Tag Archives: cause of diabetes

Is Diabetes Caused by Poor Regulation of Glucagon?

From Shutterstock.com

Glucagon is produced in the alpha cells and works to increase blood sugar levels. Insulin is from the beta cells.

Most folks assume that the hormone called insulin is at the heart of diabetes: either there’s not enough of it or it’s not working right.

But thats’s not the only possible mechanism for diabetes. I’ve written several times here about the glucagon-centric theory of diabetes, which is most closely associated with Roger Unger, M.D. If you’re interested in a scientific review article on glucagon and type 2 diabetes, here’s one:

Reference: Xiao C. Li and Jia L. Zhuo. Current Insights and New Perspectives on the Roles of Hyperglucagonemia in Non Insulin-dependent Type 2 DiabetesCurrent Hypertension Reports. Oct 2013; 15(5): 10.1007/s11906-013-0383-y.  doi: 10.1007/s11906-013-0383-y

Steve Parker, M.D.

low-carb mediterranean diet

Front cover of book


Filed under Causes of Diabetes

Dr. Roger Unger and his Glucagon-Centric Diabetes Model

Perhaps we’ve been wrong about diabetes all along: the problem isn’t so much with insulin as with glucagon.

At least one diabetes researcher would say that’s the case. Roger Unger, M.D., is a professor at the University of Texas Southwestern Medical Center. That’s one of the best medical schools in the U.S., by the way.

Glucagon is a hormone secreted by the alpha cells of the pancreas; it raises blood sugar. (There are also glucagon-secreting alpha cells in the lining of the stomach, and I believe also in the duodenum.) In the pancreas, the insulin-producing beta cells are adjacent to the glucagon-secreting alpha cells. Released insulin directly suppresses glucagon. So if your blood sugar’s too high, as in diabetes, may be you’ve got too much glucagon action rather than too little insulin action.

From Shutterstock.com

Don’t ask me what delta cells do

Dr. Unger says that insulin regulates glucagon. If your sugar’s too high, your insulin isn’t adequately keeping a lid on glucagon. Without glucagon, your blood sugar wouldn’t be high. All known forms of diabetes mellitus have been found to have high glucagon levels (if not in peripheral blood, then in veins draining glucagon-secreting organs).

This is pretty well proven in mice. And maybe hamsters. I don’t know if we have all the pertinent evidence in humans, because it’s harder to do the testing.

Here’s Dr. Unger’s glucagon-centric theory of the pathway to insulin-resistant type 2 diabetes: First we over-eat too many calories, leading to insulin over-secretion, leading to increased fat production (lipogenesis) and storage in pancreatic islet cells as triglycerides, in turn leading to increased ceramide (toxic) in those islet cells, leading to pancreas beta cell death (apoptosis) and insulin resistance in the alpha cell (so glucagon is over-produced), all culminating in type 2 diabetes.

For a diagram of this, click forward minute 40 and 10 seconds in the video below.

If this is all true, so what? It could lead to some new and more effective treatments for diabetes. Dr. Unger says that in type 2 diabetes, we need to suppress glucagon. Potential ways to do that include a chemical called somatostatin, glucagon receptor antibodies, and leptin (the latter mentioned in a 2012 article, I think). The glucagon-centric theory of diabetes also explains why type 1 diabetics rarely have totally normal blood sugars no matter how hard they try: we’re ignoring the glucagon side of the equation. I don’t yet understand his argument, but he also says that giving higher doses of insulin to T2 diabetics may well be harmful. I’m guessing the insulin leads to increased accumulation of lipids (and the associated toxic ceramide) in cells.

Not making sense? Try this YouTube video:

Steve Parker, M.D.

PS: Dr. Unger Says: “Without insulin, you can’t get fat.”

Apoptosis: the second p is apparently silent.

h/t George Henderson


Filed under Causes of Diabetes

What Causes Type 2 Diabetes?

diabetic diet, low-carb Mediterranean Diet, low-carb, Conquer Diabetes and Prediabetes

Stop reading this sciencey post when you get bored

According to Roy Taylor, “type 2 diabetes is a potentially reversible metabolic state precipitated by the single cause of chronic excess intraorgan fat.” The organs accumulating fat are the liver and pancreas. He is certain “…that the disease process can be halted with restoration of normal carbohydrate and fat metabolism.” I read Taylor’s article published earlier this year in Diabetes Care.

[Do you remember that report in 2011 touting cure of T2 diabetes with a very low calorie diet? Taylor was the leader. The study involved only 11 patients, eating 600 calories a day for eight weeks.]

Dr. Taylor (M.D.) says that severe calorie restriction is similar to the effect of bariatric surgery in curing or controlling diabetes. Within a week of either intervention, liver fat content is greatly reduced, liver insulin sensitivity returns, and fasting blood sugar levels can return to normal. During the first eight weeks after intervention, pancreatic fat content falls, with associated steadily increasing rates of insulin secretion by the pancreas beta cells.

bariatric surgery, Steve Parker MD

Band Gastric Bypass Surgery (not the only type of gastric bypass): very successful at “curing” T2 diabetes if you survive the operation

Taylor’s ideas, by the way, dovetail with Roger Unger’s 2008 lipocentric theory of diabetes. Click for more ideas on the cause of T2 diabetes.

Here are some scattered points from Taylors article. He backs up most of them with references:

  • In T2 diabetes, improvement in fasting blood sugar reflects improved liver insulin sensitivity more than muscle insulin sensitivity.
  • The more fat accumulation in the liver, the less it is sensitive to insulin. If a T2 is treated with insulin, the insulin dose is positively linked to how much fat is in the liver.
  • In a T2 who starts insulin injections, liver fat stores tend to decrease. That’s because of suppression of the body’s own insulin delivery from the pancreas to the liver via the portal vein.
  • Whether obese or not, those with higher circulating insulin levels “…have markedly increased rates of hepatic de novo lipogenesis.” That means their livers are making fat. That fat (triglycerides or triacylglycerol) will be either burned in the liver for energy (oxidized), pushed into the blood stream for use elsewhere, or stored in the liver. Fatty acids are components of triglycerides. Excessive fatty acid intermediaries in liver cells—diglycerides and ceramide—are thought to interfere with insulin’s action, i.e., contribute to insulin resistance in the liver.
  • “Fasting plasma glucose concentration depends entirely on the fasting rate of hepatic [liver] glucose production and, hence, on its sensitivity to suppression by insulin.”
  • Physical activity, low-calorie diets, and thiazolidinediones reduce the pancreas’ insulin output and reduce liver fat levels.
  • Most T2 diabetics have above-average liver fat content. MRI scans are more accurate than ultrasound for finding it.
  • T2 diabetics have on average only half of the pancreas beta cell mass of non-diabetics. As the years pass, more beta cells are lost. Is the a way to preserve these insulin-producing cells, or to increase their numbers? “…it is conceivable that removal of adverse factors could result in restoration of normal beta cell number, even late in the disease.”
  • “Chronic exposure of [pancreatic] beta cells to triacylglycerol [triglycerides] or fatty acids…decreases beta cell capacity to respond to an acute increase in glucose levels.” In test tubes, fatty acids inhibit formation of new beta cells, an effect enhanced by increased glucose concentration.
  • There’s a fair amount of overlap in pancreas fat content comparing T2 diabetics and non-diabetics. It may be that people with T2 diabetes are somehow more susceptible to adverse effects of the fat via genetic and epigenetic factors.
  • “If a person has type 2 diabetes, there is more fat in the liver and pancreas than he or she an cope with.”
  • Here’s Dr. Taylor’s Twin Cycle Hypothesis of Etiology of Type 2 Diabetes: “The accumulation of fat in liver and secondarily in the pancreas will lead to self-reinforcing cycles that interact to bring about type 2 diabetes. Fatty liver leads to impaired fasting glucose metabolism and increases export of VLDL triacylglcerol [triglycerides], which increases fat delivery to all tissues, including the [pancreas] islets. The liver and pancreas cycles drive onward after diagnosis with steadily decreasing beta cell function. However, of note, observations of the reversal of type 2 diabetes confirm that if the primary influence of positive calorie balance is removed, the the processes are reversible.”
diabetic diet, etiology of type 2 diabetes, Roy Taylor, type 2 diabetes reversal

Figure 6 from the article: Dr. Taylor’s Twin Cycle Hypothesis of Etiology of Type 2 Diabetes

  • The caption with Figure 6 states: “During long-term intake of more calories than are expended each day, any excess carbohydrate must undergo de novo lipogenesis [creation of fat], which particularly promotes fat accumulation in the liver.”
  • “The extent of weight gloss required to reverse type 2 diabetes is much greater than conventionally advised.” We’re looking at around 15 kg (33 lb) or 20% of body weight, assuming the patient is obese to start.  “The initial major loss of body weight demands a substantial reduction in energy intake. After weight loss, steady weight is most effectively achieved by a combination of dietary restriction and physical activity.”

Dr. Taylor doesn’t specify how much calorie restriction he recommends, but reading between the lines, I think he likes his 600 cals/day for eight weeks program. That will have a have a high drop-out rate. I suspect a variety of existing ketogenic diets may be just as successful and more realistic, even if it takes more than eight weeks. I wonder how many of the 11 “cures” from the 2011 study have persisted.

Steve Parker, M.D.

Reference: Taylor, Roy. Type 2 diabetes: Etiology and reversibility. Diabetes Care, April 2013, vol. 36, no. 4, pp:1047-1055.

Update December 16, 2013:

Some wild and crazy guys tried this method at home. Click for results.

h/t commenter PhilT.


Filed under Causes of Diabetes

Pancreas Beta Cells May be Key to the Cause of Type 2 Diabetes

…according to an article I found in Diabetes Care. As background, be aware that one theory holds that T2 diabetes is caused primarily by body tissue insulin resistance, separate from what’s going on in the pancreas beta (β) cells that produce insulin to control blood sugar.

Some quotes:

Although it has long been assumed that insulin resistance is the leading factor in the pathogenesis of type 2 diabetes, evidence for the importance of the pancreatic β-cells has accumulated over the past decades. In fact, the vast majority of genes associated with type 2 diabetes have been linked to the β-cell, and impairments in β-cell mass and in insulin secretion have been reported in numerous studies in patients with type 2 diabetes.


It has also been suggested that obesity causes type 2 diabetes through impaired insulin action. Undoubtedly, the risk of developing type 2 diabetes increases markedly with BMI. However, if obesity were really the cause of type 2 diabetes, one would expect the vast majority of obese individuals to develop hyperglycemia, whereas in reality ∼80% of obese individuals remain free of diabetes. These findings suggest that obesity and insulin resistance are indeed important cofactors that increase the individual risk of diabetes but that the actual cause of the disease seems to be clearly linked to the β-cells.


The conundrum of whether loss of mass or loss of function underlies the β-cell defects in type 2 diabetes is not likely to be conclusively solved on the basis of the evidence we have reviewed here. Decreased cell mass and acceleration of the biological processes resulting in β-cell loss have been described in type 2 diabetes by a number of laboratories. On the other hand, several lines of evidence suggest that β-cell functional defects may exist in type 2 diabetes.

Both viewpoints tacitly assume that 1) type 2 diabetes is a rather homogeneous entity, at least when it comes to β-cell biology, and 2) overall islet secretory capacity is a linear function of the product between β-cell number and isolated β-cell function. It is possible that neither assumption holds true.

The most likely scenario, indeed, is that a variable combination of the two processes, loss of mass and loss of function, is at work in type 2 diabetes. Indeed, there appears to be a tight relationship between mass of pancreatic β-cells and functional insulin secretion.


Filed under Causes of Diabetes

One Potential Cause of Type 2 Diabetes: Sugar Consumption

Robert Lustig and associates looked at sugar consumption and diabetes rates in 175 countries and found a strong link between sugar and type 2 diabetes.  It’s not proof of causation, just suggestive.  From the abstract:

“Duration and degree of sugar exposure correlated significantly with diabetes prevalence in a dose-dependent manner, while declines in sugar exposure correlated with significant subsequent declines in diabetes rates independently of other socioeconomic, dietary and obesity prevalence changes. Differences in sugar availability statistically explain variations in diabetes prevalence rates at a population level that are not explained by physical activity, overweight or obesity.”

Read the rest.

Reference: Basu S, Yoffe P, Hills N, Lustig RH (2013) The Relationship of Sugar to Population-Level Diabetes Prevalence: An Econometric Analysis of Repeated Cross-Sectional Data. PLoS ONE 8(2): e57873. doi:10.1371/journal.pone.0057873

1 Comment

Filed under Uncategorized

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.


Filed under Causes of Diabetes

What Causes Type 2 Diabetes?

“Beats me. I teach math!”

I have no simple answer for you, unfortunately.

You can lower your risk of type 2 diabetes significantly by avoiding overweight and obesity, by exercising regularly, and by choosing the right parents.  These provide clues as to the causes of diabetes.  The Mediterranean diet also prevents diabetes.

UpToDate.com offers a deceptively simple answer:

Type 2 diabetes mellitus is caused by a combination of varying degrees of insulin resistance and relative insulin deficiency. [Insulin is the pancreas hormone that lowers blood sugar.] Its occurrence most likely represents a complex interaction among many genes and environmental factors, which are different among different populations and individuals.

So, what causes the insulin resistance and relative insulin deficiency?

Understanding the pathogenesis [cause] of type 2 diabetes is complicated by several factors. Patients present with a combination of varying degrees of insulin resistance and relative insulin deficiency, and it is likely that both contribute to type 2 diabetes. Furthermore, each of the clinical features can arise through genetic or environmental influences, making it difficult to determine the exact cause in an individual patient. Moreover, hyperglycemia itself can impair pancreatic beta cell function and exacerbate insulin resistance, leading to a vicious cycle of hyperglycemia causing a worsening metabolic state.

The UpToDate article then drones on for a several thousand words discussing mouse studies, various genes, free fatty acids, adiponectin, leptin, amylin, insulin secretion, insulin resistance, impaired insulin processing, insulin action, body fat distribution, inflammation, various inflammatory markers, low birth weight, high birth rate, prematurity, etc.  More excerpts:

Increased free fatty acid levels, inflammatory cytokines from fat, and oxidative factors, have all been implicated in the pathogenesis of metabolic syndrome, type 2 diabetes, and their cardiovascular complications.

Insulin resistance may, at least in part, be related to substances secreted by adipocytes [fat cells] (“adipokines” including leptin adiponectin, tumor necrosis factor alpha, and resistin).

Type 2 diabetes most likely represents a complex interaction among many genes and environmental factors.

That’s the simplest answer I can give now.

Steve Parker, M.D.

Reference: “The Pathogensis of Type 2 Diabetes Mellitus”  by David K McCulloch, MD, and R Paul Robertson, MD, at UpToDate.com, updated June 2012, and accessed November 19, 2012.


Filed under Causes of Diabetes