When I was a medical student at McGill in the late 1970s, we learned a straightforward explanation for the cause of Type 2 diabetes, the most common form of diabetes in adults, accounting for about 90 per cent of all diabetes cases. We were told the insulin resistance responsible for Type 2 diabetes was caused by high levels of insulin. Hyperinsulinemia–increased insulin levels in the blood–was said to “downregulate” insulin receptors, making cells with those receptors less responsive to the insulin message. From a physiology point of view, this makes perfect sense. It’s analogous to the development of tolerance that can happen with regular heroin use when a person no longer responds to the drug in the way they did initially.
Sometime in the 1980s this explanation for the cause of insulin resistance was abandoned. Instead, the medical community adopted a new theory that insulin resistance comes first, and is behind high insulin levels in Type 2 diabetes. To overcome insulin resistance, the pancreas secretes larger-than-normal amounts of insulin, resulting in so-called “reactive hyperinsulinemia.” The cause of this insulin resistance is never clearly explained, although obesity, chronic inflammation, and genes are all said to contribute.
When I ask prominent endocrinologists about how insulin resistance comes about in this new paradigm, they say, sometimes condescendingly: “It’s too complicated for a psychiatrist to understand.” That may be. But I’m also an engineer, and when I studied at the University of Waterloo the saying was “BBB”, short for “Bulls**t Baffles Brains.” I consider myself to be a critical thinker, so if the new explanation for what causes insulin resistance is incomprehensible to me, that’s probably because it’s nonsense.
Why did the medical community make a 180-degree reversal of its theory for the cause of Type 2 diabetes? Why discard a nice, coherent, easy-to-test explanation and replace it with a theory no one seems able to describe in terms that an engineer and physician can understand? Time to apply another useful saying: “Follow the money.”
Who profits from this paradigm shift? To answer this question, let’s compare the consequences of diabetes management approaches under the old paradigm and the new one. If we follow the old theory that high insulin levels cause insulin resistance, then treatment involves lowering insulin levels, assuming that insulin resistance is reversible. Since the main stimulus to insulin secretion is the level of glucose in the blood, we can get the pancreas to release less insulin by decreasing the amount of glucose going into the bloodstream. For people who eat regularly, that main source of blood glucose is carbohydrates in the diet, i.e., sugars and starches.
Treatment options for lowering blood glucose include medications such as acarbose, which reduces the absorption of dietary carbohydrates in the small bowel. Metformin, the first-line treatment of choice for Type 2 diabetes, is believed to have a similar effect and may also contribute to weight loss. Traditional and folk remedies for obesity and Type 2 diabetes, including yerba maté tea and the gourd bitter melon, may act in the same way. An easier route for some would be to lower the amount of carbohydrates in the diet, and/or pick foods with a low glycemic index. Research demonstrates a low-carb diet can reduce or even eliminate the need for medication to control blood sugar, in effect, curing diabetes in some patients, and, more importantly, showing that Type 2 diabetes is likely caused by diet for people with susceptible genes.
If we follow the new paradigm and believe obesity, inflammation and genes cause insulin resistance, what can we do? Lose weight? Many find this impossible. Reduce inflammation? Difficult if we don’t know its cause. Change our genes? Maybe in the future. Typically the victim is blamed for overeating and not exercising enough. In the absence of effective ways to reduce insulin resistance in this paradigm, the usual solution is medication to control blood sugar levels.
Some commonly prescribed anti-diabetic medications stimulate the pancreas to produce more insulin, while others act at the level of the insulin receptor to decrease insulin resistance. And of course, insulin itself, typically given in amounts way larger than what the pancreas secretes in normal individuals, can help people overcome insulin resistance. Yes, blood sugar levels will decrease. But there are side effects: insulin itself, and many of the medications that increase insulin or increase its effectiveness, may cause weight gain. And if obesity is a cause of insulin resistance, there is no way these treatments can stop a patient’s diabetes. Instead, for many victims, the diabetes just gets worse.
So let’s follow the money. If today’s treatment approaches don’t cure diabetes and may even make it worse, who benefits? Drug companies, who gain customers for life due to diabetes and its many complications, including vascular disease, dementia, kidney and eye problems, even cancer. Medical device manufacturers profit when diabetic patients need cardiac pacemakers, artificial valves, and prosthetic limbs. Kidney failure requires expensive machines, products and dialysis facilities. Many professions, including physicians, pharmacists, dietitians, physiotherapists, social workers, occupational therapists, and others are called upon to provide care and diabetics need hospitals, clinics, blood test labs, MRI machines, offices, exercise machines, and more. Simply put, the new paradigm is good for the economy. It’s too bad that patients must suffer.
If the theory that high insulin levels cause insulin resistance has no scientific basis, where is the research disproving this hypothesis? And why aren’t the current treatment approaches truly helping Type 2 diabetics fight a disease that has huge health consequences? I don’t mind being wrong. Show me the evidence!
Dear Dr. Olders,
A very intriguing, thought provoking question, outstandingly framed and convincingly, lucidly and superbly articulated! Thank you!! "What gets us into trouble is not what we don't know; it's what we know for sure that just ain't so." - Mark Twain.
"If the theory that high insulin levels cause insulin resistance has no scientific basis, where is the research disproving this hypothesis? And why aren’t the current treatment approaches truly helping Type 2 diabetics fight a disease that has huge health consequences? I don’t mind being wrong. Show me the evidence!"
Please search through the literature using terms such as hyperinsulinemic clamp studies in animals and you will find more than adequate evidence to refute the notion that merely hyperinsulinemia can cause type 2 diabetes.
Interesting thing is that even in the 70s they had more than ample evidence to discard the stated notion but they chose to ignore it - patients with insulinoma were known since the 20s - all or at least some patients should have ended up with insulin resistance and type 2 diabetes, if the hypothesis was correct!
Here are some studies from the 90s on patients with insulinomas, showing that insulin resistance is apparently common:
Del Prato, S., A. Riccio, S. Vigili de Kreutzenberg, M. Dorella, A. Avogaro, M. C. Marescotti, and A. Tiengo (1993) Metabolism 42:24-29.
Mechanisms of fasting hypoglycemia and concomitant insulin resistance in insulinoma patients.
To gain further insight into the pathogenesis of fasting hypoglycemia in patients with insulin-secreting adenoma of the pancreas, we studied seven patients affected by insulinoma (age, 42 +/- 7 years; body mass index [BMI], 27 +/- 2 kg/m2) and seven normal subjects. In insulinoma patients, hepatic glucose production (HGP) and glucose utilization (Rd) were evaluated by infusion of 3-3H-glucose at spontaneous fasting plasma glucose concentration, after restoration of euglycemia and during euglycemic insulin clamp (40 mU/m2/min). In insulinoma patients, fasting plasma glucose concentration (2.8 +/- 0.2 v 4.5 +/- 0.1 mmol/L; P
“The insulin paradox”! Insulin resistant individuals are not able to maintain the extent of hyperinsulinemia that is essential to avoid insulin resistance. The development of type 2 diabetes is the consequence. The quandary is as follows. Although individuals, who are overtly insulin resistant, secrete enough insulin to be nondiabetic, they tend to have enhanced risks of developing a constellation of (metabolic?) abnormalities. Such risks have been termed as “the metabolic syndrome”. The term “Insulin
Resistance Syndrome” has been advanced as an alternative name for the “metabolic syndrome” or “dysmetabolic syndrome”. The basis for such term is that insulin resistance and consequent hyperinsulinemia, which is compensatory, influence the plausibility of an individual developing a cluster of cognate abnormalities. Certain individuals exhibiting these syndromes are believed to eventually develop diabetes as they lose the capacity to secret large quantities of insulin required to override insulin resistance. It is considered that most of these insulin resistant individuals do not develop diabetes. But somehow, they have a higher propensity to develop cardiovascular disorders (CVD) and are more subject to clinical consequences of insulin resistance and of compensatory hyperinsulinemia. Risk of obesity falls under this umbrella. In the light of your comments, this is a convenient paradigm because clinicians do not have to primarily tackle insulin resistance but can meander to managing obesity and CVD.
According to NIDDK, NIH, the exact causes of insulin resistance have not been completely understood. Scientists consider excess weight and physical inactivity to be the major contributors to the development of insulin resistance.
Ethnicity; certain diseases; hormones; use of steroids; some medicines; advancing age, sleep problems, especially sleep apnea; and cigarette smoking are thought to be other causes.
Here are two distinctly different scenarios:
- An induced downregulation of insulin receptor as a compensatory response to hyperinsulinemia caused by insulin infusion in an experimental animal or as a consequence of insulinoma
- Primary insulin resistance due to obesity, mutated receptor or any number of components in the chain of events that leads to insulin action etc. - causing the compensatory overproduction and secretion of insulin from beta-cells to overcome the obvious lack of insulin action
Although a full understanding of etiology of type 2 diabetes is not available but enough segmental information is available to refute the notion that hyperinsulinemia (which has to happen for some reason) in itself is the primary cause of T2DM.
Sir Karl Popper, the great philosopher of science, pointed out that science makes advances by testing and rejecting falsifiable hypotheses. The theory that high insulin levels cause insulin resistance is eminently falsifiable, so I would like someone to present evidence that disproves it, if such evidence is out there.
The alternate theories that have been proposed, for example, “the exact causes of insulin resistance have not been completely understood. Scientists consider excess weight and physical inactivity to be the major contributors,” or “Although a full understanding of etiology of type 2 diabetes is not available but enough segmental information is available to refute the notion that hyperinsulinemia (which has to happen for some reason) in itself is the primary cause of T2DM”, are not falsifiable hypotheses, in my opinion. Karl Popper would have considered such hypotheses as unscientific.
High fructose (and products such as fructose supplemented juices and beverages, and other products such as jams and marmalade) ingestion has been linked with substantive decrease in insulin sensitivity in some cases. The ingestion of fructose in Western diets has been estimated to be enormous (62.4 lb. /year in 1997; Putnam J: Food consumption, prices, and expenditures, 1970–91. Economic Research Service. 1999, Washington, DC: US Department of Agriculture). Even though fructose does not seem to cause acute elevation in insulin levels It has been considered that chronic ingestion of fructose indirectly fosters high insulin levels. Other factors that have been linked with high insulin are lipid overload, circulating free fatty acids, and adipose tissue functions. Insulin sensitivity and glucose homeostasis have been associated with functional adipose tissues, which are necessary for normal secretion of adipokines that increase insulin sensitivity.
More insulin: some pills stimulate the pancreas to produce more insulin i.e. glyburide, glipizide, glimepiride, tolazamide, chlorpropamide and tolbutamide. These insulin secretagogues stimulate pancreas to produce more insulin.
Hello friends -
I have helped a lot of people that have been diagnosed with Diabetes mellitus type 2 get back to "normal" fasting plasma glucose levels of ≥ 7.0 mmol/l (126 mg/dl) in merely weeks. My personal conclusion is, based on my own experience, that this is a lifestyle disease. Dietary changes as low-carbohydrate and calorie-restricted diets seem to have "cured" this "disease" almost instantly. I'm new to this whole world of science and taking it all in by day and learning as I go through my undergraduate program.
I have found a study that aimed to determine effects of a strict low-carbohydrate diet on insulin sensitivity and lipid levels on obese patients with type-2 diabetes. Link: http://annals.org/article.aspx?articleid=718265&wptouch_preview_theme=enabled
Appreciate some input and feedback on my experiences as well as links to studies on this subject.
Robert
Dr. Older and Dr. Alam have both made excellent points, but I would appreciate a few references from Dr. Alam to back up his claims that insulinomas do not contribute to insulin resistance.
As a beta-cell biologist, I have always worked under the paradigm that insulin resistance leads to increased insulin output from the pancreas up until a point at which the beta-cells fail secrete enough insulin to keep up with insulin resistance, and then you have hyperglycemia/diabetes.
I think there is ample evidence that insulin resistance will lead to hyperinsulinemia AND that excess insulin secretion will lead to insulin resistance (and generally weight gain—yet another factor). I am much more curious as to which comes first in the earliest phases of the disease, long before hyperglycemia becomes symptomatic to the point of diagnosis.
This “chicken vs. egg” problem of insulin resistance vs hyperinsulinemia will likely continue to be debated because each contributes to the other, and there is evidence to support both arguments. That said, here are a few references suggesting that hyperinsulinemia may precede insulin resistance in type 2 diabetes as a contribution to the discussion.
Hansen BC, Bodkin NL. Beta-cell hyperresponsiveness: earliest event in development of diabetes in monkeys. Am. J. Physiol. 1990;259(3 Pt 2):R612–617.
Weyer C, Hanson RL, Tataranni PA, Bogardus C, Pratley RE. A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia. Diabetes 2000;49(12):2094–2101.
Dankner R, Chetrit A, Shanik MH, Raz I, Roth J. Basal-state hyperinsulinemia in healthy normoglycemic adults is predictive of type 2 diabetes over a 24-year follow-up: a preliminary report. Diabetes Care 2009;32(8):1464–1466.
Thank you, Dr. Nunemaker, for the Hansen reference - I had not come across that paper before.
Here are some other references supporting the hypothesis that hyperinsulinemia precedes insulin resistance:
Pettitt DJ, Moll PP, Knowler WC et al. Insulinemia in children at low and high risk of NIDDM. Diabetes Care. 1993;16:608-615.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8462388
Arslanian SA, Saad R, Lewy V, Danadian K, Janosky J. Hyperinsulinemia in african-american children: decreased insulin clearance and increased insulin secretion and its relationship to insulin sensitivity. Diabetes. 2002;51:3014-3019.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12351441
Kim B, McLean LL, Philip SS, Feldman EL. Hyperinsulinemia induces insulin resistance in dorsal root ganglion neurons. Endocrinology. 2011;152:3638-3647.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21810948
Marangou AG, Weber KM, Boston RC et al. Metabolic consequences of prolonged hyperinsulinemia in humans. Evidence for induction of insulin insensitivity. Diabetes. 1986;35:1383-1389.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3533684
Gray SL, Donald C, Jetha A, Covey SD, Kieffer TJ. Hyperinsulinemia precedes insulin resistance in mice lacking pancreatic beta-cell leptin signaling. Endocrinology. 2010;151:4178-4186.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20631001
Kelly CT, Mansoor J, Dohm GL, Chapman WH, Pender JR, Pories WJ. Hyperinsulinemic syndrome: The metabolic syndrome is broader than you think. Surgery. 2014
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=24962189
Iozzo P, Pratipanawatr T, Pijl H et al. Physiological hyperinsulinemia impairs insulin-stimulated glycogen synthase activity and glycogen synthesis. Am J Physiol Endocrinol Metab. 2001;280:E712-9.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11287353
Del Prato S, Leonetti F, Simonson DC, Sheehan P, Matsuda M, DeFronzo RA. Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man. Diabetologia. 1994;37:1025-1035.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7851681
Rizza RA, Mandarino LJ, Genest J, Baker BA, Gerich JE. Production of insulin resistance by hyperinsulinaemia in man. Diabetologia. 1985;28:70-75.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3884419
Garvey WT, Olefsky JM, Marshall S. Insulin induces progressive insulin resistance in cultured rat adipocytes. Sequential effects at receptor and multiple postreceptor sites. Diabetes. 1986;35:258-267.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3512337
Insulin>insulin receptor>insulin receptor substrate 1/2>PI3K>PKB>GLUT4 membrane translocation>glucose influx in cystosol and utilized or stored as fuel or source for energy. In case of genetic defect in any of the downstream signaling component like insulin receptor substrate 1/2>PI3K>PKB>GLUT4 leads to decrease glucose influx, and high level of glucose is builds up in blood, which is termed type 2 diabetes. hyperinsulinemia not seems to be the primary caus eof type 2 diabetes because hyperglycemia occur first independent of hyperinsulinemia.
Glycemic control is like a religion. It is nice to see somebody actually thinking. My father was an engineer and he said the difference between him and me is a physician was engineers start at zero and work up and physicians have to start at the end of work backward. The zero point is actually an inherited capillary deficiency marked by a a thickened leaky basement membrane. The capillaries leak in enclosed spaces such as the pancreas, back of the retina in the nephron where leakage causes strangulation and a slow death of those cells. All that is seen after that is secondary to those injuries.
- I believe there is a third type of diabetes, which I'm calling type III, that involves over eating, then fiddling with the hypothalamic fuel center, producing increased insulin in order to deal with the high-fat loads, and a subsequent compensatory signal to the liver to reduce sensitivity to insulin basically I think in order to prevent hypoglycemia during the time of the elevated insulin levels helping to store excess fat load. This is why "diabetics" will resume normal glucose is with a little bit of weight loss "Makes the diabetes go away. What is going away is elevated blood sugar a surrogate not the disease of capillaries. The high glucose level from not having enough insulin activated at the receptor level due to hypothalamic suppression is a protective mechanism not a pathological one. People with elevated and son levels are the cause of the diabetic worldwide epidemic based on the World Health Organization criteria of 126. this is scientifically illogical. To make the diagnosis of diabetes like any other disease there needs to be clinical correlates otherwise the diagnosis become simply a Surrogate lab test and over identifies millions of people which of course will need pharmacological treatment but who will never develop true vascular diabetes. Giving insulin to my T3 folks with "insulin resistance" and already high insulin levels is negligent
"Dr. Older and Dr. Alam have both made excellent points, but I would appreciate a few references from Dr. Alam to back up his claims that insulinomas do not contribute to insulin resistance."
Craig, my apologies for not coming back to your response - thanks to NIH looming deadlines. ;)
In our hands, in experimental animals, it was fairly straightforward. If we continuously infused insulin to create hyperinsulinemia and hypoglycemia, native islets responded by lowering their insulin output. If the condition persisted for days and weeks, not only the insulin gene transcription and contents of stored insulin diminished, the mass of beta cells significantly reduced. Once the insulin infusion was stopped, rats were back to normal in about 2 days - no insulin resistance!
Similar observations were made by implanting insulinoma followed by removal of the tumor, and using dexamethasone (to induce insulin resistance). This work was published ages ago and can be easily found through a simple search. For example, some of our old work can be found here (and I'm sure many other groups have done a great deal more):
http://www.ncbi.nlm.nih.gov/pubmed/8105694
http://www.ncbi.nlm.nih.gov/pubmed/1644920
http://www.ncbi.nlm.nih.gov/pubmed/1607075
http://www.ncbi.nlm.nih.gov/pubmed/1449084
http://www.ncbi.nlm.nih.gov/pubmed/2038344
Normal beta cells are exquisitely fine-tuned for responding to variation in glucose levels. It seems irrational to think that without any reason they suddenly start dumping excess insulin, which in itself causes insulin resistance.
One has to be careful while discerning the difference between cause and effect.
"Arslanian SA, Saad R, Lewy V, Danadian K, Janosky J. Hyperinsulinemia in african-american children: decreased insulin clearance and increased insulin secretion and its relationship to insulin sensitivity. Diabetes. 2002;51:3014-3019."
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12351441
Henry, I randomly pulled up one of your quoted publication, as shown above.
I have only read their abstract and here is what it states:
"This suggests that increased insulin secretion in AA children is not merely a compensatory response to lower insulin sensitivity. Dietary factors may have a role. Additional studies are needed to determine whether metabolic/nutritional factors, possibly mediated through free fatty acids, may play a role in the hyperinsulinism observed in AA children."
Perhaps I am failing to understand your point and you may be able to better clarify how does the conclusion of authors support your contention.
Tausif, that Arslanian article points out that one aspect of the hyperinsulinemia manifested by AA children may be due to dietary factors. That is exactly what I said in my original post: "Since the main stimulus to insulin secretion is the level of glucose in the blood, we can get the pancreas to release less insulin by decreasing the amount of glucose going into the bloodstream. For people who eat regularly, that main source of blood glucose is carbohydrates in the diet, i.e., sugars and starches".
Henry, I do not quite follow the source of confusion!
Isn't that's what the entire community also think?
Dear Dr. Kline,
Your comments on a third type of diabetes brings to mind a ketosis-prone type 2 diabetes, which is suggested to manifest disease-specific metabolic defects. Insulin sensitivity is considered to decrease to an equal extent in both ketosis-prone type 2 diabetes and classical type 2 diabetes; nevertheless Insulin sensitivity is conceived to improve more significantly in non–insulin-dependent ketosis-prone type 2 diabetes, provided there is correction of hyperglycemia. Ketosis-prone type 2 diabetes is believed to be distinct from type 1 diabetes and type 2 diabetes in terms of specific characteristics of clinical pathophysiology and proneness to glucose toxicity.
Dr. Kandaswami: yep good point a c-peptide will measure the intrinsic insulin and I would imagine the ketosis prone are really very low insulin producers like T1
"Please clarify, Tausif. What is it that the entire community thinks?"
Part of the conclusion of the publication we were discussing - dietary stimuli causing compensatory modulation in insulin secretion (paraphrased).
Once again, the point being that hyperinsulinemia does not happen without a reason.
So we agree - hyperinsulinemia does not happen without a reason. And would you agree that in individuals with a genetic predisposition, a diet rich in carbohydrates could cause hyperinsulinemia, either through higher levels of secretion, or through decreased breakdown of insulin, or through both?
"And would you agree that in individuals with a genetic predisposition, a diet rich in carbohydrates could cause hyperinsulinemia, either through higher levels of secretion, or through decreased breakdown of insulin, or through both?"
Not quite the way you phrase it...
If by genetic predisposition you mean mutated insulin receptor or one of the proximal signal transduction component, then obviously the compensatory response of beta cell will increase insulin secretion because of persisting hyperglycemia. Primary cause of diabetes (hyperglycemia) in such a case is dysfunctional or partially functional insulin action. Your contention that hyperinsulinemia, irrespective of how it happens (my conjecture from your above post), causes T2DM seems flawed.
So we're back to where we were at the beginning: there is a hypothesis (not mine; as I said before, this was what we were taught in med school) that hyperinsulinemia causes insulin resistance. You disagree, calling it flawed, but seem unable to provide convincing evidence that the hypothesis is wrong.
Dear Dr. Kline,
Your comments about other variants of diabetes are important, but I'm afraid that the label "type 3 diabetes" has already been taken, to describe some manifestations of Alzheimer's dementia in which insulin resistance in the brain appears to play a role (see: Steen E, Terry BM, Rivera EJ et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease--is this type 3 diabetes? J Alzheimers Dis. 2005;7:63-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15750215 ).
The question of which comes first, the insulin resistance or the hyperinsulinemia, may play a role in the brain also. Type 1 diabetics may provide clues: these individuals seem to be at quite low risk of developing AD, which I would suggest is because they have little chance of being hyperinsulinemic, at least for prolonged periods of time.
Henry
"...there is a hypothesis (not mine; as I said before, this was what we were taught in med school) that hyperinsulinemia causes insulin resistance. You disagree, calling it flawed,"
Since you seem to be interested in the hypothesis you were taught, perhaps you should provide a credible evidence of causal relationship to us (readers) demonstrating that hyperinsulinemia in itself causes T2DM.
"but seem unable to provide convincing evidence that the hypothesis is wrong."
Apparently, either you did not care to read the citations I provided or did not fully understand the experiments described therein...
But just for fun, here is another hypothesis in a similar vein:
Ownership of an S-class Mercedes by parents is associated with lower infant mortality.
True?
Is there a causal relationship? ;)
"Type 1 diabetics may provide clues: these individuals seem to be at quite low risk of developing AD, which I would suggest is because they have little chance of being hyperinsulinemic, at least for prolonged periods of time."
Please provide some credible evidence.
AAIC does not support your statement - in fact, quite the opposite:
"WASHINGTON, DC, July 20, 2015 – The first study of dementia risk, including Alzheimer’s disease, in older adults with type 1 diabetes (T1D) was reported today at the Alzheimer’s Association International Conference® 2015 (AAIC® 2015) in Washington, D.C. People in the study with T1D were 93% more likely to get dementia (73% after adjustment for heart health risk factors) compared with people without diabetes."
https://www.alz.org/aaic/releases_2015/Mon8amET.asp
https://intensivedietarymanagement.com/insulin-resistance-good-t2d-7/
https://intensivedietarymanagement.com/insulin-causes-insulin-resistance-hormonal-obesity-x/
Thank you for the link to the AAIC 2015 conference press release, Tausif. After reading Rachel Whitmer’s abstract, I wrote to her asking for more information. In the meantime, the abstract clarifies that she was looking at dementia of all types, not just AD. Out of 490,344 patients over 60, only 230 (0.05%) had T1DM, and 16% of these (ie, 37) developed dementia. Compare this to a retrospective chart review of over 5 million patients either hospitalized or seen in clinics over 10 years at Yale-New Haven Hospital. Over 800,000 were over 65 years of age; 14,485 (0.018%) were diagnosed with T1DM, and 12,389 (0.015%) with AD, but only 10 patients had both T1DM and AD. Rdzak GM, Abdelghany O. Does insulin therapy for type 1 diabetes mellitus protect against Alzheimer’s disease. Pharmacotherapy. 2014;34:1317-1323. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=25280207
Bottom line: the numbers are tiny, and the definitive studies may not have been done yet. So I’ll keep an open mind.
With respect to your five references, Tausif: the last reference “Expression of reg/PSP, a pancreatic exocrine gene: relationship to changes in islet beta-cell mass.” actually may support the hypothesis that hyperinsulinemia causes insulin resistance. Your article describes an experiment in which insulinoma cells were implanted into rats; after 7-10 weeks, these rats became severely hypoglycemic. After at least a week of hypoglycemia, the insulinoma cells were removed. Figure 2A in the article shows blood glucose levels in normal rats, in rats with the insulinoma cells, and then for days 1 through 4 after resection of the tumor cells.
The rebound hyperglycemia following tumor resection demonstrates either insulin resistance, or lack of insulin due to suppression of islet cells, or some combination of the two. The time course of the steep reduction in blood glucose levels from day 1 to day 2 post-resection, compared to a gradual, linear increase in beta-cells (figure 2C), suggests that at least some of the improvement in hyperglycemia was due to a decrease in insulin resistance immediately following the drop in insulin levels.
I was unable to see how the other four articles might contribute to disproving the hypothesis that hyperinsulinemia can cause insulin resistance. Neither of these two terms appears in the abstract for “Coordinate regulation of amylin and insulin expression in response to hypoglycemia and fasting”. The first two articles referenced deal with glucocorticoid-induced diabetes. Since glucocorticoids stimulate gluconeogenesis in liver and may promote glycogenolysis in muscle cells, while also affecting insulin receptors and beta-cells, it’s not clear to me how this would disprove the hypothesis that hyperinsulinemia can cause insulin resistance.
Henry:
"The rebound hyperglycemia following tumor resection demonstrates either insulin resistance, or lack of insulin due to suppression of islet cells, or some combination of the two. The time course of the steep reduction in blood glucose levels from day 1 to day 2 post-resection, compared to a gradual, linear increase in beta-cells (figure 2C), suggests that at least some of the improvement in hyperglycemia was due to a decrease in insulin resistance immediately following the drop in insulin levels."
In our studies, the effect of continuous infusion of insulin or implantation of insulinoma resulted in compensatory reduction in endogenous beta cell mass. It was our conclusion that the insulin production capacity of pancreatic beta cells was significantly reduced to the degree that when the tumor was resected (or insulin infusion was stopped, in another study), the remaining beta cells were unable to fully control glucose levels. However, in a short few days, hyperglycemia induced increase in beta cell mass was able to establish euglycemia.
Your second point is invalid simply because a portion of normal islets (beta cells) are sufficient to maintain euglycemia. However, under normal circumstances, we and other animals have considerable reserve capacity (perhaps to deal with unusually challenging situations). In our studies, further increase in beta cell mass beyond the point of establishing euglycemia simply reflects building the islet mass back to the normal levels.
Dear Charlotte,
Thank you for the links to Jason Fung's website. Very interesting author!
Henry
Thank you for triggering a great discussion (lasting over a year now!).
I am as well interested in answering the same question, simply because solving for x in this "equation" will offer the solution for the most of world healthcare problems today! In my opinion, we underestimate the impact of chronic inflammation on occurrence of hyperinsulinemia. While hyperinsulinemia is associated with fewer exposed insulin receptors, it is not necessarily the cause - but, likely, the consequence. It makes sense that the pancreas will produce more insulin if not achieving needed glucose-lowering with the existing number of receptors. I believe that what leads to fewer insulin receptors is the chronic inflammation.
Pre-diabetes condition is an inflammatory, not yet hyperinsulinemic, state. This alone suggests that inflammation would come first and then hyperinsulinemia will follow. Clinical studies indicate that exercise can re-establish insulin sensitivity and they also show an association with lower inflammation markers' levels. It would seem that - in fact - we solved for x since a while ago, but we fail at taking advantage of what we know.
"Knowing is not enough, we must apply. Willing is not enough, we must do."
Yeah, inflammation is in there, but i think it is coming from micro vessels through tears. The basic pathology in diabetes is abnormal capillaries, from birth, that explain virtually everything. They leak when they shouldn't and don't fenestrate when they should (thus slower migration of macrophages and maybe the reason for more carbuncles noted during Joslin's time)
I think if you, or I, were in the process of eating and eating to put on weight before our ancestral migration or same for hibernating bear, or an eskimo curlew bird readying for a 1500 mile nonstop migratory flight, or a sumo wrestler were in the midst of gorging, we would call forth additional insulin for job #2 - storage of calories, getting fat, adding to our camel fat hump. We would then have elevated insulin levels working like mad while eating enough before the mastodon rotted. If we eat enough to overwhelm the insulin storing capacity of the calories, our blood sugars would rise. This is why "diabetes" (read high glucose in this pseudodiabetes condition) can be "reversed" (read lower the glucose). So your glucose goes from 129 to 124 and your diabetes is gone? Come on. Bernard in 1850's invented critical thinking which we seem to ignore. This is not alchemy.
Tom kline md phd
raleigh, the bathroom state
Alice:
Prediabetes is claiming a normal state is abnormal. So if one is to violate definitions of normal our science slides off the edge of the world.
Normal xrays in smokers "pre lung cancer"? Fertile women "pre-pregnant" ? Alchemy.
ps the only country in the world to recognize prediabetes as a disease is us americans. Preliminary studies of "intervening" for prediabetes have of course failed. Good PT Barnum sales pitch to corral more "diabetics" and then of course hand them over to the pharmaceutical companies contributing millions (check it out) at ADA. Who came up with this idea anyway?
Hummmmm
tom kline again
Thomas:
"Bernard in 1850's invented critical thinking which we seem to ignore."
What does that make everyone who lived before 1850?
OMG!!! You say just what many of us think but few dare to say. It's all because of the money.The food multinationals have everything in their hands: illness and treatment (both chronic). I will share with you certain articles which explain the ironies of medical life...
--> Banting Lecture 2011 Hyperinsulinemia: Cause or Consequence?
Barbara E. Corkey. Diabetes 2012
--> Diabetes: Have We Got It All Wrong? Hyperinsulinism as the culprit: surgery provides the evidence. WALTER J. PORIES, MD, FACS G. LYNIS DOHM, PHD . Diabetes care, 2012.
--> Postprandial insulin assay as the earliest biomarker for diagnosing pre- diabetes, type 2 diabetes and increased cardiovascular risk .
DiNicolantonio JJ, et al. Open Heart 2017
--> Hyperinsulinemic syndrome: The metabolic syndrome is broader than you think. Kelly et al. Surgery 2014.
--> β-Cell Failure or β-Cell Abuse? Erion K, Corkey BE. Front Endocrinol (Lausanne). 2018 Sep
--> Mild Suppression of Hyperinsulinemia to Treat Obesity and Insulin Resistance. Melisa Page. Cell Meyabolism 2018
--> Hyperinsulinemia Drives Diet-Induced Obesity Independently of Brain Insulin Production. Mehran et al. 2012.
In this last article from Mehran is striking as what you call "new theory", now it happens to be "OLD PARADIGM" and vice versa. See figure 7.
We can discuss this further. Thank you for your contributions.
LZ Caroline Bonner
The answer is Ms. clever hypothalamus. When the more important to hypothalmamic management of calories and calorie storage =- the fats are hitting the blood stream signals are sent out from hypothalmus to decrease liver cells etc to not overreact to the increased insulin about to occur in order to store the all important camel hump fats in that great and active organ our fat blanket. Carbos, amino acids, psssh not so important right now they only have half the calories, you guys sit tight until we get these 2x calories dudes stored. But we up there in the hypothalmus calorie center are going to start jacking the insulin to store the fats, oh dear we may induce hypoglycemia withthese high insulin levels so I am going instruct you hepatocytes to cool it by shutting down some insulin receptors. Just to excite all the blood sugar contro,l loose your legs, eyesight and kidneys, freaks we will call this "insulin resistance" and stanford (where i was for a bit) researchers can become famous the world round as discoverers of the cause of diabetes type two. To bad out foxed by the Mr. brain who knows what it is doing and doesn't cause any disease I know of.
Thomas kline md phd