Perhaps it is chronic exposure to elevated blood sugar levels, or elevated proinsulin levels, or elevated NEFA. All hypotheses to be tested yet.
* There is compelling evidence to suggest that the main problem in many (all?) types of insulin insufficiency is with the conversion of proinsulin to insulin. This may point to different kinds of treatments or cures.
I am left wondering about these questions:
* Does this rule out hepatic insulin resistance as an accelerator? If your liver's response to the down regulating effect of insulin is low, can that increase your risk? What is the effect of visceral fat on insulin sensitivity. Is a fatty liver likely to be less responsive to the down regulating effects of insulin?
* What about fat within the pancreas - does that hinder the conversion of proinsulin to insulin?
* Does variation in visceral fat, via the above mechanisms, explain why starvation diets sometimes seem to cure T2 diabetes? Is the primary benefit of exercise for diabetics that it improves the regulation of hepatic glucose production, perhaps by reducing visercal fat levels and improving hepatic insulin sensitivity?
* What does this say about the role of carbs in the onset of T2 diabetes? I suppose if you overeat and have a lot of carbs in the diet, then glucose output from the liver needs to be strongly downregulated, simply because a lot of dietary glucose is readily available. But if you are not overeating, and have a high carb diet, wouldn't you still need a stronger suppression of glucose production in the liver than for someone who is on a low carb, moderate protein, high fat diet?
This is wild speculation (the best sort IMO).
I think there's more than enough evidence that excessive NEFA release and/or inefficient NEFA trapping is at the root of this all. More later on the next post re: this paper.
'Iron overload is a risk factor for diabetes. The link between iron and diabetes was first recognized in pathologic conditions hereditary hemochromatosis and thalassemia but high levels of dietary iron also impart diabetes risk. Iron plays a direct and causal role in diabetes pathogenesis mediated both by β cell failure and insulin resistance. Iron also regulates metabolism in most tissues involved in fuel homeostasis, with the adipocyte in particular serving an iron-sensing role. The underlying molecular mechanisms mediating these effects are numerous and incompletely understood but include oxidant stress and modulation of adipokines and intracellular signal transduction pathways.'
https://www.cell.com/cell-metabolism/abstract/S1550-4131(13)00055-7
And about iron and fatty acids: 'Studies on iron binding by free fatty acids'
http://www.ncbi.nlm.nih.gov/pubmed/8276425
'The effect of various saturated and unsaturated fatty acids on iron binding and the translocation of this complex into the organic phase were studied. ...It was seen that saturated and monounsaturated fatty acids translocated more iron compared to polyunsaturated fatty acids. ...It appears that the free carboxyl group on the fatty acid is essential ...Thus it seems that free fatty acids are capable of forming a complex with iron.'
Yeah, I'm a bit busy ;-) but there's definitely (well, I shouldn't say that but the preponderance of evidence all points to) something NEFA related that initiates the downspiral of the beta cell. But let me ask you this Jane, there is ample work out there showing this early beta cell dysfunction and near miraculous remissions with short (a week or so) courses of insulin therapy. Even the phenomenally metabolically damaged (morbidly obese diabetics) demonstrate a remarkably high remission rate with GBP surgery. I'm no fan of the latter, but why is not the former (relatively inexpensive and safe -- it's insulin after all!) standard care?
About NEFA: do you remember a paper from 2011 showing that a high fat diet can cause diabetes in mice? Here's the abstract.
'A connection between diet, obesity and diabetes exists in multiple species and is the basis of an escalating human health problem. The factors responsible provoke both insulin resistance and pancreatic beta cell dysfunction but remain to be fully identified. We report a combination of molecular events in human and mouse pancreatic beta cells, induced by elevated levels of free fatty acids or by administration of a high-fat diet with associated obesity, that comprise a pathogenic pathway to diabetes. Elevated concentrations of free fatty acids caused nuclear exclusion and reduced expression of the transcription factors FOXA2 and HNF1A in beta cells. This resulted in a deficit of GnT-4a glycosyltransferase expression in beta cells that produced signs of metabolic disease, including hyperglycemia, impaired glucose tolerance, hyperinsulinemia, hepatic steatosis and diminished insulin action in muscle and adipose tissues. Protection from disease was conferred by enforced beta cell–specific GnT-4a protein glycosylation and involved the maintenance of glucose transporter expression and the preservation of glucose transport. We observed that this pathogenic process was active in human islet cells obtained from donors with type 2 diabetes; thus, illuminating a pathway to disease implicated in the diet- and obesity-associated component of type 2 diabetes mellitus.'
http://www.nature.com/nm/journal/v17/n9/full/nm.2414.html
And from the Discussion:
'Although FFAs seem to promote beta cell function in some contexts, the chronic elevation of FFAs increases mitochondrial oxidation and reactive oxygen species and has been observed in beta cell cultures with diminished GSIS and reduced glucose transporter expression (34, 35). Our observations that the antioxidant N-acetylcysteine inhibits FFA-induced attenuation of Foxa2 and Hnf1a function are consistent with those findings.'
So the problem is that glucose transporters need to be glycosylated to stay on the cell surface, and fatty acids cause oxidative stress which prevents this. Of course glycosylation requires manganese, which also protects against oxidative stress. I have a friend in Australia who tells me manganese deficiency is linked to diabetes in the Chinese population he studies.
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Type 2 Diabetes
Etiology and reversibility
Roy Taylor, MD, FRCP
Diabetes Care April 2013 vol. 36 no. 4 1047-1055
"Type 2 diabetes can be understood as a potentially reversible metabolic state precipitated by the single cause of chronic excess intraorgan fat."
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