HYPOGLYCEMIAMODERATOR- DR. RAJESH RAIPRESENTED BY- DR. SHUBHAM JAIN

“Hypoglycemia is simply defined as a low blood glucose level”.

GLUCOSE METABOLISM GLUCOSE is derived from 3 sources:-Intestinal AbsorptionGlycogenolysisGluconeogenesis.

Systemic Glucose Balance Normally rates of endogenous glucose influx into the circulation and efflux out of the circulation are regulated by Plasma glucose lowering hormone- Insulin (regulatory)Plasma glucose raising hormones- Glucagon and Epinephrine. (counterregulatory)Hypoglycemia occurs when rates of glucose appearance in the circulation fails to keep pace with rates of glucose disappearance from the circulation.

Responses to Hypoglycemia:-Falling plasma glucose concentrations cause a sequence of responses.• Decreased secretion glucose regulatory hormone i.e Insulin and Increased secretion of glucose counterregulatory hormones, including glucagon and epinephrine, occurs as glucose levels fall just below the physiologic range.

Clinical Manifestations of Hypoglycemia:-The symptoms and signs of hypoglycemia are nonspecific.Clinical hypoglycemia, sufficient to cause symptoms and signs is most convincingly documented by Whipple Triad:-

1. Symptoms, signs or both consistent with hypoglycemia2. A low reliably measured plasma glucose concentration3. Resolution of those symptoms and signs after the plasma glucose

concentration is raised.

Neuroglycopenic symptoms are a direct result of brain glucose deprivation.

- Cognitive impairments, behavioral changes, psychomotor abnormalities, and at lower levels- seizure and comaNeurogenic (or autonomic) symptoms are largely the result of the perception of physiologic changes caused by the sympathoadrenal discharge triggered by hypoglycemia.- Adrenergic symptoms- palpitations, tremors and anxiety/ arousal- Cholinergic symptoms- sweating, hunger and paresthesia's.

Maintenance of Systemic Glucose Balance:-Glucose utilization largely by the brain is continuous and the delivery of exogenous glucose from dietary carbohydrates is intermittent.• Systemic glucose balance is normally maintained and hypoglycemia and hyperglycemia are prevented, by dynamic, minute - to – minute regulation of endogenous glucose production from the Liver and Kidneys and of glucose utilization by tissues outside CNS, such as muscle.

The key physiologic defenses against falling glucose concentrations are:-1. A decrease in Insulin2. An increase in Glucagon3. An increase in Epinephrine (when Glucagon is

deficient).

CLINICAL HYPOGLYCEMIA• Clinical Hypoglycemia is defined as, “a plasma glucose concentration low enough to cause symptoms or signs, including impairment of brain functions”.The glycemic thresholds for symptoms and signs of hypoglycemia are dynamic-They shift to lower plasma glucose concentrations in patients with recurrent hypoglycemia-To higher concentrations in those with poorly controlled diabetes mellitus.Documentation of Whipple Triad is important when hypoglycemia is suspected in a person who does not have diabetes mellitus.

Causes of Hypoglycemia in Adults:-

Broadly classified into:-A. Hypoglycemia in persons with Diabetes.B. Hypoglycemia in persons without Diabetes.

HYPOGLYCEMIA IN PERSONS WITH DIABETESClinical Problem of Hypoglycemia in Diabetes:-• Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes.• It causes recurrent morbidity in most T1DM and in many of those with advanced T2DM, and is sometimes fatal.• Hypoglycemia in diabetes is caused by pharmacokinetically imperfect treatment with an insulin secretagogue ( sulfonylurea or a glinide) or with insulin that results in episodes of therapeutic hyperinsulinemia

Frequency of Hypoglycemia in Diabetes:-

• Hypoglycemia is a fact of life for people with T1DM.

• The average patient suffers untold numbers of episodes of asymptomatic hypoglycemia and approximately:-

- 2 episodes of symptomatic hypoglycemia per week

- Roughly one episode per year of severe, at least temporarily disabling hypoglycemia often with seizure or coma.

• The overall incidence of hypoglycemia during treatment of T2DM with an insulin secretagogue, or even with insulin, is lower than that in patients with T1DM.

Clinical Definition and Classification of Hypoglycemia in Diabetes:-• ADA/ Endocrine Society (ES) Workgroup on hypoglycemia defined hypoglycemia in diabetes as-

“ All Episodes of Abnormally low plasma glucose concentration that expose the individual to potential harm”• ADA/ES workgroup recommended that people with diabetes become concerned about the possibility of developing hypoglycemia at a self monitored plasma glucose concentration of 70mg/dL (3.9mmol/L).

PATHOPHYSIOLOGY OF GLUCOSE COUNTEREGULATION IN DIABETES:-Insulin Excess:-• Episodes of therapeutic hyperinsulinemia, produced by treatment with insulin secretagogue (sulfonylurea or a glinide) or with insulin, are a prerequisite for the development of iatrogenic hypoglycemia.• Iatrogenic hypoglycemia is typically the result of interplay of relative or mild or moderate absolute therapeutic hyperinsulinemia and compromised physiologic and behavioral defenses against falling plasma glucose concentrations.

Defective Glucose Counterregulation:-

• In the setting of absolute endogenous insulin deficiency, insulin levels do not decrease as plasma glucose levels fall, first defense is lost.

• The decrement in intraislet insulin is normally a signal to stimulate glucagon secretion. So glucagon levels do not increase as plasma glucose levels falls further. So second defense is also lost.

• Finally, the increase in epinephrine levels, a third defense, in response to a given level of hypoglycemia is typically attenuated.

• Affected patients are at >25-fold greater risk of severe iatrogenic hypoglycemia during aggressive glycemic therapy for their diabetes.

Hypoglycemia Un-Awareness:-• The attenuated sympathoadrenal response to hypoglycemia cause HYPOGLYCEMIA UNAWARENESS i.e loss of the warning adrenergic and cholinergic symptoms, that previously allowed patient to recognize developing hypoglycemia.• Affected patients are at six fold increased risk of severe iatrogenic hypoglycemia during aggressive glycemic therapy of their diabetes.

Hypoglycemia Associated Autonomic Failure (HAAF):-• The concept of HAAF in diabetes propose that recent iatrogenic hypoglycemia or sleep or exercise cause both defective glucose counterregulation and hypoglycemic unawareness.• These impaired responses create a vicious cycle of recurrent iatrogenic hypoglycemia.

Risk Factors for Hypoglycemia in Diabetes:-

Treatment of Hypoglycemia in Diabetes:-

Most episodes of symptomatic hypoglycemia or of asymptomatic hypoglycemia detected by self monitoring or CGM are effectively self treated by ingestion of glucose tablets or carbohydrate. With ongoing hyperinsulinemia, the glycemic response to oral glucose is transient , lasting for less than 2hours.Therefore, ingestion of a snack or meal shortly after the glucose level is raised is usually advisable. In a patient who is unable or unwilling to take orally, parentral therapy is necessary.

Glucagon administration can be life saving, but it often causes substantial, albeit transient, hyperglycemia, nausea and vomiting.• Smaller doses of glucagon (150mcg), repeated if necessary is found to be effective without side effects.

HYPOGLYCEMIA IN PERSONS WITHOUT DIABETESAlthough hypoglycemia is common in persons with diabetes, it is distinctly uncommon in persons who do not have diabetes because of the effectiveness of the normal physiological and behavioral defenses against falling plasma glucose concentrations.

Therefore in the absence of diabetes, a thorough evaluation for hypoglycemia is recommended only for patients in whom Whipple Triad is documented.Venous sampling is standard in the clinical setting, but it is the arterial plasma glucose concentration that fuels the brain.

ILL or Medicated Individual:-• Drugs are the most common cause.

• In addition to insulin and insulin secretagogue, offending drugs include Alcohol.

• Hepatogenous hypoglycemia occurs most commonly when destruction of liver is rapid and massive (toxic hepatitis).

•The pathogenesis of hypoglycemia in some patients with renal failure is unknown and likely multifactorial, attributed to drugs, sepsis or inanition.

• The pathogenesis of hypoglycemia occasionally seen in patients with cardiac failure is unknown.

• Sepsis is relatively a common cause of hypoglycemia.

• Hypoglycemia can be caused by inanitation.

• Hormones deficiencies resulting in hypoglycemia are not common.

• Non-islet cell tumor hypoglycemia (NICTH) is rare.-NICTH is often the result of overproduction of incompletely processed pro-insulin like growth factor 2 (pro-IGF-2).-The pro-IGF-2 binds poorly to its binding proteins and therefore more freely enters tissue spaces, where its insulin-like actions cause hypoglycemia.

Seemingly Well Individual:-In individuals with no evidence of drug, critical illness, hormone deficiency, or non-islet cell tumor as cause of their hypoglycemia, the differential diagnosis narrows to two categories:-- Accidental, surreptitious, or even malicious hypoglycemia.- Endogenous hyperinsulinism.

• Medical, pharmacy, and hospital errors can result in hypoglycemia.• Surreptitious hypoglycemia is more common in people with knowledge of, and access to, glucose lowering medications.• Malicious hypoglycemia can be accomplished by administration of an insulin secretagogue or insulin.

• Insulinomas ( insulin secreting pancreatic beta cell tumors) are prototypical, but not the only cause of endogenous hyperinsulinemic hypoglycemia.

- They usually present with history of episodes of Neuroglycopenia occurring in fasting state.

- Insulinomas are rare, an incidence of 1 in 2,50,000.

• Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS), or Post Gastric by-pass hypoglycemia .

- They are characterized by spells of nueroglycopenia caused by endogenous hyperinsulinemic hypoglycemia occurring typically after a meal.

- NIPHS is less common than insulinoma.

• Autoimmune hypoglycemia caused by an antibody to insulin is rare.

- Affected individuals often have a history of autoimmune disorders.

- Hypoglycemia occurs in late postprandial period as insulin, which is secreted in response to meal, and when bound to circulating antibody dissociates from the antibody in an unregulated fashion.

- Diagnosis is made by finding high titer serum insulin antibodies and high plasma insulin levels during episode of hypoglycemia.

Treatment:- Prevention of ongoing or recurrent hypoglycemia requires treatment that corrects the hypoglycemic mechanism.• Offending drugs can be discontinued or their dosage reduced.• Critical illnesses often be treated.• Deficient hormones such as cortisol, can be replaced.• Reduction of non-islet cell tumor mass with surgery, irradiation or chemotherapy.- Treatment with glucocorticoid, growth hormone, or even octreotide may alleviate hypoglycemia

• In unresectable disease empirical treatments can be tried.• In NIPHS or post gastric by-pass hypoglycemia.Diet, include frequent feedings, an alpha-glucosidase inhibitor, diazoxide, or octreotide can be tried.• Treatment of autoimmune hypoglycemia is problematic, but disorder is sometimes self-limited.• Failing these treatments, frequent feedings during the day and bedtime administration of large doses of uncooked starch or even overnight intragastric glucose infusion may be necessary.

References:-1.Harrisons Principles of Internal Medicine- 19th edition.2.Williams Textbook of Endocrinology- 13th edition.3.Joslins- Diabetes Mellitus- 14th edition.

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