Drugs: Insulin and insulin secretagogues (glibenclamide, sulfunylurea) suppress glucose production and stimulate glucose utilization (but others like metformin etc don't cause hypoglycemia); Ethanol blocks gluconeogenesis but not glycogenolysis; other drugs a. w/ hypoglycemia: ACEis and ARBs, BBs, quinolone antibiotics, indomethacin, quinine, and sulfonamides

Impact and Frequency:
(1) insulin (or insulin secretagogue) doses excessive, ill-timed, or of the wrong type;
(2) influx of exogenous glc reduced (e.g., during an overnight fast or after missed meals or snacks);
(3) insulin-independent glc utilization incr (e.g., during exercise);
(4) sensitivity to insulin incr (e.g., w/ improved glycemic control, in middle of the night, late after exercise, or with increased fitness or weight loss);
(5) endogenous glc production reduced (e.g., after alcohol ingestion);
(6) insulin clearance reduced (e.g., in renal failure)

Hypoglycemia Unawareness: attenuated sympathoadrenal response to hypoglycemia--> hypoglycemia unawareness—i.e., loss of warning adrenergic and cholinergic symptoms that previously allowed the patient to recognize developing hypoglycemia and therefore to abort the episode by ingesting carbohydrates. Affected patients are at a sixfold increased risk of severe iatrogenic hypoglycemia during aggressive glycemic therapy of their diabetes;

(3) a β-cell secretagogue such as a sulfonylurea: clinical and biochemical pattern similar to that of an insulinoma but can be distinguished by presence of circulating secretagogue

اگر تست fasting مثبت باشد Imaging انجام میدهیم (most sensitive: sono during endoscopy)

Surgical resection; medical therapy w/ diazoxide or octreotide used if resection not possible (to raise blood glc?)

primary β-cell disorder or an insulin secretagogue: failure of insulin secretion to fall to very low levels during hypoglycemia; assessed by measurement of plasma insulin, C-peptide, proinsulin, and glc [ ]s during hypoglycemia. (harf ostad ra be khater biavar)

Critical diagnostic findings:
[plasma insulin] ≥3 μU/mL
[plasma C-peptide] ≥0.6 ng/mL
[plasma proinsulin] ≥5.0 pmol/L
[plasma glc] <55 mg/dL w/ symptoms of hypoglycemia.

low [plasma β-hydroxybutyrate] + an increment in plasma glc level of >25 mg/dL after IV administration of glucagon indicate increased insulin (or IGF) actions

diagnostic strategy:
(1) measure plasma glc, insulin, C-peptide, proinsulin, and β-hydroxybutyrate [ ]s and to screen for circulating oral hypoglycemic agents during an episode of hypoglycemia
(2) assess symptoms during the episode and seek their resolution following correction of hypoglycemia by IV injection of glucagon

endogenous hyperinsulinemic disorders u. cause fasting hypoglycemia, a diagnostic episode may develop after a relatively short outpatient fast.
Serial sampling during an inpatient diagnostic fast of up to 72 h or after a mixed meal is more problematic.

nesidioblastosis: fasting hypoglycemia, diffuse islet involvement w/ β-cell hypertrophy and sometimes hyperplasia

noninsulinoma pancreatogenous hypoglycemia: postprandial hypoglycemia, similar islet pattern

Postgastric bypass postprandial hypoglycemia: also diffuse islet involvement

to insulin: binds post-meal insulin and then gradually disassociates--> late postprandial hypoglycemia

(2) a low plasma [glc] measured with a precise method (not a glucose monitor),

tight glc control: a high prevalence of severe hypoglycemia

first defense against hypoglycemia lost: insulin levels do not decr as plasma glc fall;

second defense against hypoglycemia lost: decrement in intraislet insulin: normally a signal to stimulate glucagon secretion, glucagon levels do not incr as plasma glc levels fall further;

third defense against hypoglycemia lost: incr in epinephrine levels, in response to a given level of hypoglycemia typically attenuated; glycemic threshold for sympathoadrenal (adrenomedullary epinephrine and sympathetic neural norepinephrine) response is shifted to lower plasma glc concentrations

HAAF in Diabetes:
recent antecedent iatrogenic hypoglycemia (or sleep or prior exercise)--> defective glc counterregulation + hypoglycemia unawareness--> vicious cycle of recurrent iatrogenic hypoglycemia

Hypoglycemia unawareness + reduced epinephrine component of defective glucose counterregulation: reversible by as little as 2–3 weeks of scrupulous avoidance of hypoglycemia in most affected patients.

lower HbA1c levels or lower glycemic goals that, all
other factors being equal, increase the probability of recent antecedent hypoglycemia.

in renal failure: reduced clearance of insulin, reduced mobilization of gluconeogenic precursors in renal failure, reduced glc production

Sepsis : relatively common cause; Incr glc utilization induced by cytokine production in macrophage rich tissues such as the liver, spleen, and lung

in cardiac failure: Hepatic congestion and hypoxia may be involved

Factitious hypoglycemia: surreptitious or even malicious administration of insulin or an insulin secretagogue;
insulin secretagogue--> hypoglycemia w/ incr C-peptide levels
exogenous insulin--> hypoglycemia w/ low C-peptide levels reflecting suppression of insulin secretion

pseudohypoglycemia: low measured glucose concentrations can be artifactual—e.g., result of continued glc metabolism by formed elements of the blood ex vivo, particularly in presence of leukocytosis, erythrocytosis, or thrombocytosis or with delayed separation of the serum from the formed elements

Hypoglycemia (diabetic or non): most commonly caused by drugs (used to treat diabetes mellitus or by exposure to other drugs, including alcohol)

Common signs: diaphoresis and pallor. Heart rate and systolic BP typically incr but may not be raised in an individual who has experienced repeated, recent episodes of hypoglycemia.

shift to higher-than normal glc levels in poorly controlled diabetes--> experience symptoms of hypoglycemia when glc levels decline toward normal range (pseudohypoglycemia).

shift to lower-than-normal glc levels in recurrent hypoglycemia; e.g., patients with aggressively treated diabetes or an insulinoma have symptoms at glucose levels lower than those that cause symptoms in healthy individuals

Plasma [glc] normally maintained within a relatively narrow range—70–110 mg/dL in the fasting state

cortisol + GH: not normally critical. However, it becomes critical when deficient

RECOGNITION AND DOCUMENTATION

Blood should be drawn, whenever possible, before giving glc to allow documentation of a low plasma [glc]. Convincing documentation of hypoglycemia requires fulfillment of Whipple’s triad. Thus, the ideal time to measure plasma glc level: during a symptomatic episode. A normal glucose level: excludes hypoglycemia as the cause of the symptoms.
A low glucose level confirms that hypoglycemia is the cause of the symptoms, provided the latter resolve after the glucose level is raised. When the cause of the hypoglycemic episode is obscure, additional measurements—made while the glucose level is low and before treatment—should include plasma insulin, C-peptide, proinsulin, and β-hydroxybutyrate levels; also critical are screening for circulating oral hypoglycemic agents and assessment of symptoms before and after the plasma glucose concentration is raised. When the history suggests prior hypoglycemia and no potential mechanism is apparent, the diagnostic strategy is to evaluate the patient as just described and assess for Whipple’s triad during and after an episode of hypoglycemia. On the other hand, while it cannot be ignored, a distinctly low plasma glucose concentration measured in a patient without corresponding symptoms raises the possibility of an artifact (pseudohypoglycemia)