Approach to Approach to HypoglycemiaHypoglycemia

Diabetics and Non-DiabeticsDiabetics and Non-Diabetics

IncidenceIncidence

In (DCCT), 10-30% of type 1 diabetics per yearIn (DCCT), 10-30% of type 1 diabetics per year

Of those,10% require 3Of those,10% require 3rdrd party Intervention party Intervention

In the (UKPDS),(30-35%)of type 2 diabetics on Insulin In the (UKPDS),(30-35%)of type 2 diabetics on Insulin require 3require 3rdrd party Intervention party Intervention

CausesCauses

DrugsDrugs Insulin- most common cause,Insulin- most common cause, Timing, dose, typeTiming, dose, type clearance of insulin (eg, renal failure); clearance of insulin (eg, renal failure); altered counter regulation altered counter regulation SulfonylureasSulfonylureas Metformin does Metformin does notnot cause hypoglycemia cause hypoglycemia High dose salicylates, b –blockers, quinine,quinolonesHigh dose salicylates, b –blockers, quinine,quinolones

Renal failureRenal failure

Second gluconeogenic organSecond gluconeogenic organ decreased clearance of renally excreted drugs or their metabolites decreased clearance of renally excreted drugs or their metabolites

(eg, insulin, chlorpropamide, metabolite of glyburide)(eg, insulin, chlorpropamide, metabolite of glyburide)

Hepatic FailureHepatic Failure

Decreased glycogenolysis Decreased glycogenolysis Decresed gluconeogenesisDecresed gluconeogenesis Large functional reserve,( 20% func required to prevent Large functional reserve,( 20% func required to prevent

hypoglycemia)hypoglycemia) Genetic defects in glycometabolic pathwaysGenetic defects in glycometabolic pathways Finally, compromised drug metabolism (tolbutamide, glyburide, Finally, compromised drug metabolism (tolbutamide, glyburide,

glipizide )glipizide )

Endocrinopathies Endocrinopathies

Adrenal (glucocorticoid) insufficiencyAdrenal (glucocorticoid) insufficiency

Growth hormone deficiencyGrowth hormone deficiency

Glucagon deficiency Glucagon deficiency

Pituitary disease ( decreased combined corticotropin and GH Pituitary disease ( decreased combined corticotropin and GH deficiecy)deficiecy)

Poisoning Poisoning (ethanol, propanolol, salicylates)(ethanol, propanolol, salicylates)

Ethanol inhibits gluconeogenesisEthanol inhibits gluconeogenesis

Ethanol-induced Ethanol-induced hypoglycemiahypoglycemia occurs 12-72 hrs after ingestion occurs 12-72 hrs after ingestion

NeoplasmNeoplasm Non–islet-cell tumors Non–islet-cell tumors Mesenchymal tumors, Mesenchymal tumors, hepatocellular carcinoma, hepatocellular carcinoma, adrenocortical tumors, adrenocortical tumors, carcinoid tumors, carcinoid tumors, leukemia, and lymphomasleukemia, and lymphomas Most of these tumors secrete IGF –II moleculeMost of these tumors secrete IGF –II molecule Some also secrete Glucagon- like peptide(GLP-1) and Somatostatin Some also secrete Glucagon- like peptide(GLP-1) and Somatostatin

Insulinoma Insulinoma Pancreatic β-cell tumors that secrete InsulinPancreatic β-cell tumors that secrete Insulin Small,solitary, benign( < 10% malignant)Small,solitary, benign( < 10% malignant)

Inability of insulinoma cells to suppress insulin secretion during low Inability of insulinoma cells to suppress insulin secretion during low levels of circulating glucose, leading to severe hypoglycemialevels of circulating glucose, leading to severe hypoglycemia

Diagnosis and Tumor LocalizationDiagnosis and Tumor Localization Very high Insulin levelsVery high Insulin levels spiral CT, arteriography, ultrasonography spiral CT, arteriography, ultrasonography

Treatment of ChoiceTreatment of Choice EnucleationEnucleation Recurrence at 10 yrs is 6% and 20 yrs is 10%Recurrence at 10 yrs is 6% and 20 yrs is 10%

Islet Hyperplasia Islet Hyperplasia

Also called nesidioblastosis or diffuse islet hyperplasiaAlso called nesidioblastosis or diffuse islet hyperplasiaor the syndrome of noninsulinoma pancreatogenous hyperinsulinismor the syndrome of noninsulinoma pancreatogenous hyperinsulinism

Represent hyperplastic processes and budding of islet cells from Represent hyperplastic processes and budding of islet cells from ducts (nesidioblastosis). Now interpreted as precursor to MEN 1, ducts (nesidioblastosis). Now interpreted as precursor to MEN 1, with molecular evidence.with molecular evidence.

Heterozygous knockout of the Heterozygous knockout of the MEN1MEN1 gene in the mouse show gene in the mouse show multiple giant hyperplastic islets that precede insulinoma. multiple giant hyperplastic islets that precede insulinoma.

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), these Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), these infants have an identifiable genetic mutations in sulfonylurea infants have an identifiable genetic mutations in sulfonylurea receptor 1 (SUR1) ,potassium channel Kir6.2, glucokinase.receptor 1 (SUR1) ,potassium channel Kir6.2, glucokinase.

Autoimmune causesAutoimmune causes

Anti-insulin receptor antibodyAnti-insulin receptor antibody Rarely, Rarely, hypoglycemiahypoglycemia is caused by autoantibodies that bind the is caused by autoantibodies that bind the

insulin receptor and mimic the biologic action of insulin insulin receptor and mimic the biologic action of insulin Most patients have elevated ESR, +ve ANAMost patients have elevated ESR, +ve ANA

Anti-insulin antibodyAnti-insulin antibody autoantibodies against insulin bind free circulating plasma insulin autoantibodies against insulin bind free circulating plasma insulin

when its concentration is high and release insulin when the when its concentration is high and release insulin when the concentration of free plasma insulin drops.concentration of free plasma insulin drops.

Release of insulin at inappropriate times can cause Release of insulin at inappropriate times can cause hypoglycemiahypoglycemia..

SymptomsSymptoms

Adrenergic Symptoms Adrenergic Symptoms usually seen early with a rapid decline usually seen early with a rapid decline inin blood glucose and include blood glucose and include

tachycardia, tachypnea, vomiting, and diaphoresis tachycardia, tachypnea, vomiting, and diaphoresis

NeuroglycopenicNeuroglycopenic usually associated with slower or prolonged usually associated with slower or prolonged hypoglycemia, hypoglycemia, include include

poor feeding, altered mental status, lethargy, and seizures poor feeding, altered mental status, lethargy, and seizures

Classification of HypoglycemiaClassification of Hypoglycemia

Fasting Fasting hypoglycemiahypoglycemia occurs in the postabsorptive period occurs in the postabsorptive period

(ie, hours after a meal)(ie, hours after a meal)

Reactive (Reactive (postprandialpostprandial) ) hypoglycemiahypoglycemia. .

Reactive Reactive hypoglycemiahypoglycemia is controversial is controversial

low postprandial plasma glucose levels alone are not low postprandial plasma glucose levels alone are not sufficient sufficient

10% to 30% of normal individuals undergoing oral GTT 10% to 30% of normal individuals undergoing oral GTT have plasma glucose <50 mg/Dl, with no symptoms have plasma glucose <50 mg/Dl, with no symptoms

Only patients with severe (eg, loss of consciousness, Only patients with severe (eg, loss of consciousness, traumatic injury or accident) attributed to postprandial traumatic injury or accident) attributed to postprandial hypoglycemiahypoglycemia require further workup. require further workup.

Dumping Syndrome/ Alimentary HypolycemiaDumping Syndrome/ Alimentary Hypolycemia

Alimentary Alimentary hypoglycemiahypoglycemia presents 2 hrs after a meal presents 2 hrs after a meal

Pathophysiology Pathophysiology disruption of controlled gastric emptyingdisruption of controlled gastric emptying decreased transit time decreased transit time rapid elevation in plasma glucose that triggers rapid elevation in plasma glucose that triggers

exaggerated insulin response. exaggerated insulin response. abnormal insulin then causes a precipitous drop in blood abnormal insulin then causes a precipitous drop in blood

glucoseglucose

Pathophysiology of HypoglycemiaPathophysiology of Hypoglycemia

Responses to Hypoglycemia is our ability to suppress insulin in Responses to Hypoglycemia is our ability to suppress insulin in response to hypoglycemiaresponse to hypoglycemia

In DiabeticsIn Diabetics, it does not occur as Insulin is supplied exogenously, it does not occur as Insulin is supplied exogenously

Main defense is increased release of counterregulatory hormones, as Main defense is increased release of counterregulatory hormones, as Glucagon, Epinephrine, Cortisol, and Growth hormone Glucagon, Epinephrine, Cortisol, and Growth hormone

Glucagon Glucagon stimulates both glycogenolysis and gluconeogenesisstimulates both glycogenolysis and gluconeogenesis

EpinephrineEpinephrine acts via ß-adrenergic receptors and stimulates acts via ß-adrenergic receptors and stimulates glycogenoalysis and gluconeogenesisglycogenoalysis and gluconeogenesis

Also acts on alpha-2-receptors to inhibit insulin secretionAlso acts on alpha-2-receptors to inhibit insulin secretion

Cortisol and Growth hormoneCortisol and Growth hormone contribute only after prolonged contribute only after prolonged hypoglycemia by limiting peripheral uitilization of glucose.hypoglycemia by limiting peripheral uitilization of glucose.

Counterregulatory effects of Epinephrine during Hypoglycemia

Glucagon and epinephrine secretion rises when plasma Glucagon and epinephrine secretion rises when plasma glucose concentrations fall below 65 to 70 mg/dL (3.6 to glucose concentrations fall below 65 to 70 mg/dL (3.6 to 3.9 mmol/L)3.9 mmol/L)

Growth hormone secretion increases when plasma Growth hormone secretion increases when plasma

glucose concentrations fall below 60 to 65 mg/dL (3.3 to glucose concentrations fall below 60 to 65 mg/dL (3.3 to 3.6 mmol/L)3.6 mmol/L)

Cortisol secretion increases when plasma glucose Cortisol secretion increases when plasma glucose concentrations fall below 60 mg/dL (3.3 mmol/L).concentrations fall below 60 mg/dL (3.3 mmol/L).

Hypoglycemia UnawarenessHypoglycemia Unawareness

50% of type 1 patients undergo diminution in their epinephrine response 50% of type 1 patients undergo diminution in their epinephrine response to hypoglycemia,to hypoglycemia,

Further patients lose the autonomic warning symptoms of hypoglycemia Further patients lose the autonomic warning symptoms of hypoglycemia

and may recognize (or even fail to recognize) the condition only when and may recognize (or even fail to recognize) the condition only when somatic neurologic function becomes impaired. somatic neurologic function becomes impaired.

Usually associated with duration of diabetes and autonomic neuropathyUsually associated with duration of diabetes and autonomic neuropathy

May also occur when patients are switched to intensive insulin regimens. May also occur when patients are switched to intensive insulin regimens.

The introduction of intensified treatment regimens can lower the glucose The introduction of intensified treatment regimens can lower the glucose level that triggers epinephrine release and adrenergic symptoms.level that triggers epinephrine release and adrenergic symptoms.

The DCCT trial showed that even brief periods of antecedent The DCCT trial showed that even brief periods of antecedent hypoglycemia can suppress counter-regulatory responses during hypoglycemia can suppress counter-regulatory responses during subsequent hypoglycemic episodes.subsequent hypoglycemic episodes.

DiagnosisDiagnosis

Establishing the causeEstablishing the cause History (liver failure, sepsis, autoimmune disease, neoplasm, alcohol, History (liver failure, sepsis, autoimmune disease, neoplasm, alcohol,

drugs)drugs)

Establishing fasting hypoglycemiaEstablishing fasting hypoglycemia Supervised 72 hour fast testSupervised 72 hour fast test In hospital setting to lower risk to the patient In hospital setting to lower risk to the patient Usually hypoglycemia develops in first 48 hours of the fast in 95% of Usually hypoglycemia develops in first 48 hours of the fast in 95% of

casescases

72-HOUR FAST72-HOUR FAST

ProtocolProtocol  

Date the onset of the fast as the time of the last intake of calories

Discontinue all non essential medications

Allow the patient to drink calorie-free and caffeine-free beverages

Collect blood specimens for measurement of plasma glucose, insulin, C-peptide, and proinsulin every six hours until the plasma glucose concentration is below 60 mg/dL (3.3 mmol/L) at this point, the frequency of sampling should be increased to every one to two hours.

Test end points and durationTest end points and duration

the plasma glucose concentration is ≤45 mg/dL (2.5 the plasma glucose concentration is ≤45 mg/dL (2.5 mmol/L) mmol/L)

the patient has symptoms or signs of hypoglycemia, the patient has symptoms or signs of hypoglycemia, 72 hours have elapsed, 72 hours have elapsed, or when the plasma glucose concentration is less than or when the plasma glucose concentration is less than

55 mg/dL (3 mmol/L) if Whipple's triad is present55 mg/dL (3 mmol/L) if Whipple's triad is present Plasma beta-hydroxybutyrate and sulfonylurea levels are Plasma beta-hydroxybutyrate and sulfonylurea levels are

measuredmeasured 1 mg of glucagon is given intravenously and the plasma 1 mg of glucagon is given intravenously and the plasma

glucose measured 10, 20, and 30 minutes later.glucose measured 10, 20, and 30 minutes later.

In normal subjects, the following thresholds have been identified in In normal subjects, the following thresholds have been identified in graded glucose reductionsgraded glucose reductions

Insulin secretion decreases,(BG < 80), followed by increase in Insulin secretion decreases,(BG < 80), followed by increase in Glucagon and Epinephrine, growth hormone( BG <65) and Cortisol Glucagon and Epinephrine, growth hormone( BG <65) and Cortisol (BG<60)respectively (BG<60)respectively

Normal subjects do not have symptomatic hypoglycemia after a Normal subjects do not have symptomatic hypoglycemia after a prolonged fast because prolonged fast because

Gluconeogenesis accounts for approximately 50 percent of glucose Gluconeogenesis accounts for approximately 50 percent of glucose production after an overnight fast and for almost all glucose production after an overnight fast and for almost all glucose production after 42 hours or more of fastingproduction after 42 hours or more of fasting

Interpretation of values after 72 hour test

].].

Relation of Plasma Glucose and Proinsulin

Hypoglycemia Pathway

Principles of TreatmentPrinciples of Treatment

Principles of therapyPrinciples of therapy

Priority in treating hypoglycemia to maintain plasma glucose geater Priority in treating hypoglycemia to maintain plasma glucose geater than 50 mg/dl, either snacks vs IV dextrosethan 50 mg/dl, either snacks vs IV dextrose

The second priority is to address the underlying cause. removal or The second priority is to address the underlying cause. removal or adjustment of the offending drug, appropriate hormone replacement adjustment of the offending drug, appropriate hormone replacement for patients with deficiency, resection of the tumor in Insulioma.for patients with deficiency, resection of the tumor in Insulioma.

Patients with autoantibodies against the insulin receptor can be Patients with autoantibodies against the insulin receptor can be treated with high-dose glucocorticoid (prednisone, 60 mg/d) to treated with high-dose glucocorticoid (prednisone, 60 mg/d) to prevent prevent hypoglycemiahypoglycemia

Most episodes of asymptomatic hypoglycemia and mild to moderate Most episodes of asymptomatic hypoglycemia and mild to moderate symptomatic hypoglycemia are effectively self-treated by ingestion symptomatic hypoglycemia are effectively self-treated by ingestion of glucose tablets or carbohydrate in the form of juices, soft drinks, of glucose tablets or carbohydrate in the form of juices, soft drinks, milk, crackers, candy, or a meal.milk, crackers, candy, or a meal.

A commonly recommended dose of glucose is 16-20 g of oral A commonly recommended dose of glucose is 16-20 g of oral glucose.glucose.

However, the glycemic response to oral glucose is transient, However, the glycemic response to oral glucose is transient, usually less than 2 hours in insulin-induced hypoglycemiausually less than 2 hours in insulin-induced hypoglycemia

Parenteral treatment is necessary when a hypoglycemic patient is Parenteral treatment is necessary when a hypoglycemic patient is unable or unwilling (because of neuroglycopenia) to take unable or unwilling (because of neuroglycopenia) to take carbohydrate orally. carbohydrate orally.

Most common 1 amp of D50,(?glucose)Most common 1 amp of D50,(?glucose)

Glucagon is commonly injected subcutaneously or intramuscularly Glucagon is commonly injected subcutaneously or intramuscularly standard dose, 1 mg .standard dose, 1 mg .

less useful in T2DM than it is in T1DM as stimulates insulin secretionless useful in T2DM than it is in T1DM as stimulates insulin secretion

Hypoglycemia related to endogenous hyperinsulinism is often curable Hypoglycemia related to endogenous hyperinsulinism is often curable by the surgical removal of an insulinoma. by the surgical removal of an insulinoma.

If this is not possible because of multiple or metastatic tumors, If this is not possible because of multiple or metastatic tumors, Diazoxide can be used, (100-800 mg/day) raises the plasma glucose Diazoxide can be used, (100-800 mg/day) raises the plasma glucose concentration by suppressing insulin secretion.concentration by suppressing insulin secretion.

Side effects include hypotension,brain edema,, gastrointestinal side Side effects include hypotension,brain edema,, gastrointestinal side effects effects

Other treatments include octreotide or calcium channel antagonistsOther treatments include octreotide or calcium channel antagonists

Sort term treatment of hypoglycemia associated with non–beta cell Sort term treatment of hypoglycemia associated with non–beta cell tumors involves short-term measures pending effective medical, tumors involves short-term measures pending effective medical, surgical, or radiotherapeutic treatment can be done by glucocorticoid surgical, or radiotherapeutic treatment can be done by glucocorticoid or growth hormone or growth hormone

Remissions of autoimmune hypoglycemias have been associated with Remissions of autoimmune hypoglycemias have been associated with immunosuppressive therapy, including glucocorticoids, but controlled immunosuppressive therapy, including glucocorticoids, but controlled trials are lacking. trials are lacking.

The treatment of hypoglycemia related to hepatic or renal disease, The treatment of hypoglycemia related to hepatic or renal disease, cardiac failure, or sepsis includes short-term measures and, treatment cardiac failure, or sepsis includes short-term measures and, treatment or management of the underlying disease process. or management of the underlying disease process.

Hypoglycemic ComaHypoglycemic Coma

Recovery from hypoglycemia may be delayed, because of cerebral Recovery from hypoglycemia may be delayed, because of cerebral edema. Unconsciousness lasting more than 30 minutes after plasma edema. Unconsciousness lasting more than 30 minutes after plasma glucose is corrected is called posthypoglycemic coma, IV mannitol (40 glucose is corrected is called posthypoglycemic coma, IV mannitol (40 g as a 20% solution over 20 minutes) or glucocorticoids (e.g., g as a 20% solution over 20 minutes) or glucocorticoids (e.g., dexamethasone, 10 mg), or both can be used along with maintenance dexamethasone, 10 mg), or both can be used along with maintenance of normal plasma glucose levelsof normal plasma glucose levels

CASE 1 — A 39-year-old man was referred for evaluation of repeated episodes of CASE 1 — A 39-year-old man was referred for evaluation of repeated episodes of sweating, slurred speech, and confusion during the last four years that could sweating, slurred speech, and confusion during the last four years that could be aborted by eating. On two occasions, he drove his car off the side of the be aborted by eating. On two occasions, he drove his car off the side of the road; both times he was found to be confused, his serum glucose road; both times he was found to be confused, his serum glucose concentrations ranged from 30 to 40 mg/dL (1.7 to 2.2 mmol/L), and he concentrations ranged from 30 to 40 mg/dL (1.7 to 2.2 mmol/L), and he improved after intravenous glucose administration.improved after intravenous glucose administration.

After fasting for 12 hours, he began to sweat and became confused and After fasting for 12 hours, he began to sweat and became confused and combative. Serum values at that time were as follows:combative. Serum values at that time were as follows:

      Glucose - 22 mg/dLGlucose - 22 mg/dL  Insulin - 110 microU/mL (660 pmol/L)  Insulin - 110 microU/mL (660 pmol/L)  C-peptide - 3200 pmol/L (0.03-1 nmol/L)  C-peptide - 3200 pmol/L (0.03-1 nmol/L)

      Proinsulin - 800 pmol/L (2-31 pmol/L)Proinsulin - 800 pmol/L (2-31 pmol/L)      Glucose increase after Glucose increase after glucagonglucagon - 39 mg/dL (2.2 mmol/L) - 39 mg/dL (2.2 mmol/L)

  Sulfonylurea – negative  Sulfonylurea – negative

What is the nost likely Diagnosis?What is the nost likely Diagnosis?A) Surreptious Insulin useA) Surreptious Insulin useB) Antibodies to Insulin receptorB) Antibodies to Insulin receptorC) InsulinomaC) InsulinomaD) None of the aboveD) None of the above

Comment — This is a classic case of insulinoma. The patient was healthy but had episodes of Comment — This is a classic case of insulinoma. The patient was healthy but had episodes of neuroglycopenia. Whipple's triad (symptoms of hypoglycemia, low serum glucose concentrations at the neuroglycopenia. Whipple's triad (symptoms of hypoglycemia, low serum glucose concentrations at the same time, and relief of symptoms by glucose administration) was satisfied. That the hypoglycemia was same time, and relief of symptoms by glucose administration) was satisfied. That the hypoglycemia was caused by endogenous insulin was confirmed by the high serum insulin, C-peptide and proinsulin caused by endogenous insulin was confirmed by the high serum insulin, C-peptide and proinsulin concentrations, and supported by the low serum beta-hydroxybutyrate concentration and the small rise in concentrations, and supported by the low serum beta-hydroxybutyrate concentration and the small rise in serum glucose after intravenous serum glucose after intravenous glucagonglucagon administration. administration.

CASE 2 — A 27-year-old man was referred by his local physician for evaluation of CASE 2 — A 27-year-old man was referred by his local physician for evaluation of hypoglycemia found incidentally during a work-up for peptic ulcer disease. Past hypoglycemia found incidentally during a work-up for peptic ulcer disease. Past medical history included gastric by pass surgery for morbid obesity 2 years medical history included gastric by pass surgery for morbid obesity 2 years ago. During the last four months, he had several episodes of weakness and ago. During the last four months, he had several episodes of weakness and feeling "shaky inside" late in the evening. During the night he would feeling "shaky inside" late in the evening. During the night he would periodically drink soda. When symptomatic, reflectance meter blood glucose periodically drink soda. When symptomatic, reflectance meter blood glucose values measured by the patient using equipment purchased for his seven-year-values measured by the patient using equipment purchased for his seven-year-old daughter (diagnosed with type 1 diabetes one year earlier) had been in the old daughter (diagnosed with type 1 diabetes one year earlier) had been in the range of 40 to 50 mg/dL (2.2 to 2.8 mmol/L). Serum values after an overnight range of 40 to 50 mg/dL (2.2 to 2.8 mmol/L). Serum values after an overnight fast were:fast were:

      Glucose - 36 mg/dL (2.0 mmol/L)Glucose - 36 mg/dL (2.0 mmol/L)  Insulin - 140 microU/mL (840 pmol/L)  Insulin - 140 microU/mL (840 pmol/L)  C-peptide - <33 pmol/L(0.03-1nmol/L)  C-peptide - <33 pmol/L(0.03-1nmol/L)

      Proinsulin - 0.9 pmol/L(2-31 pmol/L)Proinsulin - 0.9 pmol/L(2-31 pmol/L)

What is he most likely diagnosis?What is he most likely diagnosis? A) InsulinomaA) Insulinoma B) Insulin antibodiesB) Insulin antibodies C) Exogenous Insulin administrationC) Exogenous Insulin administration D) Alimentary hypoglycemiaD) Alimentary hypoglycemia

The low serum C-peptide and proinsulin values indicate that the hyperinsulinemia The low serum C-peptide and proinsulin values indicate that the hyperinsulinemia (140 microU/mL (840 pmol/L)) was due to exogenous insulin administration.(140 microU/mL (840 pmol/L)) was due to exogenous insulin administration.

Thanks.Thanks.

CASE 8 — A 76-year-old woman was referred for the evaluation of postprandial adrenergic CASE 8 — A 76-year-old woman was referred for the evaluation of postprandial adrenergic symptoms with occasional visual changes. There was one episode of confusion while on a symptoms with occasional visual changes. There was one episode of confusion while on a telephone call to her daughter. During an episode of light headedness, sweating, weakness and telephone call to her daughter. During an episode of light headedness, sweating, weakness and irritability two hours after breakfast (which occurred while under observation), serum values were irritability two hours after breakfast (which occurred while under observation), serum values were as follows:as follows:

Glucose                                    51 mg/dl (2.8 mmol/L) Glucose                                    51 mg/dl (2.8 mmol/L) Insulin                                       6.4 microU/mL (45.9 pmol/L) Insulin                                       6.4 microU/mL (45.9 pmol/L) C-peptide                                  2.6 ng/mL  (858 pmol/L) C-peptide                                  2.6 ng/mL  (858 pmol/L) Betahydroxybutyrate                   0.1 mmol/L Betahydroxybutyrate                   0.1 mmol/L Glucose increase after Glucose increase after glucagonglucagon   46 mg/dL (2.6 mmol/L)    46 mg/dL (2.6 mmol/L) Sulfonylurea                              negative Sulfonylurea                              negative

A mixed meal test was performed because of the presence of postprandial symptoms A mixed meal test was performed because of the presence of postprandial symptoms accompanied by biochemical evidence of insulin-mediated hypoglycemia. Biochemical testing accompanied by biochemical evidence of insulin-mediated hypoglycemia. Biochemical testing 180 minutes after a mixed meal revealed the following:180 minutes after a mixed meal revealed the following:

Glucose                                     43 mg/dl (2.4 mmol/L) Glucose                                     43 mg/dl (2.4 mmol/L) Insulin                                      22.0 microU/ml (157.8 pmol/L) Insulin                                      22.0 microU/ml (157.8 pmol/L) C-peptide                                   4.7 ng/ml (1551 pmol/L) C-peptide                                   4.7 ng/ml (1551 pmol/L)

The biochemical tests confirmed insulin-mediated hypoglycemia. The differential diagnosis The biochemical tests confirmed insulin-mediated hypoglycemia. The differential diagnosis included noninsulinoma pancreatogenous hypoglycemia (Islet cell hypertrophy/nesidioblastosis), included noninsulinoma pancreatogenous hypoglycemia (Islet cell hypertrophy/nesidioblastosis), which is associated with postprandial hypoglycemia, insulin autoimmune hypoglycemia which is associated with postprandial hypoglycemia, insulin autoimmune hypoglycemia (postprandial or fasting hypoglycemia), or insulinoma, which more commonly presents as fasting (postprandial or fasting hypoglycemia), or insulinoma, which more commonly presents as fasting hypoglycemia. (hypoglycemia. (See "See "NoninsulinomaNoninsulinoma pancreatogenouspancreatogenous hypoglycemia" hypoglycemia" and and see "see "InsulinomaInsulinoma"").).