Are Gender Differences in the Responses to Hypoglycemia Relevant to Iatrogenic Hypoglycemia in Type 1 Diabetes?

Philip E. Cryer

Division of Endocrinology, Diabetes, and Metabolism General Clinical Research Center and Diabetes Research and Training Center Washington University School of Medicine St. Louis, Missouri 63110

Address correspondence and requests for reprints to: Philip E. Cryer, M.D., Campus Box 8127, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110. E-mail: pcryer{at}imgate.wustl.edu


    Introduction
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 Introduction
 References
 
Iatrogenic hypoglycemia is the limiting factor in the glycemic management of type 1 diabetes mellitus (T1DM) and advanced type 2 diabetes mellitus (T2DM) (1). Because of the interplay of relative or absolute therapeutic insulin excess—which must occur from time-to-time because of the pharmacokinetic imperfections of all insulin replacement regimens—and of compromised physiological and behavioral defenses against falling plasma glucose concentrations, the clinical syndromes of defective glucose counterregulation, and hypoglycemia unawareness, hypoglycemia is a barrier to true glycemic control in T1DM (2, 3) and insulin-requiring T2DM (4, 5). As a result, albeit at lower rates, long-term complications of diabetes occur despite aggressive attempts to reduce glycemia. For example, retinopathy developed or progressed in 14% of the patients with T1DM treated intensively (compared with 32% of those treated conventionally) in the Diabetes Control and Complications Trial (2), and a microvascular end point developed in 8% of the patients with T2DM treated intensively (compared with 11% of those treated conventionally) in the United Kingdom Prospective Diabetes Study (4). In the short term, hypoglycemia often causes recurrent (and sometimes persistent) physical morbidity, psychosocial morbidity, or both. It can be fatal; an estimated 2–4% of deaths of people with T1DM have been attributed to hypoglycemia.

Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors that normally prevent or rapidly correct hypoglycemia (1). Despite the actions of other potentially important glucose-raising hormones, neurotransmitters, and substrates, hypoglycemia develops or progresses when glucagon and epinephrine are deficient and insulin is present. The secretion of all three of these key hormones is typically altered in patients with established (i.e. C-peptide negative) T1DM (1). Insulin levels do not decrease and glucagon levels do not increase as plasma glucose concentrations fall. Thus, the first and second physiological defenses against hypoglycemia are lost, leaving the patient largely dependent on the third defense, increases in epinephrine. However, the epinephrine response is often attenuated. That is a critical pathophysiological event. Patients with combined deficiencies of their glucagon and epinephrine responses to falling plasma glucose concentrations have been shown to be at 25-fold or greater higher risk of severe iatrogenic hypoglycemia than those with deficient glucagon but normal epinephrine responses during intensive therapy of T1DM (6, 7). They have the clinical syndrome of defective glucose counterregulation.

Loss of the warning, largely neurogenic (autonomic) symptoms of developing hypoglycemia constitutes the clinical syndrome of hypoglycemia unawareness (or impaired awareness of hypoglycemia, as some prefer, because the loss can be partial) (1). Absent these warning symptoms, the first manifestation of a hypoglycemic episode is neuroglycopenia, and that is often too late for the patient to recognize and self-treat (i.e. to make the appropriate behavioral response such as ingestion of carbohydrate) the episode. Hypoglycemia unawareness is also associated with a high frequency of severe iatrogenic hypoglycemia in T1DM.

Reduced responsiveness of the sympathochromaffin system—the adrenal medullae, which release epinephrine and some norepinephrine into the circulation, and the sympathetic nervous system, which releases norepinephrine and acetylcholine from its postganglionic neurons—to falling glucose concentrations is a key pathophysiological feature of both defective glucose counterregulation and hypoglycemia unawareness (1). These reduced responses to a given level of hypoglycemia are the result of shifts of their glycemic thresholds to lower plasma glucose concentrations. Responses can be elicited, but lower glucose concentrations are required. Although classical diabetic autonomic neuropathy may contribute to the reduced sympathochromaffin responses in affected patients (8), these responses are typically reduced in the absence of that complication (9). They are now known to be the result of recent antecedent hypoglycemia. Recent antecedent hypoglycemia has been shown to reduce autonomic and symptomatic responses, among other neuroendocrine responses, to a given level of hypoglycemia in nondiabetic individuals (10, 11) and in patients with T1DM (9). It shifts the glycemic thresholds for these responses to lower plasma glucose concentrations.

The concept of hypoglycemia-associated autonomic failure in T1DM (1, 9), a functional disorder distinct from classical diabetic autonomic neuropathy, posits that: 1) periods of relative or absolute therapeutic insulin excess in the setting of absent glucagon responses lead to episodes of hypoglycemia; 2) these episodes, in turn, cause reduced autonomic (including epinephrine) responses to falling glucose concentrations on subsequent occasions; and 3) these reduced autonomic responses result in both reduced symptoms of developing hypoglycemia (i.e. hypoglycemia unawareness) and—because epinephrine responses are reduced in the setting of absent glucagon responses—impaired physiological defenses against developing hypoglycemia (i.e. defective glucose counterregulation). Thus, a vicious cycle of recurrent hypoglycemia is created and perpetuated. Perhaps the most compelling support for this functional construct is the finding, in three independent laboratories, that hypoglycemia unawareness and, at least in part, the reduced epinephrine component of defective glucose counterregulation are reversible in many affected patients with T1DM after as little as 2 weeks of scrupulous avoidance of iatrogenic hypoglycemia (12, 13, 14).

With this background, Davis et al. (15) address an apparent clinical paradox in this issue of the journal. Substantial evidence indicates that the magnitude of an array of neuroendocrine and metabolic responses, including that of the sympathochromaffin system, to hypoglycemia are reduced in women compared with men, including those without (16, 17, 18, 19) and those with (20) T1DM. This seems to be due to reduced responsiveness to a given level of hypoglycemia in women because the glycemic thresholds for many responses are similar in women and men (18, 19). The mechanism(s) of this gender difference is not known. The reduced glucagon and epinephrine responses in nondiabetic women and the reduced epinephrine responses in T1DM women (glucagon responses are typically absent in T1DM) are reflected biologically in reduced rates of endogenous glucose production during hypoglycemia. However, despite this evidence that women defend less effectively against hypoglycemia than men, the frequency of iatrogenic hypoglycemia seems to be similar in women and men with T1DM. For example, in the Diabetes Control and Complications Trial (3) the numbers of episodes of severe hypoglycemia were similar in women (1870 episodes) and men (1908 episodes). Whereas the severe hypoglycemia event rate was higher in women in the conventional therapy group (23.3 vs. 14.6 episodes per 100 patient-years; P < 0.05), that was not the case in the intensive therapy group (58.7 vs. 63.6 episodes per 100 patient-years). Thus, the relative risk of severe hypoglycemia during intensive therapy was 2.52 (95% confidence intervals, 1.87–3.38) in women and 4.35 (95% confidence intervals, 3.20–5.90) in men.

Given the concept of hypoglycemia-associated autonomic failure in T1DM summarized earlier, Davis et al. (15) hypothesized that a gender difference in the blunting effects of recent antecedent hypoglycemia might explain why women with T1DM do not have an increased frequency of iatrogenic hypoglycemia despite reduced counterregulatory (i.e. sympathochromaffin) responses. They studied nondiabetic women (n = 7) and men (n = 8) in four separate 2-day protocols. Neuroendocrine and metabolic responses to hyperinsulinemic hypoglycemia (2.9 ± 0.1 mmol/L, 52 ± 2 mg/dL) were measured the morning of day 2 on all four occasions following two 2-h hyperinsulinemic glucose clamps at 5.1 ± 0.1 mmol/L (92 ± 2 mg/dL), 3.9 ± 0.1 mmol/L (70 ± 2 mg/dL), 3.3 ± 0.1 mmol/L (60 ± 2 mg/dL), or 2.9 ± 0.1 (52 ± 2 mg/dL) on day 1. The central finding was that day 1 hypoglycemia produced less blunting of the day 2 responses to hypoglycemia in the women compared with the men. Furthermore, because of less blunting, the magnitude of many of the day 2 responses was similar in the women and the men following hypoglycemia (3.9, 3.3, or 2.9 mmol/L) on day 1. The sympathochromaffin and glucagon responses are particularly notable because of their relevance to glucose counterregulation. Compared with those following day 1 euglycemic clamps (5.1 mmol/L):

Day 2 plasma epinephrine responses were reduced only following day 1 clamps at 2.9 mmol/L in women but were reduced following day 1 clamps at 3.9, 3.3, and 2.9 mmol/L in men. Day 2 plasma norepinephrine and muscle sympathetic nerve activity (MSNA; microneurography) responses, the latter probably a more sensitive and undoubtedly a more specific measure of sympathetic neural activity than the plasma norepinephrine concentration, were not reduced following any of the day 1 clamps in women, but norepinephrine responses were reduced following day 1 clamps at 3.3 and 2.9 mmol/L and MSNA responses were reduced following day 1 clamps at 3.9, 3.3, and 2.9 mmol/L in men.
Day 2 plasma epinephrine and norepinephrine concentrations and MSNA burst frequencies were similar in women and men following day 1 clamps at 3.9, 3.3, and 2.9 mmol/L.
Day 2 plasma glucagon responses were reduced only following day 1 clamps at 2.9 mmol/L in men. However, day 2 glucagon concentrations were lower in women (rather than similar in women and men as with the sympathochromaffin measures) following all day 1 clamps.

Furthermore, although rates of endogenous glucose production during the day 2 hypoglycemic clamps following day 1 clamps at 5.1 and 3.9 mmol/L were reduced in women, they were not reduced following day 1 clamps at 3.3 and 2.9 mmol/L in women. Finally, whereas the glucose infusion rates required to maintain the 2.9 mmol/L day 2 glucose clamps were lower in women following day 1 clamps at 5.1 and 3.9 mmol/L in women, they were not lower following day 1 clamps at 3.3 and 2.9 mmol/L in women.

Thus, the findings of Davis et al. (15) are consistent with their suggestion that lesser blunting effects of recent antecedent hypoglycemia on the responses to subsequent hypoglycemia, particularly less blunting of the sympathochromaffin responses, in women might explain why women with T1DM do not have an increased frequency of iatrogenic hypoglycemia. However, several caveats might be considered. First, as the authors emphasize, they studied nondiabetic women and men, not those with T1DM. Second, their sample sizes were rather small. Although the internal consistency of the data is reassuring, the fact remains that the conclusions are based, in part, on the relative absence of effects of antecedent hypoglycemia in women. Third, the studies may not have been concurrent (the data from the men were published in 1997), although it is stated that "The subjects were studied under identical experimental conditions and over a similar time frame." Fourth, with the notable exception of MSNA, most of the responses following day 1 euglycemic (5.1 mmol/L) clamps were reduced in the women compared with the men, as expected (16, 17, 18, 19, 20). In essence, the women started with lower baseline responses.

Finally, these data have practical implications for the study of glucose counterregulation. To the extent that antecedent hypoglycemia has less blunting effects on responses to subsequent hypoglycemia in women compared with men, it will be more difficult to study the nuances, mediators, and mechanisms of such effects in populations that include both women and men.

Received April 10, 2000.

Accepted April 10, 2000.


    References
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