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Monday, April 20, 2015

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

Random Bump:

There has been some discussion of diagnosing diabetes type going on in my comments of late and I thought this might be a good post to bump in response.  It's pretty specific, but contains links to some background blogging.

I think it would be safe to say that I'm of the belief -- and the scientific evidence seems overwhelming in support -- that peripheral insulin resistance is either non-existent or plays a minor role in T2 diabetes.  

Nonetheless, the concept of IR remains, but for the most part is diagnosed using a fasting HOMA-IR score based on fasting insulin and glucose levels.  This is considered a measure of hepatic IR, but even here appears to be a flawed measure.    The "swamped insulin receptor" model is flawed.  Not saying it doesn't perhaps play a role, but glucose uptake is not the first defect nor the main determinant of elevated circulating glucose.  

The WHO even classified Type 2 Diabetes as such (1999):
7.2 Type 2 (predominantly insulin resistance with relative insulin deficiency or predominantly an insulin secretory defect with/without insulin resistance)
There is much evidence for the latter, and the former?  Well, it seems the evidence points far more conclusively to relative insulin deficiency vs. any sort of receptor swamping dysfunctional clogged sink model.  

This is also why I believe LC will never "cure" T2, because the GSIS is the first thing to go with chronic carb restriction.  This is well known and why low carbers are told to "carb load" with 150 grams for several days before a standard OGTT.   Insulin does far more than regulate blood glucose levels, it should be a no brainer in my opinion to aim for NORMAL insulin signaling/glucose regulation where possible.





Original Publish Date:  10/21/2013

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.

15 comments:

Wuchtamsel said...

Without any reasonable doubt there IS a preponderance of evidence that there IS a certain link between diet and type 2 diabetes. But it's probably neither carbs nor fat percentage, but general overnutrition and resulting obesity.
Of course there is a chance to develop T2D after being slim for a lifetime, but it's comparably small, like the chance to suffer CVD with a lifelong low bloodpressure and low LDL-C.
Yet there clearly is a direct link between obesity and T2D and fattening people will give them T2D with good certainty.

billy the k said...

Maintaining a robust first-phase insulin response has to be a primary aim of those wishing to eat normal-type carb intakes while avoiding IGT, pre-diabetes and T2DM. Because if you lack a robust Phase-1, when you eat carbs you'll fail to promptly shut down your liver glucose output so that you'll now have to contend with the double-whammy of exogenous plus endogenous sourced glucose coming into your blood, making your postmeal BG rise much higher than otherwise, and so taking longer to normalize and requiring more total insulin to do so. Ralph DeFronzo's review article (Pathogenesis of NIDDM: A Balanced Overview. Diabetes Care. 1992; 15 (3) 318-68) gave the following welcome news in this matter:
"...loss of first-phase insulin secretion does not appear to be the primary defect responsible for NIDDM. Recent studies have shown that progression from normal to IGT or to NIDDM is associated with a reduction in insulin sensitivity and an increase in insulin secretion with an intact first-phase response. Although the first-phase response is characteristically lost in patients with well-established NIDDM, this defect does not occur until the fasting plasma glucose concentration rises to 115-120mg/dl. Moreover, tight metabolic control partially restores the defect in first-phase insulin response, indicating that the defect is acquired and not inherited."

So if one's fasting BG is below 115mg/dl there appears to still be room to turn things around (i.e., get that accumulated fat out of your liver and pancreas).

Also: Stefan Fajans (Classification and Diagnosis of Diabetes. in: Ellenberg & Rifkin's Diabetes Mellitus. 5th ed. Chap.20) gave the following info which I think is good to keep in mind for those wishing to maintain a robust first-phase insulin response:

"In the past, it was recommended that the patient should consume a diet containing 250g of carbohydrate or more, and calories for maintenance of body weight, for at least 3 days before the test [GTT] to obtain the best reproducibility of the test and to minimize falsely abnormal results. Ingestion of smaller amounts of carbohydrate (150 to 200g) is probably sufficient to prevent plateau or diabetic-type curves in healthy subjects. Presently, no formal dietary preparation is recommended unless it is estimated that less than 150g of carbohydrate per day has been consumed. A LOW CARBOHYDRATE DIET PRECEDING THE GLUCOSE TOLERANCE TEST OBLITERATES THE FIRST-PHASE INSULIN RESPONSE TO ADMINISTERED GLUCOSE THAT IS MOST IMPORTANT IN DETERMINING NORMAL GLUCOSE TOLERANCE."

Jethro Bodine said...

It's pathetic that the LCHF camp resorts to - in your case - ungentlemanly attacks when they cannot respond to facts.

This brings my next off topic question: Are there any peer reviewed studies conducted by any of the LCHF gurus, Feinman, the comedian, Dr. Eades, Swede doctor, Taubes, Dr. Attia, Jimmy, Sisson, Dr. Davis and anybody else I have missed?

charles grashow said...

http://www.proteinpower.com/drmike/lipid-hypothesis/eat-less-move-die-anyway/

Kade Storm A.K.A. Hedonist said...

True, and yet we still have more of this. . .

http://www.youtube.com/watch?v=1Rp9N9S5cNo&list=UUCFMZHxKvSFn-wLjaV2hf1g#t=132

carbsane said...

This would explain LCers that are wedded to their blood glucose monitors becoming carb cripples. If you're eating LC and then have a carby meal and you don't have the insulin spike, glucose goes up up up and stays up for far too long and oh noes I have the beetus!!

billy the k said...

Quite so. There is an apt phrase used in the study of ecosystems: "You can't do just one thing." This applies as well to our own internal "ecosystem" when we play with diets. To lower our blood sugar level we're told: "Just eat less sugar!" [carbs]. But you can't do just one thing. Trapdoors of unsuspected feedback-loops get triggered. P.J. Randle (the "Randle Cycle") showed how metabolic mayhem occurs due to insufficiently suppressed NEFA release as a result of "the endocrine and NUTRITIONAL
disorders [which] include diabetes, starvation, CARBOHYDRATE DEPRIVATION..." [emphasis mine] (The Glucose Fatty Acid Cycle: Its Role in Insulin Sensitivity and the Metabolic Disturbances of Diabetes Mellitus. Lancet;1963: 785-89). While photocopying the last page of this classic study, I happened to notice that the very next article was co-authored by Randle. It was a further confirmation of his main idea, and, to my mind, the best "cautionary-tale" yet for those thinking about doing low-carbs for the long haul (Effects of Low-Carbohydrate Diet and Diabetes Mellitus on Plasma Concentrations of Glucose, Non-Esterified Fatty Acid, and Insulin During Oral Glucose-Tolerance Tests. Lancet; 1963: 790-94):

Five normal, healthy young men (ages 23-36), whose daily intake of carbs was more than 200g, were given 50g and 100g glucose-tolerance tests. The same men then had repeat 100g GTT's after five days on a diet containing less than 50g/day carbs (fat and protein unrestricted) and two further tests two and five weeks after returning to a high-carb diet. After only five days on less than 50g/day carbs, this reduced carb intake produced the following results:

1. Elevated fasting blood sugar level [i.e., by an average +22%, from 86 to
105mg/dl]
2. Elevated post-glucose load peak BG rise [i.e., +80% rise, that is, from
105 to 188mg/dl vs from 86 to 134mg/dl]
3. Elevated fasting NEFA's [by an average of +119%, that is, from 350 to
768µmol]
4. Elevated fasting insulin levels [by an average of +319%, that is, 16 vs
67µunits/ml]

Of particular importance: "The fasting NEFA concentration was increased on a low-carbohydrate diet in spite of a rise in the plasma concentrations of insulin and glucose to levels which, with a high-carbohydrate diet, would have lowered the plasma concentration of NEFA."

Steve Phinney would likely say: "Unfair! Not enough time for adaptation to the low-carb intake." Peter 'Hyperlipid' believes that the "physiological insulin resistance" that necessarily occurs with low-carb intakes can be very easily reversed by a few days of increased carbs. Randle, however, reported that "after resumption of the normal diet the plasma concentrations [of insulin and NEFA's] returned slowly to normal, BUT DEFINITE ABNORMALITIES WERE STILL FOUND AFTER FOURTEEN DAYS, AND SOME MAY HAVE PERSISTED FOR THIRTY-FIVE DAYS."

Sanjeev Sharma said...

Any thoughts about how this playse out with beta cells exposed to NEFA for longer than "normal" - the intermittent fasters vs 3-meals-per-day, but still short compared to long term low-carbing?

The studies are coming down on overall health benefits of IF so

beta cells exposed to NEFA for short time periods = good

slightly longer periods (IF) = better

long term NEFA (low carbing) = bad

NEFA plus glucose = worst

Deepak Dwarakanath said...

This is in response to billy the k:


There is this blogger from North Carolina who's been mentioned on CarbSane; he was diagnosed w/ diabetes

Deepak Dwarakanath said...

Furthering the post by billy the k, there is this

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Hello_I_Love_You said...

DeFronzo's article is what's used in diabetes literature and is considered fairly accurate. That's why the FBG and A1c are considered reliable tests for diagnosing T2 diabetes: "Recent studies have shown that progression from normal to IGT or to NIDDM is associated with a reduction in insulin sensitivity and an increase in insulin secretion with an intact first-phase response." The first phase insulin response does deteriorate but after the two steps above. That's why there is a convergence between the FBG >125 and A1c>6.5 criteria. When the fasting rises to 125, then you've lost glucose tolerance and can't pass the OGTT. 6.5 is the mean BG of about 145. At that level, you pretty much have irreversible insulin resistance and can't lower BG after 2H under 200. There is a typical graph that illustrates the rising FBG with the OGTT and A1c cut off points for T2D dx.

Hello_I_Love_You said...

Actually factors 1-3 do happen but 4 doesn't. Your fasting insulin usually stays low when you low carb, whether you are insulin sensitive or not. #4 doesn't seem to make sense. That's why one badge of honor when you low carb is low FI. But low FI doesn't necessarily indicate great insulin sensitivity, just that you don't eat much carbs.

One other abnormality when you have that physiological insulin resistance is if your NEFA goes up and stays up, then you enter the state of "low T3 or euthyroid illness," bka, nonthyroid illness. Typically, sick people often develop autoimmune diseases in that kind of state.

http://www.ncbi.nlm.nih.gov/pubmed/3117601
http://www.ncbi.nlm.nih.gov/pubmed/3920236

billy the k said...

H_I_L_Y: thanks for commenting on this earlier topic.
Permit this additional comment:
You mentioned: "When the fasting rises to 125, then you've lost glucose tolerance and can't pass the OGTT....At that level, you pretty much have irreversible insulin resistance and can't lower BG after 2H under 200."

Once past a fasting BG level of 120 mg/dl, I agree that one has lost glucose tolerance; however, the problem now isn't an "irreversible insulin resistance" but rather an absolute deficiency of insulin per se:
As DeFronzo explains it in the following three of his papers:
The Triumvirate: ß-Cell, Muscle, Liver; A Collusion Responsible For NIDDM (p.668)

Pathogenesis of NIDDM (p. 320)

Insulin Resistance: A Multifaceted Syndrome Responsible For NIDDM, Obesity, Hypertension, Dyslipidemia, and Atherosclerotic Disease (p. 176)

"...plasma insulin response to ingested glucose increases progressively until fasting glucose concentration reaches 120 mg/dl. Thereafter, further increases in fasting glucose level are associated with a progressive decline in insulin secretion."

This progressive decline in insulin secretion is such that a diabetic person with a fasting
BG level of 150 -160 mg/dl is now secreting an amount of insulin that is similar to that in a healthy non-diabetic individual—i.e., defined by DeFronzo as having a fasting BG of 80 mg/dl. and having a mean plasma insulin concentration of ~45µU/ml."

The person with a fasting BG that has climbed to 120 mg/dl now has an insulin problem, not an insulin resistance problem.
Losing weight to reduce insulin resistance won't be able to fix matters now.
This person is now on the wrong side of "Starling's Curve."
I think we can agree that we don't ever want to be there.

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