Hypoglycemia in Diabetes – Pathophysiology, Prevalence, and Prevention

I liked this book and I gave it 3 stars on goodreads. Much of it was a review of stuff also covered in Sperling et al. (or elsewhere, see also this blog-post which actually includes some of the same data included in the coverage below), but there was some new stuff as well. I’ve added some relevant observations from the book below – I incidentally do not think most of the stuff included in this post should be at all hard to read for people who do not have diabetes.

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“Hypoglycemia is a fact of life for most people with type 1 diabetes […] The average patient suffers untold numbers of asymptomatic episodes, two episodes of symptomatic hypoglycemia per week (thousands of such episodes over a lifetime of diabetes), and one episode of severe, temporarily disabling hypoglycemia, often with seizure or coma, per year.

Given increased recognition of the magnitude of the problem of iatrogenic hypoglycemia in type 1 diabetes, and practical improvements in the glycemic management of diabetes, over the nearly two decades since the Diabetes Control and Complications Trial (DCCT) was reported in 1993 (DCCT 1993), one might anticipate that hypoglycemia would have become less of a problem. Unfortunately, there is no evidence of that in population-based studies. For example, in their study reported in 2007, the U.K. Hypoglycaemia Study Group (UK Hypo Group 2007) found the incidence of severe hypoglycemia in patients with type 1 diabetes treated with insulin for 15 years (320 episodes per 100 patient-years) to be threefold higher than in individuals treated for 65 years of age, and those visits [are] almost entirely because of hypoglycemia (Budnitz et al. 2011). […] Overall, hypoglycemia is less frequent in type 2 diabetes than in type 1 diabetes […] the risk of hypoglycemia is relatively low in the first few years of insulin treatment of type 2 diabetes […], [however] the risk increases substantially, approaching that in type 1 diabetes, later in the course of type 2 diabetes […] The prospective, population-based study of Donnelly and colleagues […] indicates that the overall incidence of hypoglycemia in insulin-treated type 2 diabetes is approximately one-third of that in type 1 diabetes […] Because the prevalence of type 2 diabetes is ~20-fold greater than that of type 1 diabetes […] most episodes of iatrogenic hypoglycemia, including severe iatrogenic hypoglycemia, occur in people with type 2 diabetes.”

“The physical morbidity of an episode of hypoglycemia ranges from unpleasant symptoms, such as palpitations, tremulousness, anxiety, sweating, hunger, and paresthesias (Towler et al. 1993), and cognitive impairments with behavioral changes, to seizure, coma, or, rarely, death (Cryer 2007). […] Hypoglycemia causes functional brain failure that is corrected in the vast majority of instances after the plasma glucose concentration is raised […] Prolonged, profound hypoglycemia can cause brain death, but that is very rare and most fatal episodes are the result of other mechanisms, presumably cardiac arrhythmias […] One cardiac mechanism is impaired ventricular repolarization, reflected in a prolonged corrected QT (QTc) interval in the electrocardiogram, which is known to be associated with lethal ventricular arrhythmias. […] Older estimates were that 2 to 4% of people with type 1 diabetes died from hypoglycemia (Deckert et al. 1978; Tunbridge 1981; Laing et al. 1999). More recent reports in type 1 diabetes include hypoglycemic mortality rates of 4% (Patterson et al. 2007), 6% (DCCT/EDIC 2007), 7% (Feltbower et al. 2008), and 10% (Skrivarhaug et al. 2006).”

“The first defense against falling plasma glucose concentrations is a decrease in pancreatic β-cell insulin secretion. The second defense is an increase in pancreatic α-cell glucagon secretion. The third defense, which becomes critical when glucagon is deficient, is an increase in adrenomedullary epinephrine secretion. If these three physiological defenses fail to abort the episode, lower plasma glucose levels trigger a more intense sympathoadrenal (sympathetic neural as well as adrenomedullary) response that causes symptoms and thus awareness of hypoglycemia that prompts the behavioral defense [which is ingestion of carbohydrates]. […] All of these defenses are typically compromised in type 1 diabetes and advanced type 2 diabetes […] compromised glucose counterregulation is the key feature of the pathogenesis of iatrogenic hypoglycemia in type 1 diabetes and advanced type 2 diabetes. Hypoglycemia in diabetes is typically the result of the interplay of relative or absolute therapeutic insulin excess and compromised physiological and behavioral defenses against falling plasma glucose concentrations […] In fully developed (i.e., C-peptide–negative) type 1 diabetes, circulating insulin levels do not decrease as plasma glucose concentrations decline through or below the physiological range. […] Furthermore, circulating glucagon levels do not increase as plasma glucose concentrations fall below the physiological range […] Thus, both the first defense against hypoglycemia — a decrease in insulin levels — and the second defense against hypoglycemia — an increase in glucagon levels — are lost in type 1 diabetes. Therefore, patients with type 1 diabetes are critically dependent on the third defense against hypoglycemia, an increase in epinephrine levels. However, the epinephrine secretory response to hypoglycemia is typically attenuated in type 1 diabetes […] Through mechanisms yet to be clearly defined but often thought to reside in the brain […], the glycemic threshold for sympathoadrenal — both adrenomedullary and sympathetic neural — activation is shifted to lower plasma glucose concentrations by recent antecedent hypoglycemia […], as well as by prior exercise […] and by sleep […] The reduced responses to a given level of hypoglycemia cause the clinical syndromes of defective glucose counterregulation and hypoglycemia unawareness [which is] impairment or even complete loss of the warning, largely neurogenic symptoms that previously prompted the behavioral defense, the ingestion of carbohydrates. Hypoglycemia unawareness—or more precisely impaired awareness of hypoglycemia—is common in type 1 diabetes […] Compared with patients with type 1 diabetes who have absent insulin and glucagon responses but have normal epinephrine responses, patients with absent insulin and glucagon responses and reduced epinephrine responses have been shown to be at 25-fold […] or greater […] increased risk for severe iatrogenic hypoglycemia during aggressive glycemic therapy […] At least in part because of the clinical importance of hypoglycemia in people with diabetes, studies of the molecular and cellular physiology and pathophysiology of the CNS [central nervous system]-mediated neuroendocrine, including sympathoadrenal, responses to falling plasma glucose concentrations are an increasingly active area of fundamental neuroscience research.”

“The risk factors for hypoglycemia in people with diabetes […] follow directly from the pathophysiology of glucose counterregulation in diabetes […]. The principle is that iatrogenic hypoglycemia in type 1 diabetes and advanced type 2 diabetes is typically the result of the interplay of relative or absolute therapeutic insulin excess and compromised physiological and behavioral defenses against falling plasma glucose concentrations, i.e., hypoglycemia-associated autonomic failure (HAAF) in diabetes.

People with diabetes are not immune to hypoglycemia caused by mechanisms other than the treatment of their diabetes […]. Those include 1) an array of drugs […] including alcohol, 2) critical illnesses such as renal, hepatic or cardiac failure, sepsis, or inanition, 3) hormone deficiency states such as adrenocortical failure, 4) nonislet tumor hypoglycemia, 5) endogenous hyperinsulinism, and 6) accidental, surreptitious, or even malicious hypoglycemia. However, aside from drug effects, those mechanisms are very uncommon. […] if all other factors are the same, patients treated to lower, compared with higher, A1C levels are at higher risk for hypoglycemia. Stated differently, studies with a control group treated to a higher A1C level consistently report higher rates of hypoglycemia in the group treated to a lower A1C level in type 1 diabetes […] and type 2 diabetes […] lower mean plasma glucose concentrations and greater plasma glucose variability are also associated with a higher risk of hypoglycemia […] Improved glycemic control before and during pregnancy is particularly important in the short term because it improves pregnancy outcomes in women with type 1 diabetes. But, it increases the frequency of hypoglycemia substantially […] In one series, 45% of 108 women with type 1 diabetes suffered severe hypoglycemia during their pregnancies; compared with a prepregnancy rate of 110 per 100 patient-years, the incidence was the equivalent of 530, 240, and 50 episodes per 100 patient-years in the first, second, and third trimesters, respectively (Neilsen et al. 2008).”

“Based on a systematic review and meta-analysis of randomized controlled trials published up to 2012, Yeh et al. (2012) concluded that CSII [Continuous subcutaneous insulin infusion] (compared with MDI [multiple daily injection]), real-time CGM [continuous glucose monitoring] (compared with SMPG [self-monitored plasma glucose]), and sensor-augmented CSII (compared with MDI and SMPG) had not been shown to reduce the incidence of severe hypoglycemia in type 1 or type 2 diabetes. […] these technologies may, or may not, be shown to reduce the frequency of hypoglycemia in the future.”