If your guru's ideas have an expiration date, maybe it's time to find one whose ideas have a longer shelf life.

Have you just stumbled upon an old book, blog post, interview, etc. from your favorite guru only to have someone exclaim how old that is and how your guru's opinions have changed?  It might be time for a new guru.

Quick background here.  First, no I haven't dropped the Paleo ApprovED issue, but there are some things related and lots of stuff unrelated going on that have eaten up time and energy to blog on the subject.  It is a sensitive issue and needs more "care" than your run of the mill blogging.  It is also rather stressful and defeats one of the purposes of this blog as an outlet for my sarcastic side -- for which a post such as this is perfectamundo!    So that said, as I was looking for a post on Robb Wolf's blog (this one) my search also popped up the following post:

Insulin: Anorexic?

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Insulin Secretion in the Progression of Type 2 Diabetes ~ First/Early Phase

Another one that fell through the cracks in the draft bin.   A continuation of the posts discussing:  β-Cell dysfunction vs insulin resistance in type 2 diabetes: the eternal “chicken and egg” question.   The primary post on this article here.  There may be some repetition from other posts that have been published in the interim, but what the heck, I'm publishing it up.

I've screenshot and C&P'd the relevant section that I'll be discussing in this post.  If it is difficult to read, etc., you can of course go to the original paper.

The main point of this section is to highlight the loss of first phase insulin secretion that precedes frank diabetes.  In Figure 2 we see that the (yellow) NGT response is a spike in insulin production within the first few minutes.  

In nondiabetic individuals, approximately 50% of the total daily insulin is secreted during basal periods, suppressing lipolysis, proteolysis, and glycogenolysis. The remainder of insulin secretion is postprandial.  In response to a meal, there is a rapid and sizable release of preformed insulin from storage granules within the beta cell.  This "first phase" of insulin secretion promotes peripheral utilization of the prandial nutrient load, suppresses hepatic glucose production, and limits postprandial glucose elevation. First-phase insulin secretion begins within 2 minutes of nutrient ingestion and continues for 10 to 15 minutes. The second phase of prandial insulin secretion follows, and is sustained until normoglycemia is restored....

... First-phase insulin secretion is often represented in clinical studies by the acute insulin response to an intravenous glucose bolus ...  it demonstrates the sensitivity to and insulin response of the beta cell specifically to the glucose stimulus. It is this loss of beta-cell glucose sensitivity and responsiveness that declines early in the development of type 2 diabetes, even while responses to amino acid and other stimuli are preserved

source (free membership may be required to view)

This paper discusses a perfused cat pancreas, but it sums up the insulin response to acute stimuli:  

• Insulin secretion is biphasic in response to either glucose or amino acid stimuli.
• Glucose caused a much more pronounced first phase release than did a complete amino acid mixture; whereas glucose and the amino acid mixture stimulated late second phase insulin secretion equipotently.

And another repeat of the graphic of glucose, insulin and proinsulin secretion following OGTT from this post and paper.  The "early" insulin release is shown to be the first to go here as well.  I discussed the relationship of and a clarification about "first phase" insulin response and the physiological relevance here.  This is shown in the diagram below right and a quote from the paper discussed in that post:

An increasing body of evidence indicates that the early insulin response following glucose ingestion plays a critical role in the maintenance of postprandial glucose homeostasis. The early surge in insulin concentration is capable of limiting the initial glucose excursion mainly through the prompt inhibition of endogenous glucose production, with the insulin mediated curtailment of glucagon secretion being particularly relevant.

Lastly, let's talk a bit about fatty acids. About a year ago I discussed this paper regarding how chronic exposure of beta cells to fatty acids (I use the acronym NEFA) essentially depletes the insulin content and/or production capability of the cells. The bottom line of that paper was while NEFA are involved in GSIS and contribute to this acute insulin secretion, they are also responsible for basal insulin release. Glucose stimulates both insulin secretion and transcription of proinsulin from which more insulin can be made, while NEFA stimulate secretion but not the refilling of the well. From the paper:

If this is so, the insulin content of the β-cell cannot be rapidly replenished after acute stimulation of insulin release by FFA. Under normal circumstances, only a small proportion of the β-cell’s insulin intracellular store is released after an acute stimulation by a secretagogue, so that short-term FFA-induced insulin release would have little adverse effect on the β-cell’s secretory capacity. However, chronic exposure to FFA could severely deplete the internal insulin stores since there is apparently no biosynthetic backup to compensate for FFA-induced insulin hypersecretion.

This may be one reason why low carb diets don't appear to improve insulin secretion similarly to interventions like the "crash diet".   I blogged about this study a while back demonstrating that NEFA release from adipocytes is not appropriately suppressed with a low carb diet.

In summary, while this is by no means comprehensive, I'd like to revisit in the near future, the dietary causes, if any, and the scientific evidence of same, in the development and/or progression of type 2 diabetes and wanted to publish this up as background.

Celebrity Diabetes ~ Tom Hanks now

Before Paula Deen got in hot water over racial issues, she was the subject of controversy a few years back with her belated disclosure that she had Type 2 diabetes, and then became a spokesperson for Novo Nordisk's Victoza.  The "mainstream" balked, including rebukes from fellow celebrity chefs for using so much butter in her cooking while hiding the effect it had on her health.  When the news hit the LC community, it of course went nuts.  I discussed this pretty thoroughly HERE.  A quick summary might be that the low carbers didn't like that people blamed the fat in her foods and finger pointed at the carbs (ignoring sedentary lifestyle entirely).  Further, they didn't like that she was dieting per mainstream guidelines and using Victoza rather going on a LC diet.   Stress certainly has taken a toll on Deen, but she seems to have maintained her weight loss, perhaps even losing a few more pounds.  It would be interesting to get an update on her condition, but somehow I doubt we will.

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The LoBAG Diets for treatment of Type II Diabetes and IGF-I: Updated & Expanded

Bump ...

Does dietary protein raise blood glucose?  Not in normal or Type 2 diabetics it doesn't.  This will be the topic of a post today or tomorrow.  There is a disturbing, in my opinion, trend in the low carb community to now demonize protein.  Your usual Atkins style diet is no longer "good enough" or "well formulated" enough for most.  This keto kraze has gotten really krazy!

As far as I'm concerned, the danger of people like Jimmy Moore is no better epitomized than by this trend.  You have lots of people regurgitating his claims that his liver makes too much glucose out of protein and this is implicated in his weight issues.  Nevermind all of the evidence to the contrary.  Leaving weight loss aside, yes, this is anecdotal, but we have no other "evidence" to go by!  Long term low carbers seem to have worsening glucose tolerance over time.  Almost to a one, and these are people who were not diabetic or in some cases even IR (by HOMA) at baseline.  

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The Vascular Functions of Insulin

Random Replay

Was having a discussion on FB about insulin this morning and while going through some blog posts this one popped up.  I find reading some old stuff interesting at times ... this is over 3 years old.  

If someone goes on a low carb diet and this manages their hyperglycemia, this is a classic example of treating symptoms while not addressing the cause of the problem which is pancreatic beta cell dysfunction, and in the case of the T2, coupled with hepatic insulin resistance.  

What low carb doesn't do is restore normal insulin secretion and signaling, and insulin plays many roles in the body beyond glucose transport.  For one, it also assists amino acid transport (and protein synthesis) which is why the IR often have elevated circulating levels of the most insulinogenic (e.g. insulin requiring) amino acids, the BCAAs.  

This post is a flashback of some of the other things insulin does.  Further it discusses the role of NEFA in all of this ... the forgotten biomarker I think most low carbers with whacky lipids should have measured as they are likely elevated.  

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Will NuSI clear the bar?

Gary Taubes is out with a new article in Scientific American ... rehashing the same old same old, and essentially getting paid to write a press release for NuSI.  

What Makes You Fat: Too Many Calories, or the Wrong Carbohydrates?

Rigorously controlled studies may soon give us a definitive answer about what causes obesity—excessive calories or the wrong carbohydrates

We get the rehashing of how WWII stopped Bergmann and Bauer's Lipophilia Hypothesis from becoming the working hypothesis for obesity, and yet another primer on calories vs. carbohydrates.  We again are asked to ignore the obvious -- that Americans are definitely eating more, on average, with no concurrent need for those calories, and likely moving a bit less as well.   The obesity epidemic that supposedly was instigated by the low fat craze is blamed on the fact that much of our additional caloric load is in the form of carbohydrates.  This is not supported by one of Gary Taubes' own paradoxical cultures, the Pima, who did not eat a low carb diet prior to the 1900's, let alone billions of humans all over the globe.   Or .... despite the "modern paleo's" insistence, the paleolithic diet in the literature -- both cited for the basis of the diet and that used in clinical trials.  

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Bump: The Diabetes "Crash" Cure & Pancreatic Fat

Today's 8/15/13 bump was inspired by a comment by Tsimblist (thanks!) alerting me to this paper:  Type 2 Diabetes Etiology and reversibility

Reversal of type 2 diabetes to normal metabolic control by either bariatric surgery or hypocaloric diet allows for the time sequence of underlying pathophysiologic mechanisms to be observed. In reverse order, the same mechanisms are likely to determine the events leading to the onset of hyperglycemia and permit insight into the etiology of type 2 diabetes. Within 7 days of instituting a substantial negative calorie balance by either dietary intervention or bariatric surgery, fasting plasma glucose levels can normalize. This rapid change relates to a substantial fall in liver fat content and return of normal hepatic insulin sensitivity. Over 8 weeks, first phase and maximal rates of insulin secretion steadily return to normal, and this change is in step with steadily decreasing pancreatic fat content.

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July 18, 2013 Over the Hump Bump II: Insulin Wars II: Mark Sisson

Part II of my CarbSane is so cruel and vitriolic in her criticisms of Mark Sisson bumpfest today.  Crying Wolf II , Bump I

This one is especially  ironic given point 9-of-12 of Mark's email to Grashow blamed lack of dietary discipline and sloth for my weight.   Here he says that doesn't work anyway!  {shakes head}

Be sure to notice how I misquoted, misrepresented and ridiculed Mark Sisson, took pot shots at his appearance and denigrated him on a personal level.  Oh wait.  That didn't happen.  This post was originally viewed by around 400 people and didn't even crack the Top10 list at the time.

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The Myth of Starving Cells II and NEFA Levels Again.

UPDATE (and a tiny bump for feed subscribers):  I noticed a bit of traffic to a prior related post, so I'm just linking to that one here as well:  Insulin Doing Its Thang! And Still No Starving Cells.  It discusses another study by Keith Frayn that shows increased NEFA uptake into the muscle cells of men with hyperinsulinemia.  It may be worth a read for newer readers along with The Myth of Starving Cells.

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Original Content:

A little sidetrack here, but I came across an article the other day. I just had to blog on it before I forgot!  

A little background as well -- A couple of years ago I wrote:  The Myth of Starving Cells.  As the story goes, as related by science journalist Gary Taubes, to Low Carb Diet Doctor Mike Eades, to Fat Head Naughton, insulin traps our fat in our fat cells, causing "internal starvation" as the rest of our cells go without, triggering hunger and overeating.   We overeat because we are getting fat, or some nonsense like that.   In the post, I discussed studies demonstrating the opposite is true.  In obesity, there is failure to properly suppress NEFA release from fat cells, NEFA are elevated in the fasted state, and irrespective of absolute concentration, NEFA delivery to cells is higher.  The last point leading to accumulation of fat within ectopic cells, such as muscle cells (called intramyocellular triglyceride or lipid, IMTG, IMCT or IMCL).  The cells have plenty of fat fuel to burn ... indeed this is a problem!

So I was looking for a  link to that Ebbeling et.al. study the other day -- this one: Effects of Dietary Composition on Energy Expenditure During Weight-Loss Maintenance.  In the study, a group of obese people were put on a relatively high protein (25%), relatively low fat (30%) and moderate carb (45%) diet and lost between 10 and 15% of their initial body weight.  After which they were weight stabilized and then fed one of three maintenance diets for 4 weeks in randomized cross-over fashion.  These diets were P/F/C:  low fat = 20/20/60 , low GI = 20/40/40, and low carb = 30/60/10.  

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Stick a Toothpick in It? Taubes' 4-pronged Carb/Insulin "Fork" Loses its Tines

I'm bumping this today, because in the weeks to come I hope to update, flesh out, and reference it fully.  Looking back at something written almost 2 and a half years ago it seems rough, but nonetheless it  still summarizes what I call TWICHOO and the arguments against it pretty well.  

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This post updated slightly 6/22/2012.   Original publication date 1/23/11

In the comments at Jimmy's blog on my interview podcast, several comments either directly or by inference say I failed to make my case against Taubes.  Well, I think I did pretty much get to what I consider the four prongs of Taubes carb/insulin hypothesis, but I've decided to try and summarize this in a blog post.  Another common comment is that I'm somehow nit-picking at minutia, basically if folks lose weight on low carb, it doesn't matter the details of why.  To those, if they are reading this, I would say that any objective view of my arguments would lead to the conclusion that these are NOT minor details, they are the sum total of Taubes' evidence in support of his hypothesis.  Not only has he NEVER debunked the calorie-based theories on obesity, but almost all evidence in support of his "alternate" theory HAS been.  

I will not be referencing this post, it's all been done before here, and I don't have the time to trace down every link etc.  

So, what do the four prongs of the fork stuck in the potato above represent?  

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Revisiting Taubes' Four Facts from the Sixties

In Good Calories Bad Calories, Gary Taubes wrote the somewhat shockingly definitive summary paragraph below (I've separated out the numbered statements for clarity):  

By the mid-1960s, four facts had been established beyond reasonable doubt:

(1) carbohydrates are singularly responsible for prompting insulin secretion;

(2) insulin is singularly responsible for inducing fat accumulation;

(3) dietary carbohydrates are required for excess fat accumulation; and

(4) both Type 2 diabetics and the obese have abnormally elevated levels of  circulating insulin and a “greatly exaggerated” insulin response to carbohydrates in the diet, ... (Kindle Locations 8010-8014)

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Could Early Insulin Therapy for T2 be Coming to Canada?

A short post here, because I have no peer review study to refer to. But Nigel Kinbrum recently blogged on this media report: New treatment might put Type 2 diabetes in remission.

This report touted 75% remission from T2 using self-administered insulin of 4 injections per day for one month.  This is less aggressive than reported in other studies (some summarized here, table below) 

Most of these used insulin infusions for a couple of weeks and early response rate was around 90%.  This treatment may be more practical (and cost effective?) but perhaps not intensive enough to to get the optimum outcome.  Still, 75% is impressive.  The article discusses that they want to follow up with an oral diabetic drug to "save" the pancreas, which the studies above involved lifestyle "treatment" only.

So this article is about a year old and I wondered if it ever made the literature.  I did a PubMed on Dr. Bernard Zinman and got no love.  But a Google Scholar search seems to indicate that Zinman is involved in establishing treatment protocols in Canada.  Were I a diabetic or at risk in Canada, I would consider this very good news indeed.  I would absolutely want to try to put my diabetes into remission and re-establish functional beta cells.  If there are any Canadians in the audience, I'd appreciate if you have any info to add.  For now this is just a "bookmark" of sorts. 

First Phase Insulin ~ Physiological Relevance?

Something I've been reading a lot lately would be along the lines of "first phase insulin response is deficient/missing from the early stages of diabetes".   This is true, but even in the peer review literature that term seems to be misused to equate with the acute spike in insulin levels to a high oral glucose load.  However the first phase insulin response, hereinafter FPIR, is a non-physiologic phenomenon sometimes used to assess pancreatic function.  

First-phase insulin secretion: does it exist in real life?  Considerations on shape and function  (decluttered  of references, please see origina, some parts bullet-pointed, etc. for clarityl)

IN THE PAST THREE DECADES, the relevance of insulin secretion abnormalities in the pathogenesis of type 2 diabetes mellitus have been extensively debated, and a consensus has been reached that, to fulfill its pivotal role in regulating glucose metabolism, insulin secretion must not only be quantitatively appropriate, but also possess qualitative, dynamic features that optimize insulin action on target tissues. In particular, increasing emphasis has been placed on the importance of the so-called first-phase insulin secretion to glucose homeostasis.  The aim of this review is to address the following questions:

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Ancestral Rabbit Starvation Medical Vacations! The next craze?

I came across this study a bit ago and it caught my eye as I was transfering some stuff between computers:  Marked Improvement in Carbohydrate and Lipid Metabolism in Diabetic Australian Aborigines After Temporary Reversion to Traditional Lifestyle

The rationale for the present study was that temporarily reversing the urbanization process in diabetic Aborigines should improve all aspects of their carbohydrate and lipid metabolism that are linked to insulin resistance. Ten full-blood, diabetic Aborigines from the Mowanjum Community (Derby, Western Australia) agreed to be tested before and after living for 7 wk as hunter-gatherers in their traditional country in northwestern Australia. They were middle aged (53.9 ±1.8 yr) and overweight (81.9 ± 3.4 kg), and all lost weight steadily over the 7-wk period (average, 8 kg). A detailed analysis of food intake over 2 wk revealed a low energy intake (1200 kcal/person/day). Despite the high contribution of animal food to the total energy intake (64%), the diet was low in total fat (13%) due to the very low fat content of wild animals.

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Chronic Exposure to Free Fatty Acid Reduces Pancreatic β-Cell Insulin Content by Increasing Basal Insulin Secretion That Is Not Compensated For by a Corresponding Increase in Proinsulin Biosynthesis Translation

Coming next in the discussion of diabetes I am going to discuss insulin secretion in greater detail.  I was reminded of this post in the writing process.  So ... Bump!

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Original Publish Date:  4/4/11

Chronic Exposure to Free Fatty Acid Reduces Pancreatic β-Cell Insulin Content by Increasing Basal Insulin Secretion That Is Not Compensated For by a Corresponding Increase in Proinsulin Biosynthesis Translation

JD McGarry contributing author.

{Please note:  Excerpts from the text will be edited somewhat to avoid "cluttering" references, statistical values, and some rounding of numbers.  Text will sometimes be presented in bullet form or with paragraph breaks to ease reading.  It is not my intent to plagiarize nor to alter the content.  If anyone feels I've altered the content in any meaningful way, do please let me know!}  Direct quotes will be indented.

FFA are an important physiological fuel for islets, and act as a supplemental nutrient secretagogue to potentiate insulin release acutely in the presence of glucose.

Translation:   β-cells run on fatty acids but this fuel also serves to stimulate insulin secretion.

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Exogenous Insulin Stimulates Endogenous Insulin Production

Continuing with our discussion on diabetes ...

In my last post on the topic, I introduced this paper:  β-Cell dysfunction vs insulin resistance in type 2 diabetes: the eternal “chicken and egg” question.  This got me to thinking again about early insulin treatment for Type 2.  In an ideal world a more thorough post on EIT for T2 would precede this one, but I've got a paper on this open in the browser and don't want to forget it.  There are, however, several studies out there employing insulin early in the diagnosis of diabetes that have had remarkable results and this is worth revisiting briefly here.  Three of these studies are summarized in the table below from this paper

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β-Cell dysfunction vs insulin resistance in type 2 diabetes: the eternal “chicken and egg” question

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.

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Insulin/Proinsulin/etc. in Normal, IGT and T2 Diabetics

One more on the measurement side of things since these type posts are easier to put the finishing touches on to get out the door.  This is another older paper, and I'm trying to track down more info on newer/current analyses and their specificity.  Unlike the last discussion here, I want to focus on the secretory capacity of the  β-cell through the progression of diabetes.  

Serum proinsulin levels at fasting and after oral glucose load in patients with Type 2 (non-insulin-dependent) diabetes mellitus (1988).  

• 40 newly diagnosed with T2 diabetes + 21 IGT -- No medications or special diet
• BMI < 27 in men, < 25 in women
• Controls were weight matched to study group participants.

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Measuring Insulin Levels, Hyperinsulinemia and Insulin Resistance

A slight detour in my current endeavors to put forth some information regarding the etiology of diabetes, insulin resistance and β-cell function, before I get to the two major reviews that prompted this.

To review, in my last post, discussing this paper, a seminal observation/conclusion can be summed up as follows:   Insulin is formed in stepwise fashion from a larger protein (preproinsulin) that has a terminal signaling chain cleaved forming proinsulin that is then folded, cross-linked and has one of the three main chains cleaved in the last step(s) resulting in a protein with two parallel chains, insulin.  I like this newer representation I found below because it provides the numbers in the amino acid sequence at which the cuts are made.  This is important to better understanding the papers I'm going to discuss here.

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What is Diabetes?

"the proinsulin disorder in diabetes is not 

only ubiquitous but it is also precocious"

As a second post setting up for future discussions on insulin resistance and it's role in diabetes (especially type 2)  I wanted to share the following paper with you here:

PROINSULIN, PROAMYLIN AND THE BETA CELL ENDOPLASMIC RETICULUM: THE KEY FOR THE PATHOGENESIS OF DIFFERENT DIABETES PHENOTYPES

It is a long paper, almost 18 full pages of text, and more than 9 to list the 298 (yikes!) references. I will by no means attempt to address it in its entirety here, rather I shall focus on the section entitled "INCREASED PROINSULIN AS THE MAIN BETA CELL SECRETORY DEFECT".  But first, the abstract of this 2007 paper:

Based on our clinical and epidemiological data, we have sustained for a long time the unitary character of the various phenotypes of the diabetic syndrome. In this paper, we add several arguments sustaining that the unitary character of diabetes is related to a common primary defect in the function of the beta cell endoplasmic reticulum, leading to an inadequate processing of the two main secretory molecules: pre-proinsulin and pre-proamylin. The post-translational changes of these molecules might explain the main proapoptotic and anti-regenerative pathogenic mechanisms leading to a progressive decrease in the β cell mass/function. In our view, the increased proinsulin levels encountered in various diabetes phenotypes could be not only a marker of beta cell dysfunction but also could indicate the main β cell defect, suggesting also its location.

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