Insulin overdose is the most common cause of hypoglycemia. In an outpatient setting, it is frequently the result of a missed meal or an increased amount of exercise and less often the result of inadvertent injection of short acting in place of long-acting insulin. Occasionally, an overdose is intentional, particularly among adolescents. Rarely, overdoses represent attempts at suicide and homicide [29]. The rapidity of onset [30] and duration of hypoglycemia [31] depend on the type of insulin (see Table 106.1).

Hypoglycemia is often more severe among patients with long-standing type 1 diabetes due to the presence of a defective counterregulatory response and hypoglycemia unawareness. Impaired glucagon and epinephrine responses are common [32]. When counterregulation is impaired, adrenergic warning signals like tremor, diaphoresis, and tachycardia may not occur and neuroglycopenic symptoms can develop rapidly. The phenomenon is sometimes described as hypoglycemia-associated autonomic failure [33]. Inadequate counterregulatory responses can also delay recovery from hypoglycemia.

Hypoglycemia in ICU patients can result from rapid changes in clinical status, medications that impair counterregulation (e.g., high-dose β-adrenergic blockers), and the presence of intercurrent disease processes. Although insulin-induced hypoglycemia is easily diagnosed in the ICU, it is crucial to determine exactly why it occurred.

Intensive insulin management is demanding [34]; occasionally, insulin is administered either in the wrong dose or in response to a factitiously elevated blood glucose measurement or to the wrong patient. Even the most careful attempts to lower blood glucose in the ICU to levels less than 110 mg per dL can frequently be associated with hypoglycemia [35,36,37,38,39]. Failure to adjust insulin infusion rate after decreasing nutritional support is common [2]. Total parenteral nutrition solutions containing insulin can produce hypoglycemia [3], particularly if improvement in a patient’s underlying condition leads to reduced peripheral insulin resistance. Insulin-induced hypoglycemia in the ICU can be related to adrenal insufficiency, renal failure, sepsis or drug toxicity, continuous venovenous hemofiltration with bicarbonate replacement fluid, and need for inotropic support [3].

“Factitious” hypoglycemia should be suspected in anyone with access to insulin or oral hypoglycemic agents, including healthcare workers and relatives of persons with diabetes. The diagnosis can be difficult. These patients are trying to frustrate rather than facilitate a diagnosis, and they may devise ingenious methods to conceal their actions. Insulin intended for surreptitious injection has been found hidden in electronic devices and body cavities. Surreptitious use of oral hypoglycemic agents, which act by increasing endogenous insulin secretion, can be particularly problematic to diagnose [40,41]. Factitious hypoglycemia can represent malingering, attempted suicide or homicide, Münchausen syndrome, and Münchausen-by-proxy syndrome [29]. It has also been reported to result from adulteration of herbal and counterfeit prescription drugs with oral agents [42,43].

Insulinomas are insulin-secreting pancreatic islet tumors. They are uncommon but do represent the most common form of pancreatic islet neoplasm. Most (> 90%) are nonmalignant. They are typically small and difficult to visualize radiographically. To evaluate a patient with suspected
insulinoma, fasting immunoreactive insulin (IRI; measured in microunits [μU] per milliliter) and glucose (milligrams per deciliter) should be obtained. Insulinoma is usually associated with an IRI/glucose ratio > 0.3. Elevated levels of C-peptide and proinsulin help confirm the diagnosis by documenting that the source of insulin is endogenous. Proinsulin is typically elevated up to 25% of the insulin concentration in cases of insulinoma [44].

It can be difficult to differentiate among insulinoma, factitious hypoglycemia due to self-administration of insulin, and abuse of oral hypoglycemic agents. When intentional insulin overdose is suspected, insulin measurements are of limited value. Patients with factitious hypoglycemia may have circulating anti-insulin antibodies that interfere with the radioimmunoassay for insulin. This is true even if human insulin is injected. These patients may appear to have elevated levels of insulin, just as would patients with an insulinoma. In this circumstance, simultaneous glucose, insulin, and C-peptide concentrations are helpful. Insulin and C-peptide are normally cosecreted by the pancreas in equimolar quantities, but the latter is not present in insulin for injection. Absence of C-peptide in a patient with unexplained fasting hypoglycemia strengthens the possibility of surreptitious use of insulin. If oral hypoglycemic agent abuse is suspected, both serum and urine should be screened.

Rarely, complex endocrine tumors may secrete insulin [45]. Hypoglycemia due to ectopic secretion of insulin by nonendocrine tumors is very rare [46,47,48,49].

Nesidioblastosis (nonmalignant islet cell hyperplasia) is a rare form of nonmalignant islet cell adenomatosis that leads to insulin-mediated hypoglycemia. In infants, nesidioblastosis is typically characterized by islet hyperplasia, β-cell hypertrophy, and increased β-cell mass. It can be either diffuse or focal and is sometimes termed persistent hyperinsulinemic hypoglycemia of infancy (PHHI) [50,51,52,53]. Rapid diagnosis of the childhood form is crucial to avoid hypoglycemic damage to the maturing CNS. Several different genetic mutations have been associated with the disorder cases [51,52,54,55,56,57]. Special cases of hyperinsulinemic hypoglycemia in infancy include Costello syndrome [58] and the Beckwith–Wiedemann syndrome, which is due to defects in pancreatic β-cell potassium channels [59].

A small number of cases of adult nesidioblastosis have been reported [51,60,61]. The pathological findings are reportedly less consistent than in infants [62], and the cause is unknown. Additional cases of PHH have been diagnosed in adults who had previously undergone Roux-en-Y gastric bypass surgery for weight reduction [63]. Whether these cases represent nesidioblastosis [63,64], “dumping syndrome,” or a reactive process leading to or unmasking a defect in β-cell function [65] is unclear, perhaps in part because the pathological diagnosis of nesidioblastosis is difficult [62]. Treatment options include diazoxide, streptozocin, calcium channel blockade [66], octreotide (discussed later), percutaneous gastrostomy into the remnant stomach [67], as well as partial pancreatectomy [64].

Autoimmune hypoglycemia can result from autoantibodies directed against insulin itself or autoantibodies directed against the insulin receptor [68]. Both can occur in either insulin-treated [69] or nondiabetic individuals, and both types of autoantibodies can be found in the same patient [70]. About 90% of cases have been reported from Japan [71]. Serum insulin concentrations typically are extremely high, usually higher than those produced by insulinomas. It is assumed that in these cases, glucose administration causes excessive insulin response because the antibodies buffer most of the insulin secreted [72].

Endogenous antibodies that bind to and activate the insulin receptor can also cause hypoglycemia [73]. Some, but not all cases, are associated with other autoimmune disorders [74,75,76], and a few have occurred in patients with myeloma [77]. Previous exposure to exogenous insulin is not necessary, but some patients may have an abnormal insulin molecule [78]. Metformin may be helpful in the management of some cases [79]. Some cases respond to immunosuppressive therapy [73]. The natural history of this syndrome is that the antireceptor antibodies disappear and the syndrome resolves over a time course of months to years [28].

Hypoglycemia can occur after pancreas and islet transplantation [80], but it is generally not a significant clinical problem [81,82]. Islet transplantation has been reported to resolve hypoglycemia unawareness [83]. There is a report of nesidioblastosis-like transformation of a successful pancreas allograft [84].

Certain tumors not of pancreatic islet origin are associated with fasting hypoglycemia clinically indistinguishable from that caused by islet cell neoplasms. Whereas insulinomas are typically quite small, nonpancreatic neoplasms associated with hypoglycemia tend to be large mesenchymal tumors. The large size initially suggested that excessive glucose utilization by the tumor was the cause of the hypoglycemia, but subsequent studies suggest that most cases result from secretion of high-molecular-weight insulin-like growth factor II (pro-IGF-II or “big IGF-II”) [85,86]. Pro-IGF-II levels decrease significantly and hypoglycemia resolves after successful tumor resection [87,88,89,90,91,92]. Abnormal processing of the IGF-II molecule may play a role in some cases [88,90,93]. Nonislet cell neoplasms associated with hypoglycemia include gastrointestinal stromal cell tumors [94], hemangiopericytoma [95,96,97], hepatoma [98,99], uterine tumors [100], renal tumors [101], mesenteric sarcomas [102], colorectal cancer [103], gastric cancer [104], adrenocortical carcinoma, lymphoma, poorly differentiated thyroid cancer [105], somatostatinoma [106], phylloides tumor [107], and leukemia [108]. Multiple myeloma may also cause hypoglycemia via an antibody-mediated mechanism described later [76].

The diagnosis of hypoglycemia due to production of pro-IGF-II by nonislet cell tumors requires the exclusion of insulinoma. As noted earlier, this can be done by obtaining simultaneous insulin and glucose measurements during hypoglycemia. The observation of increased blood glucose concentration after intravenous administration of glucagon, an index of adequate glycogen stores, may also help discriminate between insulin and IGF-secreting tumors [109]. Methods have been developed for measuring serum pro-insulin-like growth factor-II directly [86]. Hypoglycemia associated with high levels of IGF-I has rarely been reported [110].

After insulin, these are the most common cause of hypoglycemia [111] (Tables 106.2 and 106.3). Sulfonylureas reduce serum glucose by increasing insulin secretion, inhibiting glycogenolysis and gluconeogenesis, and enhancing the response of target tissues to the effects of insulin [112]. Severe hypoglycemia is not common with appropriate administration of these drugs [113], but it can be observed in several contexts [114]. In all age groups, the condition is most often observed in the context of decreased carbohydrate intake. Maternal treatment of diabetes with glyburide can lead to postpartum hypoglycemia in neonates [115]. In patients between the ages of 11 and 30 years, perhaps two-thirds of hypoglycemic comas are due to sulfonylurea agents [41]. Half of these cases are suicide attempts [111]. In patients with type 2 diabetes older than 60 years, sulfonylurea-induced hypoglycemia is a frequent complication [114,116].

Liver disease decreases the clearance of tolbutamide, acetohexamide, tolazamide, glipizide, glyburide, and glimepiride (Table 106.2). Metabolites of sulfonylureas are excreted in urine with one exception; 50% of glyburide metabolites are excreted in bile. Accordingly, sulfonylurea-induced hypoglycemia is often observed in older individuals in the setting of acute or chronic starvation superimposed on mild to moderate liver or renal failure.

The half-life of some sulfonylureas is > 24 hours and the duration of action is often even longer (Table 106.1). Hepatic and renal insufficiency can extend their half-lives. Patients with sulfonylurea-induced hypoglycemia should therefore be hospitalized after initial resuscitation with glucose. They require continued treatment with oral and intravenous glucose for a minimum of 18 to 24 hours.

When oral agent overdosage is suspected, serum and urine should be screened for sulfonylurea compounds. Sulfonylurea drugs circulate bound to proteins, and drugs of several classes can displace sulfonylureas and enhance their hypoglycemic effect (Table 106.3). The constellation of insulin concentration ≥ 3.9 μU per mL, C-peptide ≥ 1.4 ng per mL, and glucose < 49 mg per dL may be helpful in diagnosing sulfonylurea-induced hypoglycemia [40].