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Author: Anastassios G. Pittas, M.D.
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1. Goals

  • To review the hormonal regulation of maintaining euglycemia
  • To learn the pathologic causes of hypoglycemia

2. Learning Objectives

  • To understand the physiologic sequential response to a declining glucose level
  • To appreciate the redundancy of the various counterregulatory systems available to prevent hypoglycemia
  • To define hypoglycemia and know the symptoms of hypoglycemia
  • To develop an approach in creating a differential diagnosis of hypoglycemia
  • To understand the causes and treatment of fasting hypoglycemia, with emphasis on evaluation and treatment of insulinoma
  • To understand the causes and treatment of non-fasting hypoglycemia, with emphasis on the idiopathic post-prandial syndrome

3. Review: Hormonal Regulation of Euglycemia

The body has plenty of reserve fuel in the form of carbohydrate, fat and protein. However, the central nervous system, as well as other tissues such as red blood cells and the renal medulla, cannot use fat or protein for energy. Most importantly, the central nervous system is almost entirely dependent on glucose for its energy requirements and it uses about 100 g / 24 hour. The brain may also use ketones and lactate during prolonged fasting. The main reason for preventing and treating hypoglycemia is to avoid CNS injury which may be manifested as seizures, decreased consciousness which may progress to coma and possibly long term brain damage from long term exposure to hypoglycemia.

To prevent CNS dysfunction, the body is able to maintain glucose levels within a very narrow range for days without eating. In the fasting state, the liver is primarily responsible for maintaining euglycemia by releasing glucose (initially from glycogenolysis and subsequently from gluconeogenesis). The body's main glucose reserve, liver glycogen, is about 100 g. The kidney also contributes to maintaining euglycemia by providing glucose through gluconeogenesis by the renal cortex. The kidney is thought to supply as much as 25% of the body's glucose needs, especially during prolonged fasting.

When the blood glucose level falls, the body attempts to return it to normal by several counterregulatory mechanisms. The principal hypoglycemic sensors in the body are in glucose-responsive neurons in the hypothalamus (carotid body), the pancreatic beta islet cells and the liver (portal vein). These sensors trigger a complex but highly integrated counterregulatory system (shown in Table 1) that maintains a glucose level above the threshold required for normal brain function.

Table 1. Hormonal Regulation of Hypoglycemia
Glucose level Response Response mediated by Effect of response
< 80 mg /dl Insulin shuts off Low Glucose level,
Alpha adrenergic effects of circulating Catecholamines
Sympathetic Innervation of beta islet cells
Decreased muscle and adipose glucose uptake
Increased glycogenolysis (liver)
Increased gluconeogenesis (liver & kidney)
Increased lipolysis (adipose)
< 70 mg/dl Autonomic system activated Low Glucose level Decreased insulin secretion
Increased glucagon secretion
Increased glycogenolysis (liver & muscle)
Increased gluconeogenesis (liver & kidney)
Increased lipolysis (adipose)
< 70 mg/dl Hunger rises Parasympathetic system Eating
< 70 mg/dl Glucagon rises Low Glucose level, declining insulin
Beta adrenergic effects of circulating Catecholamines
Sympathetic innervation of alpha islet cells
Increased glycogenolysis (liver)
Increased gluconeogenesis (liver)
< 60 mg/dl Growth Hormone rises Low Glucose level Increased lipolysis
Antagonizes insulin action in muscle
< 60 mg/dl ACTH (and Cortisol) rise Low Glucose level Increased lipolysis and muscle breakdown

Certain hormonal responses are triggered at glucose levels higher than those required to cause symptoms. Symptoms of hypoglycemia, often non-specific, can be divided in autonomic and neuroglycopenic (due to brain neuronal glucose deprivation), as shown in Table 2.

Table 2. Symptoms of Hypoglycemia
Autonomic symptoms (glucose < 65 mg/dl)
Adreno-Medullary
Neural- Sympathetic
Tremor, anxiety, palpitations
Neural-Parasympathetic Hunger, sweating, paresthesias
Neuroglycopenic symptoms (glucose < 50 mg/dl)
Glucose < 50 mg/dl Weakness, blurred vision,
Impaired cognition (lethargy, confusion)
Glucose < 30 mg/dl Coma, seizures

The glucose threshold for developing these symptoms, especially the neuroglycopenic ones, depend on the individual. Elderly patients with compromised CNS vascular supply, for example, may experience impaired cognition at a higher threshold level of glucose. Symptoms of autonomic activation are often obvious to the patient but neuroglycopenic symptoms may be subtle and can include small degrees of irritability and inability to concentrate that may go unnoticed. In chronic hypoglycemia, autonomic symptoms may not precede neuroglycopenic symptoms

The complexity of the protective mechanisms emphasizes the importance of maintaining euglycemia. How these mechanisms raise the glucose level is described below and summarized in Table 1.

  • Declining insulin level results in less glucose utilization by insulin dependent tissues (muscle, adipose). Insulinopenia also enhances glycogenolysis by liver and gluconeogenesis by liver and kidney and lipolysis by adipose tissue.
  • Catecholamines constitute an important counterregulatory mechanism as they exert multi-organ effects. Increased catecholamines inhibit insulin and stimulate glucagon secretion and induce glycogenolysis in liver and muscle (thereby providing muscle with own source of glucose) and gluconeogenesis in liver and kidney. Catecholamines induce lipolysis (breakdown of triglycerides in adipose tissue) providing substrate to the liver and kidney for gluconeogenesis. Catecholamines are also responsible for symptoms which serve as a warning of the need to eat.
  • The parasympathetic nervous system promotes hunger which, in turn, promotes eating.
  • Increased glucagon stimulates glycogenolysis and gluconeogenesis in liver only. Catecholamines and glucagon are the most important hormones in the maintenance of euglycemia.
  • Increased growth hormone plays a minor role in counteracting acute hypoglycemia but may be important in ensuring substrate supply (to liver and kidney) for gluconeogenesis by stimulating lipolysis. It also antagonizes the action of insulin in muscle, thereby limiting glucose use.
  • Increased cortisol probably plays little or no role in responding to acute hypoglycemia but may be important in ensuring sustained gluconeogenesis by stimulating lipolysis and protein catabolism. Cortisol is also toxic to the beta islet cell causing further decrease in insulin secretion.

In the fasting state (4-6 hours after a meal, also known as post absorptive), euglycemia is maintained by glucose output by the liver through glycogenolysis (and to a lesser extent by the renal cortex through gluconeogenesis). After an overnight fast, about half of the hepatic glucose production comes from glycogenolysis and half from gluconeogenesis. After 42 hours of fasting, glycogen stores are depleted and all glucose production comes from gluconeogenesis. Gluconeogenesis is the formation of glucose from glycerol (derived from lipolysis of triglycerides), amino acids (derived from breakdown of muscle) and lactate (derived from blood cell elements). Oxidation of free fatty acids (derived from lipolysis of triglycerides) supply energy required for gluconeogenesis, and provide ketoacids which can be used as alternative fuel by the CNS. A healthy liver has a production capacity for glucose output finely tuned to match glucose use. A prolonged fast will result in hypoglycemia only if there is a defect in the ability to maintain euglycemia. The main issue in hypoglycemia is almost always poor glucose output by the liver. This probably holds true even in states of insulin excess where we usually think of excessive glucose uptake as the problem; excessive glucose uptake and elimination does occur but it is the inhibitory action of insulin on the liver and alpha pancreatic cells (suppressing glucagon) that keep the glucose level down. The hormonal regulation of blood glucose is also shown schematically in Figure 1, below.

Figure 1. Regulation of Blood Glucose
Figure. Regulation of Blood Glucose

4. Definition of Hypoglycemia

Symptoms of hypoglycemia can be non-specific; therefore symptoms alone cannot define hypoglycemia. Often, symptoms may not be recognized. Moreover, symptoms are idiosyncratic, namely unique to the individual. Hypoglycemia is clinically defined by the Whipple's triad:

  1. Symptoms suggestive of hypoglycemia (see Table 2)
  2. A documented low blood glucose level
  3. Improvement of symptoms and glucose levels by administration of glucose

Note that the above definition does not include an absolute level of glucose. This level is often defined as a blood glucose < 50 mg/dl, but it is better to define low blood glucose as a blood glucose "too low for the individual". In fact, hormonal changes as part of normal physiology start at a level below 75-80 mg/dl. However, the wide range of glucose levels seen in normal individuals preclude the use of an absolute glucose level for defining hypoglycemia. For example,

  • Fasting plasma glucose in healthy individuals is less than 100 mg/dl. With modest fasting (12-24 hours), glucose of healthy men may fall as low as 50 mg/dl while 10-15% of healthy women will have a glucose that falls below 50 mg/dl.
  • During oral glucose tolerance testing, 10-25% of healthy individuals have a glucose level less than 50 mg/dl following the glucose peak, often without symptoms.
  • When healthy individuals underwent continuous glucose monitoring during a normal day, approximately 50% of them had a glucose level less than 50 mg/dl at some point during the day without symptoms.

Very low levels (< 40 mg/dl) are frequently symptomatic and may indicate an abnormality.

5. Etiology and Classification of Hypoglycemia

The traditional separation of causes of hypoglycemia into fasting (at least 6 hours following a meal) and non-fasting (or "reactive") helps guide clinicians in thinking about the etiology. Since hypoglycemia (especially in the outpatient setting) may be difficult to document, symptoms and/or signs are the main driving force for pursuing the diagnosis. Timing of symptoms and signs at varying times after eating or in the fasting state is important, especially if observed by someone else.

5.1. Fasting Hypoglycemia

Fasting hypoglycemia can be a life threatening condition. As mentioned previously, symptoms of hypoglycemia may not be obvious and a patient can be misdiagnosed as having a psychiatric disorder if the hypoglycemia is not recognized. Documenting hypoglycemia is often quite difficult because it may not be persistent but may occur erratically. The causes of fasting hypoglycemia can be subdivided in those occurring with appropriate (low) insulin level and those occurring with inappropriate hyperinsulinemia. Therefore, the most important tests when someone presents with symptoms/signs suggestive of hypoglycemia are measuring the glucose and a simultaneous insulin level.

5.1.1. Appropriate (Low) Insulin Level

Hypoglycemia with appropriate (low) insulin level often occurs in patients who are ill or have an obvious medical condition that predisposes them to hypoglycemia. Below are some common causes.

5.1.1.1. Alcohol

Alcohol hypoglycemia usually occurs in the absence of overt liver disease and it is more likely if the patient is fasting or exercising or is sensitive to alcohol; it is less likely if the patient is obese. The alcohol directly interferes with hepatic gluconeogenesis but not glycogenolysis. The energy required for metabolism of alcohol is diverted away from the energy needed to take up lactate, a substrate of gluconeogenesis. So, patients who drink alcohol may become hypoglycemic after 12-24 hours when the glycogen stores are depleted. An additional challenge is the fact that neuroglycopenic symptoms of hypoglycemia may be confused with alcohol intoxication. Conclusion: if you drink, eat!

5.1.1.2. Endocrine deficiencies

Certain endocrine deficiencies are associated with poor gluconeogenesis, poor glycogenolysis, or both. These include: adrenal insufficiency (primary or secondary), hypopituitarism (loss of ACTH and growth hormone), isolated growth hormone deficiency (very rare), hypothyroidism (uncommon cause of hypoglycemia), isolated glucagon deficiency (rare), and sympathetic nervous system defects.

5.1.1.3. Liver insufficiency / failure

Liver insufficiency / failure from any cause may result in deficient glycogen stores or inadequate gluconeogenesis. In advanced liver failure, the defects may be severe enough to cause hypoglycemia.

5.1.1.4. Renal insufficiency / failure

The renal cortex has the capacity to produce glucose by gluconeogenesis. However, isolated renal failure is rarely associated with hypoglycemia. More often, renal failure is associated with hypoglycemia in patients with diabetes who are on insulin or insulin secretagogues as insulin is cleared by the kidney. Therefore, in renal insufficiency, a dose adjustment of diabetes therapy is often necessary to avoid hypoglycemia.

5.1.1.5. Septic shock

Hypoglycemia can occur due to decreased gluconeogenesis.

5.1.1.6. Pregnancy

Pregnancy is associated with lower glucose level because of decreased gluconeogenesis due to decreased substrate supply (diversion of energy to fetus). Decreased nutrient intake may precipitate symptomatic hypoglycemia.

5.1.1.7. Tumors

Non-endocrine such as large mesenchymal tumors may be associated with hypoglycemia. Although the pathogenesis is incompletely understood, it is believed that these tumors may secrete an insulin like substance that may be biologically active (Insulin like Growth Factor type 2, IGF-2). An alternative hypothesis is that these tumors are so large that they require a significant amount of glucose the liver/kidney are unable to match. Complete removal of the tumor cures the hypoglycemia.

5.1.1.8. Inborn errors of carbohydrate metabolism

Inborn errors of carbohydrate metabolism (glycogen storage disease, gluconeogenic enzyme deficiencies) are rare and present during the first days of life. Infants present with fasting hypoglycemia, especially at night. Treatment consists of frequent feedings.

5.1.2. Inappropriate (High) Insulin Level

5.1.2.1. Insulin reaction in patients with diabetes

This is the most common cause of hypoglycemia, due to an imbalance between insulin supply and insulin requirements. Hypoglycemia is a fact of life for patients with type 1 diabetes, with severe episodes occurring about once a year. More common in those with good glycemic control. In addition to physical morbidity due to symptoms, the psychological morbidity of hypoglycemia is significant and may limit attempts at optimal control of diabetes. In patients with type 2 diabetes, those on oral insulin secretagogues (see next section) or insulin are at highest risk for hypoglycemia.

It is important to recognize that in patient with diabetes glycemic thresholds for symptoms are dynamic. Patients with poor control may develop symptoms of "hypoglycemia" at glucose concentrations higher that those required to elicit symptoms in patients without diabetes.

Causes include insulin overdose (due to poor vision, inadequate understanding etc.) or erroneous dosing of insulin secretagogue medication (see below), inadequate food intake or excessive exercise (which results in increased glucose uptake by muscle and accelerated insulin uptake from injection site if it is near the exercising muscle). Other reasons for patients with diabetes to be prone to hypoglycemia include: impaired glucose counterregulatory mechanisms (deficient glucagon response in type 1 diabetes, deficient catecholamine response associated with autonomic neuropathy), hypocortisolism (concomitant autoimmune primary adrenal insufficiency disease in type 1 diabetics), gastroparesis (due to delayed gastric emptying), pregnancy, renal insufficiency (decreased insulin degradation and impaired renal cortex gluconeogenesis) and various medications (ACE Inhibitors, beta-blockers).

5.1.2.2. Insulin secretagogue overdose in type 2 diabetes patients.

Insulin secretagogues are oral hypoglycemic agents that work by stimulating insulin release from beta islet cells and, therefore, have the potential to cause hypoglycemia. Sulfonylureas (the most commonly prescribed type of these medications) are cleared by the kidney, so elderly patients with compromised renal function are at risk for developing hypoglycemia while on these agents. Short acting insulin secretagogues cause less hypoglycemia (see lecture on diabetes treatment). Hypoglycemia due to insulin secretagogue may be confused with insulinoma (see 5.1.2.6).

5.1.2.3. Factitious hypoglycemia (self induced or inadvertent)

Factitious hypoglycemia is usually due to insulin administration or intake of oral insulin secretagogues. Patients often have easy access to these medications (e.g. health professional, patient with diabetes or his/her relative). This form of hypoglycemia has been the means for suicide and murder.

5.1.2.4. Autoimmune hypoglycemia

Autoimmune hypoglycemia is extremely rare. There are two mechanisms: (1) Insulin auto antibodies bind to insulin after it is secreted following a meal; hypoglycemia occurs 3-4 hours later as insulin-antibody immune complexes dissociate. (2) Insulin receptor autoantibodies that bind to insulin receptor mimicking the action of insulin.

5.1.2.5. Pentamidine

Pentamidine used for treatment/prophylaxis of PCP in patients with AIDS can cause hypoglycemia by direct injury to the beta islet cells causing hyperinsulinemia. Following the acute injury and destruction of the beta cells, patients may experience hyperglycemia.

5.1.2.6. Excess Insulin Secretion (Insulinoma)

Excess insulin secretion is usually due to an Insulinoma, an insulin secreting tumor of the beta islet cells. Insulinoma, although a favorite diagnosis among medical students and residents and a frequent source of exam questions, is rare: it comprises only 1% of all suspected cases of hypoglycemia. They are more common in men (M:F 8:1). Nearly all insulinomas are found in the pancreas and 90% of them are single and benign. They arise from the cells of the ductal/acinal system of the pancrease. Insulinomas may be familiar and associated with other endocrine neoplasia as part of the Multiple Endocrine Neoplasia syndrome type 1. Insulinomas most often cause fasting hypoglycemia and symptoms are often neuroglycopenic in nature, probably related to the acute and extreme hypoglycemia associated with them.

On testing, a high insulin level (> 6 microU/ml) coexisting with a clearly low glucose level ( < 45 mg/dl). However, the insulin assay cannot differentiate between endogenous or exogenous insulin, so that simultaneous measurement of C-peptide is often necessary to distinguish between endogenous hyperinsulinemia from an insulinoma or administration of insulin secretagogue medications (in both occasions, C-peptide level will be high, > 0.2 nmol/l) and exogenous from insulin administration (C-peptide will be suppressed, < 0.2 nmol/l). Another useful marker may be the level of pro-insulin, a precursor of insulin that is cleaved to insulin and C-peptide. Insulinomas are inefficient producers of insulin and often they produce and release pro-insulin in greater proportion than normal beta islet cells, so that the pro-insulin / insulin ratio in patients with insulinoma is often greater than 30%.

The diagnosis is not always straightforward as many patients with proven insulinoma are euglycemic most of the time. One must then turn to dynamic testing (Suppression Testing) (see below).

Once the diagnosis of insulinoma is confirmed based on dynamic testing (described below), the tumor needs to be localized prior to an attempt for surgical resection. Imaging modalities include:

  • Abdominal CT.
  • Abdominal MRI.
  • Ultrasound of the pancreas.
    • Transabdominal
    • Endoscopic
  • Angiography. The tumor appears as a "blush" after injection of dye. Arteriography is invasive, can have false positives as well as false negatives and it is therefore not used frequently.
  • Arterial Calcium stimulation with hepatic venous sampling for insulin. The pancreatic arterial supply is injected with calcium which stimulates insulin secretion from neoplastic beta islet cells (but not from normal beta islet cells). Insulin is sampled at the hepatic vein. Documenting a step-up in insulin may help localize the insulinoma at the pancreatic site supplied by the specific artery.
  • Intra-operative ultrasound perused when-pre-operative localization is not successful.

Treatment of insulinoma is surgical removal. Note that 5% of insulinomas are multiple, 5% are malignant. Reversible hyperglycemia is often seen after surgery. Cure approaches 80%.

If surgery is not successful or is not possible, e.g., with metastatic carcinoma, the following medical therapy is given: diazoxide which inhibits secretion of insulin but has no effect on tumor growth, somatostatin analogue of octreotide which modestly inhibits release of insulin, streptozotocin, an antineoplastic as well as anti-beta-cell.

5.1.3. Dynamic Testing for Fasting Hypoglycemia

Provocative testing for hypoglycemia is done with the Prolonged Fasting Test (also known as "72 hour Fasting"). This is a classic suppression test used to differentiate between the various causes of fasting hypoglycemia with inappropriate hyperinsulinemia. The principle behind the test is simple: the patient begins to fast and as the glucose level falls, insulin secretion should shut off and all other hormonal responses should occur to maintain euglycemia; if hypoglycemia occurs, then pathology is present. The test is stopped when symptoms suggestive of hypoglycemia develop AND the blood glucose falls below 55 mg/dl., after 72 hours or if glucose is 45mg/dl regardless of the presence of symptoms.

At the end of the prolonged fasting, the following blood measurements are made: glucose, insulin, pro-insulin, C-peptide, beta-hydroxybutyrate and sulfonylurea. Then, 1 mg of glucagon is injected intravenously and plasma glucose is measured after 10, 20 and 30 minutes. The patient is then fed.

Interpretation of Prolonged Fasting Test (the details are not necessary to know but the principles behind the test are important to understand).

  • High insulin > 3 microU/ml with a low glucose < 55 mg/dL indicates inappropriate hyperinsulinemia
  • To verify endogenous production of insulin, C-peptide must be elevated. Pro-insulin is also checked. Pro-insulin may comprise a higher proportion of immunoreactive insulin ( >30 %) in patients with insulinoma compared to normal individuals.
  • To rule out exogenous administration of hypoglycemic agents, blood is tested for the presence of insulin secretagogues (e.g. sulfonylureas).
  • Because Insulin is antiketogenic, plasma beta-hydroxybutyate concentrations are lower in insulinoma patients when compared to normals after a fast.
  • Insulin is antiglycogenolytic and hyperinsulinemia permits retention of glycogen in the liver even after a fast. Normal subjects will have released all of their glycogen stores at the end of the fast (as insulin is shut off and glucagon levels are high). As a result, patients with insulinoma will increase their plasma glucose following glucagon injection more than normal.

5.2. Postprandial Hypoglycemia

Postprandial hypoglycemia may be classified as structural / organic or functional.

5.2.1. Structural / Organic

5.2.1.1. Alimentary

This is due to rapid emptying of gastric contents to the small intestine producing a rapid elevation of insulin (via vagal signals and enteropeptides) which then leads to hypoglycemia. This is usually seen after gastric surgery but rapid transit may occur without surgery. Treatment consists of small frequent meals.

5.2.1.2. Type 2 Diabetes

In early type 2 diabetes, the first phase of insulin release is often lost and the second phase is prolonged. It is thought that the delayed insulin secretory peak after glucose absorption causes hypoglycemia in the latter stages following a meal (3-5 hours later). The frequency of this observation is unknown as not all patients with the same delayed insulin effect develop hypoglycemia. One must speculate that those who do are more sensitive to the same amount of insulin and/or have an unknown defect in their counterregulatory defenses. Treatment consists of weight reduction, small meals with low glycemic index and insulin secretagogues which augment first phase insulin secretion.

5.2.1.3. Endocrine Deficiency

Endocrine deficiency is very rare as a post-prandial cause of hypoglycemia.

5.2.2. Functional

5.2.2.1. Idiopathic Postprandial Syndrome

This is a confusing condition and a frustrating diagnosis to give a patient as there is no good diagnostic test and no effective treatment. Unfortunately, it is this category that most patients with symptoms suggestive of hypoglycemia fall into. This syndrome was formerly known as functional or "reactive" hypoglycemia. The syndrome consists of a constellation of symptoms including but not limited to light-headedness, headache, dizziness, weakness, poor concentration, and tremulousness, often occurring a few hours following a meal. These symptoms were attributed to hypoglycemia based on reproduction of the patient's symptoms in association with a low blood glucose following a oral glucose tolerance test (OGTT).

However, it turns out that most of these patients suspected of postprandial hypoglycemia probably do not have it. If they do have hypoglycemia, it is transient and often not related to their symptoms. Some have argued against this diagnosis for the following reasons: Many healthy individuals have a very low glucose level at some point during an OGTT without symptoms. The reverse happens often as well, that is people often show symptoms during OGTT without a documented low blood glucose. The "meal" usually given to test these patients for post prandial hypoglycemia in the 5 hour OGTT is the standard 75 g or 100 g glucose drink. A major argument against using this test is that this is not a normal meal and and it is not the meal that caused the symptoms in the first place. Thus, it is better to use a standard "mixed meal" that mimics what the patient usually eats. When this is done, the prevalence of hypoglycemia plummets. For all these reasons, some authorities advise against using the standard 5 hour OGTT to make the diagnosis of postprandial hypoglycemia.

Treatment of this syndrome focus on dietary interventions: a low carbohydrate diet (or at least one low in refined carbohydrate) with multiple small meals is often recommended although that is not usually successful. Most of these patients remain symptomatic and they only transfer their care to another health care professional who is able to perform additional diagnostic work-up and potentially offer them treatment.

6. References

  • Service J (Editor). Hypoglycemic Disorders.Endocrinology and Metabolism Clinics of North America, September 1999.
  • Wolfsdorf JI, Holm IA, Weinstein DA. Glycogen storage diseases. Phenotypic, genetic, and biochemical characteristics, and therapy. Endocrinol Metab Clin North Am 1999 Dec;28(4):801-23.
  • Greenspan FS and Gardner DG (Editors). Lange: Basic & Clinical Endocrinology, 6th Edition, 2001 pp 699-715.
  • Cryer PE, Davis SN and Shamoon H. Hypoglycmia in Diabetes.Diabetes Care 2003:26:6:1902
  • Cryer PE. Diverse Causes of Hypoglycemia-Associated Autonomic Failure in Diabetes. N Engl J. Med 2004:350:22:2272-2279.