In this issue of Diabetes, Joy et al. (1) report that in healthy individuals hyperinsulinemic hypoglycemia, compared with hyperinsulinemic euglycemia, reduced endogenous nitric oxide (NO)-mediated endothelial vasodilation, activated inflammatory processes, impaired fibrinolytic balance, and increased proatherothrombotic mechanisms and that repeated episodes of hypoglycemia on two consecutive days further impaired vascular function by additionally reducing both endogenous and exogenous NO-mediated endothelial function. Because the data during both day one and day two hyperinsulinemic-hypoglycemic clamps were contrasted with day one hyperinsulinemic-euglycemic clamps, the data implicate hypoglycemia, rather than hyperinsulinemia, in the development of these responses. However, their mechanisms, particularly any relationship with the documented sympathoadrenal responses to hypoglycemia and the attenuated sympathoadrenal responses to hypoglycemia following recent antecedent hypoglycemia (2,3), were not determined. These translational data support the notion that iatrogenic hypoglycemia may contribute to the pathogenesis of atherosclerotic vascular disease in diabetes (4,5) and extend that to include a further effect of recurrent hypoglycemia.

Iatrogenic hypoglycemia causes recurrent morbidity in most people with type 1 diabetes and many with advanced type 2 diabetes and is sometimes fatal. Notably, 8% of the deaths of patients with diabetes who participated in the Diabetes Control and Complications Trial (DCCT) were attributed to hypoglycemia (6). Hypoglycemia attenuates sympathoadrenal and symptomatic responses to the same level of subsequent hypoglycemia (2,3) and thus causes hypoglycemia-associated autonomic failure (HAAF) in diabetes (3,7,8). HAAF includes both defective glucose counterregulation and impaired awareness of hypoglycemia. This phenomenon is the result of a shift in the glycemic thresholds for sympathoadrenal and symptomatic responses to falling plasma glucose concentrations. Patients with tightly controlled, frequently hypoglycemic diabetes have these responses at lower-than-normal falling glucose levels (9), whereas patients with poorly controlled, frequently hyperglycemic diabetes have these responses at higher-than-normal falling glucose levels (9,10). HAAF, the result of recent antecedent hypoglycemia, is clearly maladaptive as it is associated with a 25-fold (11) or greater (12) increased risk of severe iatrogenic hypoglycemia during intensive glycemic therapy of diabetes.

Iatrogenic hypoglycemia is also maladaptive in that it causes cardiac arrhythmias (13), and severe hypoglycemia is associated with death (14,15), including arrhythmic death (15). Although hypoglycemia causes an attenuated sympathoadrenal response to the same level of subsequent hypoglycemia (2,3,6,7), that does not preclude a greater sympathoadrenal response to more marked hypoglycemia. If HAAF led to an episode of marked hypoglycemia that triggered a massive sympathoadrenal discharge that caused a fatal arrhythmia, HAAF would again be maladaptive. This scenario need not be frequent. It would occur only once in a lifetime.

Sudden death of patients with diabetes caused by a sympathoadrenal discharge triggered by hypoglycemia, deduced in humans (14,16), has been supported by studies of the mechanism of cardiovascular death during marked hyperinsulinemic hypoglycemia in rats (17,18). The electrocardiographic findings included premature atrial and ventricular contractions but the sequence of progressive atrioventricular block and bradycardia most often preceded death (17). These sequences were sympathoadrenal catecholamine mediated, as was evidenced by the finding that nonselective β-adrenergic antagonism (with propranolol), but not α-adrenergic antagonism, prevented atrioventricular block and reduced hypoglycemic mortality from 33% to zero.

Interestingly, however, hypoglycemic mortality was 21% in control rats, 36% in streptozotocin diabetic rats, and 4% in rats exposed to prior recurrent moderate hypoglycemia (17). As expected from the earlier human studies (2,3), the plasma epinephrine response to hypoglycemia was attenuated in the latter animals (17). Similarly, hypoglycemic mortality was reduced in diabetic rats exposed to prior recurrent moderate hypoglycemia (18). These findings suggest an adaptive aspect of HAAF. This possibility was also supported by the finding of a lower risk of death in patients with type 2 diabetes assigned to intensive glycemic therapy who experienced more hypoglycemia in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (19) and a somewhat similar pattern in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial (20).

Thus, available data suggest that recurrent iatrogenic hypoglycemia and the resulting HAAF in diabetes (6,7) are both maladaptive and adaptive (Fig. 1). HAAF is maladaptive in that it increases the frequency of severe hypoglycemia (11,12) and, therefore, could play a role in the occurrence of a fatal hypoglycemic arrhythmic death (1315) and may contribute to the pathogenesis of atherosclerotic vascular disease (1,4,5). On the other hand, HAAF appears to be adaptive in that it reduces the most devastating effect of severe hypoglycemia—death (1720).

Figure 1

Maladaptive and adaptive aspects of HAAF in diabetes.

Figure 1

Maladaptive and adaptive aspects of HAAF in diabetes.

See accompanying article, p. 2571.

Acknowledgments. The author thanks Janet Dedeke, his previous administrative assistant, for help in the preparation of the manuscript.

Funding. The original data cited here were previously supported, in part, by U.S. Public Health Service grants R37-DK27085, M01-RR00036, and P60-20579 and postdoctoral fellowship and research grants from the American Diabetes Association.

Duality of Interest. P.E.C. has served as a consultant to Boehringer Ingelheim, Calibrium, Novo Nordisk, and Pfizer in the past year. No other potential conflicts of interest relevant to this article were reported.

1.
Joy
NG
,
Tate
DB
,
Younk
LM
,
Davis
SN
.
Effects of acute and antecedent hypoglycemia on endothelial function and markers of atherothrombotic balance in healthy humans
.
Diabetes
2015
;
64
:
2571
2580
[PubMed]
2.
Heller
SR
,
Cryer
PE
.
Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans
.
Diabetes
1991
;
40
:
223
226
[PubMed]
3.
Dagogo-Jack
SE
,
Craft
S
,
Cryer
PE
.
Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia
.
J Clin Invest
1993
;
91
:
819
828
[PubMed]
4.
Giménez
M
,
Gilabert
R
,
Monteagudo
J
, et al
.
Repeated episodes of hypoglycemia as a potential aggravating factor for preclinical atherosclerosis in subjects with type 1 diabetes
.
Diabetes Care
2011
;
34
:
198
203
[PubMed]
5.
Ceriello
A
,
Novials
A
,
Ortega
E
, et al
.
Evidence that hyperglycemia after recovery from hypoglycemia worsens endothelial function and increases oxidative stress and inflammation in healthy control subjects and subjects with type 1 diabetes
.
Diabetes
2012
;
61
:
2993
2997
[PubMed]
6.
Orchard
TJ
,
Nathan
DM
,
Zinman
B
, et al.;
Writing Group for the DCCT/EDIC Research Group
.
Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality
.
JAMA
2015
;
313
:
45
53
[PubMed]
7.
Cryer
PE
.
The barrier of hypoglycemia in diabetes
.
Diabetes
2008
;
57
:
3169
3176
[PubMed]
8.
Cryer
PE
.
Mechanisms of hypoglycemia-associated autonomic failure in diabetes
.
N Engl J Med
2013
;
369
:
362
372
[PubMed]
9.
Amiel
SA
,
Sherwin
RS
,
Simonson
DC
,
Tamborlane
WV
.
Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release
.
Diabetes
1988
;
37
:
901
907
[PubMed]
10.
Boyle
PJ
,
Schwartz
NS
,
Shah
SD
,
Clutter
WE
,
Cryer
PE
.
Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics
.
N Engl J Med
1988
;
318
:
1487
1492
[PubMed]
11.
White
NH
,
Skor
DA
,
Cryer
PE
,
Levandoski
LA
,
Bier
DM
,
Santiago
JV
.
Identification of type I diabetic patients at increased risk for hypoglycemia during intensive therapy
.
N Engl J Med
1983
;
308
:
485
491
[PubMed]
12.
Bolli
GB
,
De Feo
P
,
De Cosmo S, et al. A reliable and reproducible test for adequate glucose counterregulation in type 1 diabetes
.
Diabetes
1984
;
33
:
732
737
[PubMed]
13.
Chow
E
,
Bernjak
A
,
Williams
S
, et al
.
Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk
.
Diabetes
2014
;
63
:
1738
1747
[PubMed]
14.
Cryer
PE
.
Glycemic goals in diabetes: trade-off between glycemic control and iatrogenic hypoglycemia
.
Diabetes
2014
;
63
:
2188
2195
[PubMed]
15.
Mellbin
LG
,
Rydén
L
,
Riddle
MC
, et al.;
ORIGIN Trial Investigators
.
Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial
.
Eur Heart J
2013
;
34
:
3137
3144
[PubMed]
16.
Frier
BM
,
Schernthaner
G
,
Heller
SR
.
Hypoglycemia and cardiovascular risks
.
Diabetes Care
2011
;
34
(
Suppl. 2
):
S132
S137
[PubMed]
17.
Reno
CM
,
Daphna-Iken
D
,
Chen
YS
,
VanderWeele
J
,
Jethi
K
,
Fisher
SJ
.
Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation
.
Diabetes
2013
;
62
:
3570
3581
[PubMed]
18.
VanderWeele
JJ
,
Daphna-Iken
D
,
Chen
YS
,
Hoffman
RS
,
Clark
AL
,
Fisher
SJ
.
Antecedent recurrent hypoglycemia reduces lethal cardiac arrhythmias induced by severe hypoglycemia in diabetic rats
.
Diabetes
2014
;
53
(
Suppl. 1
):
A39
[abstract]
19.
Seaquist
ER
,
Miller
ME
,
Bonds
DE
, et al.;
ACCORD Investigators
.
The impact of frequent and unrecognized hypoglycemia on mortality in the ACCORD study
.
Diabetes Care
2012
;
35
:
409
414
[PubMed]
20.
Zoungas
S
,
Patel
A
,
Chalmers
J
, et al.;
ADVANCE Collaborative Group
.
Severe hypoglycemia and risks of vascular events and death
.
N Engl J Med
2010
;
363
:
1410
1418
[PubMed]