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Hypothesis and theory article, type 2 diabetes mellitus: a pathophysiologic perspective.

• Department of Medicine, Duke University, Durham, NC, United States

Type 2 Diabetes Mellitus (T2DM) is characterized by chronically elevated blood glucose (hyperglycemia) and elevated blood insulin (hyperinsulinemia). When the blood glucose concentration is 100 milligrams/deciliter the bloodstream of an average adult contains about 5–10 grams of glucose. Carbohydrate-restricted diets have been used effectively to treat obesity and T2DM for over 100 years, and their effectiveness may simply be due to lowering the dietary contribution to glucose and insulin levels, which then leads to improvements in hyperglycemia and hyperinsulinemia. Treatments for T2DM that lead to improvements in glycemic control and reductions in blood insulin levels are sensible based on this pathophysiologic perspective. In this article, a pathophysiological argument for using carbohydrate restriction to treat T2DM will be made.

Introduction

Type 2 Diabetes Mellitus (T2DM) is characterized by a persistently elevated blood glucose, or an elevation of blood glucose after a meal containing carbohydrate ( 1 ) ( Table 1 ). Unlike Type 1 Diabetes which is characterized by a deficiency of insulin, most individuals affected by T2DM have elevated insulin levels (fasting and/or post glucose ingestion), unless there has been beta cell failure ( 2 , 3 ). The term “insulin resistance” (IR) has been used to explain why the glucose levels remain elevated even though there is no deficiency of insulin ( 3 , 4 ). Attempts to determine the etiology of IR have involved detailed examinations of molecular and intracellular pathways, with attribution of cause to fatty acid flux, but the root cause has been elusive to experts ( 5 – 7 ).

Table 1 . Definition of type 2 diabetes mellitus.

How Much Glucose Is in the Blood?

Keeping in mind that T2DM involves an elevation of blood glucose, it is important to understand how much glucose is in the blood stream to begin with, and then the factors that influence the blood glucose—both exogenous and endogenous factors. The amount of glucose in the bloodstream is carefully controlled—approximately 5–10 grams in the bloodstream at any given moment, depending upon the size of the person. To calculate this, multiply 100 milligrams/deciliter × 1 gram/1,000 milligrams × 10 deciliters/1 liter × 5 liters of blood. The “zeros cancel” and you are left with 5 grams of glucose if the individual has 5 liters of blood. Since red blood cells represent about 40% of the blood volume, and the glucose is in equilibrium, there may be an extra 40% glucose because of the red blood cell reserve ( 8 ). Adding the glucose from the serum and red blood cells totals about 5–10 grams of glucose in the entire bloodstream.

Major Exogenous Factors That Raise the Blood Glucose

Dietary carbohydrate is the major exogenous factor that raises the blood glucose. When one considers that it is common for an American in 2021 to consume 200–300 grams of carbohydrate daily, and most of this carbohydrate is digested and absorbed as glucose, the body absorbs and delivers this glucose via the bloodstream to the cells while attempting to maintain a normal blood glucose level. Thinking of it in this way, if 200–300 grams of carbohydrates is consumed in a day, the bloodstream that holds 5–10 grams of glucose and has a concentration of 100 milligrams/deciliter, is the conduit through which 200,000–300,000 milligrams (200 grams = 200,000 milligrams) passes over the course of a day.

Major Endogenous Factors That Raise the Blood Glucose

There are many endogenous contributors that raise the blood glucose. There are at least 3 different hormones that increase glucose levels: glucagon, epinephrine, and cortisol. These hormones increase glucose levels by increasing glycogenolysis and gluconeogenesis ( 9 ). Without any dietary carbohydrate, the normal human body can generate sufficient glucose though the mechanism of glucagon secretion, gluconeogenesis, glycogen storage and glycogenolysis ( 10 ).

Major Exogenous Factors That Lower the Blood Glucose

A reduction in dietary carbohydrate intake can lower the blood glucose. An increase in activity or exercise usually lowers the blood glucose ( 11 ). There are many different medications, employing many mechanisms to lower the blood glucose. Medications can delay sucrose and starch absorption (alpha-glucosidase inhibitors), slow gastric emptying (GLP-1 agonists, DPP-4 inhibitors) enhance insulin secretion (sulfonylureas, meglitinides, GLP-1 agonists, DPP-4 inhibitors), reduce gluconeogenesis (biguanides), reduce insulin resistance (biguanides, thiazolidinediones), and increase urinary glucose excretion (SGLT-2 inhibitors). The use of medications will also have possible side effects.

Major Endogenous Factors That Lower the Blood Glucose

The major endogenous mechanism to lower the blood glucose is to deliver glucose into the cells (all cells can use glucose). If the blood glucose exceeds about 180 milligrams/deciliter, then loss of glucose into the urine can occur. The blood glucose is reduced by cellular uptake using glut transporters ( 12 ). Some cells have transporters that are responsive to the presence of insulin to activate (glut4), others have transporters that do not require insulin for activation. Insulin-responsive glucose transporters in muscle cells and adipose cells lead to a reduction in glucose levels—especially after carbohydrate-containing meals ( 13 ). Exercise can increase the glucose utilization in muscle, which then increases glucose cellular uptake and reduce the blood glucose levels. During exercise, when the metabolic demands of skeletal muscle can increase more than 100-fold, and during the absorptive period (after a meal), the insulin-responsive glut4 transporters facilitate the rapid entry of glucose into muscle and adipose tissue, thereby preventing large fluctuations in blood glucose levels ( 13 ).

Which Cells Use Glucose?

Glucose can used by all cells. A limited number of cells can only use glucose, and are “glucose-dependent.” It is generally accepted that the glucose-dependent cells include red blood cells, white blood cells, and cells of the renal papilla. Red blood cells have no mitochondria for beta-oxidation, so they are dependent upon glucose and glycolysis. White blood cells require glucose for the respiratory burst when fighting infections. The cells of the inner renal medulla (papilla) are under very low oxygen tension, so therefore must predominantly use glucose and glycolysis. The low oxygen tension is a result of the countercurrent mechanism of urinary concentration ( 14 ). These glucose-dependent cells have glut transporters that do not require insulin for activation—i.e., they do not need insulin to get glucose into the cells. Some cells can use glucose and ketones, but not fatty acids. The central nervous system is believed to be able to use glucose and ketones for fuel ( 15 ). Other cells can use glucose, ketones, and fatty acids for fuel. Muscle, even cardiac muscle, functions well on fatty acids and ketones ( 16 ). Muscle cells have both non-insulin-responsive and insulin-responsive (glut4) transporters ( 12 ).

Possible Dual Role of an Insulin-Dependent Glucose-Transporter (glut4)

A common metaphor is to think of the insulin/glut transporter system as a key/lock mechanism. Common wisdom states that the purpose of insulin-responsive glut4 transporters is to facilitate glucose uptake when blood insulin levels are elevated. But, a lock serves two purposes: to let someone in and/or to keep someone out . So, one of the consequences of the insulin-responsive glut4 transporter is to keep glucose out of the muscle and adipose cells, too, when insulin levels are low. The cells that require glucose (“glucose-dependent”) do not need insulin to facilitate glucose entry into the cell (non-insulin-responsive transporters). In a teleological way, it would “make no sense” for cells that require glucose to have insulin-responsive glut4 transporters. Cells that require glucose have glut1, glut2, glut3, glut5 transporters—none of which are insulin-responsive (Back to the key/lock metaphor, it makes no sense to have a lock on a door that you want people to go through). At basal (low insulin) conditions, most glucose is used by the brain and transported by non-insulin-responsive glut1 and glut3. So, perhaps one of the functions of the insulin-responsive glucose uptake in muscle and adipose to keep glucose OUT of the these cells at basal (low insulin) conditions, so that the glucose supply can be reserved for the tissue that is glucose-dependent (blood cells, renal medulla).

What Causes IR and T2DM?

The current commonly espoused view is that “Type 2 diabetes develops when beta-cells fail to secrete sufficient insulin to keep up with demand, usually in the context of increased insulin resistance.” ( 17 ). Somehow, the beta cells have failed in the face of insulin resistance. But what causes insulin resistance? When including the possibility that the environment may be part of the problem, is it possible that IR is an adaptive (protective) response to excess glucose availability? From the perspective that carbohydrate is not an essential nutrient and the change in foods in recent years has increased the consumption of refined sugar and flour, maybe hyperinsulinemia is the cause of IR and T2DM, as cells protect themselves from excessive glucose and insulin levels.

Insulin Is Already Elevated in IR and T2DM

Clinical experience of most physicians using insulin to treat T2DM over time informs us that an escalation of insulin dose is commonly needed to achieve glycemic control (when carbohydrate is consumed). When more insulin is given to someone with IR, the IR seems to get worse and higher levels of insulin are needed. I have the clinical experience of treating many individuals affected by T2DM and de-prescribing insulin as it is no longer needed after consuming a diet without carbohydrate ( 18 ).

Diets Without Carbohydrate Reverse IR and T2DM

When dietary manipulation was the only therapy for T2DM, before medications were available, a carbohydrate-restricted diet was used to treat T2DM ( 19 – 21 ). Clinical experience of obesity medicine physicians and a growing number of recent studies have demonstrated that carbohydrate-restricted diets reverse IR and T2DM ( 18 , 22 , 23 ). Other methods to achieve caloric restriction also have these effects, like calorie-restricted diets and bariatric surgery ( 24 , 25 ). There may be many mechanisms by which these approaches may work: a reduction in glucose, a reduction in insulin, nutritional ketosis, a reduction in metabolic syndrome, or a reduction in inflammation ( 26 ). Though there may be many possible mechanisms, let's focus on an obvious one: a reduction in blood glucose. Let's assume for a moment that the excessive glucose and insulin leads to hyperinsulinemia and this is the cause of IR. On a carbohydrate-restricted diet, the reduction in blood glucose leads to a reduction in insulin. The reduction in insulin leads to a reduction in insulin resistance. The reduction in insulin leads to lipolysis. The resulting lowering of blood glucose, insulin and body weight reverses IR, T2DM, AND obesity. These clinical observations strongly suggest that hyperinsulinemia is a cause of IR and T2DM—not the other way around.

What Causes Atherosclerosis?

For many years, the metabolic syndrome has been described as a possible cause of atherosclerosis, but there are no RCTs directly targeting metabolic syndrome, and the current drug treatment focuses on LDL reduction, so its importance remains controversial. A recent paper compared the relative importance of many risk factors in the prediction of the first cardiac event in women, and the most powerful predictors were diabetes, metabolic syndrome, smoking, hypertension and BMI ( 27 ). The connection between dietary carbohydrate and fatty liver is well-described ( 28 ). The connection between fatty liver and atherosclerosis is well-described ( 29 ). It is very possible that the transport of excess glucose to the adipose tissue via lipoproteins creates the particles that cause the atherosclerotic damage (small LDL) ( Figure 1 ) ( 30 – 32 ). This entire process of dietary carbohydrate leading to fatty liver, leading to small LDL, is reversed by a diet without carbohydrate ( 26 , 33 , 34 ).

Figure 1 . Key aspects of the interconnection between glucose and lipoprotein metabolism.

Reducing dietary carbohydrate in the context of a low carbohydrate, ketogenic diet reduces hyperglycemia and hyperinsulinemia, IR and T2DM. In the evaluation of an individual for a glucose abnormality, measure the blood glucose and insulin levels. If the insulin level (fasting or after a glucose-containing meal) is high, do not give MORE insulin—instead, use an intervention to lower the insulin levels. Effective ways to reduce insulin resistance include lifestyle, medication, and surgical therapies ( 23 , 35 ).

The search for a single cause of a complex problem is fraught with difficulty and controversy. I am not hypothesizing that excessive dietary carbohydrate is the only cause of IR and T2DM, but that it is a cause, and quite possibly the major cause. How did such a simple explanation get overlooked? I believe it is very possible that the reductionistic search for intracellular molecular mechanisms of IR and T2DM, the emphasis on finding pharmaceutical (rather than lifestyle) treatments, the emphasis on the treatment of high total and LDL cholesterol, and the fear of eating saturated fat may have misguided a generation of researchers and clinicians from the simple answer that dietary carbohydrate, when consumed chronically in amounts that exceeds an individual's ability to metabolize them, is the most common cause of IR, T2DM and perhaps even atherosclerosis.

While there has historically been a concern about the role of saturated fat in the diet as a cause of heart disease, most nutritional experts now cite the lack of evidence implicating dietary saturated fat as the reason for lack of concern of it in the diet ( 36 ).

The concept of comparing medications that treat IR by insulin-sensitizers or by providing insulin itself was tested in the Bari-2D study ( 37 ). Presumably in the context of consuming a standard American diet, this study found no significant difference in death rates or major cardiovascular events between strategies of insulin sensitization or insulin provision.

While lifestyle modification may be ideal to prevent or cure IR and T2DM, for many people these changes are difficult to learn and/or maintain. Future research should be directed toward improving adherence to all effective lifestyle or medication treatments. Future research is also needed to assess the effect of carbohydrate restriction on primary or secondary prevention of outcomes of cardiovascular disease.

Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Author Contributions

The author confirms being the sole contributor of this work and has approved it for publication.

Conflict of Interest

EW receives royalties from popular diet books and is founder of a company based on low-carbohydrate diet principles (Adapt Your Life, Inc.).

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: type 2 diabetes, insulin resistance, pre-diabetes, carbohydrate-restricted diets, hyperinsulinemia, hyperglycemia

Citation: Westman EC (2021) Type 2 Diabetes Mellitus: A Pathophysiologic Perspective. Front. Nutr. 8:707371. doi: 10.3389/fnut.2021.707371

Received: 09 May 2021; Accepted: 20 July 2021; Published: 10 August 2021.

Reviewed by:

Copyright © 2021 Westman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Eric C. Westman, ewestman@duke.edu

This article is part of the Research Topic

Carbohydrate-restricted Nutrition and Diabetes Mellitus

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• Pediatric Review
• Published: 09 June 2009

The accelerator hypothesis: a review of the evidence for insulin resistance as the basis for type I as well as type II diabetes

• T J Wilkin 1  

International Journal of Obesity volume  33 ,  pages 716–726 ( 2009 ) Cite this article

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Although some 40 years have passed since type I diabetes was first defined, its cause remains unknown. The autoimmunity paradigm of immune dysregulation has not offered an explanation for its rising incidence, nor means of preventing it, and there is arguably good reason to consider alternatives. The accelerator hypothesis is a singular, unifying concept that argues that type I and type II diabetes are the same disorder of insulin resistance, set against different genetic backgrounds . The hypothesis does not deny the role of autoimmuniy, only its primacy in the process. It distinguishes type I and type II diabetes only by tempo, the faster tempo reflecting the more susceptible genotype and (inevitably) earlier presentation. Insulin resistance is closely related to the rise in overweight and obesity, a trend that the hypothesis deems central to the rising incidence of all diabetes in the developed and developing world. Rather than overlap between the two types of diabetes, the accelerator hypothesis envisages overlay—each a subset of the general population differing from each other only by genotype. Indeed, it views type I and type II diabetes as a continuum, where the infinitely variable interaction between insulin resistance and genetic response determines the age at which β-cell loss becomes critical. Adult diabetes is not viewed as an entity, but rather as diabetes presenting in adulthood. Childhood diabetes, similarly, is diabetes presenting in childhood. The increasing incidence of both is primarily the result of lifestyle change and the rise in body weight that has resulted

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We thank the many colleagues, editors, reviewers and audiences who, by their questions and critiques, have shaped the accelerator hypothesis.

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Wilkin, T. The accelerator hypothesis: a review of the evidence for insulin resistance as the basis for type I as well as type II diabetes. Int J Obes 33 , 716–726 (2009). https://doi.org/10.1038/ijo.2009.97

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Received : 07 December 2008

Revised : 16 February 2009

Accepted : 11 April 2009

Published : 09 June 2009

Issue Date : July 2009

DOI : https://doi.org/10.1038/ijo.2009.97

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Type 2 Diabetes Research At-a-Glance

The ADA is committed to continuing progress in the fight against type 2 diabetes by funding research, including support for potential new treatments, a better understating of genetic factors, addressing disparities, and more. For specific examples of projects currently funded by the ADA, see below.

Greg J. Morton, PhD

University of Washington

Project: Neurocircuits regulating glucose homeostasis

“The health consequences of diabetes can be devastating, and new treatments and therapies are needed. My research career has focused on understanding how blood sugar levels are regulated and what contributes to the development of diabetes. This research will provide insights into the role of the brain in the control of blood sugar levels and has potential to facilitate the development of novel approaches to diabetes treatment.”

The problem: Type 2 diabetes (T2D) is among the most pressing and costly medical challenges confronting modern society. Even with currently available therapies, the control and management of blood sugar levels remains a challenge in T2D patients and can thereby increase the risk of diabetes-related complications. Continued progress with newer, better therapies is needed to help people with T2D.

The project: Humans have special cells, called brown fat cells, which generate heat to maintain optimal body temperature. Dr. Morton has found that these cells use large amounts of glucose to drive this heat production, thus serving as a potential way to lower blood sugar, a key goal for any diabetes treatment. Dr. Morton is working to understand what role the brain plays in turning these brown fat cells on and off.

The potential outcome: This work has the potential to fundamentally advance our understanding of how the brain regulates blood sugar levels and to identify novel targets for the treatment of T2D.

Tracey Lynn McLaughlin, MD

Stanford University

Project: Role of altered nutrient transit and incretin hormones in glucose lowering after Roux-en-Y gastric bypass surgery

“This award is very important to me personally not only because the enteroinsular axis (gut-insulin-glucose metabolism) is a new kid on the block that requires rigorous physiologic studies in humans to better understand how it contributes to glucose metabolism, but also because the subjects who develop severe hypoglycemia after gastric bypass are largely ignored in society and there is no treatment for this devastating and very dangerous condition.”

The problem: Roux-en-Y gastric bypass (RYGB) surgery is the single-most effective treatment for type 2 diabetes, with persistent remission in 85% of cases. However, the underlying ways by which the surgery improves glucose control is not yet understood, limiting the ability to potentially mimic the surgery in a non-invasive way. Furthermore, a minority of RYGB patients develop severe, disabling, and life-threatening low-blood sugar, for which there is no current treatment.

The project: Utilizing a unique and rigorous human experimental model, the proposed research will attempt to gain a better understanding on how RYGB surgery improves glucose control. Dr. McLaughlin will also test a hypothesis which she believes could play an important role in the persistent low-blood sugar that is observed in some patients post-surgery.

The potential outcome: This research has the potential to identify novel molecules that could represent targets for new antidiabetic therapies. It is also an important step to identifying people at risk for low-blood sugar following RYGB and to develop postsurgical treatment strategies.

Rebekah J. Walker, PhD

Medical College of Wisconsin

Project: Lowering the impact of food insecurity in African Americans with type 2 diabetes

“I became interested in diabetes research during my doctoral training, and since that time have become passionate about addressing social determinants of health and health disparities, specifically in individuals with diabetes. Living in one of the most racially segregated cities in the nation, the burden to address the needs of individuals at particularly high risk of poor outcomes has become important to me both personally and professionally.”

The problem: Food insecurity is defined as the inability to or limitation in accessing nutritionally adequate food and may be one way to address increased diabetes risk in high-risk populations. Food insecure individuals with diabetes have worse diabetes outcomes and have more difficulty following a healthy diet compared to those who are not food insecure.

The project: Dr. Walker’s study will gather information to improve and then will test an intervention to improve blood sugar control, dietary intake, self-care management, and quality of life in food insecure African Americans with diabetes. The intervention will include weekly culturally appropriate food boxes mailed to the participants and telephone-delivered diabetes education and skills training. It will be one of the first studies focused on the unique needs of food insecure African American populations with diabetes using culturally tailored strategies.

The potential outcome: This study has the potential to guide and improve policies impacting low-income minorities with diabetes. In addition, Dr. Walker’s study will help determine if food supplementation is important in improving diabetes outcomes beyond diabetes education alone.

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The theory of treating Type 2 diabetes

Affiliation.

• 1 University Hospital Birmingham NHS Trust, Selly Oak Hospital, UK.
• PMID: 11063278
• DOI: 10.1038/sj.ijo.0801419

Type 2 diabetes mellitus is a chronic, progressive disease affecting many millions of people worldwide. It carries a great burden of morbidity and premature mortality for the individual, and places great demands on healthcare systems and resources. We now know from clinical studies that improved control of Type 2 diabetes can to some degree reduce its burden. We also know that in the context of a clinical trial, the treatments available to us can do much to improve control in many patients (although all will fall short of 'normality'). International guidelines for management of Type 2 diabetes, quite correctly, encourage us to strive for levels of control where we believe the risk of complications is lowest. But is this happening in everyday practice? Data from a survey in three countries show that there is a great difference between the theory of diabetes care and the reality of clinical practice, with levels of glycaemic control in most patients falling short of desired levels. A consideration of the pathophysiology of Type 2 diabetes reveals that it is a complex syndrome focussing on the progressive failure of the pancreatic beta-cell. By acknowledging this fact, and addressing our therapeutic efforts appropriately, we may help to span the gap between theory and reality.

• Diabetes Mellitus, Type 2 / epidemiology
• Diabetes Mellitus, Type 2 / physiopathology
• Diabetes Mellitus, Type 2 / therapy*
• Hyperglycemia / complications*
• Hyperglycemia / prevention & control
• Hyperglycemia / therapy
• Practice Guidelines as Topic / standards*
• Risk Assessment
• Risk Factors

Why our understanding of obesity and diabetes may be wrong: A Q&A with surgeon Peter Attia

Peter Attia gives a talk that brought the house down at TEDMED 2013.

Surgeon Peter Attia sees a disconcerting paradox at work when it comes to our health: while people are talking about eating healthily and exercising perhaps more than ever, we’re seeing no reduction in the rates of obesity and diabetes. As it stands, more than 8% of Americans are diabetic and an additional 26% are pre-diabetic — which represents a 400% increase since 1970. The answer to this riddle is not simply that people are lazy or unable to follow through on what they know is best for them. Attia wonders if, perhaps, our medical understanding of the relationship between obesity and diabetes may be wrong.

“Looking back on that night, I’d love so desperately to believe that I treated that woman with the same empathy and compassion that I’d shown the 27-year-old newlywed who’d come to the ER three nights earlier with lower back pain that turned out to be advanced pancreatic cancer. I passed no judgment on her — obviously she had done nothing to bring this on herself,” says Attia. “So why was it just a few nights later that as I stood in this same ER and determined that my diabetic patient did indeed need an amputation, why did I hold her in such bitter contempt?”

The answer: this woman had Type 2 diabetes and was obese. Running through Attia’s mind was the idea that, if she had just watched what she ate and exercised  a little, she wouldn’t be in this position.

Three years later, however, Attia’s framework shifted. Despite eating well and exercising often, he began to gain weight himself. He developed metabolic syndrome, a pre-cursor to diabetes in which a person becomes insulin resistant. He started to question the assumptions he and the majority of the medical community made about diabetes. He wondered: could it be that insulin resistance caused obesity and not the other way around? Could it be that, in the same way a bruise forms in order to protect the body after an injury, that gaining weight is a coping mechanism for a deeper problem at the cellular level?

“What if we’re fighting the wrong war—fighting the obesity rather than insulin resistance? Even worse, what if blaming the obese means we’re blaming the victims? What if some of our fundamental ideas about obesity are just wrong?” asks Attia in this talk. “If we’re willing to be wrong, to challenge the conventional wisdom with the best experiments science can offer, we can solve this problem.”

Attia’s talk comes out just as a study was published in The New England Journal of Medicine  that revealed a surprising result. The study randomly assigned more than 5000 overweight patients with Type 2 diabetes either a lifestyle intervention that promoted weight loss or standard diabetes support. After 13.5 years of observation, patients who did the intervention had been hospitalized less often than those in the control group and measured better on “secondary” measures.  But they fared no better than the control group when it came to heart attacks, death from cardiovascular causes, and nonfatal strokes — leading the trial to be stopped. It’s a study that shows these interacting health issues may not work in the ways we’ve assume.

To hear Attia’s hypothesis about this connection and to hear his call for us to test all theories rigorously in order to save lives, watch his talk . And below, read excerpts from a Facebook Q&A that Attia did last week with the TEDMED community.

Sound Body Sound Mind Foundation asked:

What do you think is the greatest cause of obesity?

Attia responds:

The greatest cause of obesity may be that we’re applying the wrong treatment. For about 40 years, health authorities have been telling people struggling with obesity to do the same thing over and over again: eat less and exercise more. This does not appear to be successful. This would suggest that either this treatment is incorrect or it is correct and no one can follow it. Either way it’s probably time for a new treatment.

Courtney Olean Paige asks:

How does the quality of our current knowledge of the role of nutrition compare to the quality of our knowledge in other areas of health?

Attia answers:

The short answer is “poor.” The slightly more nuanced answer is that it is poor because it is very difficult to evaluate nutritional interventions in humans. Unlike laboratory mice, for example, controlling for intake and behavior is very difficult when human subjects live in a free environment. Complicating this further, most studies that try to evaluate human subjects in a free living environment are unable to adequately measure what the subjects are consuming. So the net result has been perhaps a greater reliance on epidemiology or poorly controlled studies than would be ideal in other fields of health.

Nicole Batiste asks:

Why does nutrition seem like such an unimportant subject for so many scientists in the health and medical space?

This is an important question and I can only provide a peanut gallery response. I think nutrition science falls into a little bit of a no man’s land. On the one hand, it is expensive to do properly the way, for example, major drug research is done. On the other hand, there is no great opportunity to monetize the results through intellectual property. So there’s a bit of a funding void. While everyone would agree that it’s probably more important that we know what to eat to be healthy than to know which drug to take to improve condition X, the economic forces appear to be conspiring against this elucidation.

Scott McCollum asks:

What are your thoughts on the gut microbiome and obesity? Where’s the current research at and where is it headed?

The current body of evidence certainly suggests that the gut biome plays a role not only in obesity, but more importantly insulin resistance and metabolic dysregulation. Perhaps one of the most amazing clinical observations is the amelioration of diabetes in patients undergoing gastric bypass prior to losing any weight post surgery. This at least suggests that the weight loss per se is not the issue in type two diabetes. Rather, something in the gastric bypass may be altering flora in the gut, which may in fact be altering the underlying insulin resistance. The most interesting question form my vantage point is this: Can the benefit of gastric bypass on the insulin resistant patient be achieved through a dietary intervention that also interrupts the gut biome? Stay tuned.

Brian Burke aks:

The public perception that fat is bad is so engrained that most people don’t remotely question it. It’s hard to get people on board when one of our main points is that the U.S. government is recommending outdated information. To the average person, I sound like a conspiracy nut. What does the general public need to hear to think differently?

My belief is that it is not at all a conspiracy, though I understand why it may appear as one. Rather, I think it’s an example of how inconclusive science coupled with confirmation bias and selection bias has reinforced itself over a generation. Whether dietary fat or any particular type of dietary fat (e.g., saturated fat) is harmful needs to be addressed by rigorous prospective experimental trials. This is exactly the type of science that the  Nutrition Science Initiative [the nonprofit of which Attia is president and co-founder] hopes to facilitate.

Karyn Toso asks:

Is there such a thing as “food addiction”? And that people with such “addiction” need to stay away from certain foods (sugar, flour, etc.) completely, much as an alcoholic cannot even have a single drink?

Karyn, there is a lot of evidence suggesting that certain types of food (it may be different foods for different people) do elicit a brain chemistry response virtually indistinguishable from that elicited by known addictive stimulants such as gambling or opiates. What’s a little sad to contemplate is that this may not be a coincidence, and may in fact be the direct result of industrial process of food chemistry.

Dana Schmidt adds:

I am wondering if we can limit the amount of high fat, high salt and high fructose corn syrup. One thought it not being able to purchase any of these products with food stamps. What are your thoughts on that?

At some point there will be a role for policy intervention in combating metabolic diseases. However, the biggest mistake that could happen in the short term would be, in my opinion, a policy intervention that is not grounded in rigorous science. In fact, it was exactly this desire to leap to policy change prior to conclusive science that, I believe, set us on the path to where we are today. So before we consider placing limits on food purchased with food stamps, I think it’s worth taking the time to know exactly what the health implications are of the choices we give people. Unfortunately, this requires doing a great amount of scientific work.

Read the full Q&A with Attia on Facebook »

Check out the work of the Nutrition Science Initiative »

Or read Attia’s blog, The Eating Academy »

• Subscribe to TED Blog by email

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The deep roots of diabetes

February 2014, updated July 2020

The modern diabetes epidemic is caused, not by a virulent pathogen, but by the spread of an even stealthier invader: the Western lifestyle. As people around the world have begun to eat less healthily, lead more sedentary lives, and live to older ages, adult onset diabetes (type 2 diabetes) has become common in places where the disease was previously unknown. Between 1985 and 2002, the number of people with diabetes grew from 30 million to 217 million, and this figure is expected to exceed 366 million by 2030. But the epidemic has not been even-handed. Even accounting for differences in lifestyle, some  populations  have been hit particularly hard. Mexicans and Latin Americans, for example, have nearly twice the chance of developing diabetes that non-Hispanic white Americans do. New research addresses these disparities. Last month, scientists announced that they’d discovered a  gene  that helps explain the difference in diabetes risk among many populations. In a strange twist, the gene version in question traces its ancestry back to Neanderthals! What exactly is going on here?

Where's the evolution?

To understand the  evolutionary  back story, you first need to know a little about the gene itself. The gene in question encodes a  protein  that helps move certain lipids into liver cells. The diabetes-contributing version of this gene differs from the standard gene version by five  mutations —and these seem to alter the function of the protein enough to increase diabetes risk. Carriers of the mutated version of the gene are more likely to get diabetes at a younger age and with a lower degree of obesity than non-carriers.

Anyone can carry this gene—but the new research found that it is more common in some populations than others. Among people with many Native American ancestors, the likelihood of carrying at least one copy of the mutated gene is greater than 50%. Among East Asians, the frequency is about 10%. Among people with mainly European ancestors, the gene version is extremely rare, and it seems to be not present at all in Africans. Because people from Mexico and Latin America are much more likely to have Native American ancestry, they are also much more likely to carry this gene version, and hence, have higher odds of developing diabetes.

So diabetes risk in modern populations is tied to that population’s evolutionary history. That should come as no surprise. Recent research has uncovered hundreds of gene versions contributing to diseases that range from asthma to Alzheimer’s disease. The surprise in this research lies in the provenance of the disease-contributing gene.

Something about the new gene version struck the researchers as surprising: it had evolved too much. In big, slow-to-reproduce organisms like humans, mutations take a while to accumulate and evolution proceeds fairly slowly. Based on human  DNA ‘s usual rates of evolution, this diabetes gene version must have started diverging from the standard version almost 800,000 years ago. That’s before our modern human anatomy had evolved and long before we had left Africa. Now, there’s nothing surprising about a really old gene—but if this gene version first evolved in Africa in the ancestral lineage of all humans, then why don’t all human populations, in particular Africans, carry it?

The researchers  hypothesized  that perhaps the diabetes-contributing linked gene version didn’t actually evolve in our direct ancestral lineage, but in Neanderthals, as shown in the diagram below. In this scenario, the gene version would have acquired many of its mutations in the Neanderthal lineage some time after the human and Neanderthal lineages split from one another. When modern humans eventually left Africa between 60,000 and 80,000 years ago and arrived in Europe and the Middle East, Neanderthals were already living there. Those humans and Neanderthals interbred, introducing some Neanderthal DNA (including the diabetes-linked gene version) into the human lineage—but not into all humans. Human lineages that had remained in sub-Saharan Africa never encountered Neanderthals and so did not wind up carrying any Neanderthal DNA. This scenario would help explain how the diabetes-contributing gene could be so old  and  not be found in Africans.

Through recent advances in recovering DNA from ancient bones, the  genomes  of several Neanderthal individuals have been reconstructed. The researchers searched through the DNA sequences of these samples and found what they were looking for. One of the Neanderthals (a newer  fossil  discovery from Denisova Cave) carried the diabetes-linked sequence! It seems that this gene version, now common among people of Native American ancestry, is a relic from the period of our history when humans walked the earth alongside other  hominids .

This discovery does  not  mean that people of Native American descent (or for that matter anyone who carries the diabetes gene version) are particularly closely related to Neanderthals. Human populations from all over the world seem to have similar degrees of Neanderthal ancestry (between 1 and 4%); we all just carry different subsets of Neanderthal-derived genes—that is, unless your ancestors are from sub-Saharan Africa, where many people have no Neanderthal ancestry at all.

Neither does this discovery mean that Neanderthals had diabetes. Type 2 diabetes is a disease of the modern world, borne of a  mismatch  between modern, unhealthy lifestyles and a metabolism that, for the vast majority of our evolutionary history, existed in an environment where food was relatively scarce and lots of physical activity was necessary to survive. In that harsh environment, even individuals carrying genes that contribute to diabetes when food is plentiful and sedentary lifestyles are common are unlikely to develop diabetes. This helps explain how such genes can be common today. At no point in our evolutionary history have they been exposed to the rigors of  natural selection . Only recently have such genes become detrimental to human health!

This discovery highlights the importance of evolutionary history in understanding and improving human health. Even the deepest roots of our past, which lead back to Africa and to our  common ancestors  with other, now- extinct  hominid  species , may become relevant at your next doctor’s appointment. And we are just beginning to understand these ramifications. Advances in DNA technology have only recently allowed us to study the intersections between ancient DNA, large-scale genomic data, and modern epidemiology. So stay tuned to learn more about the results of these exciting investigations!

News update, July 2020

Studies conducted over the last decade have found that non-African populations carry much more Neanderthal DNA (2-6% of their genomes) than do African populations and people of African descent.  This seemed reasonable.  After all, Neanderthals lived in Europe and Asia, while modern humans evolved in Africa.  Early human populations that left Africa would have met and interbred with Neanderthals along the way, and carried Neanderthal DNA with them as they migrated around the world.  Those that remained in Africa would never have encountered Neanderthals at all. But this past year, new research has revised that story.  It turns out that Africans  do  carry a significant amount of Neanderthal DNA after all (though still less than non-African populations). This DNA doesn’t come from interbreeding with Neanderthals though.  It was introduced by people from Europe migrating  back  to Africa and interbreeding with populations there over the last 20,000 years. The new research makes it clear just how much mixing there has been among closely related early human species and among populations of modern humans throughout our history.

• Read more about it
• Discussion questions
• Related lessons & resources

Primary literature:

• Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., ... Pääbo, S. (2010). A draft sequence of the Neandertal genome. Science. 328: 710-722. Read it »
• The SIGMA Type 2 Diabetes Consortium. (2013). Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico. Nature. doi:10.1038/nature12828. Read it »

News articles:

• A quick review of the discovery from NPR
• An in-depth summary of the new research  from PLoS Blogs

Understanding Evolution resources:

• Background information on DNA and mutations
• A review of common misconceptions about natural selection
• An overview of the many ways that evolution is relevant to medicine and human health
• In your own words, explain why this diabetes-linked gene version is not found among Africans.
• If the diabetes-contributing gene version had arisen in our direct ancestral lineage 800,000 years ago, what would you expect to observe in terms of the distribution of the gene version across different populations? Explain your reasoning.
• In your own words, explain why the diabetes-contributing gene version was not weeded out of human populations by natural selection long ago.
• Do some research, and find an example of a human disease with a genetic component that has different frequencies in different populations. Describe the disease and the gene version that contributes to it. Describe the population in which the gene version is common.
• Advanced:  Do some research on type 2 diabetes, and review the concept of  evolutionary fitness . Do you think that this disease decreases a person’s evolutionary fitness? Explain your reasoning.
• Advanced:  Based on your answer to the item above, do you think that natural selection is acting against the diabetes-contributing gene version in modern populations? Explain why or why not.
• Teach about human evolution : In this lab for grades 9-16, students describe, measure, and compare cranial casts from contemporary apes, modern humans, and fossil hominids to discover some of the similarities and differences among these forms and to see the pattern leading to modern humans.
• Teach about our relatedness to Neanderthals : In this online activity for grades 9-12, students compare the number of mutations in the mitochondrial genomes of Neanderthals and humans to determine ancestry and relatedness.
• Teach about the DNA of ancient human relatives : In this news brief for grades 9-16, students learn about the extraction of DNA from a 40,000 year old fossil bone, which didn't match up to the known genetic sequences of either humans or Neanderthals!

How to use Evo in the News with students .

• Chen, L., Wolf, A. B., Fu, W., Li, L., and Akay, J. M., (2020). Identifying and interpreting apparent Neanderthal ancestry in African individuals.  Cell . 180: 677-687.
• Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., ... Pääbo, S. (2010). A draft sequence of the Neandertal genome.  Science.  328: 710-722.
• Smyth, S., and Heron, A. (2006). Diabetes and obesity: the twin epidemics.  Nature Medicine . 12: 75-80.
• The SIGMA Type 2 Diabetes Consortium. (2013). Sequence variants in  SLC16A11  are a common risk factor for type 2 diabetes in Mexico.  Nature . doi:10.1038/nature12828

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Research challenges 'sugar hypothesis' of diabetic cataract development

In preclinical models, investigators uncovered a novel mechanism underlying the development of diabetic cataracts that undermines current hypothesis.

New findings from investigators at Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system, contradict previous notions about sugar's role in the onset of diabetic cataracts. Using an animal model that more closely recapitulates type 2 diabetes in humans, the research team found early signs of damage in the eye before the onset of type 2 diabetes, suggesting that diabetic complications may start during the pre-diabetic state. Results are published in the Journal of Biomedical Science.

A pitfall in the scientific process is not that a theory could be false, but that it is taken for granted when it seems logical and not challenged with new experiments," said Ali Hafezi-Moghadam, MD, PhD, director of the Molecular Biomarkers Nano-Imaging Laboratory (MBNI) in the Department of Radiology at the Brigham and an associate professor at Harvard Medical School. "The evidence we have collected here calls the long-believed theory about diabetic cataracts into question, begging us to reexamine the current dogma that has been relied on for explaining diabetes-associated cataracts."

Cataracts -- the clouding of the lens of the eye -- are the number one cause of blindness worldwide and are a common complication of type 2 diabetes. The current hypothesis behind diabetic cataract development is coined "the sugar hypothesis" and suggests that high blood sugar -- a hallmark of diabetes -- precedes cataract development. The working assumptions underlying the sugar hypothesis describe higher levels of glucose in the lenses of people with diabetes convert to a sugar alcohol molecule called sorbitol, which induces structural changes to the lens of the eye that precede cataract development. While unproven, researchers rarely investigate this theory further due to cataracts' treatable nature.

Hafezi-Moghadam and colleagues studied the Nile grass rat, a model that they originally reported spontaneously develops type 2 diabetes when kept in captivity and closely mimics the condition in humans. Much like humans with type 2 diabetes, these animals first develop insulin resistance and high blood insulin levels before their blood glucose rises above normal. Using a specialized technique termed stereo microscopy with dual bright-field illumination, researchers observed the development of dot-like microlesions, which predisposed cataract formation, in the inner cortical regions of the lens. Unexpectedly, they noticed that in nearly half of the animals tested, these microlesions appeared before the animals developed hyperglycemia, or high blood sugar, suggesting that it was not raised blood glucose levels themselves leading to cataract development.

Instead, researchers identified that immune cells were migrating from specialized structures in the eye called the ciliary bodies toward the lens. In these areas, where the immune cells traversed the capsule of the lens, they found that the epithelial cells that normally cover the inner surface of the lens capsule changed their identity and behaved differently. These changes, also referred to as epithelial-mesenchymal transformation (EMT), were followed by seemingly unorganized cell growth, cell death, and cell migrations into the body of the lens. In some regions, the newly transformed cells simply vacated their original positions and made their way into the lens. Such cellular changes, however small in dimensions, significantly compromise the function of the lens.

While still too early to tell what exactly causes the immune cells and epithelial cells to behave the way they do, the researchers conclude that their study urges further investigation of prevailing theories. It may also bring the medical community a step closer to understanding the cellular mechanisms underlying the origins of diabetic complications during the pre-diabetic stage of the disease. And once we understand the pathogenesis, Hafezi-Moghadam envisions, we can start to search for how to prevent people with diabetes from developing cataracts and potentially other complications elsewhere in the body.

"While cataracts today are easily removable with surgery, this procedure comes with the risk of complications and is expensive, both for individuals and our healthcare system," said Hafezi-Moghadam. "With over 500 million people worldwide and 37 million Americans having diabetes, the great majority of whom have type 2, there is an incentive for trying to find non-surgical ways of preventing, slowing, or even reversing this complication. Perhaps one day it will become possible to avoid performing these surgeries altogether. And that requires that we return to the basics of the cellular processes underlying cataract development."

Funding : This work was supported by NIH Impact Award (DK108238-01, AHM), and JDRF

Innovation Award (INO-2016-222-A-N, AHM).

• Immune System
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Materials provided by Brigham and Women's Hospital . Note: Content may be edited for style and length.

Journal Reference :

• Ehsan Ranaei Pirmardan, Yuanlin Zhang, Aliaa Barakat, Marzieh Naseri, Christoph Russmann, Ali Hafezi-Moghadam. Pre-hyperglycemia immune cell trafficking underlies subclinical diabetic cataractogenesis . Journal of Biomedical Science , 2023; 30 (1) DOI: 10.1186/s12929-023-00895-6

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Barriers to Diabetes Prevention

Limitations of current prediabetes assessment tools, limitations of treatment approaches, clinical experience, case 1: j.n., case 2: j.w., case 3: d.w., clinical applications, 1. screen for diabetes., 2. in patients with prediabetes, stratify the likelihood of near-term progression to diabetes., 3. initiate appropriate interventions., 4. monitor effectiveness of intervention., acknowledgments, using a quantitative measure of diabetes risk in clinical practice to target and maximize diabetes prevention interventions.

Paul A. Rich, MD, is a physician at Comprehensive Physician Associates, LLC, in Youngstown, Ohio. Charles F. Shaefer, MD, FACP, is a physician at University Physicians, Primary Care, in Augusta, Ga. Christopher G. Parkin, MS, is president of CGParkin Communications, Inc., in Boulder City, Nev. Steven V. Edelman, MD, is a professor of medicine at the University of Southern California, San Diego.

Note of disclosure:   The authors have received consulting fees from Tethys, Bioscience, Inc., which developed the PreDx test.

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Paul A. Rich , Charles F. Shaefer , Christopher G. Parkin , Steven V. Edelman; Using a Quantitative Measure of Diabetes Risk in Clinical Practice to Target and Maximize Diabetes Prevention Interventions. Clin Diabetes 1 April 2013; 31 (2): 82–89. https://doi.org/10.2337/diaclin.31.2.82

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A n estimated 79 million American adults are at risk for developing type 2 diabetes, based on a condition referred to as prediabetes. 1   Although there is currently no cure for type 2 diabetes, studies have definitively shown that the progression from prediabetes to diabetes can be delayed or prevented through lifestyle modifications and pharmacological treatment. 2 – 4   Unfortunately, the vast majority of people with prediabetes are undiagnosed. Indeed, a recent study by Geiss et al. 5   found that < 8% of U.S. adults with prediabetes are aware of their condition.

Given the growing diabetes epidemic and the alarming prevalence of unawareness among those at risk for developing this disease, the American Diabetes Association (ADA) recommends screening of all patients who are at risk for prediabetes or who may have undiagnosed diabetes ( Table 1 ). 6  

Individuals meeting the criteria in Table 1 should have their glycemic status assessed by fasting plasma glucose (FPG), oral glucose tolerance test (OGTT), or A1C. As shown in Table 2 , the diagnosis of prediabetes is based on glucose or A1C values that are higher than normal but not at levels diagnostic of diabetes. 6  

According to ADA recommendations, individuals who are identified as having prediabetes should be referred to an ongoing support program that targets weight loss and increased physical activity, and these programs should be covered by third-party payers. 6   The ADA further recommends that treatment with metformin be considered for at-risk patients who have a BMI ≥ 35 kg/m 2 , are < 60 years of age, and/or are women with prior gestational diabetes. 6  

Criteria for Testing Adult Patients for Prediabetes or Diabetes 6  

Given the significant clinical and economic costs associated with type 2 diabetes, it is crucial that diabetes prevention be a priority for the health care system. However, it is also important to consider that a relatively small percentage of individuals who have prediabetes will progress to overt type 2 diabetes within 5 years. The 5-year conversion rate from prediabetes to type 2 diabetes ranges from 10% 7   to 23% 8   depending on the diagnostic criteria used.

Because considerable resources are required to provide diabetes prevention programs to the ever-increasing number of patients with prediabetes, accurate tools are needed to identify prediabetic individuals who are most likely to progress to type 2 diabetes. This should allow for more efficient and effective use of health care resources and optimize health care outcomes.

Criteria for Diagnosis of Prediabetes or Diabetes 6  

This article discusses the clinical application of a validated prognostic test (PreDx, Tethys Bioscience, Inc., Emeryville, Calif.) that provides clinicians with an estimate of the 5-year likelihood of progression to type 2 diabetes for patients who have been identified through screening as having prediabetes. 9 – 12   Patient cases are presented to demonstrate how the PreDx test can be used within various clinical scenarios to facilitate implementation of diabetes prevention therapies (lifestyle-based and pharmacological) and then monitor the effectiveness of those interventions.

Although efforts have been made to address the significant and growing epidemic of diabetes, strategies to activate clinicians to aggressively screen for and treat individuals with prediabetes have been minimally successful. We have identified two major obstacles to these diabetes prevention efforts: 1 ) limitations of current assessment tools and 2 ) constraints on clinicians' time and resources.

Screening for prediabetes is the essential first step in diabetes prevention, and although current tools and assessment protocols are relatively effective for the initial identification of at-risk individuals, they do not adequately address the need to identify individuals who are at the highest risk for progressing to diabetes in the near term. These tools and approaches are either difficult to implement in clinical practice or lack the specificity required for accurate detection of high-risk individuals.

The OGTT is a specific indicator of diabetes risk and is considered to be the gold standard for detection of prediabetes. 13   However, its complexity, poor reproducibility, associated costs, time requirements, and patient inconvenience often inhibit routine use in clinical practice. 6 , 14 , 15   The OGTT is rarely performed for purposes other than clinical research and to assess glycemia status in women during pregnancy.

A fasting plasma glucose test to assess for impaired fasting glucose (IFG) can be performed easily in most clinical settings. However, this method of screening for prediabetes casts a very wide net, identifying ~ 26% of the adult population as at risk (prediabetes), 16   with minimal stratification for level of risk of progressing to type 2 diabetes.

Furthermore, although A1C testing has recently been added to the armamentarium of prediabetes detection options, 6   use of A1C levels often fails to identify most adults with prediabetes. 17 – 19   A recent study by Fajans et al. 17   found that ~ 33% of individuals with early diabetes or impaired glucose tolerance (IGT) have A1C levels < 5.7%. Moreover, there is growing evidence questioning the reliability of the A1C test. Many factors can influence glycation and, thus, the test's accuracy. 17 , 20   These include weaknesses in analytical methods, ethnicity, and various medical conditions such as presence of hemoglobinopathies, iron deficiency, any type of anemia, chronic liver disease, and fast or slow glycation. 20  

Other methods, such as measuring components of the metabolic syndrome or calculating risk scores based on clinical measures (e.g., lipid levels, blood pressure, and waist circumference), have also been used to identify patients most likely to develop diabetes. 21   However, these approaches require multiple measures and also suffer from low specificity. 8 , 22  

Lifestyle interventions such as dietary modification, physical exercise, and modest weight loss have been shown to prevent or delay the progression from prediabetes to frank type 2 diabetes. 2 , 23 , 24   Because these interventions often involve significant changes in eating habits and physical activity, patients need initial counseling to help them understand the changes they are being asked to make, as well as ongoing support and encouragement from their health care providers to sustain those new behaviors.

Unfortunately, many patients do not receive the level of care they need to make and sustain these changes; barely half of patients receive the preventive, chronic disease, and acute care services recommended by national health care organizations and agencies. 25  

A key contributor to this suboptimal care is lack of physician time. 26 , 27   Yarnell et al. 27   determined that clinicians would require 21.7 hours/day to effectively meet the needs of a typical patient population of 2,500. Looking specifically at diabetes prevention interventions used in the Diabetes Prevention Program, 2   it is noteworthy that these interventions required ~ 75% of staff time to treat the 25% of patients randomized to the intensive lifestyle intervention group.

Pharmacological treatment with metformin has also been shown to delay or prevent progression to diabetes. However, treatment with metformin in elderly patients has shown limited effectiveness. 28   Furthermore, use of metformin is not approved by the U.S. Food and Drug Administration (FDA) in individuals with prediabetes, 29   and many clinicians are reluctant to prescribe this medication without strong evidence for its necessity.

Given the growing, worldwide diabetes epidemic, there is an everincreasing need for new testing methodologies that can accurately diagnose individuals who have the highest likelihood of developing diabetes and that can support both clinicians and patients in initiating and sustaining effective prevention strategies. The PreDx test is a relatively new prognostic blood test that may help clinicians address these issues.

The PreDx test is a multimarker blood test that can be used in primary care practices to help determine the 5-year likelihood of a patient progressing from prediabetes to type 2 diabetes. 9   Early detection of these highest-risk individuals may facilitate more effective patient management by enabling clinicians to focus health care resources earlier and to more effectively initiate and monitor diabetes prevention interventions.

The multimarker PreDx test is based on seven biomarkers (glucose, A1C, insulin, C-reactive protein, ferritin, interleukin-2 receptor α, and adiponectin) that are independently associated with diabetes risk. 22   The test measures these markers in a fasting blood sample, and its results, along with patients' sex and age, are placed into an algorithm that generates an objective and quantitative score to distinguish among people at high, moderate, and low 5-year probability of developing type 2 diabetes. 10 – 12   This information enables clinicians to focus interventions on the relatively few patients who are genuinely at a high 5-year risk of developing diabetes, thus avoiding unnecessary treatment and expenses for patients who are less likely to develop diabetes within the next 5 years.

A study by Kolberg et al. 10   demonstrated that the performance characteristics of the PreDx test were similar to those of the OGTT but superior to all other methodologies, including FPG, A1C, fasting insulin, and the HOMA-IR (homeostasis model of assessment—insulin resistance) for predicting the 5-year likelihood of type 2 diabetes. The PreDx test was also found to be superior to metabolic syndrome components and clinical risk scores for detection of near-term conversion to diabetes. 9 , 11   Furthermore, unlike the OGTT, the PreDx test requires only a single blood draw and does not involve monitoring patients over a 2-hour time period.

In a recent analysis of the European Diabetes Prevention Study, Tuomilehto et al. 30   demonstrated that the test not only identifies those who are most likely to develop diabetes, but also facilitates monitoring the efficacy of therapeutic interventions through follow-up testing, thus enabling clinicians to modify the intervention if the PreDx test indicates that it has not been successful.

The PreDx test report ( Figure 1 ) provides a single numerical score from < 1 to 9.9 (lowest to highest risk) that indicates each patient's likelihood of progressing to type 2 diabetes within the next 5 years. On the first page, the PreDx score, which is categorized as “low” (green), “moderate” (yellow), or “high” (red), is presented, as is the patient's absolute 5-year diabetes risk (%). The patient's risk relative to the general population is also provided. For example, a score of 5.8 corresponds to a 4.6% 5-year risk of developing type 2 diabetes, which represents a 1.4-fold increase in risk compared to the 5-year risk in the general population (3.4%). 9   The second page of the report provides results and reference ranges of the individual biomarkers used to determine the PreDx score.

Because the PreDx test requires a simple fasting blood draw using standard sample collection and handling procedures, it is relatively easy to incorporate into routine clinical practice. However, cost-effectiveness is also an important factor when considering adoption of new diagnostic technology. In a recent health economic analysis by Sullivan et al., 31   use of the PreDx test in combination with fasting glucose measurement showed an incremental cost-effectiveness ratio (ICER) of $17,000 per quality-adjusted life year (QALY) gained at 5 years and produced a cost savings at 10 years. Without using the PreDx test, detection of high-risk patients based only on FPG resulted in an ICER of $235,000 per QALY gained at 5 years and $94,600 per QALY gained at 10 years. Based on this analysis, the authors concluded that the cost-effectiveness of diabetes prevention may be improved by identification of high-risk individuals using the PreDx test.

Sample of the PreDx test report form. The test report provides the PreDx score, as well as the corresponding absolute and relative 5-year likelihood of progression to type 2 diabetes. The individual analytes that are used to calculate the PreDx score and their reference ranges are also provided.

The clinical utility of the PreDx test is twofold: 1 ) to stratify patients with prediabetes according to their 5-year likelihood of developing type 2 diabetes and 2 ) to monitor and quantify the impact of lifestyle and/or pharmacological interventions. A key advantage of the PreDx test is its potential to motivate patients to make necessary lifestyle modifications to reduce their risk.

Many clinicians have reported that use of the PreDx test has motivated their highest-risk patients to make significant lifestyle changes that could delay or prevent the progression to type 2 diabetes. 22   Albeit anecdotal, these clinician-reported changes in patient motivation are supported by a recent study by Markowitz et al. 32   that looked at how genetic testing for diabetes risk affects motivation. Most study participants reported that “higher” risk results would prompt them to modify their health behaviors.

Other studies have shown that presenting A1C results to patients in graphic formats is linked to improved glycemic control. 33 , 34   These studies suggest that providing patients with an objective measure of risk can be an effective motivator for making lifestyle changes.

There is also growing evidence that use of the PreDx test positively affects clinician behaviors, prompting more intensive management of high-risk patients. A retrospective study 35   using comprehensive electronic medical records from a health care system treating ~ 3.2 million patients found that those who received the PreDx test were more likely to have follow-up monitoring of biometric risk factors by a physician than patients who did not receive the test. In addition, patients with high PreDx scores were more intensively treated for risk factor control than those with lower PreDx scores or no test. Moreover, there was significant improvement in risk factors for patients who received the PreDx test.

Using the PreDx test in our own practices, we have observed similar findings with many of our patients. The following case studies are representative of our experiences.

J.N. is a 62-year-old white man who is, 6′1″ tall and has a family history of coronary artery disease (CAD) and hypertension but no history of type 2 diabetes. In 2001, he was surgically treated for CAD and is currently taking medication for dyslipidemia and hypertension. J.N. is a nonsmoker and drinks alcohol occasionally.

Previous efforts to encourage J.N. to make lifestyle changes to reduce his cardiovascular risk have been unsuccessful. He continues to eat an unhealthy diet (high in calories and saturated fat) and remains sedentary with no formal exercise program.

J.N. was seen in the clinic for an annual physical exam in November 2010 ( Table 3 ). Although his FPG was only slightly elevated, the PreDx score indicated that J.N. was at very high risk for developing type 2 diabetes within the next 5 years (PreDx score 8.5, 5-year diabetes risk of 16.5%).

We adjusted his lipid and blood pressure medication doses based on his elevated LDL cholesterol and blood pressure, counseled J.N. on the need for lifestyle changes, and referred him to a formal diabetes prevention program at a local hospital. Although J.N. elected not to participate in a formal program, he initiated a diet and exercise routine consisting of cycling ~ 10 miles daily and eating a reduced-calorie diet that was high in fiber and low in saturated fat.

At his next annual exam (March 2012), his blood pressure, fasting glucose, and lipid levels were improved, and his PreDx score was significantly lower (PreDx score 4.5). This reduced his 5-year diabetes risk from a baseline of 16.5% to 2.8%—less than half of the 5-year risk of the general population within his age-group (6.7%). 4  

Physical Assessment and Laboratory Values, Case 1

Physical Assessment and Laboratory Values, Case 2

J.W. is a 71-year-old white man who is 5′10″ tall and has a history of hypertension, hyperlipidemia, obesity, and IFG dating back to 2008. He is a nonsmoker and has a family history of heart disease and diabetes.

When seen in March 2011, J.W. weighed 263 lb (BMI 37 kg/m 2 ) and had elevated blood pressure, lipid, and fasting glucose levels ( Table 4 ). His PreDx score was 9.2, giving him an absolute 5-year risk for diabetes of 28.6%.

J.W. was counseled on the need to modify his diet, exercise regularly, and lose weight. When he returned for follow-up in September 2011, he had lost 70 lb, reduced his BMI to 27 kg/m 2 , and significantly improved his blood pressure and lipid status. Although his PreDx score had decreased to 7.0, he was still at relatively high risk for developing diabetes despite the significant weight loss.

At his next follow-up visit in March 2012, J.W. had gained 5 lb and his FPG had risen to 101 mg/dl. His PreDx score had increased to 8.0, giving him a 12.2% 5-year diabetes risk. At that visit, we started J.W. on metformin (500 mg/day). Four months later, he had lost 1 lb, his FPG was < 100 mg/dl, and his PreDx score had dropped to 4.3, reducing his 5-year diabetes risk to 2.6%—less than half of the risk of the general population within his age-group (6.7%). 4  

D.W. is a 58-year-old white man who is 6′1″ tall and has a history of hypertension, hyperlipidemia, obesity, arterial fibrillation, and IFG dating back to 2010. He is a nonsmoker and has a family history of CAD.

When seen in January 2012, D.W. weighed 281 lb (BMI 38 kg/m 2 ) and had normal blood pressure and elevated lipid and fasting glucose levels ( Table 5 ). Despite his elevated FPG of 110 mg/dl, which placed him in the prediabetes glucoregulatory category, his PreDx score was 6.3. This gave him a 5-year diabetes risk of 5.6%.

Although D.W. was strongly counseled on the need to reduce his weight through diet modification and exercise to address his cardiovascular risk, we determined that prescribing a diabetes medication to help prevent diabetes was unwarranted at this time. We will continue to closely follow D.W. to help support his lifestyle modification efforts, and we will use fasting glucose and, if necessary, a follow-up PreDx test to monitor his glucoregulatory status and any changes in his diabetes risk.

Physical Assessment and Laboratory Values, Case 3

The three patient cases presented in this article illustrate how the PreDx test can both motivate patients to make necessary lifestyle changes and guide treatment decisions regarding referral to formal diabetes prevention programs and/or pharmacological interventions. In the first case, the PreDx test prompted the patient to initiate intensive dietary modification and a regular exercise program to reduce his diabetes risk. As demonstrated in the second case, the PreDx test not only helped motivate the patient to lose a significant amount of weight but, on follow-up, it provided an indication that lifestyle changes were not effective enough and that pharmacological treatment with metformin was needed. The third patient case provides an example of how the PreDx test can help us more efficiently use resources. Reliance on the FPG value alone may have prompted us to initially prescribe a diabetes medication that could have potentially affected the patient's employment status and health care coverage and could have important side effects. Instead, we focused our attention on lifestyle intervention efforts and his other cardiovascular risk factors.

It is important to note that, although the three cases presented above illustrate the use of the PreDx test in white men, a recent analysis using blood samples from the Insulin Resistance and Atherosclerosis Study (a study in a multiethnic U.S. cohort) demonstrated that PreDx test performance characteristics were similar in whites, Hispanics, and African Americans and did not differ based on sex. 36   Many insurers currently provide reimbursement for the test; the reimbursement rate varies by payer.

To help clinicians effectively use the PreDx test in their practices, we have constructed a straightforward, four-step process to identify and implement diabetes prevention efforts in patients with prediabetes.

Use the screening criteria presented in Table 1 to identify and screen all patients who may be at risk for diabetes or prediabetes. Patients meeting the criteria in Table 1 should have their glucoregulatory status assessed using FPG, A1C, or OGTT. Although each method has advantages and disadvantages, all are adequate for assessing the presence of diabetes or prediabetes as defined by the ADA. 6     Table 2 presents the glycemic thresholds for diabetes and prediabetes.

Use the PreDx test to assess the patient's 5-year likelihood of progressing from prediabetes to type 2 diabetes. As discussed above, the PreDx test classifies patients as low, moderate, or high risk and provides an estimate of the 5-year likelihood of progressing to type 2 diabetes. Because all patients with prediabetes are at risk for macrovascular and potentially microvascular disease regardless of the PreDx score, clinicians must appropriately manage blood pressure, lipids, and body weight through lifestyle and/or pharmacological interventions.

Patients with normal glucose regulation or prediabetes should be re-screened for diabetes with one of the above-mentioned tests (Step 1) annually, or sooner if they develop symptoms of diabetes.

In patients with prediabetes, based on the PreDx test in conjunction with other clinical information, appropriate lifestyle and/or pharmacological interventions should be instituted. We know that lifestyle interventions such as weight loss and regular physical activity can prevent or delay the development of type 2 diabetes. 2   However, changing health habits is a difficult task for most patients. All patients with prediabetes, irrespective of their PreDx score, should receive counseling related to increased diabetes risk and the importance of good nutrition and physical activity for diabetes prevention and general health.

As deemed appropriate and based on the clinical picture and PreDx score, we recommend that patients be referred to a formal diabetes prevention program in their community where they can receive counseling and support from qualified health care providers. If a community program is not available or if the patient is unwilling or unable to participate in such a program, clinicians can provide lifestyle counseling and support during clinic visits. The National Diabetes Education Program (NDEP), in partnership with the National Institutes of Health, offers clinicians a comprehensive guide (G.A.M.E. P.L.A.N.) for diabetes prevention strategies and patient counseling. The guide can be downloaded free of charge from the NDEP Web site ( http://ndep.nih.gov/publications/PublicationDetail.aspx?PubId=71 ). The National Diabetes Prevention Program also provides information and resources to clinicians and patients. These resources can be obtained from the Centers for Disease Control and Prevention at its Web site ( http://www.cdc.gov/diabetes/prevention ).

In addition to lifestyle changes, pharmacological interventions with metformin, thiazolidinediones, and α-glucosidase inhibitors have also been shown to be effective in slowing or preventing the progression to type 2 diabetes. 2 – 4   There are no medications approved by the FDA for treatment of prediabetes. However, if the risk:benefit profile for individual patients is deemed to be favorable, these medications may be considered for use in combination with lifestyle interventions or when behavioral interventions have failed. 6  

After initiating the above interventions, clinicians may then use the PreDx test quarterly or biannually to monitor treatment effectiveness, make any necessary adjustments to patients' treatment plan, and provide feedback to patients to sustain and enhance motivation and engagement in their diabetes prevention efforts.

The diabetic epidemic shows no signs of slowing. With an estimated 79 million American adults currently considered to be at risk for developing type 2 diabetes, 1   providing the necessary clinical and financial resources to deliver intensive preventive care to all of these individuals will be a difficult (if not impossible) task. Although it is clear that diabetes prevention should remain a high priority for patients, clinicians, and payers, it is also crucial that new technologies such as the PreDx test be used to accurately diagnose individuals who have the highest likelihood of developing diabetes in the near term to enhance the clinical efficacy of prevention efforts and ensure the viability of the national health care system.

Funding for the development of this article was provided by Tethys Bioscience, Inc., of Emeryville, Calif., which developed the PreDx test.

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Evolutionary Medicine

Understanding evolution in sickness and health, diabetes and evolution.

Although obesity is an unfavorable trait, there is evidence that in the past storing fat was quite beneficial. The body was apt to store fat to prepare for long periods of famine in our ancient history. This thrifty gene hypothesis was originally proposed by James Neel . Obesity leads to many health complications, one of the most common being Diabetes.

There are a high percentage of Native American populations that have Type 2 Diabetes. Unnatural Causes: Bad Sugar , a documentary,  delves into the many ways that other factors have contributed to the genetic predisposition of Diabetes in the Pima Indian population of Arizona. Many of these factors happen to be political/economic issues. For instances, the Coolage dam diverted water from the Gila River (major water source in the Pima community) away from the reservation.  The Pima Indians were left with little water resources for their crops and for survival, making them one of the poorest populations in America at the time. This severely affected the Pima economically and culturally. They had to learn to survive without water and adequate food.  Many of the Pima died from starvation during this time of famine. Within 30 years of building the dam there were more than 500 cases of diabetes among the Pima Indians. This supports the thrifty genotype hypothesis. Their bodies were used to not receiving adequate nutrition so the body evolved to hold onto more fat than usual for survival. After a while the government provided food subsidies, but they were not healthy options. The Pima community did not have markets where fresh produce was abundant so they had to rely on processed food that had low nutritional value, provided by the American governemtn. This resulted in even higher rates of diabetes in the population today.

I think that the story of the Pima community in Arizona is a good example of our class discussion on how the human genome evolves simultaneously with our environment and culture.  There is evidence that many minority groups, such as African Americans, that have experienced extreme hard ship in history have high rates of diabetes as well.

2 thoughts on “ Diabetes and Evolution ”

This study of the Pima community definitely peaked my interest, so much so, I did some additional research regarding this case study. I think this is such a fascinating case and the point you bring up about the ability of evolution to work in coordination with the environment and culture is evident. Furthermore, it makes me wonder of the time constraints within which evolution works. Considering the time it took for (according to this theory) this adaptation to occur, makes me consider now with once again changed conditions, how long it may be before the population may adapt once again to its change in diet? Further, would the adaptation be a complete return to the previous levels of storing fat now that diet has been restored for quite some time, or would it, long in the future, only “tweak” the change that has manifested only slightly? Further, an article I read (link provided below) also studied a Mexican Pima community which were genetically the same as the Pima of Arizona, however they did not share the similar past and lack of nutrition. Of the 35 Mexican Pimas studied, only 3 had diabetes, and the population overall was not overweight. This provides an interesting experimental control to the case study of the Pima Indians of Arizona, and may lend to corroborate the theory posed by this article.

Link: http://www.diabetes.niddk.nih.gov/DM/pubs/pima/obesity/obesity.htm

That article was very interesting! To answer your question, I think that it will be a long time before this population adapts to its environment. It has not nearly been long enough for the genome to match up to the current food sources available. Unfortunately, I also do not think that the quality of the food available to this Pima population will improve any time soon. Even higher rates of diabetes and other diseases will probably become evident in the future because of this.

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Prioritizing Health | ACC.24 Research in the Consumer News

May 03, 2024

Cardiology Magazine

Research from ACC.24 also finds its way to patients and the general public. Here's a roundup of some of these key studies making headlines in major news outlets.

E-Cigarette Use Increases HF Risk: A 19% higher risk of developing heart failure (HF) was found among users of e-cigarettes, vs. nonusers in a prospective observational study. Over the median 45-month follow-up, 3,242 of 175,667 participants (average age 52 years, 60.5% women) developed HF. The increased risk was statistically significant for HF with preserved ejection fraction (HFpEF) but not for HF with reduced ejection fraction (HFrEF). "I think this research is long overdue, especially considering how much e-cigarettes have gained traction," said lead author Yakubu Bene-Alhasan, MD . Surveys indicate about 5% to 10% of U.S. teens and adults use e-cigarettes.

More Greenspace, Better Heart Health: People living in areas with more sidewalks were 9% less likely to suffer a major adverse cardiovascular event than those who did not, and participants living in neighborhoods with vertical green space – trees and clear sky – were 5% less likely, over a 27-month follow-up. The study authors found no significant association with horizontal greenspace (grass). "A lot of research has shown that environmental factors strongly affect our health," said lead author Zhuo Chen, PhD. "If we can find a way to stratify this risk and provide interventions before cardiovascular events happen, then we could save a lot of lives."

Eggs and CVD Risk: At four months, no difference was found in cholesterol levels between participants who ate ≥12 fortified eggs per week and those who ate fewer than two eggs, in a prospective, randomized, study with 140 patients (≥50 years, average age 66 years, 50% women, 27% Black) who had either experienced one cardiovascular event or had two cardiovascular risk factors. The 0.64 mg/dL reduction in HDL-C and 3.14 mg/dL in LDL-C found in the fortified egg group was not significant compared with the non-egg group. "While this is a neutral study, we did not observe adverse effects on biomarkers of cardiovascular health and there were signals of potential benefits of eating fortified eggs that warrant further investigation in larger studies as they are more hypothesis generating here," said Nina Nouhravesh, MD, the study's lead author.

Nearby AEDs Rarely Used: AEDs are more readily available in public spaces, but their use for an out-of-hospital cardiac arrest (OHCA) was low in a study of 1,799 cases in Kansas City, MO, between 2019-2022 using data from a national registry. An AED was within a four-minute walk for half of the 270 cases that occurred in public but was used in only 13 cases; bystander CPR was given in only 42%. Of the OHCA cases that occurred at home, an AED was within a four-minute walk for a quarter of them, but was not used for any, and CPR was given in 42% of cases. Mirza S. Khan, MD, et al., noted identifying this gap could help with ongoing efforts to improve signage around AEDs, provide apps or mapping tools to help people locate them and increase education and awareness through community volunteer training programs.

High Stress and Genetics Increase ACS Risk: People with a high genetic stress sensitivity have a higher risk of acute coronary syndromes (ACS) in response to stressful cultural or political events, such as Christmas, presidential elections and major sporting events, by as much as 34%, identifying a new risk factor for screening.

ADHD Stimulants and Heart Damage: Young adults prescribed stimulant medications for attention-deficit/hyperactivity disorder (ADHD), compared with those who were not, were 17% more likely to have cardiomyopathy at one year and 57% more likely at eight years. After 10 years, only 0.72% and 0.53% of patients developed cardiomyopathy, respectively. Pauline Gerard, the lead author said, the risk is real but small.

Anxiety, Depression and CV Risk in Younger Women: Screening for cardiovascular risk factors should start at a younger age in women with a history of anxiety or depression, which was found to be associated with a near doubling in risk of developing high blood pressure, high cholesterol or diabetes over a 10-year period in those <50 years compared with women without either condition, putting them on par for risk with men the same age.

Higher CAC Levels in Post Menopausal Women: More data highlight the increased risk in women after menopause, with a study showing a rise in coronary artery calcium (CAC) among those taking a statin. Between two scans taken a year apart, there was a median 8-point rise in CAC among women with a baseline CAC of 1-99, twice the median seen in men, and a median 31-point rise in those with a baseline CAC of 100-399, nearly double the rise seen in men.

Sleep, Alcohol, Sodium: Looking at modifiable risk factors, three different studies provide concrete steps for reducing risk. One, get more sleep. Less than seven hours a night was associated with a 7% higher risk of developing hypertension, and this spiked to 11% for those sleeping less than five hours. Two, drink less alcohol. Young and middle-aged women who drink eight or more alcoholic drinks a week had a 45% higher risk of cardiovascular disease vs. those with a low intake and 29% higher vs. those with a moderate intake. Binge drinking was associated with a 68% increased risk. Three, eat less sodium. A new study found that 89% of participants with cardiovascular disease eat double the recommended daily maximum intake of 1,500 mg, consuming an average of 3,096 mg sodium.

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Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Hypertension, Sleep Apnea

Keywords: Cardiology Magazine, ACC Publications, Heart Injuries, Heart Disease Risk Factors, Cardiomyopathies, Hypertension, Sleep, ACC Annual Scientific Session, ACC24

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