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Epidemiology and Genetics



Diagnosis of Hypoglycemia


Differential Diagnosis

Etiology and Mechanisms of Action

Anatomy and Physiology (Structure and Function)

Physiological and Nutritional Functions of the Pancreas

Physiological and Nutritional Functions of the Liver

Physiological and Nutritional Functions of the Adrenal Glands



Endocrinology and Biochemistry (Regulation and Metabolism)






Nutritional Therapy




Functional and Practical Medicine


Scientific Summary

Functional Summary

Pathophysiological Aspects of Hypoglycemia Benefited by Nutritional Therapy

Life Extension’s Integrated Protocol



Hypoglycemia is a condition of abnormally low blood glucose levels.  Diabetic patients commonly take insulin or sulfonylurea drugs to lower high blood glucose levels. When these drugs are used in excess, the blood glucose can lower to hypoglycemic levels. This improper use of drugs accounts for at least half of all cases of hypoglycemia. Other factors that can lead to hypoglycemia include genetic defects, tumors, and certain severe disease conditions. Genetic defects can result in deficiencies in enzymes necessary to release glucose from glycogen, or to convert amino acids or other precursors into glucose. Intolerances to fructose, galactose or leucine can result in glucose depletion. Certain tumors can result in an excessive production of insulin or of an insulin-like hormone. Diseases of the liver, kidney, pituitary or adrenal gland can result in lowered production of glucose. Excessive alcohol consumption can also inhibit glucose formation.


Treatment of acute hypoglycemia commonly consists of taking glucose or sucrose either orally or by infusion. An alternative treatment that is gaining in favor is the use of the drug Diazoxide, which counteracts the effect of insulin. Nutritional therapy provides long-term control of hypoglycemia. Proper dietary choices decrease the stimulus for insulin secretion. Chromium is essential for the activity of insulin, and helps to stabilize blood glucose levels. The amino acid glutamine can be converted to glucose through the process of gluconeogenesis. Carnitine supplementation may be beneficial under certain conditions of carnitine deficiency.


Epidemiology and Genetics




The overall prevalence of hypoglycemia in the U.S. population is difficult to ascertain. Most studies on the subject are related to the prevalence of hypoglycemia among diabetics. Young children receiving insulin for Type I diabetes have an overall prevalence of 10%, ranging from 4.4% during the day, and 18.8% at night.1 Patients with Type II diabetes have a variety of treatment options. Prevalence of hypoglycemia is 12% for those patients receiving dietary treatments alone, 16% for those receiving drugs alone, and 30% for those receiving any insulin.2 Detailed discussions on types of diabetes and treatments are described in the Diabetes chapter of this book.


Women are apparently more susceptible to reactive hypoglycemia (occurring after meals) than are men. This is due to reductions in inherent counter regulatory responses in women, particularly in the secretion of glucagon and epinephrine hormones.  However, men and women with Type I diabetes have a similar prevalence of hypoglycemia.3




Many genetic defects can lead to hypoglycemia. The prevalence can vary widely among different ethnic groups. Reactive hypoglycemia resulting from the consumption of normal food components is usually diagnosed in childhood. Fructose intolerance and galactosemia are due to enzyme deficiencies that cause failures in the conversion of these simple sugars into glucose.4 Leucine sensitivity causes hypoglycemia due to an increased secretion of insulin. 56


Other hereditary defects in metabolism can result in hypoglycemia. Fatty acids, the components of fats, can be used as an alternate source of energy instead of glucose. Genetic defects can result in deficiencies of enzymes that are necessary for the metabolism of fatty acids.78This faulty metabolism results in a greater need to depend upon blood glucose for the body’s energy requirements. Glycogen is a readily available storage form of glucose found in the liver. A group of rare genetic disorders result in enzyme deficiencies that prevent glycogen from being broken down to glucose. 9


Diagnosis of Hypoglycemia



The symptoms of hypoglycemia can be divided into two categories: adrenergic (or autonomic) responses and central nervous system responses. 10 Adrenergic symptoms include palpitations, tremor, anxiety, sweating, hunger, and abnormal sensations. These symptoms are due to secretion of the hormones epinephrine and norepinephrine from the adrenal cortex.


Central nervous system responses include behavioral changes, confusion, fatigue, seizure, visual disturbances, stupor, and coma. The brain requires a continuous supply of glucose, and these symptoms are due to glucose deprivation.


Differential Diagnosis


The wide variety of non-specific symptoms of hypoglycemia makes it apparent that a differential diagnosis is required. Many persons feel that their symptoms are due to hypoglycemia when they are actually due to other causes.


A process known as Whipple’s Triad can be important in making the diagnosis:

1. Symptoms consistent with hypoglycemia

2. A low plasma glucose concentration, and

3. Relief of symptoms after the plasma glucose level is raised. 10

Plasma is simply the fluid portion of the blood.


The classic diagnostic test for hypoglycemia is the 72-hour fast. 11 Measurements of plasma glucose, insulin, and other components are made every 6 hours during the fast. Symptoms of hypoglycemia should be apparent before the fast is completed. Analysis of the data should broadly differentiate the cause of the hypoglycemia.  The analysis could indicate if the hypoglycemia is due to tumors, excessive use of insulin or sulfonylurea drugs, or factors not related to the effect of insulin. If the glucose level is normal, but the patient has symptoms, the disorder is non-hypoglycemic.  Treatment of the underlying cause of the hypoglycemia can then be performed in order to alleviate the condition.


Anatomy and Physiology (Structure and Function)


Physiological and Nutritional Functions of the Pancreas


The pancreas is composed of two major kinds of tissues:12

  1. The acini are grape-like clusters that are connected to the duodenum of the small intestine by means of the pancreatic duct. The acinus cells synthesize enzymes responsible for the digestion of carbohydrates, proteins and fats. These enzymes are secreted as pancreatic juice into the duodenum to complete the digestion of foods.
  2. The Islets of Langerhans consist of a large number of small clusters of cells. They contain two types of cells, alpha and beta. The alpha cells produce the hormone glucagon, while the beta cells produce the hormone insulin.



Physiological and Nutritional Functions of the Liver


The liver is a large organ that is richly supplied with blood vessels and secretory ducts. It performs a wide variety of essential functions in the body.  The liver synthesizes most essential blood proteins, including albumin, carrier proteins, coagulation factors, hormones and growth factors. Drugs and toxins are converted into soluble forms that can be readily excreted from the body. The liver produces and excretes bile that aids in the digestion of fats. The liver helps to prevent hypoglycemia through the process of gluconeogenesis, which is the conversion of amino acids and other precursors into glucose. Glycogen is a readily available form of glucose that is stored in the liver. Vitamins A, D, and B12 are also stored there.


Physiological and Nutritional Functions of the Adrenal Glands


There are two adrenal glands, each situated on the upper portion of the two kidneys. Each adrenal gland consists of two distinct parts. The inner adrenal medulla secretes the hormone epinephrine (adrenalin) that stimulates the breakdown of glycogen in the liver to glucose. The outer adrenal cortex secretes two types of hormones known as mineralocorticoids and glucocorticoids. The mineralocorticoids help maintain the salt and water balance in the body. The primary glucocorticoid activity results from cortisol, also known as hydrocortisone. Cortisol acts to raise blood glucose by its role as an insulin antagonist and by promoting gluconeogenesis. Cortisol promotes the transport of amino acids and fatty acids into the liver, and activates enzymes necessary for the conversion of those molecules into glucose. 12




Pathophysiology is the physiology of disordered function that leads to hypoglycemia. The major conditions are as follows:

  1. Reactive hypoglycemia – This category refers to hypoglycemia that is provoked after meals.
    1. Hereditary fructose intolerance, galactosemia, and leucine sensitivity. These rare conditions make their appearance early in childhood. Fructose intolerance and galactosemia are due to the lack of enzymes necessary for their metabolism. These deficiencies result in the buildup of intermediates that inhibit gluconeogenesis. Leucine sensitivity causes excess leucine to bind to the beta cells. This binding stimulates the release of additional insulin in a manner similar to sulfonylurea drugs. 56
    2. Alimentary hypoglycemia is due to surgery in the upper gastrointestinal tract. The resultant anatomical changes allow rapid glucose absorption from the intestine, provoking an excessive insulin secretion after meals.
    3. Pre-Type II diabetes patients may show adrenergic symptoms occurring 4-5 hours after eating. This reaction is due to over-secretion of insulin and indicates early malfunctioning of the ß-cells.
  2. Tumors
    1.  ß-cell adenoma or carcinoma. Tumor cells are rapidly growing and overactive which leads to an over production of insulin. These conditions are uncommon.
    2.  Large non-ß-cell tumors. Certain types of tumors in the liver, adrenal cortex, and digestive tract can secrete insulin-like growth factor that acts in a manner similar to insulin.


  1. Inherited metabolic disorders
    1. Deficiencies of enzymes that are necessary to synthesize glucose from amino acids or other precursor substances (gluconeogenesis).
    2. Deficiencies of enzymes that oxidize fatty acids to serve as a source of energy. 8 This can result in increased demands being placed on glucose as a source of energy.
    3. Deficiencies in enzymes that break down glycogen into glucose.
  2. Hormonal deficiencies due to adrenal or pituitary disease that limit the secretion of growth hormone or cortisol. It should be noted that lack of these hormones will usually only cause hypoglycemia during conditions of fasting.10
  3. Alcohol use – alcohol can have an inhibitory effect on gluconeogenesis.


Endocrinology and Metabolism (Regulation and Metabolism)


“ The level of blood glucose is maintained within a narrow range despite wide variations in food intake and activity level “.10The two key hormones involved in maintaining blood glucose levels within this narrow range are glucose and glucagon, which have opposite effects.


  When there is a large influx in blood glucose levels (such as after meals), glucose is transported across the beta cell membrane by means of the GLUT2 glucose transporter.13 Within the cell, the glucose is further metabolized, generating the high energy ATP molecule. The ATP inhibits the ATP-sensitive potassium channel on the cell membrane, leading to insulin secretion. This secreted insulin then binds to receptor sites on the cells with the aid of chromium, perhaps as a complex known as glucose tolerance factor. This binding initiates a molecular signaling process that leads to the following effects of insulin:

1. Activation of glucose uptake by the cells and its utilization. Insulin stimulates the GLUT4 glucose transporter, which permits glucose uptake by the cells. Insulin also stimulates the phosphorylation of glucose, the first step in glycolysis, which is the breakdown of glucose to produce energy.

2. Inhibition of glycogen breakdown into glucose. Glycogen is a storage form of glucose found primarily in the liver, and serves as a readily available source of glucose. Insulin activates the enzyme glycogen synthase to promote synthesis of glycogen, while inactivating glycogen phosphorylase to inhibit breakdown of glycogen.

3. Inhibition of gluconeogenesis, the formation of glucose from non-carbohydrate sources.  Insulin inhibits the enzyme phosphoenolpyruvate carboxykinase, the key enzyme that directs metabolites toward the gluconeogenesis pathway. 13


Low blood levels of glucose stimulate the pancreatic alpha cells to secrete glucagon. The hormone binds to specific receptors on cells followed by the activation of cyclic AMP. This metabolite phosphorylates many key enzymes leading to a rise in blood glucose. In actions opposite to insulin, glycogen synthase is inhibited and phosphorylase is converted to an active form. Protein kinase is activated, leading to an increase in gluconeogenesis, and a decrease in glycolysis.


Low blood levels of glucose also stimulate secretions from the adrenal gland, but these hormones are considered less effective than glucagon. The adrenal medulla releases epinephrine, which stimulates glycogen breakdown to glucose.  Epinephrine can also promote gluconeogenesis, particularly in the kidney. 14 Cortisol is secreted from the adrenal cortex when hypoglycemia is prolonged, but it appears to have limited effect in improving glucose supply.15 


Amino acids play an important role as precursor molecules for gluconeogenesis. There are 20 “glucogenic” amino acids, with glutamine considered to be of primary importance. Low blood glucose stimulates the breakdown of these amino acids into metabolites that enter the Krebs cycle. The Krebs cycle is particularly important for the generation of high-energy molecules, but it also serves as an entry point for gluconeogenesis. These reactions are summarized in Figure 1, with the Krebs cycle shown with blue arrows.  The ketogenic amino acids cannot be used for gluconeogenesis. Pyruvate is also formed from the breakdown of glucose (glycolysis). The gluconeogenesis pathway begins with the conversion of oxaloacetate to phosphoenolpyruvate.



Table 1 – Amino acid degradation

Green boxes- glucogenic amino acids

White boxes- ketogenic amino acids

Blue arrows- Krebs cycle compounds

Pink arrows- gluconeogenic pathway

(Reproduced with permission from SparkNotes LLC)

Fatty acids are an important source of energy for the body through a stepwise breakdown process known as β-oxidation. The first step is the activation of the fatty acid by combining it with coenzyme A to form a fatty acyl CoA. Energy is generated as the fatty acyl Co A molecules are reduced in size. Fatty acids (as fatty acyl CoA) must be transported into the mitochondria of the cell where the process takes place. Fatty acids of short and medium chain length are readily able to do so, but long-chain fatty acids require a special transport process. The enzyme carnitine palmitoyltransferase catalyzes the attachment of the fatty acyl CoA to carnitine, which permits transfer across the mitochondrial membrane. After the fatty acyl CoA-carnitine complex is inside the membrane, a second palmitoyltransferase enzyme releases the free fatty acyl CoA to complete β-oxidation. Three separate acyl-CoA-dehydrogenase enzymes are required to complete beta-oxidation, which act upon fatty acyl CoAs of short, medium, and long chain lengths.16  Carnitine continues to play a role inside the mitochondria in helping to break down long-chain fatty acids. The primary end product of β-oxidation is acetyl-CoA. Most of this acetyl-CoA is further oxidized through the Krebs cycle, but some of it is converted to ketone bodies, an alternate source of energy.




Pharmacology refers to the mechanisms by which drugs exert their effects on the body. This section describes how the improper use of insulin and sulfonylurea drugs by the diabetic patient can lead to hypoglycemia. The use of diazoxide and glucagon to overcome the problem are then described.  The Diabetes chapter describes their use in detail, so only a brief summary is given here in order to provide context for this discussion.




Insulin is actually a hormone rather than a drug. Diabetes is a condition of high blood sugar caused by the failure of the pancreatic beta cells to secrete adequate insulin, or by the failure of cells to respond to insulin and take up glucose from the blood. The use of insulin to normalize blood glucose levels is a fine tuned affair, made difficult by widely fluctuating blood glucose levels. When the amount of insulin administered is greater than needed, the blood glucose level may drop faster than the ability of compensatory mechanisms to respond to it. This situation leads to hypoglycemia.


Sulfonylurea Drugs


Sulfonylurea drugs bind to the ATP-sensitive potassiumchannel on the surface of the beta cell. This binding causes inhibition of the channel and stimulation of insulin secretion. These drugs are used with patients who have pancreatic beta cells that still secrete insulin, but in inadequate amounts. Sulfonylurea drugs are classified into two groups according to the time they were introduced. “First-generation” drugs include tolbutamide, tolazamide, and chlorpropamide. “Second-generation” drugs include glyburide, glipizide, and glimepiride. The second-generation drugs have effects of shorter duration, have fewer drug interactions, and cause a lower incidence of hypoglycemia.


A class of drugs known as meglitinide analogues has recently been developed. These drugs act in a manner similar to the sulfonylurea drugs, but are of shorter duration. They are useful to moderate the glucose fluctuations associated with meal eating. Examples of these drugs are repaglinide and nateglinide.




The usual treatment of hypoglycemia caused by overdose of insulin or sulfonylurea drugs is the oral consumption of glucose or sucrose. However, several studies 17,18  have shown that administering diazoxide together with glucose was more effective in correcting hypoglycemia than glucose alone, and reduced the amount of glucose needed. Diazoxide acts by inhibiting the release of insulin by the beta cells.




Since glucagon acts in a contrary fashion to insulin, it has been found useful to treat severe hypoglycemic reactions due to insulin, particularly when oral consumption of glucose or sucrose is not possible. Glucagon treatment is not effective in patients who have been fasting or have been hypoglycemic for a prolonged period. 4


Nutritional Therapy




Chromium is now widely recognized as an essential trace element, although there is some controversy about its exact role.1920  The essentiality of chromium dates back to the mid-twentieth century, when researchers found that rats fed a chromium deficient diet based on torula yeast had difficulty removing excess glucose from the blood. When researchers switched the animals feed to brewer’s yeast, a rich, natural source of chromium, the rat’s health promptly returned to normal. The active component of the yeast was designated glucose tolerance factor, and was proposed to consist of trivalent chromium bound to protein and possibly other nutrients such as niacin. This complex combined with insulin to enhance insulin’s activity by facilitating the binding of insulin to receptor sites. Unfortunately, the structure of glucose tolerance factor has never been determined, so it is not known if it is a biologically active substance or an artifact. 19,20 Recently, another mechanism for chromium function has been proposed.21 In this model, insulin (or glucose tolerance factor) transports trivalent chromium to the cells where it is absorbed. Within the cell, the chromium binds to and activates a protein fragment known as an oligopeptide. The oligopeptide binds to the insulin receptor and initiates a series of steps that are essential for insulin action once it binds to the receptor.


The essentiality of chromium as a trace element is assured, since a specific deficiency syndrome can be demonstrated (impaired glucose uptake by the cells) that can be corrected by chromium supplementation. Dr. Anderson is a nutritional research scientist with the US Department of Agriculture’s Agricultural Research Service. For decades, he has studied chromium’s role in glucose and lipid metabolism. As early as 1981, Dr. Anderson published a report declaring that chromium is essential for proper glucose and lipid metabolism. 22 Dr. Anderson has reported on several human studies that clearly demonstrate that chromium supplementation improves glucose tolerance.2324-26 Other researchers have also demonstrated the benefit of chromium supplementation on improved glucose utilization. 27-2930,31


Are normal diets deficient in chromium? Dr. Anderson wrote that “dietary chromium intake in the US and other developed countries is roughly half of the minimum suggested intake of 50 micrograms.”32 He found that the average daily intake of chromium is less than adequate from both self-selected diets, as well as from diets formulated by dietitians.3334 The chromium requirement can depend on the type of diet consumed. A study found that subjects consuming a diet high in simple sugars lost more chromium through excretion than subjects consuming a reference diet similar in all respects except for being higher in complex carbohydrates.35 Doses well above the recommended minimum levels may be necessary to treat chronic diseases. In a study conducted in China, patients received up to 1,000 mcg of chromium per day, a dose that proved “highly effective” in relieving many of the symptoms of type II diabetes.36


How safe is Chromium? Chromium occurs in two chemical forms, called trivalent and hexavalent. The hexavalent form is usually a byproduct of the metallurgy industry, but it is never used in nutrition. Chromium in foods and dietary supplements is always trivalent which is exceptionally well tolerated. Studies with rats found that feeding diets containing trivalent chromium at several thousand times the estimated safe level for humans had no evidence of toxicity. 37 A review article provides a summary on the effectiveness of chromium and safety at high doses.38


The importance of glutamine was stated by Stumvoll and associates: “Glutamine is the most abundant amino acid in the human body and is involved in more metabolic processes than any other amino acid.”14  Glutamine is particularly important for the process of gluconeogenesis when blood glucose levels are low. With reference to Figure 1, it can be seen that glutamine enters the process by conversion to α-ketoglutarate.

This production of glucose from glutamine takes place mainly in the liver. Recently, however, it has been discovered that the kidneys can contribute as much as 25% to whole-body glucose production, a phenomenon that occurs only during hypoglycemia.14   The kidneys are especially equipped to process glutamine due to its importance in the detoxification of ammonia.

Glucose has been shown to be synthesized in the small intestines through the breakdown of glutamine during a fasting or diabetic state. Under these conditions, the small intestine contributes 20-25% to whole-body endogenous glucose production. 39,40

Will amino acid supplementation improve glucose production during hypoglycemia?  Apparently, few studies have been conducted that would directly answer that question. Hypoglycemia was induced by insulin infusions in either diabetic or non-diabetic subjects in two studies. The subjects then received amino acids by infusion. The results indicated a sharp rise in glucagon secretion in normal subjects and a modest rise in diabetic subjects following the amino acid infusions. 20,41

Another study evaluated the effect of glutamine administration in stimulating glucose production in insulin-induced hypoglycemia. 42 The researchers administered insulin to rats by intraperitoneal injection, followed by administration of glycerol, alanine, or glutamine by the same route. The gluconeogenic precursors were administered at the level of 100 mg/kg body weight, which would be equivalent to 5.5 grams for a 120 lb. human.  The results demonstrated that the gluconeogenic precursors significantly increased glucose production.


Carnitine is an amino acid that is normally present in the body in adequate amounts to meet requirements through a combination of dietary consumption and cellular synthesis. Carnitine deficiency is a result of genetic defects. The primary carnitine deficiency is due to defects in the carnitine transporter, which prevents carnitine from transporting long-chain fatty acids across the mitochondrial membrane. An additional defect is the lack of the enzyme carnitine palmitoyltransferase, which is required for the binding of carnitine to the fatty acyl CoA before transport. As a result, long chain fatty acids cannot be further broken down by β-oxidation. The actual deficiency in carnitine is due an inability of the kidneys to reabsorb carnitine. Therefore, carnitine is lost from the body through excretion. 43

A secondary type of carnitine deficiency occurs due to enzymatic defects in the pathway of mitochondrial β-oxidation, of which eleven have been identified.43 When β-oxidation cannot be completed there is an accumulation of fatty acyl CoA derivatives that can become toxic. With these blockages, the cell attempts an alternative metabolic pathway with the formation of fatty acyl carnitine derivatives. These derivatives also promote the excretion of free carnitine.

How can a carnitine deficiency lead to hypoglycemia? It is important to realize that breakdown of fatty acids is an important source of energy for the body, particularly for the heart and skeletal muscle. When this source of energy is restricted, greater demands are placed on glucose as a source of energy. These demands may become greater than the capacity to regenerate glucose through gluconeogenesis. Another consequence is that a deficiency in β-oxidation results in a lower production of high-energy ATP and acetyl-CoA molecules. The lower concentration of these molecules results in pyruvate (Figure 1) being converted to citrate in the Krebs cycle instead of being used in gluconeogenesis. In contrast, with normal β-oxidation and higher concentrations of these molecules, pyruvate is converted to oxaloacetate synthesis and gluconeogenesis. 44

Can carnitine supplementation overcome hypoglycemia due to carnitine deficiency? The results appear to be mixed.  Carnitine supplementation does not cure underlying genetic defects. When the deficiency is due to defects in the transport mechanism, sufficient carnitine may enter deficient tissues such as muscle by passive diffusion to overcome the deficiency. 45 When the deficiency is due to faulty β-oxidation enzymes, carnitine supplementation is even more problematic. The body can generate fatty acyl carnitines at a much faster rate than the availability of carnitine provided by oral supplements. Therefore, the available free carnitine in the body remains depleted.


Functional and Practical Medicine

The appearance of hypoglycemia is usually due to some underlying pathology, as healthy individuals rarely have more than transient hypoglycemia. Therefore, it is essential that persons do not self-diagnose when they have symptoms suggestive of hypoglycemia. After hypoglycemia is diagnosed, it is important to treat any underlying causes that could help alleviate the hypoglycemia.

A well-balanced diet can help to control hypoglycemia. Usually a regimen high in protein, unrefined carbohydrates (which are slow to be absorbed, such as whole-grain products and vegetables), and moderate fats is recommended. Heavily sugared foods should be avoided, and foods high in natural sugars should be restricted. This diet can help to prevent reactive hypoglycemia due to a sudden influx of glucose into the blood. Alcohol, caffeine, tobacco, and other stimulants should be avoided, because they are capable of precipitating an attack. Small meals taken often during the day are recommended to control the amount of carbohydrates entering the system.

Acute hypoglycemia focuses on immediately raising the blood sugar level. Any substance containing simple sugars, such as fruit juice, soft drinks, or candy–if taken at the onset of a hypoglycemic episode–will help to raise blood sugar quickly and ease the severity of the attack. Sugar combined with a protein source, such as a glass of milk or a piece of cheese, will help slow the absorption of glucose into the system.

Dr. Anderson calculated that most diets contain less than 60% of the minimum daily requirement for chromium. There is a wide variation in the chromium content of foods, depending on how the food is grown, transported, processed, and fortified.34 Consuming refined foods can cause a spike in insulin secretion, resulting in a decrease in chromium utilization. When subjects received a drink containing glucose and fructose (the components of sucrose, or table sugar), there was an increase in urinary chromium excretion. Chromium facilitates glucose uptake by the cells, which would tend to decrease blood glucose. However, in a broad sense, chromium helps to stabilize blood glucose levels.

Glutamine is a very abundant amino acid, so one would think that it would be normally present in adequate amounts for all metabolic functions. However, during the stress of hypoglycemia, there is a great need for increased glucose production through gluconeogenesis. Glutamine has been found to stimulate both glycogen storage in the muscle, and gluconeogenesis in the kidney.


Scientific Summary

Hypoglycemia is a condition of abnormally high blood glucose levels. The maintenance of normal levels of blood glucose is a fine-tuned affair. Insulin secreted by the pancreatic β-cells decreases blood glucose by promoting glucose uptake by cells. Glucagon is secreted by the pancreatic α-cells and increases blood glucose by promoting glucagon breakdown into glucose, and by promoting glucose synthesis.  Hormone secretions from the adrenal glands, including epinephrine and cortisol, also increase glucose production by the same mechanisms.

Hypoglycemia is a result of any disorders that cause abnormal restrictions in the release of glucose by the liver or kidneys, or that cause abnormal increases in glucose uptake by the cells. 4 The misuse of insulin and sulfonylurea drugs by diabetic patients account for about half of all the cases of hypoglycemia.  When these drugs are used in excess, there is a rapid and pronounced drop in blood glucose levels leading to hypoglycemia. Certain types of tumors can cause hypoglycemia, because the rapidly dividing cancer cells secrete large amounts of insulin or insulin-like growth factor. Many uncommon genetic defects can lead to hypoglycemia, usually detected in early childhood. Intolerance to the simple sugars lactose and galactose and the amino acid leucine are due to the lack of enzymes needed to metabolize these food components. Deficiencies in certain enzymes required in carbohydrate metabolism may restrict glucose supply by preventing glycogen breakdown into glucose, or by preventing glucose production by gluconeogenesis. Deficiencies in enzymes required for fatty acid metabolism cause an abnormally high demand for the use of glucose as a source of energy.

Treatment of acute cases of hypoglycemia involves rapid administration of glucose or other readily available carbohydrate sources. The use of the drug diazoxide can reduce the amount of glucose needed for treatment. In some acute cases, where the oral administration of glucose is not feasible, glucagon may be given. Food intolerances can be avoided by omitting the offending components from the diet. A good long-term strategy to reduce episodes of hypoglycemia is to consume a diet rich in protein and slowly available carbohydrates. Dietary supplementation of chromium, and under certain circumstances, carnitine, can help to alleviate hypoglycemia. The amino acid glutamine can help to produce glucose through the process of gluconeogenesis.

Functional Summary

The underlying cause of the patient’s hypoglycemia must be determined by consultation with his or her physician. In this manner, a long-term strategy can be devised to minimize the episodes of acute hypoglycemia. If the patient is diabetic, the use of insulin and sulfonylurea drugs must be closely monitored. The dosages could be reduced if necessary, but the patient should realize that the symptoms of hypoglycemia might recur after a period of many hours or days. The diabetic patient must also realize that the symptoms of hypoglycemia may become less noticeable over time.

When hypoglycemia is due to certain tumors, surgical, radiotherapeutic, or chemotherapeutic reduction of tumor size can alleviate hypoglycemia, even if the tumor cannot be cured. Steroid and growth hormones can be administered if deficiencies in these hormones are contributing to the hypoglycemia.

Nutritional approaches could be very helpful for the person susceptible to hypoglycemia. His or her diet should be high in protein and low in refined carbohydrates. The consumption of this diet would minimize the sudden influx of glucose into the blood, and the subsequent oversecretion of insulin. Chromium supplementation should be considered, even if the person is not sure if he or she is deficient. Chromium has a very high safety factor, and excessive intake from nutritional supplements is unlikely. Glutamine supplementation can improve the extent of gluconeogenesis, and subsequent glucose supply. Carnitine supplementation could be beneficial if genetic defects are causing a deficiency in this amino acid.

Pathophysiological Aspects of Hypoglycemia Benefited by Nutritional Therapy

To restore normal physiological levels of blood glucose caused by chromium deficiency, the following supplement is recommended:

·      Chromium capsules containing 200 mcg chromium polynicotinate.  One or two capsules daily with meals is recommended.

To increase blood glucose supply during hypoglycemia by promoting gluconeogenesis, the following supplement is recommended:

·      L-glutamine powder. Dissolve 1 teaspoon in juice or water to provide 3.9 grams glutamine per day. A larger amount may be necessary depending on body weight.  L-glutamine is most effectively utilized on an empty stomach.

When hypoglycemia is due to carnitine deficiency, the supplement indicated below is recommended. A physician should make a diagnosis of carnitine deficiency indicated by genetic defects in the enzymes required for carnitine biosynthesis, transport or metabolism.

·      L-carnitine powder. The dosage required to overcome carnitine deficiency can be considerable and should be determined by consultation with a physician, L-carnitine should be taken on an empty stomach with juice or water.

To aid in the prevention of hypoglycemic episodes, the individual should practice consuming diets high in protein and complex carbohydrates.

Life Extension’s Integrated Protocol

The following supplements are recommended and prioritized. See text for additional details.

·      Chromium capsules. One or two 200 mcg chromium polynicotinate capsules daily.

·      L-glutamine powder. At least one teaspoon of 3.9 grams daily.

·      L-carnitine powder. Amount to be determined by consultation with a physician.









Reference List


      1.   Amin R, Ross K et al. Hypoglycemia Prevalence in Prepubertal Children With Type I Diabetes on Standard Insulin Regimen: Use of Continuous Glucose Monitoring System. Diabetes Care. 2003;26:662-7.

      2.   Miller CD, Phillips LS et al. Hypoglycemia in Patients With Type 2 Diabeted Mellitus. Arch Intern Med. 1 A.D. Jul 9;161(13):1653-9.

      3.   Davis SN, Shavers C et al. Gender-Related Differences in Counterregulatory Responses to Antecedent Hypoglycemia in Normal Humans. J Clin Endocrinol Metab. 2000;85(6):2148-57.

      4.   Anonymous. Disorders of Carbohydrate Metabolism In: Berkow RB, Fletcher AJ et al. Eds. The Merck Manual of Diagnosis and Therapy. Rahway: Merck Research Laboratories; 1992:16th(91):1126-32.

      5.   Floyd JJC, Fajans SS et al. Evidence that insulin release is the mechanism for experimentaly induced leucine hypoglycemia in man. J Clin Invest. 1963 Nov;42(11):1714-9.

      6.   Shah SN. Hypoglycemia: prevention, consequences and management. J Indian Med Assoc. 2002 Mar;100(3):166-7.

      7.   Sermon K, Henderix P et al. Preimplantation genetic diagnosis for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Mol Hum Reprod. 2000 Dec;6(12):1165-8.

      8.   Taroni F, Uziel G. Fatty acid mitochondrial beta-oxidation and hypoglycaemia in children. Curr Opin Neurol. 1996 Dec;9(6):477-85.

      9.   Goldberg T, Slonim AE. Nutrition therapy for hepatic glycogen storage diseases. J Am Diet Assoc. 1993;93(12):1423-30.

    10.   Cryer P. Hypoglycemia In: Braunwald E, Fauci A et al. Eds. Harrison’s Principles of Internal Medicine. New York: McGraw-Hill; 2001:15th(334):2138-43.

    11.   Service FJ. Hypoglycemic Disorders. New Eng J Med. 1995 Apr 27;332(17):1144-52.

    12.   Guyton AC, Hall JE. Textbook of Medical Physiology. 10th ed. Anonymous.  W.B. Saunders;2000 Aug.

    13.   Powers AC. Diabetes Mellitus In: Braunwald E, Hauser Sl et al. Eds. Harrison’s Principles of Internal Medicine. New York: McGraw-Hill; 2001:15th(333):2112.

    14.   Stumvoll M, Perriello G et al. Role of glutamine in human carbohydrate metabolism in kidney and other  tissues. Kidney Int. 1999;55(3):778.

    15.   Battezzati A, Benedini S et al. Effect of hypoglycemia on amino acid and protein metabolism in healthy humans. Diabetes. 2000 Sep;49(9):1543-51.

    16.   Roth KS. Medium-chain acyl-CoA dehydrogenase deficiency.2003.Oct.15.

    17.   Johnson SF, Schade DS et al. Chlorpropamide-induced hypoglycemia: successful treatment with diazoxide. Am J Med. 1977 Nov;63(5):799-804.

    18.   Pfeifer MA, Wolter CF et al. Management of chlorpropamide-induced hypoglycemia with diazoxide. South Med J. 1978 May;71(5):606-8.

    19.   Anonymous. Mineral Deficiency and Tixicity In: Beers MH, Berkow R Eds. Merck Manual of Diagnosis and Therapy. Rahway: Merck Research Laboratories; 2005:17th(Section 1, Chapter 4):Chromium.

    20.   Caprio C, Tamborlane WV et al. Loss of potentiating effect of hypoglycemia on the glucagon response to hyperaminoacidemia in IDDM. Diabetes. 1993;42(4):550-5.

    21.   Racek J. Chromium as an essential element. Cas Lek Cesk. 2003;142(6):335-9.

    22.   Anderson RA. Nutritional role of chromium. Sci Total Environ. 1981 Jan;17(1):13-29.

    23.   Anderson RA. Nutritional factors influencing the glucose/insulin system: chromium. J Am Coll Nutr. 1997 Oct;16(5):404-10.

    24.   Anderson RA. Chromium and parenteral nutrition. Nutrition. 1995 Jan;11(1 Suppl):83-6.

    25.   Anderson RA, Polansky MM et al. Supplemental-chromium effects on glucose, insulin, glucagon, and urinary chromium losses in subjects consuming controlled low-chromium diets. Am J Clin Nutr. 1991 Nov;54(5):909-16.

    26.   Anderson RA, Polansky MM et al. Effects of supplemental chromium on patients with symptoms of reactive hypoglycemia. Metabolism. 1987 Apr;36(4):351-5.

    27.   Bahijiri SM, Mira SA et al. The effects of inorganic chromium and brewer’s yeast supplementation on glucose tolerance, serum lipids and drug dosage in individuals with type 2 diabetes. Saudi Med J. 2000;21(9):831-7.

    28.   Bahijiri SM, Mufti AM. Beneficial effects of chromium in people with  type 2 diabetes, and urinary chromium response to glucose load as a possible indicator of status. Biol Trace Elem Res. 2002;85(2):97-109.

    29.   Ravina A, Slezack L. [Chromium in the treatment of clinical diabetes mellitus]. Harefuah. 1993 Sep;125(5-6):142-5, 191.

    30.   Clausen J. Chromium induced clinical improvement in symptomatic hypoglycemia. Biol Trace Elem Res. 1988 Sep;17:229-36.

    31.   Stone WE, Tews JK et al. Incorporation of carbon from glucose into cerebral amino acids, proteins and lipids, and alterations during recovery from hypoglycaemia. J Neurochem. 1972 Feb;19(2):321-32.

    32.   Anderson RA. Essentiality of chromium in humans. Sci Total Environ. 1989 Oct 1;86(1-2):75-81.

    33.   Anderson RA, Kozlovsky AS. Chromium intake, absorption and excretion of subjects consuming self-selected diets. Am J Clin Nutr. 1985 Jun;41(6):1177-83.

    34.   Anderson RA, Bryden NA et al. Dietary chromium intake. Freely chosen diets, institutional diet, and individual foods. Biol Trace Elem Res. 1992 Jan;32:117-21.

    35.   Kozlovsky AS, Moser PB et al. Effects of diets high in simple sugars on urinary chromium losses. Metabolism. 1986 Jun;35(6):515-8.

    36.   Kleefstra N, Bilo HJ et al. [Chromium and insulin resistance]. Ned Tijdschr Geneeskd. 2004 Jan 31;148(5):217-20.

    37.   Anderson RA, Bryden NA et al. Lack of toxicity of chromium chloride and chromium picolinate in rats. J Am Coll Nutr. 1997 Jun;16(3):273-9.

    38.   Lamson DS, Plaza SM. The safety and efficacy of high-dose chromium. Altern Med Rev. 2002;7(3):218.

    39.   Mithieux G. New data and concepts on glutamine and glucose metabolism in the gut. Curr Opin Clin Nutr Metab Care. 2001;4(4):267-71.

    40.   Croset M, Rajas F et al. Rat small intestine is an insulin-sensitive gluconeogenic organ. Diabetes. 2001;50(4):740-6.

    41.   Nair KS, Welle SL et al. Effect of plasma amino acid replacement on glucagon and substrate responses to insulin-induced hypoglycemia in humans. Diabetes. 1990;39(3):376-82.

    42.   de Souza HM, Borba-Murad GR et al. Rat liver responsiveness to gluconeogenic substrates during insulin-induced hypoglycemia. Braz J Med Biol Res. 2001 Jun;34(6):771-7.

    43.   Stanley CA. Carnitine deficiency disorders in children. Ann N Y Acad Sci. 2004;1033:42-51.

    44.   Garrett RH, Grisham CM. Gluconeogenesis, Glycogen Metabolism, and the Pentose Pathway In: Anonymous. Biochemistry. New York: Saunders College Publishing; 1995(21):660-87.

    45.   Kelly A, Li C et al. Glutaminolysis and insulin secretion: from bedside to bench and back. Diabetes. 2002 Dec;51 Suppl 3:S421-S426.



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