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Physicians

HYPOGLYCEMIAEPIDEMIOLOGY:

Hypoglycemia is common in type 1 diabetes, especially in patients receiving intensive insulin therapy, in whom the risk of severe hypoglycemia is increased more than threefold in the Diabetes Control and Complications Trial (DCCT). Plasma glucose concentrations may be less than 50 to 60 mg / dL (2.8 to 3.3 mmol/L) as much as 10 percent of the time.(1) Patients with type 1 diabetes may suffer an average of two episodes of symptomatic hypoglycemia per week, thousands of such episodes over a lifetime of diabetes, and one episode of severe, at least temporarily disabling hypoglycemia per year.

Hypoglycemia is less frequent in type 2 diabetes than it is in type 1.(1,2) Population-based data indicate that the overall event rate for severe hypoglycemia (requiring the assistance of another individual) in insulin-treated type 2 diabetes is approximately 30 percent of that in type 1 diabetes (35 versus 115 episodes per 100 patient-years)(3) and that event rates for hypoglycemia requiring professional emergency medical treatment range from 40 to 100 percent of those in type 1 diabetes.(4,5)

In contrast to patients with diabetes, hypoglycemia is uncommon in individuals who do not have drug-treated diabetes mellitus.(6,7)

PATHOPHYSIOLOGY:

Hypoglycemic symptoms are related to sympathetic activation and brain dysfunction secondary to decreased levels of glucose. Stimulation of the sympathoadrenal nervous system leads to sweating, palpitations, tremulousness, anxiety, and hunger. Reduction in cerebral glucose availability (i.e. neuroglycopenia) can manifest as confusion, difficulty with concentration, irritability, hallucinations, focal impairments (e.g. hemiplegia), and, eventually, coma and death.

The adrenergic symptoms often precede the neuroglycopenic symptoms and, thus, provide an early warning system for the patient. Studies have shown that the primary stimulus for the release of catecholamines is the absolute level of plasma glucose; the rate of decrease of glucose is less important. Previous blood sugar levels can influence an individual's response to a particular level of blood sugar. However, it is important to note that a patient with repeated hypoglycemia can have almost no symptoms (hypoglycemic unawareness). The threshold at which a patient feels the hypoglycemic symptoms decreases with repeated episodes of hypoglycemia.

SIGN AND SYMPTOMS:

The symptoms of hypoglycemia in patients with and without diabetes are nonspecific. Hypoglycemia causes neurogenic (autonomic) and neuroglycopenic symptoms.

  • The neurogenic symptoms include tremor, palpitations, andanxiety / arousal (catecholamine-mediated, adrenergic) and sweating, hunger, and paresthesias (acetylcholine-mediated, cholinergic).(1,8,9) They are largely caused by sympathetic neural, rather than adrenomedullary, activation.(10)
  • The neuroglycopenic symptoms include cognitive impairment, behavioral changes, psychomotor abnormalities and, at lower plasma glucose concentrations, seizure and coma.(8,9,11) Although profound prolonged hypoglycemia can cause brain death in the unobserved patient with diabetes, the vast majority of episodes are reversed after the glucose level is raised to normal and the rare fatal episodes are generally thought to be the result of ventricular arrhythmia.(11)

In the patient without diabetes, the occurrence of neuroglycopenic symptoms provides clinically compelling evidence of an underlying hypoglycemic disorder.(12,13) Recognition of neurogenic symptoms by patients with diabetes, however, can lead to prompt self-treatment.

Patients who have only sympathoadrenal symptoms (anxiety, weakness, tremor, perspiration, or palpitations), but normal concurrent plasma glucose concentrations, and resolution of symptoms after dietary modification have a low probability of having a hypoglycemic disorder. This combination is most common in patients with postprandial symptoms.

SIGNS: Diaphoresis and pallor are common signs of hypoglycemia.(1,12) Heart rates and systolic blood pressures are raised, but not greatly. Neuroglycopenic manifestations are often observable. Occasionally, transient neurologic deficits occur. Permanent neurologic damage is rare and, should it occur, it would be more likely in a patient with diabetes and prolonged severe hypoglycemia.

LABORATORY FINDINGS: The lower limit of the normal fasting plasma glucose value is typically 70 mg / dL (3.9 mmol / L). In nondiabetic persons, the secretion of insulin decreases as glucose levels decline within the physiological range, and the release of counter regulatory hormones, glucagon and epinephrine, increases when the glucose concentration falls to 65 to 70 mg / dL (3.6 to 3.9 mmol / L). Growth hormone and cortisol secretion also increase at similar plasma glucose concentrations. These hormonal responses begin well before the onset of symptoms of hypoglycemia, which normally occur at glucose levels of 50 to 55 mg / dL (2.8 to 3.0 mmol / L).

DIAGNOSTIC TEST:

Candidates for evaluation: The presence of a hypoglycemic disorder in a person without diabetes should not be suspected solely on the basis of a low plasma glucose concentration,(12,14) as this observation is necessary but insufficient for a diagnosis and in some cases may be misleading. Only those patients in whom Whipple's triad is documented require evaluation and management of hypoglycemia.

Whipple's triad includes the following:

  • Symptoms consistent with hypoglycemia
  • A low plasma glucose concentration measured with a precise method (not a home glucose monitor) when symptoms are present
  • Relief of those symptoms after the plasma glucose level is raised.

CLINICAL EVALUATION: The first step is to review the patient's history in detail, including the nature and timing of symptoms (particularly in relationship to meals), existence of underlying illnesses or conditions, medications taken by the individual and by family members, and social history. Clinical evidence for adrenal insufficiency or nonislet cell tumor should be considered. In a patient with documented hypoglycemia, the cause may be apparent from the history and physical examination.

LABORATORY TESTING: The presence of a hypoglycemic disorder in a person without diabetes should not be inferred solely on the basis of a low plasma glucose concentration, unless the value is severely depressed (<40 mg / dL [2.2 mmol / L]).

The purpose of the initial laboratory evaluation is to document Whipple's triad.(14) Should Whipple's triad have been demonstrated previously, the goal of testing is to assess the role of insulin in the genesis of the hypoglycemia.

Patients who are fortuitously observed during an episode of symptoms and are found to have hypoglycemia at that time should have the following blood tests:

  • Glucose
  • Insulin
  • C-peptide
  • Beta-hydroxybutyrate (BHOB)
  • Proinsulin
  • Sulfonylurea and meglitinide screen

In patients with endogenous hyperinsulinism, insulin antibodies should be measured to distinguish insulin autoimmune hypoglycemia from other causes of hyperinsulinism. Insulin antibodies do not need to be drawn during hypoglycemia.

FASTING EVALUATION: There are patients in whom symptoms occur after only a short period of food withdrawal. In such patients, continued observation in the office or clinic, especially if they have fasted overnight, may result in an episode of symptomatic hypoglycemia.(14) Plasma glucose should be measured repeatedly during the period of observation. If symptoms occur and hypoglycemia is documented (plasma glucose <55 mg / dL [3 mmol / L]), the other tests described above should be performed. The results may obviate the need for a provocative test, such as the 72-hour fast.

If this approach causes neither symptoms nor hypoglycemia and if clinical suspicion remains high, the patient should undergo a 72-hour fast.

POSTPRANDIAL EVALUATION: If symptoms of hypoglycemia typically occur within five hours after eating, patients should be evaluated in the postprandial state (mixed meal test).

72-HOUR FAST: The purpose of the 72-hour fast is to provoke the homeostatic responses that keep blood glucose concentrations from falling to concentrations that cause symptoms in the absence of food. Increased release of glucagon, epinephrine and, to a lesser degree, growth hormone and cortisol are the most important components of this response. All the hormonal responses begin well before the onset of symptomatic hypoglycemia.

Normal subjects do not have symptomatic hypoglycemia after a prolonged fast because of a hormonally mediated increase in glucose production. Gluconeogenesis accounts for approximately 50 percent of glucose production after an overnight fast and for almost all glucose production after 42 hours or more of fasting.(15)

The prolonged fast will result in hypoglycemia only if there is a defect in the ability to maintain normoglycemia due, for example, to an excess of insulin. The defect should be identifiable if appropriate testing is performed.

PLASMA INSULIN: A plasma insulin concentration of 3 microU / mL (20.8 pmol / L) by immunochemiluminometric assay (ICMA) when the plasma glucose concentration is below 55 mg / dL (3.0 mmol / L) indicates an excess of insulin and is consistent with hyperinsulinemia (e.g. insulinoma).

PLASMA C-PEPTIDE: It is essential to measure plasma C-peptide at the end of the fast; measurement of plasma proinsulin can also be helpful.(16-18) Plasma C-peptide distinguishes endogenous from exogenous hyperinsulinemia.

PLASMA BETA-HYDROXYBUTYRATE: Because of the antiketogenic effect of insulin, plasma BHOB concentrations are lower in insulinoma patients than in normal subjects. All patients with insulinoma had plasma BHOB values of 2.7 mmol / L or less at the end of the fast, whereas normal subjects had higher values. A progressive rise in the concentration of BHOB after the 18-hour point of the fast is indicative of a negative fast.(19)

The plasma BHOB value, as well as the glucose response to glucagon, can be used to confirm the diagnosis in patients in whom the insulin and C-peptide values are in the borderline range (e.g. plasma insulin concentration of <3 microU/mL [20.8 pmol / L], C-peptide <0.2 nmol / L [0.6 ng / mL]) or to indicate the action of an insulin-like factor.

GLYCEMIC RESPONSE TO GLUCAGON: Insulin is antiglycogenolytic and hyperinsulinemia permits retention of glycogen within the liver. As a result, patients with insulin-mediated hypoglycemia respond to 1 mg of intravenous glucagon (a potent glycogenolytic agent) by releasing glucose. Normal subjects will have released virtually all glucose from the liver at the end of the 72-hour fast and cannot therefore respond as vigorously to intravenous glucagon as a patient with an insulinoma. At the end of the fast, patients with an insulinoma have an increase in plasma glucose of 25 mg / dL (1.4 mmol / L) or more in 20 to 30 minutes, whereas normal subjects have a smaller increment.

DETERMINING THE CAUSE OF HYPOGLYCEMIA: By observing the presence of symptoms and signs of hypoglycemia, and by making the above biochemical measurements, it is usually possible to distinguish among the various causes of hypoglycemia.(6)

  • Plasma insulin, C-peptide, and proinsulin values are elevated in patients with insulinoma, oral hypoglycemia agent-induced hypoglycemia, and insulin autoimmune hypoglycemia.

Sulfonylurea or meglitinides are present in the plasma only in oral hypoglycemic agent-induced hypoglycemia.(20)

The presence of insulin or insulin receptor antibodies can distinguish insulin autoimmune hypoglycemia from insulinoma.(21) Insulin autoimmune hypoglycemia occurs in patients who have antibodies directed to endogenous insulin or to the insulin receptor. Symptoms can occur postprandially, fasting, or in both states. In patients with insulin autoantibodies, it is presumed that insulin secreted in response to a meal binds to the antibody and then disassociates in an unregulated fashion causing hyperinsulinemia and hypoglycemia. In patients with antibodies to the insulin receptor, hypoglycemia occurs as a result of antibody activation of the receptor.

  • Plasma insulin, C-peptide, and proinsulin values are also elevated in patients with noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS). NIPHS is endogenous hyperinsulinemia due to islet hypertrophy and nesidioblastosis, a form of primary islet cell hypertrophy with neodifferentiation of islet of Langerhans cells from pancreatic duct epithelium. An unusual feature of this disorder is that hypoglycemia occurs postprandially, two to four hours after a meal. Fasting hypoglycemia, characteristic of insulinoma, is rare in this disorder.
  • Plasma insulin values are high in patients with exogenous insulin administration, whereas plasma C-peptide and proinsulin values are low.
  • Plasma insulin, C-peptide, and proinsulin concentrations are not elevated in patients with nonislet cell tumors. Nonislet cell tumors can cause hypoglycemia via a number of mechanisms not related to hypersecretion of insulin, including tumor production of insulin-like growth factor-II or more often its precursor, and tumor burden in which the tumor cell's high metabolic needs and reduced hepatic glycogen stores are thought to be responsible for hypoglycemia.

RADIOLOGIC STUDIES: Computed tomography (CT), magnetic resonance imaging (MRI), and transabdominal ultrasonography can detect most insulinomas.(22,23) The choice of procedure depends upon which tests are available and local radiologic skill. Transabdominal ultrasonography is preferred initial test.

A negative imaging study does not exclude insulinoma. If an insulinoma is not visible with initial imaging, additional studies, such as endoscopic ultrasonography, sometimes with fine-needle aspiration biopsy of detected tumors, or selective arterial calcium stimulation, are required.

Arterial calcium stimulation: A selective arterial calcium stimulation test with hepatic venous sampling can be performed to distinguish between a focal abnormality (insulinoma) and a diffuse process (islet cell hypertrophy / nesidioblastosis).

TREATMENT OPTIONS:

The mainstay of therapy for hypoglycemia is glucose. Other medications may be administered based on the underlying cause or the accompanying symptoms; however, these medications are not addressed here.

GLUCOSE SUPPLEMENT: Glucose supplements are used to raise the patient's serum glucose.

DEXTROSE (GLUCOSE-D): Dextrose is a monosaccharide absorbed from intestine and distributed, stored, and used by tissues. Parenterally injected, dextrose is used in patients unable to obtain adequate oral (PO) intake. Direct oral absorption results in rapid increase of blood glucose concentrations.

GLUCOSE-ELEVATING AGENTS: Glucose-elevating agents can act in the pancreas or the peripheral tissues to increase blood glucose levels.

GLUCAGON: Pancreatic alpha cells of islets of Langerhans produce glucagon, a polypeptide hormone. This agent exerts effects opposite of insulin on blood glucose and elevates blood glucose levels by inhibiting glycogen synthesis and enhancing formation of glucose from noncarbohydrate sources, such as proteins and fats (gluconeogenesis).

Glucagon also increases hydrolysis of glycogen to glucose (glycogenolysis) in the liver. This agent accelerates hepatic glycogenolysis and lipolysis in adipose tissue by stimulating cyclic AMP (cAMP) synthesis via adenylyl cyclase and enhancing phosphorylase kinase activity.

Glucagon may be useful when intravenous (IV) access is problematic. This agent may be administered as part of emergency medical services (EMS) protocol in patients with altered mental status and no IV access.

INHIBITORS OF INSULIN SECRETION: Agents that inhibit insulin secretion increase glucose levels by reducing peripheral glucose metabolism.

DIAZOXIDE: Diazoxide is a direct inhibitor of insulin secretion. This agent increases hepatic glucose output by inhibiting pancreatic insulin release and, possibly, through an extrapancreatic effect, as well as decreases cellular glucose uptake. Although, diazoxide has a very limited role in treating hypoglycemia, it can help improve symptoms of hypoglycemia caused by increased insulin secretion in patients awaiting surgery or those with nonresectable disease and may be indicated in some cases of insulinoma or overdosage with oral (PO) hypoglycemic agents.

Hyperglycemic effect starts within 1 hour, lasting a maximum of 8 hours if the patient's renal function normal. Patients with refractory hypoglycemia may require high dosages.

OCTREOTIDE: This agent Inhibits insulin secretion. Octreotide acts primarily on somatostatin receptor subtypes II and V. It also inhibits growth hormone secretion and has a multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, vasoactive intestinal peptides (VIP), and gastrointestinal peptides.

ANTINEOPLASTIC AGENTS: Antineoplastic agents inhibit cell growth and proliferation.

STREPTOZOCIN: Streptozocin has a high affinity for neuroendocrine cells, inhibits cell proliferation, and is cytolytic. This agent interferes with normal DNA function by alkylation and protein modification.

GOALS OF TREATMENT:

The goals of treatment for hypoglycemia are to detect and treat a low Blood sugar level promptly by using an intervention that provides the fastest rise in Blood sugar to a safe level, to eliminate the risk of injury and to relieve symptoms quickly. It is also important to avoid overtreatment since this can result in rebound hyperglycemia and weight gain.

GUIDELINES:

In 2009, The Endocrine Society published evidence-based guidelines for the evaluation and management of hypoglycemic disorders in adults.(12) These were updated in 2013 by a joint workgroup of the American Diabetes Association (ADA) and the Endocrine Society.(13)

To view “2009 Endocrine Society evidence-based guidelines for the evaluation and management of hypoglycemic disorders in adults” please visit on below page:

http://press.endocrine.org/doi/pdf/10.1210/jc.2008-1410

To view “updated version 2013 by a joint workgroup of the American Diabetes Association (ADA) and the Endocrine Society” please visit on below page:

http://press.endocrine.org/doi/pdf/10.1210/jc.2012-4127

CONSULTATION AND COUNSELLING:

Diabetic patients with episodes of hypoglycemia need education in nutrition, checking glucose levels at home, and early signs and symptoms of hypoglycemia. Recognition of early symptoms is paramount for self-treatment.

Guidelines from a workgroup of the American Diabetes Association (ADA) and the Endocrine Society address the dangers of hypoglycemia in diabetic patients. The workgroup developed 2 tools for clinicians treating those with diabetes: a patient questionnaire and a provider checklist.(24,25)

The Hypoglycemia Patient Questionnaire includes the following questions:

  • How well can you recognize the symptoms of low blood glucose?
  • How often do you have hypoglycemic episodes?
  • Have you needed assistance in the past during a hypoglycemic episode?
  • Do you check your glucose level before driving?
  • Do those close to you know how to administer glucagon?

The Hypoglycemia Provider Checklist is designed to verify that the clinician has asked the appropriate questions of the patient and has made the appropriate recommendations for managing low blood sugar.

The Hypoglycemia Provider Checklist asks clinicians if they have reviewed the Hypoglycemia Patient Questionnaire, asked the patient about circumstances surrounding severe or moderate hypoglycemia, discussed strategies to avoid hypoglycemic episodes, made appropriate medication changes, prescribed glucagon, and recommended carrying a snack or glucose tablets or other source of 15 g of carbohydrate in case of hypoglycemia episodes.

PRECAUTIONS:

Offer patient following tips, if patient is diabetic:

  • Don't skip or delay meals or snacks: If you take insulin or oral diabetes medication, be consistent about the amount you eat and the timing of your meals and snacks.
  • Monitor your blood sugar: Depending on your treatment plan, you may check and record your blood sugar level several times a week or several times a day. Careful monitoring is the only way to make sure that your blood sugar level remains within your target range.
  • Measure medication carefully, and take it on time: Take your medication as recommended by your doctor.
  • Adjust your medication or eat additional snacks if you increase your physical activity: The adjustment depends on the blood sugar test results and on the type and length of the activity.
  • Eat a meal or snack with alcohol, if you choose to drink: Drinking alcohol on an empty stomach can cause hypoglycemia.
  • Record your low glucose reactions: This can help you and us to see patterns contributing to hypoglycemia and find ways to prevent them.
  • Carry some form of diabetes identification so that in an emergency others will know that you have diabetes: Use a medical identification necklace or bracelet and wallet card.
  • Always have fast acting carbohydrate: Be sure to always have a fast-acting carbohydrate with you, such as juice or glucose tablets, so you can treat a falling blood sugar before it dips dangerously low.

If patient is non-diabetes but have recurring episodes of hypoglycemia, eating frequent small meals throughout the day is a stopgap measure to help prevent blood sugar levels from getting too low. However, this approach isn't an advisable long-term strategy. Identity and treat the underlying cause of hypoglycemia.

REFERENCES:

  • Cryer PE. Hypoglycemia in diabetes: Pathophysiology, prevalence, and prevention, 2nd, American Diabetes Association, Alexandria, VA 2012.
  • Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008; 57:3169.
  • Donnelly LA, Morris AD, Frier BM, et al. Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study. Diabet Med 2005; 22:749.
  • Holstein A, Plaschke A, Egberts EH. Clinical characterisation of severe hypoglycaemia--a prospective population-based study. Exp Clin Endocrinol Diabetes 2003; 111:364.
  • Leese GP, Wang J, Broomhall J, et al. Frequency of severe hypoglycemia requiring emergency treatment in type 1 and type 2 diabetes: a population-based study of health service resource use. Diabetes Care 2003; 26:1176.
  • Service FJ. Hypoglycemic disorders. N Engl J Med 1995; 332:1144.
  • Service FJ. Classification of hypoglycemic disorders. Endocrinol Metab Clin North Am 1999; 28:501.
  • Hepburn DA, Deary IJ, Frier BM, et al. Symptoms of acute insulin-induced hypoglycemia in humans with and without IDDM. Factor-analysis approach. Diabetes Care 1991; 14:949.
  • Towler DA, Havlin CE, Craft S, Cryer P. Mechanism of awareness of hypoglycemia. Perception of neurogenic (predominantly cholinergic) rather than neuroglycopenic symptoms. Diabetes 1993; 42:1791.
  • DeRosa MA, Cryer PE. Hypoglycemia and the sympathoadrenal system: neurogenic symptoms are largely the result of sympathetic neural, rather than adrenomedullary, activation. Am J Physiol Endocrinol Metab 2004; 287:E32.
  • Cryer PE. Hypoglycemia, functional brain failure, and brain death. J Clin Invest 2007; 117:868.
  • Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2009; 94:709.
  • Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. J Clin Endocrinol Metab 2013; 98:1845.
  • Service FJ. Diagnostic approach to adults with hypoglycemic disorders. Endocrinol Metab Clin North Am 1999; 28:519.
  • Landau BR, Wahren J, Chandramouli V, et al. Contributions of gluconeogenesis to glucose production in the fasted state. J Clin Invest 1996; 98:378.
  • Service FJ, O'Brien PC, McMahon MM, Kao PC. C-peptide during the prolonged fast in insulinoma. J Clin Endocrinol Metab 1993; 76:655.
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  • Kao PC, Taylor RL, Service FJ. Proinsulin by immunochemiluminometric assay for the diagnosis of insulinoma. J Clin Endocrinol Metab 1994; 78:1048.
  • Service FJ, O'Brien PC. Increasing serum betahydroxybutyrate concentrations during the 72-hour fast: evidence against hyperinsulinemic hypoglycemia. J Clin Endocrinol Metab 2005; 90:4555.
  • Perros P, Henderson AK, Carter DC, Toft AD. Lesson of the week. Are spontaneous hypoglycaemia, raised plasma insulin and C peptide concentrations, and abnormal pancreatic images enough to diagnose insulinoma? BMJ 1997; 314:496.
  • Lupsa BC, Chong AY, Cochran EK, et al. Autoimmune forms of hypoglycemia. Medicine (Baltimore) 2009; 88:141.
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