Tag Archives: hyperinsulinemia

December 8, 2012 · 4:34 AM

In T2 Diabetes, Which Comes First: High Insulin Levels or Insulin Resistance?

pancreas, liver, insulin, woman, teacher, books, diabetes, cause of diabetes

I couldn’t find a decent picture of a liver or pancreas, so this will have to do….

Excessive insulin output by the pancreas (hyperinsulinemia) is the underlying cause of type 2 diabetes, according to a hypothesis from Walter Pories, M.D., and G. Lynis Dohm, Ph.D.  The cause of the hyperinsulinemia is a yet-to-be-identified “diabetogenic signal” to the pancreas from the gastrointestinal tract.

This is pretty sciencey, so you’re excused if you stop reading now.  You probably should.

They base their hypothesis on the well-known cure or remission of many cases of type 2 diabetes quite soon after roux-en-y gastric bypass surgery (RYGB) done for weight loss.  (Recent data indicate that six years after surgery, the diabetes has recurred in about a third of cases.)  Elevated fasting insulin levels return to normal within a week of RYGB and remain normal for at least three months.  Also soon after surgery, the pancreas recovers the ability to respond to a meal with an appropriate insulin spike.  Remission or cure of type 2 diabetes after RYGB is independent of changes in weight, insulin sensitivity, or free fatty acids.

Bariatric surgery provides us with a “natural” experiment into the mechanisms behind type 2 diabetes.

The primary anatomic change with RYGB is exclusion of food from a portion of the gastrointestinal tract, which must send a signal to the pancreas resulting in lower insulin levels, according to Pories and Dohm.

Why would fasting blood sugar levels fall so soon after RYGB?  To understand, you have to know that fasting glucose levels primarily reflect glucose production by the liver (gluconeogenesis).  It’s regulated by insulin and other hormones.  Insulin generally suppresses gluconeogenesis.  The lower insulin levels after surgery should raise fasting glucose levels then, don’t you think?  But that’s not the case.

Pories and Dohm surmise that correction of hyperinsulinemia after surgery leads to fewer glucose building blocks (pyruvate, alanine, and especially lactate) delivered from muscles to the liver for glucose production.  Their explanation involves an upregulated Cori cycle, etc.  It’s pretty boring and difficult to follow unless you’re a biochemist.

The theory we’re talking about is contrary to the leading theory that insulin resistance causes hyperinsulinemia.  Our guys are suggesting it’s the other way around: hyperinsulinemia causes insulin resistance.  It’s a chicken or the egg sort of thing.

If they’re right, Pories and Dohm say we need to rethink the idea of treating type 2 diabetes with insulin except in the very late stages when there may be no alternative.  (I would add my concern about using insulin secretagogues (e.g., sulfonylureas) in that case also.)  If high insulin levels are the culprit, you don’t want to add to them.

We’d also need to figure out what is the source of the “diabetogenic signal” from the gastrointestinal tract to the pancreas that causes hyperinsulinemia.  A number of stomach and intestinal hormones can affect insulin production by the pancreas; these were not mentioned specifically by Pories and Dohm.  Examples are GIP and GLP-1 (glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1).

Keep these ideas in mind when you come across someone who’s cocksure that they know the cause of type 2 diabetes.

Steve Parker, M.D.

Reference:  Pories, Walter and Dohm, G. Lynis.  Diabetes: Have we got it all wrong?  Hyperinsulinism as the culprit: surgery provides the evidence.  Diabetes Care, 2012, vol. 35, p. 2438-2442.

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September 21, 2010 · 2:00 AM

Myth Busted: Alzheimer Dementia NOT Caused By Diabetes

Contrary to popular belief among the experts, type 2 diabetes is not one of the causes of Alzeimer dementia.  They may indeed be associated with each other, but that’s not causation. 

Brain CT scan

An oft-repeated theory from Gary Taubes 2007 masterpiece, Good Calories, Bad Calories, is that many of the chronic diseases of modern civilization, including Alzheimer disease, are caused by abnormal blood sugar and insulin metabolism.  Especially high insulin levels induced by a diet rich in refined carbohydrates.  If that’s the case, you’d expect to see a high prevalence of Alzheimer disease in older type 2 diabetics. 

Dr. Emily Deans (psychiatrist) has been considering this issue recently at her Evolutionary Psychiatry blog.

The brains of Alzheimer patients, under a microscope, are characterized by many senile plaques (aka neuritic plaques) and neurofibrillary tangles.  That’s the gold standard for diagnosis.  Nevertheless, brain biopsies are rarely done to diagnose Alzheimer disease in living patients, and even autopsies after death are rare.  The diagnosis usually is clinical, based on ruling out other illnesses, etc.

Nearly all the studies associating diabetes with Alzheimers disease (and other dementias) are observational or epidimiologic. [The exception is the Honolulu-Asia Aging Study.]  Establishing an association is helpful in generating theories, but establishing causation is the goal.  At least five studies confirm an association.

Neurology this year reported findings of Japanese researchers who examined the brains of 135 people who died between 1998 and 2003.  They lived in Hisayama, a town with an incredibly high autopsy rate of 74%.  These people before death had undergone an oral glucose tolerance test.  Their insulin resistance was calculated on the basis of fasting glucose and fasting insulin (HOMA-IR).  None of them showed signs of dementia at the time of study enrollment in 1988.

What Did They Find?

Twenty-one of the 135 subjects developed Alzheimer-type dementia.  The investigators don’t say if the diagnosis was based on the brain examination, or just a clinical diagnosis without a brain biopsy.  How this got beyond the article reviewers is beyond me.  [If I’m missing something, let me know in the comments section below.]  It must be a clinical diagnosis because if you don’t act demented, it doesn’t matter how many senile plaques and neurofibrillary tangles you have in your brain. 

ResearchBlogging.orgSenile plaques, but not neurofibrillary tangles, were more common  in those with higher levels of blood sugar (as measured two hours after the 75 g oral glucose dose), higher fasting insulin, and higher insulin resistance.  People with the APOE epsilon-4 gene were at even higher risk for developing senile plaques.

The researchers did not report whether the subjects in this study had been previously during life with diabetes or not.  One can only hope those data will be published in another paper.  Why make us wait? 

Average fasting glucose of all subjects was 106 mg/dl (5.9 mmol/l); average two-hour glucose after the oral glucose load was 149 mg/dl (8.3 mmol/l).  By American Association of Clinical Endocrinologists criteria, these are prediabetic levels.  Mysteriously, the authors fail to mention or discuss this.  [I don’t know if AACE criteria apply to Japanese.]  Some of these Japanese subjects probably had diabetes, some had prediabetes, others had normal glucose and insulin metabolism.

As with all good research papers, the authors compare their findings with similar published studies.  They found one autopsy study that tended to agree with their findings (Honolulu) and three others that don’t (see references below).  In fact, one of the three indicated that diabetes seems to protect against the abnormal brain tissue characteristic of Alzheimer disease.

Botton Line

Type 2 diabetes doesn’t seem to be a cause of Alzheimer disease, if autopsy findings and clinical features are the diagnostic criteria for the disease. 

If we assume that type 2 diabetics have higher than normal blood sugar levels and higher insulin levels for several years, then hyperglycemia and hyperinsulinemia don’t cause or contribute to Alzheimer dementia.  Myth busted.  [I hope that’s not copyrighted by the “Myth Busters” TV show.]

Type 2 diabetes is, however, linked with impaired cognitive performance, at least according to many of the scientific articles I read in preparation for this post.  So type 2 diabetics aren’t in the clear yet.  It’s entirely possible that high blood sugar and /or insulin levels cause or contribute to that.  [Any volunteers to do the literature review?  Best search term may be “mild cognitive impairment.”]

Type 2 diabetes is associated with Alzheimer disease, but we have no proof that diabetes is a cause of Alzheimers.  Nor do we have evidence that high blood sugar and insulin levels cause Alzheimer disease. 

Alzheimer disease is a major scourge on our society.  I’d love to think that carbohydrate-restricted eating would help keep blood sugar and insulin levels lower and thereby lessen the devastation of the disease.  Maybe it does, but I’d like to see more convincing evidence.  It’ll be years before we have a definitive answer. 

Steve Parker, M.D.

References:
Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, Sekita A, Suzuki SO, Kanba S, Kiyohara Y, & Iwaki T (2010). Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology, 75 (9), 764-70 PMID: 20739649

Heitner, J.,  et al. “Diabetics do not have increased Alzheimer-type pathology compared with age-matched control subjects: a retrospective postmortem immunocytochemical and histofluorescent study.” Neurology, 49 (1997): 1306-1311.  Autopsy study, No. of subjects not in abstract. They looked for senile plaques and neurofibrillary tangles, etc. The title says it all.

Beeri,  M.S., et al. “Type 2 diabetes is NEGATIVELY [emphasis added] associated with Alzheimer’s disease neuropathology.” J. Gerontol A. Biol Sci. Med. Sci. 60 (2005): 471-475.  385 autopsies. The title again says it all.

Arvanitakis, Z., et al. “Diabetes is related to cerebral infarction but NOT [emphasis added] to Alzheimers disease pathology in older persons.”  Neurology, 67 (2006): 1960-1965. Autopsy study of 233 Catholic clergy, about 50:50 women:men.

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December 18, 2009 · 4:18 PM

Low-Carb Killing Spree Continues

The choice is clear . . . NOT

Low-fat and low-carb diets produce equal weight loss and improvements in insulin resistance but the low-carb diet may be detrimental to vascular health, according to a new study in Diabetes.

Methodology

Researchers in the the UK studied 24 obese subjects—15 female and 9 male—randomized to eat either a low-fat (20% fat, 60% carbohydrate) or low-carb (20% carb, 60% fat) diet over 8 weeks.  Average age was 39; average body mass index was 33.6.  Most of them had prediabetes.  Food intake was calculated to result in a 500 calorie per day energy deficit (a reasonable reduced-calorie diet, in other words).  Study participants visited a nutritionist every other day, and all food was provided in exact weighed portions. 

Results

Both groups lost the same amount of weight, about 7.3% of initial body weight. 

Triglycerides dropped by a third in the low-carb group; unchanged in the low-fat cohort.  Changes in total cholesterol, LDL cholesterol, and HDL changes were about the same for both groups.

Systolic blood pressure dropped about 10 points in both groups; diastolic fell by 5 in both.

“Aortic augmentation index” fell significantly in the low-fat group and tended to rise in the low-carb group.  According to the researchers, the index is used to estimate systemic arterial stiffness.  [In general, flexible arteries are better for you than stiff ones.  “Hardening-of-the-arteries,” etc.]  The low-fat group started with a AAI of 17, the low-carb group started at 12.  They both ended up in the 13-14 range. 

Peripheral insulin sensitivity improved significantly only in the low-carb group but “there was no significant difference between groups.”  No difference between the groups in hepatic (liver) insulin resistance. 

Fasting insulin levels fell about 20% in the low-fat group and about 40% in the low-carb group, a difference not reaching statistical significance (p=0.17).

The Authors’ Conclusions

This study demonstrates comparable effects on insulin resistance of low-fat and low-carbohydrate diets independent of macronutrient content.  The difference in augmentation index may imply a negative effect of low-carbohydrate diets on vascular risk.

My Comments

Yes, you can indeed lose weight over eight weeks on both low-fat and low-carb diets, if you follow them.  So diets DO work.  No surprise.

Loss of excess body fat by either method lowers your blood pressure.  No surprise.

Once again, concerns about low-carb/high-fat diets adversely affecting common blood lipids—increasing heart disease risk—are not supported.  No surprise

Hyperinsulinemia and insulin resistance are risk factors for development of diabetes and cardiovascular disease.  Results here tend to favor the low-carb diet.  I have to wonder if a study with just twice the number of test subjects would have shown a clear superiority for the low-carb diet.

The authors imply that aortic augmentation index is an important measure in terms of future cardiovascular health.  A major conclusion of this study is that a change in this index with the low-carb diet might adveresly affect heart health.  Yet they don’t bother to discuss this test much at all.  I’m no genius, but neither are the typical readers of Diabetes.  I doubt that they are any more familiar with that index than am I, and I’d never heard of it before. 

[Feel free to educate me regarding aortic augmentation index in the comment section.]

Unfortunately, many readers of this journal article and the associated news releases will come away with the impression, once again, that low-carb diets are bad for your heart. 

I’m not convinced.

Steve Parker, M.D.   

References:

Bradley, Una, et al.  Low-fat versus low-carbohydrate weight reduction diets.  Effects on weight loss, insulin resistance, and cardiovascular risk: A randomized control trial.  Diabetes, 58 (2009): 2,741-2,748.

Nainggolan, Lisa.  Low-carb diets hit the headlines again.  HeartWire, December 11, 2009.

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