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.

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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.