Ketosis v.s. Ketoacidosis: Insulin makes the Difference

Ketosis is a word which you may have seen recently in print and online media, usually in material about a very low carbohydrate diet in which most calories come from fat and protein. One recent headline alluded to a plan by the Pentagon to increase military fitness by imposing the “keto diet” on some of its soldiers. But you might also have the impression that there is some controversy around the diet, and that ketosis, whatever it is, might not be good for you. After all, it is very similar to that word ketoacidosis which is associated with poorly controlled diabetes, the problem that put your friend’s daughter in the hospital ICU for a week. In fact, both ketosis and ketoacidosis refer to physiologic body states that occur when come chemicals called ketones are produced from normal metabolic processes that produce energy from the body’s own fat. The circumstances surrounding ketone production determine whether ketones cause ketoacidosis (bad) or ketosis (not so bad but maybe not so good over a long period of time).

How your body produces energy

Most of the time you are utilizing at least some fat to create energy and producing ketones in small amounts as the fats are metabolized. At the same time, the bulk of your energy is derived from the carbohydrates you eat, all of which, even the “healthy” grains, vegetables and fruits, become a simple sugar called glucose in the process of digestion. That is correct – for the most part, you burn sugar to produce energy. Under normal circumstances, with sufficient food and regular eating schedules, some glucose is burned immediately by all parts of the body for energy production. Any remaining glucose gets shuttled off to the liver and muscles to be clumped into long chains called glycogen and stored for use between meals. These reserves last for about 24 hours at which point your metabolism switches over to fat burning, and to breaking down a little protein, mainly from muscle, to supply the liver with building blocks for making more glucose.

The brain has special needs

At this point, you must eat again or rely on free fatty acids from the triglycerides stored in your body fat. The brain, however cannot burn free fatty acids. But it can burn some of the ketones, called ketone bodies, that come from the breakdown of triglycerides. By about three days of starvation, the brain is a ketone burning organ, supplemented by a little glucose constructed in the liver from amino acids given up by proteins. The body is in a state of ketosis, with excess ketones exhaled, giving the breath a fruity odor, and released in the urine, turning a dipstick stick test positive.

Acidity makes the difference

Ketosis is not ketoacidosis. Ketoacidosis appears when the acidity rises in all the body’s tissues while it is in a state of ketosis. Acidity is measured as pH, and a fall in the body’s pH signals rising acidity. Outside a narrow range of pH, the body’s metabolic workings begin to fail. Rising acidity produces symptoms like rapid breathing, nausea, vomiting, abdominal pain, low blood pressure, mental impairment, lethargy, heart arrhythmias and ultimately, if uncorrected, death. In otherwise healthy people, diets that promote ketosis by restricting carbohydrates do not appreciably change the body’s pH, despite the acid nature of ketones and other breakdown products of triglycerides. What keeps severe acidity and its dire consequences at bay? In short, insulin, the central hormone of metabolism.

Insulin keeps the brakes on fat burning

Insulin is secreted by the pancreas in response to eating carbohydrates. In fact insulin is such a reponsive hormone that a burst appears from the pancreas in response to anything sweet in the mouth (the so called cephalic insulin response that prepares the gut to receive expected incoming carbohydrate, even when the sweetness is artificial and no carbs arrive in the stomach). In addition to its role escorting glucose into cells for energy production, insulin keeps the brakes on fat burning. When insulin circulates at normal or high levels in response to carbohydrate ingestion, triglycerides remain locked in fat cells, unavailable for energy production. As night falls and eating ceases, the liver and muscles break down their glycogen to glucose to keep the supply up. When this supply dwindles, insulin levels fall, unleashing fat burning. Free fatty acids and ketones appear in the blood, but in a controlled manner, unless insulin disappears altogether. Then the brakes come off fat burning, fatty acids and ketones flood the system, and their acidity begins to drop the body’s pH.

Ketoacidosis comes from insulin’s diappearance in type 1 diabetes

Type 1 diabetics are the most at risk for ketoacidosis because immune attacks against the insulin producing cells in their pancreases severely diminish or obliterate insulin production. Their blood sugar levels rise because sugar cannot get into cells. Fat burning comes to the rescue for energy production, and, with little or no interference from insulin, free fatty acids and ketones pour out into the blood. In new Type 1 diabetics, before treatment with insulin, major weight loss is very common – as is presentation to an emergency room in a state of profound ketoacidosis, requiring intensive medical care. Once patients are stabilized, urinary ketones are a useful guide for adjusting insulin dose– their appearance means more insulin is needed.

Type 2 diabetes is a different problem

Type 2 diabetics have a different problem, called insulin resistance. Their cells do not allow insulin to bring glucose in from the blood. In an attempt to compensate, their pancreases make more insulin. Blood glucose levels rise, but at the same time high levels of insulin block fat breakdown, preventing the release of large amounts of potentially acidifying fuels, and diminishing the risk of ketoacidosis. But if a crisis such as trauma, infection, or surgery occurs, sugar levels can rise to extraordinary levels in Type 2 diabetics, causing huge amounts of water to be lost in urination as the body passes the sugar out through the kidneys. Severe dehydration and electrolyte abnormalities make this condition, called hyperosmolar hyperglycemia, a crisis requiring intensive care, even without acidosis. When insulin production begins to fail in Type 2 diabetics, ketoacidosis does occur and type 2 diabetics account for 20-30% of ketoacidosis cases in hospitals. One class of Type 2 diabetes drugs, the SGLT2 inhibitors known as gliflozins, has been reported to trigger ketoacidosis.

The caveat about ketosis as a dietary strategy

There is some concern, from epidemiological research, that when a very low carbohydrate diet is continued over the long term, chronic ketosis may trigger insulin resistance, the underlying problem in type 2 diabetes. Insulin resistance is not well understood, but it is associated with a cascade of health problems associated with metabolic problems. If chronic ketosis does somehow trigger insulin resistance, the enthusiasm for deliberately inducing ketosis to lose weight and improve fitness will wane. The word ketosis will fade back into the scientific world.

Posted by medical plaintalk

Physician turned medical writer.

Human Foie Gras: The New Plague of Fatty Livers

“M. Apicius [Marcus Gavius Apicius, a first century AD Roman gourmet] made the discovery, that we may employ the same artificial method of increasing the size of the liver of the sow, as of that of the goose; it consists in cramming them with dried figs, and when they are fat enough, they are drenched with wine mixed with honey, and immediately killed.”

— Pliny the Elder, The Natural History, Book VIII, Chapter 77

For thousands of years, humans have created a tasty delicacy called foie gras from the livers of certain animals. Foie gras, which means “fatty liver” in French, is made by force-feeding animals, usually geese or ducks, a mash consisting of fat-soaked grain. Fatty livers are most easily induced in animals that regularly store extra fat for energy before migration. Humans also store energy easily, and modern lifestyles, including diets heavy in fat-soaked carbohydrates, have inadvertently created an epidemic of fatty livers in people. Some researchers estimate that the problem now affects one-third of the US population.

Alcoholism was the main cause of fatty livers in the past

Doctors have long been familiar with fatty livers in alcoholics, in whom a combination of the toxicity of alcohol and dietary deficiencies converts liver cells into fat-laden bubbles. This condition is known as alcoholic steatosis and is the first step along a road that can lead to cirrhosis and liver failure. Alcoholic steatosis can be reversed if the patient stops drinking. If not, it can become progressively worse, leading to inflammation of the liver called alcoholic steatohepatitis. Ultimately this inflammatory degeneration can lead to a scarred and shrunken liver (cirrhosis) and to liver failure.

Non-alcoholic fatty liver becomes a new diagnosis

By 1980, the appearance of fatty livers and the kinds of problems that are associated with them in nondrinkers forced doctors to devise a new diagnosis—nonalcoholic fatty liver disease (NAFLD). As in alcohol fueled liver disease, NAFLD can also lead to inflammation, a condition called nonalcoholic steatohepatitis (NASH), and to cirrhosis and liver failure in some patients. Progression from NAFLD to NASH seems to require the additional effects of viral hepatitis or of toxic substances, like certain medications, both of which also play a role in some alcoholic liver disease progression.
…..and becomes a serious problem

Since the 1980s, the prevalence of NAFLD has been climbing in parallel with the numbers of people affected by the metabolic problems of obesity, insulin resistance, and type 2 diabetes. Like these problems, NAFLD is now affecting younger people, even children. By 2006, NAFLD and NASH were the leading reasons patients were referred to liver specialists. They were also the leading cause behind diagnoses that led to 4 to 10 percent of liver transplants. While it is very difficult to make accurate estimates about the overall prevalence of NAFLD, by now it is clear that it is very common in people who have abdominal obesity, insulin resistance, and type 2 diabetes—perhaps affecting as many as 75 percent of such individuals.
Why fat in the liver is bad for you

In a state of good health, the liver functions silently. Tucked up under the ribs on the right side of the abdomen, it is the size and shape of a deflated football and is the second largest organ in the body (the skin is the largest). The liver coordinates energy storage and regulation and makes proteins and cholesterol necessary to the health of all cells in the body. It also makes and secretes bile to absorb fats from the intestine and filters toxins from the blood to destroy them or ship them out with bile. The liver also stores vitamins and regulates the blood’s ability to clot in a fine-tuned range.
If necessary, the liver stores fat in its cells. Generally, this is a temporary state, and the fats are transported back to the body for use as an energy source or for storage in fat tissue. Obesity, insulin resistance, and diabetes, however, work together to keep fat in liver cells. Despite the stored fat the liver can continue to function well, producing no symptoms, unless other factors produce inflammation and scarring. NALFD is often discovered incidentally, because of abnormal liver function blood tests from inflammation, or a scan of the abdomen for other problems.

Fat plus inflammation can trigger liver failure

When fat accumulation in the liver is accompanied by inflammation or occurs in someone who already has a scarred liver from other problems, like heavy alcohol use or hepatitis, liver failure and cirrhosis ( shrinkage from scarring) may follow. It is estimated that 20 percent of those with NAFLD have inflammatory changes in their livers, moving them from a diagnosis of NAFLD to a diagnosis of steatohepatitis, or NASH, which increases their risk of developing liver failure and cirrhosis. Unfortunately, there are no easy tests to determine the presence or absence of inflammation in the liver, and patients may have no symptoms. Liver function tests may remain normal, and although liver biopsy provides a definite diagnosis, it carries some risks and thus is not a suitable screening test for patients who have no symptoms or findings.
Symptoms of liver disease

Symptoms of liver disease can be very vague until liver scarring and failure are well advanced. Fatigue, vague abdominal pain, and digestive complaints, as well as enlargement of the liver are early indicators. Jaundice (yellowing of the skin and eyes), fluid in the abdomen, poor clotting, and bleeding from the intestinal tract are late symptoms. Most people who have fatty livers will not go on to this degree of failure, just as most alcoholics do not, but there is no easy way to know who will and who won’t.

What can be done?

In the presence of NAFLD it is important to avoid liver toxins such as alcohol and many drugs. With gradual weight loss, it is possible to reverse the accumulation of fat in the liver and to reduce liver inflammation, particularly if the weight loss program includes significant exercise to improve insulin sensitivity. Even in transplanted livers, NAFLD can recur as long as obesity, diabetes, and insulin resistance remain. Obesity surgery appears to reverse some of the liver problems in affected people and may yield new insights into the mechanism of insulin resistance. While researchers are striving to develop drugs that improve insulin resistance and alter fat transport and storage mechanisms, prevention, as always, is the best advice. This will require education, patience, self-discipline, and hard work, and it is particularly important for young people. While foie gras from a goose is tasty, its development in humans is undesirable.

Posted by medical plaintalk

Physician turned medical writer.

Alzheimer’s Disease: A Power Failure?

Like Willy Sutton, the bank robber famed for his explanation of why he robbed banks (because that’s where the money is), Alzheimer’s disease researchers have aimed most of their efforts at the well-known, visible pathology of the disease, the collections of debris scattered among the dying cells in the brains of patients suffering from the dementing illness. Made of a protein known called beta-amyloid, these plaques are the cause of the progressive death of brain cells and consequent loss of mental function – or so it has been thought. Research focus on amyloid plaques has been disappointing, though, yielding neither effective treatments nor preventive strategies. Moreover, the dramatic rise in the incidence of Alzheimer’s disease (AD), from 2% of people over age 85 in 1960 to 50% in 2000 indicates that something else is in play, something other than bad genetic luck that supposedly causes beta-amyloid to accumulate and nerve cells to die.

Energy production in the brain

As attention has turned to other potential causes of AD, older research findings seemingly unrelated to AD have assumed new importance, particularly discoveries related to brain energy metabolism. The preferred fuel for the brain is glucose. Until the 1980s, researchers thought that the brain, unlike other organs, did not need use the hormone insulin to allow glucose to enter its cells. But in the 1970s insulin receptors were discovered in brain cells and insulin was found in the spinal fluid, implying that the brain did indeed use the hormone. Because progressive resistance to insulin and difficulty getting glucose into cells to provide energy are the hallmarks of type 2 diabetes, and because the rise in AD incidence paralleled rising rates of type 2 diabetes in the last few decades, researchers began to wonder if AD might be rooted in insulin resistance and impaired energy production in brain cells. Insulin resistance in the brain might also explain the results of glucose metabolism studies in the brains of people at high genetic risk for AD, showing as much as 25% decrease in the use of glucose in areas concerned with memory and learning – long before any symptoms suggestive of AD have appeared.

Insulin resistance

By 2005, the idea that insulin resistance in the brain plays a significant role in the development of AD gained traction. Since not all type 2 diabetics get AD and not all AD patients have type 2 diabetes, insulin resistance cannot be the sole cause of AD. But a high blood insulin level is one of the two biggest risk factors for the disease. The other is a genetic factor – the gene for the E4 version of a protein called apolipoprotein B (apoB). Like insulin, apoB’s function is moving the building blocks for energy production into place in the various cells of the body. ApoB is like a delivery vehicle, packed with fats and cholesterol which are necessary for building the cellular machinery in the brain and providing fatty fuel for use when glucose is unavailable.

The tie between glucose, insulin and amyloid

Does impairment of glucose metabolism in the brain have any relationship to the classic pathological components of the disease – the amyloid plaques littering the brain, the destruction of nerve cell architecture, and the non-specific inflammatory changes? There are tantalizing clues. In the brain amyloid protein is a normal waste product. What is not normal is its accumulation in clumps around nerve cells. Beta-amyloid is usually broken down by an enzyme called IDE, insulin destroying enzyme. IDE breaks down insulin much more readily than it does amyloid proteins and when insulin is present in high amounts, the amyloid waits longer to be cleaned up and precipitates out of solution, forming clumps. Uncleared amyloid also prevents insulin from attaching to nerve cells to let more glucose in, depriving them of fuel.

Competition for IDE may not explain beta-amyloid accumulation completely, but it is a link between insulin, glucose metabolism and AD. In addition, high levels of glucose in all parts of the body prompt the development of abnormal collections of proteins/glucose combinations called advanced glycation products which trigger inflammatory damage to tissues in all organs. The brain is no exception.

A link between poor sleep and AD?

Sleep is another subject beginning to gain attention in the prevention and treatment of AD. Lack of good sleep contributes to the development of the metabolic syndrome, including type 2 diabetes, though disruption of normal hormonal rhythms. In normal people and in people with sleep apnea, sleep deprivation produces measurable impairments in working memory, thinking speed, attention, vigilance, and higher cognitive functions – the same functions affected by dementing illnesses such as AD.

Reasons for optimism

Do changing theories about AD have any practical consequences? Indeed. First, there is more reason for optimism about the future. If AD rates have risen because of changing dietary habits and lifestyles, we can change them again. The factors known to produce the metabolic syndrome are weight gain, lack of exercise and poor diet. Regular exercise is recognized as a deterrent to the development of AD. Some people are beginning to feel that the low fat dietary recommendations must also be changed since they have resulted in diets high in processed foods and carbohydrates, and low in foods with high amounts of antioxidants which counter inflammation. Fat metabolism, abnormal in the metabolic syndrome, is also important in the brain, which contains 25% of the body’s cholesterol. It needs sufficient healthy fats in the diet for normal function.

The second practical implication of the changing view of AD is the application of known drug treatments for type 2 diabetes, both for attempted prevention and for treatment of AD. Clinical studies in AD patients are already under way, using medications that improve insulin resistance. Intranasal insulin has also been tried. It is delivered directly into the brain, without fear of lowering body glucose levels and has shown some promise in improving AD symptoms. These approaches are entirely new and evidence of shifting focus in research. If Willy Sutton were an AD researcher he would be changing his targets.

Terminal Lucidity and Lucid Intervals

Caregivers of Alzheimer’s patients have long reported episodes of the patient returning briefly to “themselves,” for periods of hours to days. Some dramatic cases of such returns have been reported in the terminal phases of life. All of these cases have fallen into the “we don’t know why that happens” category of clinical observations. The concept of brain cells failing to function because of lack of energy is one that fits the appearance of lucid intervals better than a theory of the disease that implicates cellular destruction alone as the underlying cause of symptoms.

Arch Gerontol Geriatr. 2012 Jul-Aug;55(1):138-42. doi: 10.1016/j.archger.2011.06.031. Epub 2011 Jul 20. Terminal lucidity: a review and a case collection.

Nahm M¹, Greyson B, Kelly EW, Haraldsson E.

Posted by medical plaintalk

Physician turned medical writer.

The Problem with Sugar: Insulin

This article is about insulin, not diabetes. Diabetic or not, you need to know about insulin. My epiphany about the importance of this hormone occurred when one of my children brought Micah, a friend with Type 1 diabetes, home for dinner. We had a healthy “Mediterranean” dinner – pasta tossed with olive oil, chicken, fresh tomatoes, and cilantro, with accompanying salad and French bread. And birthday cake. Fresh from life in a college dorm, the young friend ate with gusto – at least two helpings of everything. We all did. Later, I found him groggy and in need of two to three times his normal insulin dose. The epiphany was this: all the non-diabetics at the table that night required a lot of insulin to cover hefty carbohydrate intakes, but we were blissfully unaware of the consequences of over-indulgence. We did not have to fill syringes with extra insulin. Our pancreases did the work behind the scenes.

Awash in Insulin

Why was this realization an epiphany? Because we live in an age of excess, consuming large amounts of refined carbohydrates and frequently eating more than our energy requirements demand. We are awash in insulin of our own making and need to understand this hormone’s central role in metabolism. More and more research links insulin to the chronic diseases of civilization: high blood pressure, heart disease, obesity, and Type II diabetes (the variety in which insulin is too plentiful and doesn’t work properly, as opposed to Type I, in which the pancreas fails to produce insulin).

How insulin works

Insulin is the hormone that moves sugar from the blood into all the body’s cells. Blood sugar comes from carbohydrates in food and from glycogen made by liver and muscles as a way to store a twelve-hour supply of sugar. When glycogen stores run out and little food is coming in, as in starvation or very low calorie diets, we make sugar, first from our muscle proteins and then from our fat. The main goal of all metabolism is to keep blood sugar in a tight range – just right for the brain’s needs, because sugar is the only fuel the brain uses under normal circumstances. (It will resort to using ketone bodies, formed from fat in the liver during prolonged fasting or total carbohydrate restriction, but if sugar is available it is the preferred fuel).

Incoming dietary sugar elicits a burst of insulin from the pancreas. Insulin’s job is ferry the needed sugar to cells and to squirrel away extra sugar as glycogen and fat. Insulin is a lipogenic, or fat-producing hormone. Every time we overindulge, insulin goes into high gear to produce fat. It also raises triglyceride levels and lowers high density lipoproteins, exactly the changes in blood lipids that are associated with heart disease.

When insulin fails to work

Insulin is also mysterious. For unknown reasons, many people – one in every three of us – have a tendency to become “resistant” to insulin’s effects. Their pancreases put out more and more insulin to handle routine blood sugar levels. No one knows what makes the insulin inefficient, though fat accumulation in muscle cells may be part of the problem. This stage of “insulin resistance” goes unnoticed for years because there are no symptoms. Blood insulin levels are expensive to measure and difficult to standardize, so they are not part of any kind of routine, preventive screening.

Insulin promotes fat storage

High levels of insulin make fat storage and weight gain easier. Weight gain, particularly around the middle, promotes insulin resistance, and the pancreas responds with yet more insulin. A vicious cycle is underway. Insulin resistance can become so pronounced that blood sugar escapes control and spills into the urine. Insulin resistance is now Type II diabetes, treated with medicines that help insulin work, and ultimately, with shots of yet more insulin. Before this happens, and even afterwards, weight loss and exercise can reverse insulin resistance, leading medical researchers to believe that insulin resistance has something to do with abnormal energy processing in muscle cells. They’ve found that the muscles of some lean, healthy relatives of Type II diabetics show insulin resistance long before there is any fat in muscle, or abnormality in blood insulin levels.

Epidemic

In our sedentary age of super-sized, sugar-laced, low fiber meals, we produce far more insulin than our ancestors did. In addition, the genetic make-up of many people, particularly Hispanics, Native Americans and some African-Americans makes their insulin less effective. We don’t measure insulin levels routinely. Instead, we concentrate on easily-measured cholesterol and fret about fat in the diet. At the same time we are in the middle of an epidemic of insulin resistance and on the verge of an epidemic of Type II diabetes, which is no longer just a disease of middle and older age. For the first time in history, type II diabetes is appearing regularly in children, teens and twenty year olds.

The average American fast food diet sets people on the road to obesity, insulin resistance and type II diabetes. Lack of exercise keeps them there.In a world of easily available food that requires little or no work, the only defense against overeating is mental. Education and self- discipline are the weapons. Insulin-requiring, Type I diabetics like Micah know how much insulin has to be paid out for a big meal. The rest of us have to visualize that syringe full of extra insulin and imagine tucking away excess calories as fat. We have to see ourselves requiring more and more insulin as time goes on and becoming unable to produce enough to meet the needs of an insulin resistant body. It’s enough to make that second helping seem less desirable and regular exercise more attractive.

Keeping insulin levels under control:

Avoid weight gain
Lose any extra weight
Exercise 30 minutes per day.
Eat regular, small, balanced meals, and 25-30gm/day of fiber
Avoid the “white stuff:” Flour, sugar, white rice
If you are overweight and/or have relatives who have diabetes do all the above, and see if your doctor thinks a glucose tolerance test is warranted.

Posted by medical plaintalk

Physician turned medical writer.

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