REVIEW ILAN GABRIELY, MD HARRY SHAMOON, MD CME Diabetes Research Center, Albert Einstein Professor of Medicine, Diabetes Research CREDIT College of Medicine, New York Center, Albert Einstein College of Medicine, New York Hypoglycemia in diabetes: Common, often unrecognized ■ ABSTRACT YPOGLYCEMIA poses a major barrier to H diabetes treatment. On one hand, we Hypoglycemic episodes in patients with diabetes often go want to maintain tight glycemic control to unrecognized, and over time, patients may lose the ability prevent the vascular complications of diabetes, to sense hypoglycemia, increasing their risk. Intensive but we also have to ensure the safety and com- diabetes control is beneficial for patients with diabetes, fort of the patient by avoiding hypoglycemia— but it increases their risk of hypoglycemia, underscoring and by recognizing and treating it if it occurs. the complexity of diabetes management. Hypoglycemic events are probably com- mon, especially in patients with type 1 diabetes. ■ KEY POINTS And when patients with type 2 diabetes receive insulin, they may become more prone to hypo- Epinephrine release during hypoglycemia becomes glycemic episodes. Unfortunately, the more progressively defective in type 1 diabetes. This decrease in episodes of hypoglycemia a patient has, the epinephrine response is accompanied by an attenuated more the body’s response is blunted, decreasing autonomic neural response, which results in the clinical the patient’s awareness of an episode. syndrome of impaired awareness of hypoglycemia (ie, Thus, we need to be vigilant in monitor- lack of the warning symptoms of prevailing ing patients for increasing episodes of hypo- glycemia, and for events that a patient may not hypoglycemia). realize were caused by hypoglycemia. At every visit, one should probe for details of episodes ■ CONSEQUENCES OF HYPOGLYCEMIA that the patient recognized as being caused by hypoglycemia, but also assess whether the patient has Hypoglycemia can cause severe morbidity and experienced events that went unrecognized. sometimes death, usually depending on its severity or duration.Thus, it may be associated Although most episodes of nocturnal hypoglycemia are with a spectrum of symptoms progressing from asymptomatic, some patients complain of sleep autonomic activation to behavioral changes to disturbances (vivid dreams or nightmares), morning altered cognitive function to seizures or coma headache (feeling hungover), chronic fatigue, or mood (the latter observed only when blood glucose changes (mainly depression). levels are < 30 mg/dL or with prolonged hypo- glycemia). Furthermore, owing to patients’ (and sometimes physicians’) fear of hypoglycemia, intensive diabetes treatment may be relaxed, which ultimately results in inferior glycemic control. Other immediate and long-term con- sequences of hypoglycemia are its impact on PATIENT INFORMATION various activities of daily living such as driv- Hypoglycemia, page 343 ing, employment, and even home life. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 4 APRIL 2004 335 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. HYPOGLYCEMIA GABRIELY AND SHAMOON ■ INSULIN EXCESS, OTHER FACTORS from this study. And indeed, population-based studies in northern Europe reported 100 to Insulin excess—due either to endogenous 160 episodes of severe hypoglycemia per 100 secretion or to exogenous doses—appears to patient-years,7,8 even though glycemic control be the most consistent cause of hypoglycemia, may not have been as close to normal in these and iatrogenic hypoglycemia is the most com- studies as in the DCCT. mon scenario.1 However, other factors such as In type 2 diabetes, severe hypoglycemia dietary intake, physical activity, alcohol use, appears to be much less common, but when and drug interactions also may increase the patients with type 2 diabetes receive insulin risk of hypoglycemia.2–4 they may become as susceptible to hypo- In addition, studies over the last 2 decades glycemia as patients with type 1 diabetes. strongly suggest that deficits in glucose coun- Leese et al8 reported the following incidence terregulation are important—and perhaps rates of severe hypoglycemia (episodes per 100 dominant—factors in the development of patient-years): severe hypoglycemia.5 • In patients with type 1 diabetes—11.5 • In patients with type 2 diabetes treated ■ HOW COMMON IS HYPOGLYCEMIA? with insulin—11.8 • In patients with type 2 diabetes treated Recent clinical trials have better quantified with oral hypoglycemic drugs—0.05. the risk of hypoglycemia—in particular, severe Since recent studies also demonstrated hypoglycemia—in both type 1 and type 2 dia- that improved glycemic control prevents or betes.6–8 delays microvascular complications (neuropa- Severe hypoglycemia is operationally thy, retinopathy, and nephropathy) and per- defined as an episode that the patient cannot haps macrovascular complications (heart self-treat, so that external help is required, attacks, peripheral vascular disease, strokes) in regardless of the blood glucose concentration both type 1 and type 2 diabetes, the clinical or whether the patient experiences seizures or decision to pursue such treatment goals in the Insulin excess loss of consciousness. face of possible iatrogenic hypoglycemia must appears to be Mild or moderate hypoglycemia refers to be made on a case-by-case basis. episodes that the patient can self-treat, regard- the most less of the severity of symptoms, or when ■ THE NORMAL RESPONSE consistent blood glucose levels are noted to be lower than 60 mg/dL. Counterregulatory responses to hypoglycemia cause of The incidence of mild or moderate hypo- have been studied extensively in experiments hypoglycemia glycemic episodes is difficult to determine in humans by infusing insulin to reduce the accurately because they are rarely reported, plasma glucose concentration.9 although they are common in insulin-treated A decrease in plasma glucose normally patients. Furthermore, diabetic patients with triggers a cascade of reactions, mostly hor- hypoglycemia-associated autonomic failure monal, that rapidly return the glucose concen- (see below) might not be aware of such events. tration to baseline levels. Ultimately there is Episodes of severe hypoglycemia are better an increase in glucose production in the liver documented, although the incidence was dif- and kidneys and a decrease in peripheral glu- ferent in different studies, likely owing to dif- cose utilization (mainly in muscle and fat tis- ferences in the populations studied (eg, levels sue). Both mechanisms act in opposition to of glycemic control, intensity of insulin treat- the effects of insulin and, hence, result in the ment, diabetes education). reversal of hypoglycemia.9–11 In type 1 diabetes, the Diabetes Control Different counterregulatory mechanisms and Complications Trial (DCCT) reported 62 are activated at different threshold levels of severe hypoglycemic episodes per 100 patient- glucose concentration.9 years.6 The true risk may be higher in clinical A decrease in endogenous insulin secre- practice, however, because patients at high tion is the first defense against a falling plasma risk for severe hypoglycemia were excluded glucose concentration. This mechanism is 336 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 4 APRIL 2004 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. critical in patients with residual endogenous ■ HOW DO PATIENTS KNOW insulin secretion. In normal beta cells, insulin WHEN GLUCOSE IS LOW? secretion is suppressed at a plasma glucose threshold of about 83 mg/dL.12 Most patients recognize the early warning Of the other hormones, epinephrine and signs of hypoglycemia in time to take counter- glucagon appear to be the most potent coun- measures. The lack of such symptoms despite terregulatory factors. These hormones are hypoglycemia is termed impaired awareness of secreted promptly after plasma glucose levels hypoglycemia, a syndrome linked to defective fall, and both induce a rapid increase in counterregulation in patients with diabetes. endogenous glucose production. The glycemic thresholds for secretion of these hormones is Role of the brain normally about 68 mg/dL. Accumulating evidence suggests that the Epinephrine and glucagon appear to have brain—in particular, the ventromedial hypo- similar quantitative effects on endogenous thalamus (VMH)—plays an important role in glucose production; hence, a deficient glucose sensing. response of either hormone alone does not In dogs, the counterregulatory response to impair glucose counterregulation.12–14 For peripheral hypoglycemia can be abolished by example, most patients with recent-onset type infusing glucose directly into the brain.16 In 1 diabetes secrete less glucagon during hypo- rats, the counterregulatory response can also glycemia than people without diabetes, but be abolished by selectively destroying the they can still secrete enough epinephrine to VMH or infusing concentrated glucose solu- mount an appropriate response. tions into the ventromedial nuclei.17,18 Other major counterregulatory hormones Conversely, selective glycopenia in the cells seem to be less critical in the initial 30 to 60 within the VMH activates counterregulation, minutes of a hypoglycemic episode but are even if the peripheral blood glucose concen- important in the later stage of glucose stabi- tration is normal.19 lization.12 Cortisol and