Does Elevated Glucose Cause Dementia?

Does elevated glucose cause dementia?  Even in non-diabetics?

This would seem to be the initial conclusion based on a recent study published in the NEJM:

Glucose levels and risk of dementia.  

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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 Cause of Hyperglycemia in Type 2 Diabetes

I will forever be grateful to (former?) blogger LynMarie Daye of Adipo Insights blog for bringing the following paper to my attention:

Insulin: understanding its action in health and disease

If you're a regular reader and you haven't read it yet, what are you waiting for?  If you're a new reader it's a must (unless of course you're just here for the gossip you claim is boring and inappropriate - grin).   The article is quite long, but it is written in very understandable fashion.  A lot of info, so perhaps best digested in small segments, but well worth the effort. 

The article begins with a history lesson about a physiology professor named Sir Edward Schafer, who "appears to have named insulin and described its actions" in a book published in 1916 entitled The Endocrine Organs.  Schafer, described a substance with dual and simultaneous functions: 

• Autacoid:  excitatory or stimulatory, e.g. glucose transport, lipid synthesis 
• Chalone:  inhibitory, e.g. inhibiting lipolysis, gluconeogenesis, ketogenesis

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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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The Grand Carbohydrate-Cholesterol Switcheroo ~ Are We Repeating History?

In Deep Nutrition, one of the World's best health experts* Dr. Cate Shanahan writes this of cholesterol:

Genetic Experimentation—On You

You may have noticed the various cut-off levels over the years to identify people at “high risk” of a heart attack.  Years ago, if your total cholesterol was 300 or less, your doctor would have said you were fine. Soon, that number was lowered to 200.  Now people also watch their LDL, “safe” levels of which have been lowered from 200 to 160, to 130, to 100, and now 80.  Currently, the average person’s LDL level is still about what it’s always been, around 120–130. The controversial 2001 revision of the cholesterol guidelines means nearly half of the US population can now be labeled “high risk.”  And drug companies are raking it in.

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Aug. 1 Over the Hump Bump: Baby your Pancreas? Part I: The Tired Pancreas

Another two-fer for the Thursday post bumps again this week.  More explanation for why this set in the next bump.

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Original Publish Date:  7/26/11

In the comments on a recent post on beta cell lipotoxicity, Ned Kock (of Health Correlator blog) posted a link to a post he made a while back entitled:  Lipotoxicity or tired pancreas? Abnormal fat metabolism as a possible precondition for type 2 diabetes.  This article deals with the concept of the "tired pancreas" in the development of diabetes.  It seems that (and hopefully he corrects me if I'm wrong here) Ned and I agree that this is not a likely explanation for diabetes.   Ned summarizes the progression of obesity induced T2 diabetes from Unger & Zhou, 2001.  It is worth mentioning that Unger is often summarily dismissed from the "scientific discussion roundtable" by low carbers because of the unfortunately titled "Gluttony and Sloth" paper, that, even more unfortunately also included a biblical verse.   Unger's hypothesis is very leptin-centric, but not at all incompatible with other lipotoxicity based theories.  Basically, lipotoxicity is the result of dysfunctional adipocytes leading to excessive "spill-over" of fatty acids into circulation and accumulation in ectopic tissues.   Unger & Zhou identify dysfunction in leptin secretion and/or signaling as the initiating factor in this process.  One thing that doesn't quite add up for me here is that I keep finding citations indicating leptin action increases free fatty acids which would seem counterintuitive.  In any case ...

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July 4, 2013 Over the Hump Bump: Where does insulin resistance start? The adipose tissue

The readership in this blog continues to grow and it is not lost on me that a vast majority of current readers are unfamiliar with the bulk of my work here on this blog.  I think I'm closing in on 1000 posts which would make me one of the more prolific bloggers around ... for better or worse!  As such, I more than understand that it would be darned near impossible to catch up, etc.  So a few comments in that vein.  

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Why We Get (Sick) Fat (and Sick Livers) - Lessons from a Cafeteria Rat

Since we're talking about fructose and the liver of late, I thought I'd bump this post.  In this study groups of rats were fed one of four diets.  The "low fat" diet is better described as a high sucrose diet as 35% of the diet was sucrose.  This replaced 35% of the fat in the 45% "high fat" diet.  While the LF and HF rats gained a little more weight than the standard (also LF at 12%) chow rats, it is clear that the high fat has rather more negative metabolic effects.  I don't think the 35% sucrose diet was beneficial, rather the contrary, but that level of sucrose consumption, every single day for 10-15 weeks (which is a very long time for a human) is also hardly indicative of even SAD consumption.

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Original Posting:  3/8/11

It seems fairly generally accepted that whatever the cause or progression, the so-called Metabolic Syndrome, Syndrome X and Type 2 Diabetes are associated with a dysregulation of adipose tissue metabolism, and fat tissue that is infiltrated with macrophages and secretes excessive amounts of inflammatory molecules called adipokines (e.g. TNF-α, IL-6).   A term has been coined, adisopathy, to describe this "sick fat".  

I've recently discussed the "Cafeteria Rat" study  as pertains weight gain in general.  But the other thing about this study is that it looked at the fat tissue with the different dietary interventions.  To recap, four groups of rats were fed ad libitum different diets:

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Biomarkers: Context and Are They Causative Agents?

I received a comment recently on the Blood Sugar 140 series that prompted this post.  Actually, it prompted a post on the best predictor for T2 which will be forthcoming, but in fleshing out some background for that, I realized it was worth a post on its own. Below are links to previous post series I'm referring to:

• Blood Sugar 140: Where did the 140 mg/dL threshold come from?
• Blood Sugar 140: Context is Everything I - Diabetic vs. Non
• Blood Sugar 140: Context is Everything II: The OGTT
• Blood Sugar 140: Diabetic Neuropathy, Is it All About Hyperglycemia?

"Cliff Notes" Blood Sugar 140:  There is a commonly repeated "fact" out there that blood glucose levels over 140 mg/dL lead to nerve damage (and organ damage) generally attributed to the process of glycation.  Also implied in this is that such damage is cumulative such that any excursion over 140 is inflicting a little damage along the way.  This traces back to the following page on Jenny Ruhl's website:  Research Connecting Organ Damage with Blood Sugar Level:

The studies you will read below, some of which are not cited in the AACE guidelines, make a cogent case that post-meal blood sugars of 140 mg/dl (7.8 mmol/L) and higher and fasting blood sugars over 100 mg/dl (5.6 mmol/L) cause permanent organ damage and cause diabetes to progress.  {emphasis mine}

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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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Two Paleo Diets from Lindeberg's Group

Here's another paleo diet study:  Beneficial effects of a Paleolithic diet on cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study   It's from Lindeberg's research group but I'll refer to this one as Jonsson to distinguish it from the others.  

In a randomized cross-over study, 13 patients with type 2 diabetes, 3 women and 10 men, were instructed to eat a Paleolithic diet based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts; and a Diabetes diet designed in accordance with dietary guidelines during two consecutive 3-month periods.   ... Study participants had on average a diabetes duration of 9 years, a mean HbA1c of 6,6% units by MonoS standard and were usually treated with metformin alone (3 subjects) or metformin in combination with a sulfonylurea (3 subjects) or a thiazolidinedione (3 subjects). Mean average dose of metformin was 1031 mg per day.

The paleo diet outperformed the diabetes diet, but that is not the purpose of this post, rather to show the composition of the paleo diet tested and add it to my summary table of same.  Here are the diets compared. As with Lindeberg before this, we have a significant caloric difference between the tested diets that makes comparison difficult.

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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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