Insulin resistance, beta cell dysfunction, hyperinsulinaemia, and DiRECT

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harbottle

harbottle

Well-Known Member
Relationship to Diabetes
Type 2
There’s an argument that all T2s should have tests for IR and c-peptide, in order to determine ‘phenotype’ and find a better treatment. (i.e. high IR, low beta cell functionality, high IR and normal beta cell function, and low IR but deficient insulin production.)

I’d be happy to get a high c-peptide result (And low IR) as it means removing insulin resistance would its possible to reverse the condition.

’Classic Type 2’ is a low insulin production and high insulin resistance. I wouldn‘t be so happy with this, as reversal is not as clear cut and it means a degree of beta cell dysfunction which may or may not be reversable. (I suspect I am in this boat, though.)

The other type is ’low insulin production’ and low/no insulin resistance. This is normally ‘slim’ type 2s, which wasn’t me, as I was somewhat rotund upon diagnosis!
 
harbottle said:
’Classic Type 2’ is a low insulin production and high insulin resistance.
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Disagree .. in my view classic T2 is hyperinsulinemia.
Overproducing insulin due to insulin resistance.
 
harbottle said:
There’s an argument that all T2s should have tests for IR and c-peptide, in order to determine ‘phenotype’ and find a better treatment. (i.e. high IR, low beta cell functionality, high IR and normal beta cell function, and low IR but deficient insulin production.)

I’d be happy to get a high c-peptide result (And low IR) as it means removing insulin resistance would its possible to reverse the condition.

’Classic Type 2’ is a low insulin production and high insulin resistance. I wouldn‘t be so happy with this, as reversal is not as clear cut and it means a degree of beta cell dysfunction which may or may not be reversable. (I suspect I am in this boat, though.)

The other type is ’low insulin production’ and low/no insulin resistance. This is normally ‘slim’ type 2s, which wasn’t me, as I was somewhat rotund upon diagnosis!
Click to expand...

I was a "classic" type 2 I suspect.
Low insulin production, high insulin resistance.
Helped initially by stimulating insulin production with Januvia, and decreasing insulin resistance with exercise.
Then cleared out the visceral fat with weight loss to get my pancreas producing insulin normally, so dropped the Januvia, and cleared the insulin resistance with weight loss and exercise, so dropped all meds.

It would have been interesting to find out, and I like information, so yes, I'd be tested.
 
bulkbiker said:
Disagree .. in my view classic T2 is hyperinsulinemia.
Overproducing insulin due to insulin resistance.
Click to expand...

I don’t care what your view is.

The majority of people with T2 have both insulin resistance and a certain amount of beta cell dysfunction, and this is the phenotype considered as ‘classic’ T2 in most research.
 
harbottle said:
I don’t care what your view is.

The majority of people with T2 have both insulin resistance and a certain amount of beta cell dysfunction, and this is the phenotype considered as ‘classic’ T2 in most research.
Click to expand...
Classic T2 are producing way too much insulin their c-peptides results would be very high.

Ask any T2 who has had the test.
 
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bulkbiker said:
Classic T2 are producing way too much insulin their c-peptides results would be very high.

Ask any T2 who has had the test.
Click to expand...
If you look at it logically were T2 leading to not enough insulin being produced then the c-peptide results would be low like the T1 T1.5 LADA and MODY so there would be no point in testing.

Unless by beta cell dysfunction you mean producing too much insulin in which case the T2 would be hypoing all the time and not having elevated blood glucose levels.

So simple logic shows that a c-peptide with a classic T2 would show elevated insulin levels along with high blood sugar which means the beta cells are working and even working overtime because blood sugar levels are elevated.

I note that Prof Roy Taylor and Prof Ben Bikman are both presenting at the PHC conference this year it would be a great place to ask them both that question.
I am tempted to buy a ticket to do precisely that even though Sheffield is a long way away.
 
bulkbiker said:
If you look at it logically were T2 leading to not enough insulin being produced then the c-peptide results would be low like the T1 T1.5 LADA and MODY so there would be no point in testing.

Unless by beta cell dysfunction you mean producing too much insulin in which case the T2 would be hypoing all the time and not having elevated blood glucose levels.

So simple logic shows that a c-peptide with a classic T2 would show elevated insulin levels along with high blood sugar which means the beta cells are working and even working overtime because blood sugar levels are elevated.

I note that Prof Roy Taylor and Prof Ben Bikman are both presenting at the PHC conference this year it would be a great place to ask them both that question.
I am tempted to buy a ticket to do precisely that even though Sheffield is a long way away.
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In his DiRECT trial Taylor looked at responders (those gaining remission by weight loss) and non-responders. Both groups had been insulin deficient prior to the weight loss regimen. After it, the responders were once again producing normal levels of insulin but the non-responders were not. Hyperinsulinaemia featured nowhere in these observations. However, it may have featured in these patients long before the trial when their diabetes started.
 
childofthesea43 said:
Both groups had been insulin deficient prior to the weight loss regimen
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Insulin resistant not insulin deficient. There's a big difference.
So far as I recall they didn't measure insulin levels in DiRECT.
 
bulkbiker said:
Insulin resistant not insulin deficient. There's a big difference.
So far as I recall they didn't measure insulin levels in DiRECT.
Click to expand...
No, not resistant but deficient, not producing enough. Insulin production was tested and Taylor has written often about the beta cell recovery observed.
 
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bulkbiker said:
Insulin resistant not insulin deficient. There's a big difference.
Click to expand...
childofthesea43 said:
Insulin production was tested
Click to expand...
Not according to the write up of the original DiRECT trial it wasn't..
Do you have a link to that.. I'd be very interested..

I know Taylor's theory is that pancreatic fat causes the pancreas to produce less insulin but so far as I know he's never tested inulin to check it.
 
travellor said:
Yes, it's been very well reported, from my experience I was doing exactly that.
My beta cells recovered by weight loss.
Click to expand...
To be very pedantic your beta cell function may have been recovered via weight loss..
 
bulkbiker said:
None of those graphs have measured insulin production though.. their "Insulin response" is a proxy measurement.
Click to expand...
It was a calculation using measurements of insulin blood concentrations amongst other things.

The method as described in the 2018 cell Metabolism paper:

Beta Cell Function​

A Stepped Insulin Secretion Test with Arginine stimulation (SISTA) was used to quantitate first phase insulin secretion and maximal rate of insulin secretion (
Lim et al., 2011 , Toschi et al., 2002 ). Square wave hyperglycemia (50.4 then 100.8 mg/dl above baseline) was achieved by bolus of 20% Dextrose (Fresenius Kabi Ltd, UK) followed by variable 20% Dextrose infusion for each 30 minute step using an infusion pump (Arcomedical Infusion Ltd, UK). An arginine bolus of 5g L-Arginine hydrochloride 50% (Martindale Pharmaceuticals, UK) was diluted in 10 ml of 0.9% sodium chloride (Fresenius Kabi Ltd, UK), and injected during the second step of hyperglycemia to assess maximal insulin secretory capacity, followed by sampling every 2 min for 10 min. Blood samples for determination of C-peptide concentrations were obtained every 2 min for the first 10 min of each step, then every 5 min. Insulin secretion rates were calculated using a deconvolution method, modelling C-peptide kinetics ( Lim et al., 2011).


The Lim et al 2011 Diabetlogica paper referenced above was an early study by Taylor's group: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168743/

It gives some other details on the insulin secretion rate method:

Assessment of beta cell function​

Sixty minutes after the clamp test, two consecutive 30 min square-wave steps of hyperglycaemia (2.8 and 5.6 mmol/l above baseline) were achieved by a priming glucose dose followed by variable 20% glucose infusion [16]. Blood samples for determination of plasma glucose, insulin and C-peptide concentrations were obtained every 2 min for the first 10 min and every 5 min for the other 20 min of each step. An arginine bolus was administered during the second step of hyperglycaemia, followed by sampling every 2 min for 10 min. Insulin secretion rate was calculated using a computerised program implementing a regularisation method of deconvolution [17] and using a population model of C-peptide kinetics [18].
 
Eddy Edson said:
It was a calculation using measurements of insulin blood concentrations amongst other things.

The method as described in the 2018 cell Metabolism paper:

Beta Cell Function​

A Stepped Insulin Secretion Test with Arginine stimulation (SISTA) was used to quantitate first phase insulin secretion and maximal rate of insulin secretion (
Lim et al., 2011 , Toschi et al., 2002 ). Square wave hyperglycemia (50.4 then 100.8 mg/dl above baseline) was achieved by bolus of 20% Dextrose (Fresenius Kabi Ltd, UK) followed by variable 20% Dextrose infusion for each 30 minute step using an infusion pump (Arcomedical Infusion Ltd, UK). An arginine bolus of 5g L-Arginine hydrochloride 50% (Martindale Pharmaceuticals, UK) was diluted in 10 ml of 0.9% sodium chloride (Fresenius Kabi Ltd, UK), and injected during the second step of hyperglycemia to assess maximal insulin secretory capacity, followed by sampling every 2 min for 10 min. Blood samples for determination of C-peptide concentrations were obtained every 2 min for the first 10 min of each step, then every 5 min. Insulin secretion rates were calculated using a deconvolution method, modelling C-peptide kinetics ( Lim et al., 2011).


The Lim et al 2011 Diabetlogica paper referenced above was an early study by Taylor's group: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168743/

It gives some other details on the insulin secretion rate method:

Assessment of beta cell function​

Sixty minutes after the clamp test, two consecutive 30 min square-wave steps of hyperglycaemia (2.8 and 5.6 mmol/l above baseline) were achieved by a priming glucose dose followed by variable 20% glucose infusion [16]. Blood samples for determination of plasma glucose, insulin and C-peptide concentrations were obtained every 2 min for the first 10 min and every 5 min for the other 20 min of each step. An arginine bolus was administered during the second step of hyperglycaemia, followed by sampling every 2 min for 10 min. Insulin secretion rate was calculated using a computerised program implementing a regularisation method of deconvolution [17] and using a population model of C-peptide kinetics [18].
Click to expand...
Don't you find it odd though that a study based on "insulin production" didn't test insulin production levels?
Or at the very least c-peptide as a better proxy?

It has always seemed odd to me.. also of course in the early pre trial run for DiRECT they tested for ketones but in the main trial this doesn't seem to have been done (or at least the levels haven't been reported). Again an oddity.

I have corresponded with Prof Taylor about this but once I asked him the ketone question he went radio silence.

It's impossible to ask Prof Lean anything as he becomes very offensive/defensive if anyone has a different view.

Such a shame that all the test results from the DiRECT study haven't been anonymised and released as I'm sure there is a treasure trove of data there that could be used for alternative theories,
 
bulkbiker said:
To be very pedantic your beta cell function may have been recovered via weight loss..
Click to expand...

So you are agreeing it was because of low beta cell function at diagnosis, which recovered via weight loss.
I'm sure we all entirely agree, low beta cell function leading to low insulin.
(Unless something else can make it high?)
Thank you for your apology, now you have finally agreed insulin is low because of poor beta cell function in a type 2
 
Blood samples for determination of plasma glucose, insulin and C-peptide concentrations were obtained every 2 min for the first 10 min and every 5 min for the other 20 min of each step.
Click to expand...

It says that they used c-peptide.

They actually used an existing method to determine insulin secretion.

Here's a paper detailing its use:

diabetesjournals.org

Effect of Acute Hyperglycemia on Insulin Secretion in Humans

First-phase insulin response to intravenous glucose is impaired both in type 2 diabetic patients and in subjects at risk for the disease. Hyperglycemia can
diabetesjournals.org diabetesjournals.org

Insulin secretion rate (ISR) was reconstructed from C-peptide levels by deconvolution analysis according to the approach developed by Van Cauter et al. (12) using the sex- and age-specific version. For each glycemic step, first-phase insulin response was calculated as the area under the insulin secretion peak (6 min), whereas second-phase insulin response was defined as the average insulin secretory rate during the final 10 min of each step. The arginine response was the integral of insulin secretion over the 10 min after arginine injection. All insulin secretion values were expressed per square meter of body surface area.
Click to expand...

I'm guessing the professors went radio silence because they don't suffer fools gladly.
 
travellor said:
So you are agreeing it was because of low beta cell function at diagnosis, which recovered via weight loss.
I'm sure we all entirely agree, low beta cell function leading to low insulin.
(Unless something else can make it high?)
Thank you for your apology, now you have finally agreed insulin is low because of poor beta cell function in a type 2
Click to expand...
That's Taylor's theory.
I remain to be convinced so no it's not what I think.
I was being pedantic on Taylors behalf.

I think you still had hyperinsulinemia due to insulin resistance and your drastic dieting led to ketosis which meant the visceral fat around your organs was used as fuel.
You blood glucose levels normalised as did your insulin production leading to your remission.

As you have managed to keep the visceral fat off by following your "med diet" you have remianed in remission although you never share any results so we have to believe you.
 
harbottle said:
It says that they used c-peptide.

They actually used an existing method to determine insulin secretion.

Here's a paper detailing its use:

diabetesjournals.org

Effect of Acute Hyperglycemia on Insulin Secretion in Humans

First-phase insulin response to intravenous glucose is impaired both in type 2 diabetic patients and in subjects at risk for the disease. Hyperglycemia can
diabetesjournals.org diabetesjournals.org



I'm guessing the professors went radio silence because they don't suffer fools gladly.
Click to expand...
That's nothing to do with DiRECT though..
 
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