Type 1 Diabetes – Etiology and treatment
Although it’s not like I haven’t read some stuff about my disease over the years, the amount of textbook reading on the topic I’ve done has so far been limited to just a couple of books (and none of these have really been ‘textbooks on type 1 diabetes’); most of the stuff I know I’ve learned from the scientific literature, e.g. Diabetes Care articles, Cochrane reviews and similar, and in general the books which have dealt with diabetes which I’ve read have not been all that concerned about the various distinctions one might choose to make between the somewhat heterogenous disorders all going under the common name of ‘diabetes’. In ‘random books’ I think it’s fair to say that ‘diabetes’ usually is best translated ‘type 2 diabetes’, and the specific aspects of that disease most interesting to many book authors on health and related stuff are precisely the aspects which are completely irrelevant to type 1’s (e.g. lifestyle stuff related to prevention and disease progression in type 2’s).
So I decided to read this book to get a more solid background. Which kind of book is it? Here’s a quote from the introduction:
“The aim of Type 1 Diabetes: Etiology and Treatment is to fuse […] contemporary investigational and practical issues and make them available to those involved in the research and practice of type 1 diabetes. This volume is not intended to be a comprehensive or exhaustive treatise on the subject of diabetes. As in many such endeavors, the pace of discovery often exceeds the ability to incorporate the latest knowledge into printed text. Nevertheless, we believe that this volume presents contemporary information on contemporary issues by recognized authorities in the field. We hope it stimulates thought and action in the research and care of patients with type 1 diabetes mellitus.”
In case you were wondering, “make them available to those involved in the research and practice of type 1 diabetes” = this is not a book for patients and it’s not an undergraduate textbook; it’s mainly a book for PhD students and endocrinologists. I’d say that even if you skip the introduction you probably don’t need to read 10 pages to realize that. This is the kind of book where I’ll read all the words and then see how much of it I actually understand, occasionally looking up stuff which I’m particularly interested in; but I’ll not put in the work to actually understand all the details of what’s covered in all the chapters of this book. I don’t care enough about stuff like this to be willing to spend the time and effort it takes to understand all the details. I’ve tried to be very careful about getting at least some ‘take-away’ message out of all chapters covered so that e.g. even though I’ll not understand all the various processes which get you to the finish line, at least I know what’s at the starting line and where you end up on the other side. You may think that I’m lazy and that I’m just (mentally) skipping the hard stuff, but although this is certainly true to some extent I should add that I consider it justified to say that even though I’m mentally skipping a few steps occasionally while reading this book I’m still engaged in ‘learning in depth’ – most of the stuff covered in this book is knowledge at a level way beyond what the average patient knows about genetics, immunology, metabolic pathways etc. I actually feel reasonably sure at this point that I’d not have continued reading past the first chapter of this book if I had not read McPhee et al. first (I haven’t read that entire book yet, but I’ve read a lot of stuff relevant to the coverage here).
It would be wrong of me to only talk about the downsides to the coverage in this post, i.e. that it’s a hard book for most people to read; the flip side of course is that there are a lot of interesting details here. The book is full of stuff I didn’t know I didn’t know. Fortunately enough for my coverage of the book here, despite the fact that the book in general is somewhat inaccessible not all chapters are equally ‘bad’, and so there is also occasionally some stuff in there which I believe to be reasonably accessible even to people who don’t know a whole lot about type 1 diabetes (though I may be making assumptions about people’s background knowledge here which are not warranted). Anyway I’ve tried to pick out some of those passages in my coverage below, and on the other hand I’ve tried very hard to stay clear of stuff most readers could not possibly be expected to understand. Do ask questions if some of the stuff is unclear to you. I’ve read roughly the first 180 pages. Note that not all the stuff below is from the book; I decided to add some comments of my own towards the end of the post. I decided to bold some of the stuff below so that even people who only skim the post may get something out of it.
“By 1990, two international groups [the EURODIAB Project and the DiaMond Project] working on the epidemiology of type 1 diabetes had been developed. […] Because of these two important projects, the descriptive epidemiology of type 1 diabetes has been mapped for most of the world, and we now know more about the international variation in the incidence of type 1 diabetes than practically any other chronic disease. Within a short 15-yr time period, the epidemiology of type 1 diabetes rose from a “black hole” of ignorance to one of the best characterized chronic diseases worldwide” […]
“The variation in the incidence of type 1 diabetes worldwide is greater than that observed for any other chronic disease in children. […] the global variation in risk is enormous. A child in Helsinki, Finland is almost 400 times more likely to develop diabetes than a child in Sichuan, China (8). To put this in perspective, consider the following example. If children in the United States had the same risk of developing type 1 diabetes as children in China, then instead of 13,000 newly diagnosed children each year, there would be only 56. In other words, over 99% of the annual new cases of type 1 diabetes in the United States would be avoided. […] Interestingly, the other epidemiologic features of type 1 diabetes are remarkably similar across populations, despite the enormous variation in disease risk (9). Incidence rates among males and females do not differ significantly, and the peak age at onset for both sexes occurs near the time of puberty. Thus, compared to all other risk factors, including human leukocyte antigen (HLA) haplotypes, viral infections, or the presence of autoantibodies, the place where a child lives is the most potent determinant of type 1 diabetes risk, excluding genetic/racial differences. If we knew what was causing the geographic patterns of type 1 diabetes, we would be well on our way to preventing the disease.” […]
“Temporal trends in chronic disease incidence rates are almost certainly environmentally induced. If one observes a 50% increase in the incidence of a disorder over 20 yr, it is most likely the result of changes in the environment because the gene pool cannot change that rapidly. Type 1 diabetes is a very dynamic disease. […] the incidence of type 1 diabetes is rising [and] these findings indicate that something in our environment is changing to trigger a disease response. […] The data […] clearly indicate that environmental factors are involved in the etiology of type 1 diabetes. With the exception of a possible role for viruses and infant nutrition, the specific environmental determinants that initiate or precipitate the onset of type 1 diabetes remain unclear. Type 1 diabetes is also, in large part, genetically determined” [here’s a relevant link, I won’t go into the details here although they spend a lot of pages talking about that stuff in the book]
“Evidence that type 1 diabetes is an autoimmune disorder is based on the presence of lymphocytic infiltrates of the pancreas at the onset of the diseases (37), as well as the occurrence of autoantibodies to islet cell antigens (ICAs), tyrosine phosphatase IA-2 (IA-2), glutamic acid decarboxylase (GAD), and insulin autoantibodies (IAA) (38,39). The presence of these autoantibodies indicates that tissue damage has likely been initiated by other etiologic agents. Thus, they represent important preclinical markers rather than risk factors for the disease. […] most type 1 diabetes cases have β-cell autoantibodies at disease onset, [however] not all autoantibody positive individuals develop the disease. […] first-degree relatives who are positive for multiple autoantibodies appear to be at very high risk for developing type 1 diabetes. […] about 90% of individuals who develop type 1 diabetes have a negative family history of the disease.”
“The autoimmune response in type 1 diabetes is […] similar to most other organ-specific autoimmune disorders in that both T-cells and autoantibody-producing B-cells are involved in the immune abnormalities associated with, as well as predicting, the disease (24). The molecular biology of β-cell destruction is therefore both diverse and complicated and the detailed mechanisms are yet poorly understood. […] At the time of clinical diagnosis of type 1 diabetes, about 80% of the β-cells have been specifically destroyed.”
“We currently know that for individuals with two HLA-DQ susceptibility haplotypes, the cumulative risk of type 1 diabetes in the general Caucasian population is approximately 5% (25). However, it may range from 0.1% to >90%, depending on one’s risk factor profile, which includes age, ethnic, familial, genetic, environmental, and autoimmune determinants.” […] Diabetogenic alleles are not fully penetrant” […] There is no simple “rule” for diabetes risk […] the position of provisional loci found in T1DM colocalize or overlap with loci found in different autoimmune/inflammatory diseases […] This is consistent with the hypothesis that, like the MHC, some of these provisional loci may involve common susceptibility genes or biochemical pathways that are central to normal immune function.”
“At present, the prediction of type 1 diabetes is not a major clinical issue outside of trials for diabetes prevention. Patients, especially children, usually present acutely with diabetes with a dramatic history of polyuria, polydipsia, and weight loss. Despite what in retrospect is almost always a clear-cut clinical history of diabetes, a significant number of children have a delay in diagnosis, which increases the risk of severe metabolic decompensation with diabetic ketoacidosis (DKA), cerebral edema, and death. […] Overall in the United States, DKA occurs in 25–50% of children with new-onset diabetes, and symptomatic cerebral edema occurs in approx 1% of DKA episodes. Of those patients with clinically apparent cerebral edema, between 40% and 90% die (1). […] In the United States […] it is rare to find individuals presenting with diabetes with normal HbA1c [an indicator of average blood glucose over the last 3 months or so – US] and it is likely that the great majority have had hyperglycemia for months prior to diagnosis.”
“Diabetes mellitus is classified based on clinical criteria into type 1 and type 2 diabetes (98). Recently, a growing number of monogenic diabetes disorders have been identified (98). Type 1 diabetes develops acutely. Ketoacidosis and coma develop unless insulin is administered. Type 2 diabetes develops mostly as a result of insulin resistance associated with obesity and β-cell dysfunction and occurs insidiously, and most patients are successfully controlled by diet, exercise, or oral hypoglycemic agents. […] the overall autoantibody frequency in type 2 patients varies between 6% and 10% (105). However, the positive predictive value that a GAD65Ab positive type 2 diabetes patient [that is, a type 2 diabetic with a specific genotype] will be treated with insulin within 5 yr is 100% […] Diabetes will appear as a function of loss of β-cell mass and loss of β-cell function. Different clinical phenotypes may develop, dependent on the combination of loss of β-cell mass and loss of function. […] A different severity of inflammation may lead to variable degree of β-cell inhibition and resulting hyperglycemia […] the degree of insulin resistance is also critical (99). Some subjects may encounter a severe loss of β-cells but, despite this, may not develop diabetes because of their high insulin sensitivity […] Other subjects may develop diabetes at modest β-cell loss because they are highly insulin resistant. Therefore, it is not surprising that type 1 diabetes or autoimmune diabetes is associated with a large number of different phenotypes […] To complicate the heterogeneity of autoimmune diabetes even further, it has also been found that patients with diabetes may develop GAD65 autoantibodies after the clinical diagnosis […] In contrast to […] patients masquerading as type 2 diabetic patients [because of slow onset of disease], an acute onset of type 1 diabetes is also reported (113). These patients have lower glycosylated hemoglobin values, diminished urinary excretion of C peptide, a more severe metabolic disorder with ketoacidosis, as well as higher serum pancreatic enzyme concentrations, compared to type 1 patients with a less dramatic onset […]
“All vertebrates use insulin-producing pancreatic β-cells to achieve fuel homeostasis (1). These cells are able to measure the nutrient levels of the blood on a moment-to-moment basis and secrete insulin at rates that are exactly appropriate for the maintenance of optimal fuel levels. Therefore, the levels of circulating nutrients such as glucose, fatty acids, and amino acids are precisely controlled in mammals during fasting and feeding alike. The role of the pancreatic β-cells in fuel homeostasis is thus analogous to that of the thermostat in heating and cooling systems (2,3).” [This sounds simple enough. However it gets ‘not simple’ very fast.]
“Hypoglycemia is the limiting factor in the glycemic management of diabetes because it generally precludes maintenance of euglycemia [normal blood glucose levels, US]. […] Were it not for the potentially devastating effects of hypoglycemia, particularly on the brain, glycemic control would be rather easy to achieve. Administration of enough insulin (or any effective medication) to lower plasma glucose concentrations to or below the nondiabetic range would eliminate the symptoms of hyperglycemia, prevent diabetic ketoacidosis and the nonketotic hyperosmolar syndrome, almost assuredly prevent retinopathy, nephropathy, and neuropathy, and likely reduce atherosclerotic risk. However, the devastating effects of hypoglycemia are real and the glycemic management of diabetes is therefore complex.” [much of chapter 7, from which the above and the following quotes originate, covers stuff I’ve covered before e.g. in this post, but there was some new stuff in that chapter as well and I actually think of this as the best of the chapters I’ve read so far]
“Iatrogenic hypoglycemia is the result of the interplay of therapeutic insulin excess and compromised physiological and behavioral defenses against falling plasma glucose concentrations in T1DM […] Glucose is an obligate metabolic fuel for the brain under physiological conditions (4). (The brain can utilize other circulating substrates, including ketones such as β- hydroxybutyrate, but the blood levels of these seldom rise high enough for them to enter the brain in quantity and thus partially replace glucose, except during prolonged fasting.) Because of its unique dependence on glucose oxidation as an energy source and because it cannot synthesize glucose or store more than a few minute’s supply as glycogen, the brain requires a continuous supply of glucose from the circulation. At normal plasma glucose concentrations the rate of glucose transporter (GLUT-1) mediated blood-to-brain glucose transport down a concentration gradient exceeds that of brain glucose metabolism. However, when arterial glucose concentrations fall below the physiological range blood-to-brain glucose transport falls and ultimately becomes limiting to brain glucose metabolism and thus its functions and even its survival. Given the immediate survival value of maintenance of the plasma glucose concentration, it is not surprising that physiological mechanisms that very effectively prevent or rapidly correct hypoglycemia have evolved.”
I was considering covering these mechanisms in detail as well, but I reconsidered and decided to cut it short. However a few remarks should be included on this topic. One key point here is that one of the important reasons why diabetics are prone to hypoglycemia is that most of the normal physiological defence mechanisms against hypoglycemia are basically destroyed in diabetics. The first step in the body’s correction of low blood glucose is reduction of insulin production. This takes place way before symptoms ever occur in normal people. Type 1 diabetics who’ve taken insulin for a while don’t produce insulin on their own, so their body can’t regulate/lower insulin production – it’s already at zero. So step one in the process is deactivated. The second step in the natural process to reverse hypoglycemia involves increased glucagon secretion; glucagon is a hormone which tells the liver to convert its stores of glucogen (a type of sugar) into glucose and release them into the bloodstream. The authors note that although glucagon responses to other stimuli remain mostly intact in diabetics, the response to hypoglycemia is destroyed, for reasons not well known. So the first two defence mechanisms against hypoglycemia are completely out of the window in diabetics. The main one left is increased epinephrine secretion. Normally this one only sets in after the first two other responses have failed, but a very important point is that the set point for when this mechanism sets in depends on how often the diabetic is hypoglycemic; if hypoglycemia is common, the body will start tolerating lower blood glucose levels without initiating the remaining counterregulatory mechanism (there are a few other mechanisms at play, but they basically only apply to long-term hypoglycemia and will not play any significant role in a diabetic with acute hypoglycemia). The epinephrine response will still be initiated eventually, but the blood glucose level needed to initiate the process will be downregulated over time if hypoglycemic episodes occur often, which is problematic for reasons explained below. An important observation from the book regarding this counterregulatory mechanism:
“The development of an attenuated epinephrine response to falling glucose levels — loss of the third defense against hypoglycemia — is a critical pathophysiological event. Patients with T1DM who have combined deficiencies of their glucagon and epinephrine responses have been shown in prospective studies to suffer severe hypoglycemia at rates 25-fold (45) or more (46) higher than those with absent glucagon but intact epinephrine responses during aggressive glycemic therapy.”
The main reason things tend to go bad in these cases is presumably that if the epinephrine response is lost, the first manifestation of hypoglycemia is neuroglycopenia; the diabetic learns that she has a low blood glucose only when her brain stops working properly. This makes engaging in the correct behavioural responses (ingestion of glucose) problematic.
The concepts of hypoglycemia unawareness and what’s termed hypoglycemia-associated autonomic failure are closely related and important concepts to be familiar with:
“The concept of hypoglycemia-associated autonomic failure in T1DM […] posits that (1) periods of relative or absolute therapeutic insulin excess in the setting of absent glucagon responses lead to episodes of hypoglycemia, (2) these episodes, in turn, cause reduced autonomic (including adrenomedullary epinephrine) responses to falling glucose concentrations on subsequent occasions, and (3) these reduced autonomic responses result in both reduced symptoms of, and therefore the behavioral response to, developing hypoglycemia (i.e., hypoglycemia unawareness) and — because epinephrine responses are reduced in the setting of absent glucagon responses — impaired physiological defenses against developing hypoglycemia (i.e., defective glucose counterregulation). Thus, a vicious cycle of recurrent hypoglycemia is created and perpetuated.”
A few more concluding remarks from the chapter:
“hypoglycemia risk reduction requires consideration of both the conventional risk factors that lead to episodes of absolute or relative insulin excess — insulin (or other drug) dose, timing, and type, patterns of food ingestion and of exercise, interactions with alcohol or other drugs, and altered sensitivity to or clearance of insulin — and the risk factors for compromised glucose counterregulation that impair physiological and behavioral defenses against developing hypoglycemia […] The underlying principle is that iatrogenic hypoglycemia is the result of the interplay of insulin excess and compromised glucose counterregulation rather than insulin excess alone.”
I was well aware that diabetics can’t regulate insulin production (of course) and that this is a problem in terms of counter-regulation which makes hypoglycemia more likely, but I had no idea that ‘normal people’ had other natural counter-regulatory mechanisms which are also impacted by diabetes (to be clear, I was familiar with the concept of hypoglycemia unawareness but I’d never read about it in detail and the glycagon-response deactivation in diabetics I was not aware of. I knew that injections of glucagon is a treatment option in case of severe hypoglycemia – I’ve had such injections a few times, though fortunately not within the last decade – but I didn’t know that ‘normal people’ naturally secrete this stuff on their own if/when their blood glucose drops). In case you were wondering how to break the cycle:
“In a patient with hypoglycemia unawareness, a 2- to 3-wk period of scrupulous avoidance of iatrogenic hypoglycemia is advisable”.
Basically the idea is to avoid hypoglycemias for a while in order to change the threshold where the epinephrine response kicks in. Of course one shouldn’t change it too much in the other direction; poorly regulated diabetics tend to have thresholds higher than normal, so that they get symptoms of hypoglycemia even when their blood glucose is within the normal range. Something like that of course makes it harder for those individuals to achieve the therapeutic goals of reasonably low Hba-1c’s. I was wondering if I should mention this or not because it might get confusing but I decided to anyway; it should be noted that hypoglycemia-associated autonomic failure is a different form of nervous system dysregulation in diabetics than the one that takes place in long-term diabetics who develop diabetic autonomic neuropathy (DAN). Hypoglycemia-associated autonomic failure is reversible, whereas DAN most of the time isn’t, and DAN may have a lot of unpleasant effects aside from ‘just’ hypoglycemia unawareness – while covering the relevant chapter in McPhee not too long ago I noted that DAN may affect the enteric nervous system and cause problems with peristalsis, but this is but one of many problems caused by autonomic dysregulation; see the link above for more on this stuff. It should be noted that the authors in McPhee do not seem to be aware of the fact (at least they do not make it clear…) that not all hypoglycemia-unawareness in diabetics is related to DAN. On a different if related note it might be added that the autonomous nervous system is not the only part of the nervous system that is potentially affected by diabetes in the long run; for example sensorimotor polyneuropathy affecting the extremities is a far from uncommon complication.
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