June 3, 2008

HOMA Wrong on IR and Insulin Deficiency. Early Type 2s have Insulin Deficiency NOT Just IR.

Buried in this month's issue of the journal Diabetes is a study that, properly understood, suggests that most of what doctors "know" about Type 2 diabetes is wrong.

The study is titled β-Cell Dysfunction in Subjects With Impaired Glucose Tolerance and Early Type 2 Diabetes: Comparison of Surrogate Markers With First-Phase Insulin Secretion From an Intravenous Glucose Tolerance Test.

To understand why this study is important, you have to know that for decades scientists have evaluated insulin resistance using something called HOMA or homeostasis model assessment. HOMA is nothing more than a formula that computes insulin resistance from fasting C-peptide, fasting insulin and blood sugar. If you have had a fasting insulin or C-peptide test, you can compute your own HOMA using the Oxford University HOMA calculator.

What the scientists did in this latest study was something blindingly simple. They hooked up people who had been recently diagnosed with pre-diabetes or diabetes to an intravenous glucose tolerance test and measured their insulin and preinsulin levels. Then then compared what they found with the HOMA calculations.

What they found was "HOMA-B markedly underestimated the magnitude of the β-cell defect across declining glucose tolerance." They went on to conclude, "Subjects with IGT and early-stage, asymptomatic type 2 diabetic patients have more pronounced β-cell defects than previously estimated from epidemiological studies using homeostasis model assessment."

What this means in plain English is that contrary to what you have been reading for decades, prediabetes and early Type 2 diabetes are NOT primarily caused by insulin resistance. Instead, this study found these people had an unexpectedly high deree of insulin deficiency which was NOT apparent when they calculated HOMA using the cheap fasting tests.

This should be a shocker, but like most of the truly important research about Type 2 diabetes it probably won't even get noticed because no drug company is going to talk it up at the big ADA dog and pony show this week. Instead the medical news will be full of reports of how wonderful Drug A is and how all people with Type 2 should be taking Drug B--even if Drug B only lowers A1c from 7.5% to 7.0% and costs $200 a month.

The finding that people with pre-diabetes already show insulin secretion defects points to several things.

1. It emphasizes that there are genetic defects involved in blood sugar deterioration that have nothing to do with overeating or obesity. No one has ever found anything that connected overeating with the failure of beta cells to secrete properly.

2. It calls into question huge amounts of diabetes research done over the past decades because the HOMA formula has been used almost universally to determine if people had IR or beta cell deficiency. This study suggests that the HOMA result is wrong and so any research about insulin resistance based on HOMA is wrong. That's almost ALL large group research.

3. It makes it all the more clear why people with early diabetes diagnoses should consider a trial of insulin when lowering insulin resistance with diet or drugs like metformin does not give normal blood sugars. If your beta cells can't produce insulin, you need insulin. End of story.

4. It makes me wonder how much of the IR that doctors believe to be the sole cause of Type 2 diabetes is actually being caused by abnormally high blood sugars. it is possible that IR increases dramatically when blood sugars go over a much lower threshold than previously believed. Possibly as low as 130 mg/dl. If so, much of the IR found in Type 2 diabetes may be caused by high blood sugars caused by insulin deficiency. If that isn't a mind blower, what is?

Now mind you many people with Type 2 diabetes do have insulin resistance that is independent of their blood sugars. But they also may have decades of functioning with higher than normal blood sugars due to insulin deficiency. What the impact of that on their metabolisms may have been is unknown.

But one thing is for sure, this is a major blow to the idea that type 2 is caused by insulin resistance caused by obesity and that people with Type 2 secrete higher than normal levels of insulin which their body can't use. That belief came from studies based on HOMA calculations, but this study that measured the actual insulin secreted found that simply wasn't true.

P.S. My own HOMA calculation showed that I was twice as insulin resistant as normal. However, when I started to inject insulin I learned that I have normal insulin sensitivity in that one unit of insulin lowers my blood sugar the same amount that it would for a normal person. I use about 1/10 the total daily dose of insulin that an insulin resistant person my size would use. I thought that this discrepancy was because I have an oddball form of diabetes. But it is more likely that it is an example of just how badly this HOMA formula works for people whose fasting blood sugar has not yet reached the 200 mg/dl level which was typical of the population in which the formula was first computed.


Boz said...

When first diagnosed w/ type 2, I was put on oral meds by the doctor.But, the diabetes center nurse suggested lantus right away, which, through my ignorance, I declined. The glucovance and avandia combination was a disaster, causing water blisters on my lower legs and didn't really control my blood sugar very well. I went on lantus, byetta, and metformen, which has been a vast improvement. BTW, I had probably been diabetic for at least 6 years before seaking treatment, so in hindsight, I should have been on insulin off the bat. Thanks for all the great info and food for thought.

Scott S said...

This is useful, but I'd also be curious if it could be applied to what I like to refer to as "insulin interference" which is temporary insulin resistance usually attributed to hormone interference which causes a temporary state of insulin resistance (IR). The reason I ask is because it could also be used for a variety of reasons (applicable to both types of diabetes), and might also have applications beyond diabetes, too, although that is certainly the most obvious and immediate!

Jenny said...


My guess has long been that people with Type 1 experience what looks like IR possibly from the same reasons as some Type 2s. High blood sugars and those counterregulatory hormone surges both cause temporary IR. The counterregulatory hormones in particular, and I think people underestimate how common counterregulation may be in some of us. Certainly when Type 1s are fighting hypos they have to deal with that kind of IR.

But the HOMA calculation like the A1c is one of those things cooked up by researchers to give them the impression they know all about blood sugar without actually measuring it. Like A1c is isn't very accurate for individuals, and maybe not even groups.

Russ said...

It's going to take several rereads to absorb the entire impact of this. Yet another Everything You Know Is Wrong moment for diabetes "common knowledge." Sigh.

Anonymous said...

This makes sense based on my own experience and gut-feeling about what's going on with my own body. Thank you. Something else to discuss with my physician who fortunately has an open mind and considers her diabetic patients actually have functioning minds and know their own bodies!

PJ said...

Hi Jenny! I just found your blog. This is great!

Question: to my understanding, high blood sugar isn't what acts on the cells of the muscles to make them insulin-resistant, that happens due to the overabundance of insulin acting on the cells. So how is the high blood sugar (NOT high insulin--insulin being 'too low') causing the IR? Just curious!

Jenny said...


I'm not sure what the mechanism is, but high blood sugars do increase insulin resistance independent of the insulin level.

When I have some time, I'll look into it, but it won't be for a while.

Anonymous said...

Jenny (and Scott)--

Insulin resistance is a 'garbage term' which has become one of the gold standard methodologies used by the American Medical Association to indicate to the patient: "We KNOW, and this is what you need to do to get well." For the diabetic patient, this includes terms like A1c, dawn phenomena, rebound, overlapping pharmacokinetics, and a host of other terms used to describe what they DON'T know.

In an earlier post, Scott mentioned an article related to alpha cells, glucagon and the communication necessary with beta cells needed to achieve homeostatis in blood sugar level. Any form of diabetes means something has gone wrong with this communication between systems. We don't even know, in the various forms of diabetes, whether there is a common-denominator CAUSE, or a common-denominator SOLUTION. There has also been recent research which indicates that maintaining tight glucose control has little effect on future complications. In fact, I believe someone reported there is a rare disease with ALL of the complications of diabetes noted in the individuals WITHOUT high blood sugars or diabetes involved. That would lead to the question: Do we have more than one disease problem?

I am thankful to both of you for expressing concerns, knowledgeable opinions and literature citations. If our caregivers were more interested in their patients' health rather than the almighty dollar, we would all be closer to an answer.


Anonymous said...

We know that insulin is the hormone telling cells there is food (sugar) available and that they should eat. In people heading toward diabetes, there is too much blood sugar which can lead to two problems: 1) the cells no longer respond to insulin's call to eat (this is insulin resistance) and 2) as the body is constantly trying to produce more insulin to get rid of all that sugar in the blood, at some point it exhausts itself and just gives up (this is called insulin deficiency). Both problems can be seen in diabetes.

Jenny said...


What you describe is a common belief, but it may be incorrect.

All of the genes that have been found associated with Type 2 so far affect the ability to secrete insulin, not insulin resistance.

Hugh and Suzy said...

Why not make it really simple - if a type 2 diabetic is obese they have enough insulin and should NOT be given insulin secretagogues or insulin. They should work on their insulin resistance with exercise and diet.
On the other hand if a type 2 diabetic is thin they don't have enough insulin and should be started on injections.

Anonymous said...

Anyone in glucose toxicity should be started on insulin, I should have been but wasn't.