23/2/24, 13:44 Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus - UpToDate

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Physiologic response to hypoglycemia in healthy

individuals and patients with diabetes mellitus
AUTHORS: Philip E Cryer, MD, Michael R Rickels, MD, MS
SECTION EDITOR: David M Nathan, MD
DEPUTY EDITOR: Katya Rubinow, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jan 2024.

This topic last updated: Dec 07, 2022.

INTRODUCTION

The brain relies almost exclusively on glucose as a fuel, but it cannot synthesize or store
glucose to a substantial degree. As a result, adequate uptake of glucose from the plasma is
essential for normal brain function and survival. Given the survival value of maintenance of
the plasma glucose concentration, it is not surprising that very effective physiologic and
behavioral mechanisms have evolved that normally prevent or rapidly correct hypoglycemia.
As a result, hypoglycemia is an uncommon clinical event except in patients who use drugs
that lower glucose levels, particularly those with diabetes who use insulin, a sulfonylurea, or
a glinide. In addition to being at increased risk for hypoglycemia, patients with diabetes
treated with insulin often have impaired neurohumoral responses to and few early
symptoms of low blood glucose concentrations [1-4].

This topic will review glucose metabolism and the response to hypoglycemia in healthy
individuals and in patients with diabetes. The therapeutic approach to hypoglycemia in
patients with diabetes is discussed separately. (See "Hypoglycemia in adults with diabetes
mellitus".)

REGULATION OF GLUCOSE HOMEOSTASIS

In healthy individuals, the extracellular supply of glucose is carefully regulated primarily by

insulin and glucagon ( figure 1) [1-4]. As plasma glucose concentrations rise after a meal,

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glucose enters the pancreatic beta cells. In these cells, the enzyme glucokinase, which
phosphorylates glucose to glucose-6-phosphate, acts as the glucose sensor, initiating a
sequence of events leading to entry of calcium and insulin release. (See "Pancreatic beta cell
function".)

Insulin acts to restore normoglycemia primarily through the following two mechanisms:

● Reduction of hepatic glucose production – Insulin decreases hepatic glucose

production by diminishing both glycogenolysis and gluconeogenesis. It does so
indirectly by diminishing delivery of the gluconeogenic precursors (eg, lactate, glycerol,
and alanine and other amino acids) to the liver via its antiglycolytic, antilipolytic, and
antiproteolytic actions. Insulin also inhibits glucagon secretion by direct inhibition of
the glucagon gene in the pancreatic alpha cells, which further diminishes hepatic
glucose production. (See "Insulin action", section on 'Insulin and glucose metabolism'.)

● Promotion of glucose uptake in peripheral tissues – Insulin increases glucose uptake

by skeletal muscle and adipose tissue by translocating glucose transporters from an
intracellular pool to the cell surface.

The net effect of these responses is inhibition of hepatic glucose production and increased
peripheral utilization of the glucose load that is not taken up by the liver. As a result, plasma
glucose concentrations normally return to baseline values within several hours.

RESPONSE TO HYPOGLYCEMIA IN HEALTHY INDIVIDUALS

In the fasting state, when glucose cannot be obtained from intestinal absorption, glucose
counterregulatory mechanisms prevent or rapidly correct falling plasma glucose
concentrations ( figure 1 and table 1) [1-4]. There is a hierarchy among the defense
mechanisms, and in individuals without diabetes, the glycemic thresholds for activation of
these defenses are reproducible. The counterregulatory hormonal responses begin well
before the onset of symptoms of hypoglycemia.

Counterregulatory hormones

● The first defense against hypoglycemia is a decrease in insulin secretion as plasma

glucose concentrations decline within the physiologic range (starting at an arterialized
venous plasma glucose threshold of 80 to 85 mg/dL [4.4 to 4.7 mmol/L]) [5].

● The second defense is an increase in glucagon secretion. Glucagon acts only on the
liver, increasing glucose production by stimulating both glycogenolysis and
gluconeogenesis from alanine, among other amino acids, and glycerol. A normally

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functioning liver is necessary for an adequate response to glucagon. The glycemic

threshold for glucagon secretion is 70 to 75 mg/dL (3.9 to 4.2 mmol/L) [5,6].

● The third defense is an increase in epinephrine secretion. Acting via beta-2-adrenergic

receptors, epinephrine increases glucose production primarily from the liver and, to a
lesser extent, from the kidneys. It also promotes lipolysis in adipose tissue, increasing
the delivery of gluconeogenic substrates from the periphery. In addition, epinephrine
inhibits glucose utilization by skeletal muscle and adipose tissue, and, via alpha-2-
receptors, may further inhibit insulin secretion. As with glucagon, a normally
functioning liver is necessary for an adequate epinephrine-induced increase in hepatic
glucose production. The glycemic threshold for epinephrine secretion is 65 to 70 mg/dL
(3.6 to 3.9 mmol/L) [5,6].

● Cortisol and growth hormone contribute only if hypoglycemia persists for several
hours. These hormones limit glucose utilization and enhance hepatic glucose
production. The glycemic threshold for cortisol and growth hormone secretion are 60 to
65 mg/dL (3.3 to 3.6 mmol/L) [5,6].

Interaction between insulin and glucagon — The secretion of insulin and glucagon are
closely coupled, both anatomically and physiologically within the pancreatic islet. In the
earliest stages (within minutes) of a decreasing plasma glucose concentration within the
physiologic range, reduced insulin secretion is the most important regulatory hormone
response, and increased glucagon secretion is the most important counterregulatory
hormone response. This coordinated primary pancreatic islet response normally ensures
that fasting glucose does not fall below approximately 70 mg/dL (3.9 mmol/L), as the
decreased insulin-to-glucagon ratio to which the liver is exposed promotes an increase in
hepatic glucose production calibrated to prevent or correct low blood glucose.

Insulin, perhaps among other beta cell secretory products acting within the islet, normally
restrains glucagon secretion, and diminished insulin (or other beta cell secretory products)
within the islet provides an obligate paracrine signal to the alpha cell to secrete glucagon
during the development of hypoglycemia [7]. This effect is lost in insulin-deficient diabetes.
(See "Pancreatic beta cell function".)

Behavioral defenses — The initial autonomic (neurogenic) symptoms of sweating, anxiety,

palpitations, hunger, and tremor occur as the plasma glucose concentration falls below 55
mg/dL (3.1 mmol/L) [1-6]. These symptoms trigger the critical behavioral defense (ie,
ingestion of food) and are signaled largely by increased sympathetic neural activity. Together
with the increase in epinephrine secretion, this sympathetic neural activity and its associated
symptoms constitute the sympathoadrenal response to hypoglycemia.

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Hypoglycemia can also cause cognitive dysfunction, which occurs in healthy individuals at
plasma glucose concentrations below 50 mg/dL (2.8 mmol/L). Cognitive dysfunction can
impair behavioral defenses. More severe neurologic symptoms, including obtundation,
seizures, and coma, occur with progressive hypoglycemia. Profound and prolonged
hypoglycemia can cause brain death.

RESPONSE TO HYPOGLYCEMIA IN DIABETES

Impairment of behavioral and counterregulatory responses — Hypoglycemia in insulin-

or insulin secretagogue-treated patients with diabetes is typically the result of the interplay
between absolute or relative therapeutic insulin excess and compromised physiologic and
behavioral defenses against falling plasma glucose concentrations.

Insulin — The protective response to hypoglycemia is impaired in many patients with

diabetes ( table 1) [1-3,8]. The first defense, the ability to suppress insulin exposure, cannot
occur in patients with absolute beta cell failure, ie, those with type 1 diabetes and
longstanding type 2 diabetes. Therefore, inhibition of hepatic glucose production continues.
Thus, the main defense against hypoglycemia is increased release of counterregulatory
hormones (glucagon and epinephrine), which raise plasma glucose concentrations by
stimulating glucose production, and, for epinephrine, by antagonizing the insulin-induced
increase in glucose utilization.

Glucagon — For type 1 diabetes, the glucagon response to hypoglycemia is nearly

uniformly lost within a few years of diagnosis, whereas the progressive loss of this response
occurs more slowly in type 2 diabetes [1-3,8-11]. The diminished glucagon response is the
result of beta cell loss and failure with consequent loss of the hypoglycemia-induced decline
in intra-islet insulin. This decline normally stimulates alpha cell glucagon secretion during
hypoglycemia via a paracrine mechanism within the islet [3,12,13]. Individuals with advanced
beta cell loss still have intact glucagon responses to other stimuli such as amino acids.

Epinephrine — In the setting of absent insulin and glucagon responses, patients are
dependent upon epinephrine to protect against hypoglycemia. However, the epinephrine
response to hypoglycemia also becomes attenuated in many patients, at least in part
because of recent antecedent hypoglycemia [1,2,10,14]. In a systematic review of 63 studies,
the calculated median glycemic thresholds for activation of epinephrine was somewhat
lower in individuals with type 1 diabetes than in those without diabetes (61 versus 68 mg/dL
[3.4 versus 3.8 mmol/L]) [9]. An attenuated epinephrine response causes defective glucose
counterregulation, which is associated with a 25-fold or greater increased risk of severe
hypoglycemia [15,16].

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Autonomic symptoms — An attenuated autonomic (largely sympathetic neural) symptom

response causes impaired awareness of hypoglycemia, which is associated with a sixfold
increased risk of severe hypoglycemia [17]. A complete absence of autonomic symptom
recognition, or hypoglycemia unawareness, is associated with a 20-fold increased risk of
severe hypoglycemia [18]. In a systematic review of 63 studies that employed
hyperinsulinemic stepped-hypoglycemic clamps, the median glycemic thresholds for
autonomic and neuroglycopenic symptoms were somewhat lower in patients with type 1
diabetes (54 versus 61 mg/dL [3.0 versus 3.4 mmol/L] for both symptom sets) [9].

Hypoglycemia-associated autonomic failure — The concept of hypoglycemia-associated

autonomic failure (HAAF) in type 1 diabetes [10] and longstanding (absolute endogenous
insulin-deficient) type 2 diabetes [11] posits that recent, antecedent iatrogenic hypoglycemia
causes both defective glucose counterregulation and impaired awareness of hypoglycemia
and thus promotes a vicious cycle of recurrent hypoglycemia ( algorithm 1) [1,2,4]. It does
so by shifting the glycemic thresholds for activation of the sympathoadrenal epinephrine and
autonomic symptom responses to subsequent hypoglycemia to lower plasma glucose
concentrations. This shift, as well as a reduced magnitude of response, causes defective
glucose counterregulation by reducing epinephrine in the setting of absent insulin and
glucagon responses at a given level of hypoglycemia. It also causes impaired awareness of
hypoglycemia by reducing the autonomic symptom response. Sleep and prior exercise can
cause a similar phenomenon of attenuated sympathoadrenal epinephrine and autonomic
symptom responses to subsequent hypoglycemia and feed the cycle of recurrent
hypoglycemia in diabetes [1,2].

Mechanism — The precise mechanisms that underlie the key feature of HAAF (ie, the
attenuated sympathoadrenal epinephrine and autonomic symptom responses to falling
plasma glucose concentrations) are unknown [1,2,4]. One hypothesis is that hypoglycemia-
induced alterations in hypothalamic functions, or even a cerebral network, reduce the
sympathoadrenal response to subsequent hypoglycemia [4]. Another hypothesis is that an
increase in cortisol (or some other stress-related factor) during hypoglycemia causes a
reduced sympathoadrenal response to subsequent hypoglycemia. An impaired epinephrine
response can develop independent of an impairment in autonomic symptoms [19], an effect
possibly explained by a hypoglycemia-induced reduction in the secretory capacity of adrenal
chromaffin cells as demonstrated in a mouse model [20].

HAAF is a functional disorder distinct from classical diabetes-related autonomic neuropathy,

the result of nerve fiber loss. Nonetheless, the sympathoadrenal epinephrine response to a
given level of hypoglycemia is reduced further in patients with autonomic neuropathy
[21,22].

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Type 1 versus type 2 — Although it was originally developed in type 1 diabetes [10], the
concept of HAAF also applies to patients with type 2 diabetes treated with intensive
(basal/bolus) insulin regimens ( table 1) [11]. Endogenous insulin secretion decreases
progressively over time in type 2 diabetes [23]. As patients with type 2 diabetes develop
absolute insulin deficiency and become dependent on exogenous insulin, insulin secretion
does not decrease and glucagon secretion does not increase when plasma glucose
concentrations fall. Furthermore, antecedent hypoglycemia reduces the sympathoadrenal
epinephrine and autonomic symptom responses to subsequent falling glucose levels in type
2 diabetes [11].

Compared with type 1 diabetes [10], the features of HAAF develop later in the natural history
of type 2 diabetes [1,2,11]. This different temporal pattern of the pathophysiology of glucose
counterregulation likely explains why iatrogenic hypoglycemia is relatively uncommon early
in the course of type 2 diabetes (even during treatment with insulin), when the
glucoregulatory defenses are intact, but occurs more frequently as patients approach the
insulin-deficient end of the spectrum of type 2 diabetes, when the defenses become
compromised.

Nocturnal hypoglycemia — Most episodes of severe hypoglycemia occur during sleep.

Nocturnal hypoglycemia is frequent, even with the use of continuous subcutaneous insulin
infusion (CSII) or a basal-bolus regimen with insulin analogs [24]. Sleep is typically the
longest interprandial period and time interval between blood glucose measurements, and it
usually coincides with the time of maximal insulin sensitivity. Furthermore, sympathoadrenal
responses to hypoglycemia are diminished during sleep; therefore, people with diabetes are
less able to defend against hypoglycemia and less likely to be awakened by autonomic
symptoms [25,26]. Continuous glucose monitoring (CGM) alerts and alarms help to reduce,
but do not eliminate, nocturnal hypoglycemia and only modestly improve glucose
counterregulation in individuals affected by HAAF [27]. As discussed earlier, even
asymptomatic nocturnal hypoglycemia impairs defenses against subsequent hypoglycemia.

The notion that nocturnal hypoglycemia causes hyperglycemia the following morning (the
Somogyi hypothesis) has been discredited [28,29]. The opposite is typically found, namely, a
direct relationship between the overnight blood glucose nadir and the following morning
blood glucose value; thus, patients with morning hyperglycemia typically have high, not low,
blood glucose concentrations at night. The most common causes of morning hyperglycemia
are nocturnal growth hormone secretion [30] and hypoinsulinemia.

Strategies to prevent nocturnal hypoglycemia and the best solution for morning
hyperglycemia are discussed separately. (See "Hypoglycemia in adults with diabetes mellitus"
and "Management of blood glucose in adults with type 1 diabetes mellitus".)

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Exercise — Exercise increases glucose utilization by skeletal muscle and, therefore, can
cause hypoglycemia in patients with insulin-deficient diabetes who have near normal or
moderately elevated plasma glucose levels at the start of exercise. In addition, as noted
earlier, exercise, like hypoglycemia, can cause HAAF hours later ( algorithm 1) [1,2].
Hypoglycemia can be prevented by frequent blood glucose monitoring or CGM and, when
indicated, reduced insulin doses, carbohydrate ingestion, or both prior to exercise. (See
"Exercise guidance in adults with diabetes mellitus".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Hypoglycemia in
adults".)

SUMMARY

● Clinical relevance of hypoglycemia – Hypoglycemia is an uncommon clinical event

except in patients who use drugs that lower plasma glucose concentrations, specifically
insulin, a sulfonylurea, or a glinide. It is the limiting factor in the glycemic management
of diabetes. (See 'Introduction' above and "Hypoglycemia in adults with diabetes
mellitus".)

● Physiologic response to hypoglycemia – Glucose counterregulatory mechanisms and

behavioral defenses normally prevent or rapidly correct hypoglycemia ( figure 1 and
table 1). (See 'Response to hypoglycemia in healthy individuals' above.)

● Altered physiologic response in individuals with diabetes – The protective response

to hypoglycemia is impaired in most patients with type 1 diabetes and in many patients
with longstanding (absolute endogenous insulin-deficient) type 2 diabetes ( table 1).
(See 'Response to hypoglycemia in diabetes' above.)

● Hypoglycemia-associated autonomic failure – Hypoglycemia, even if asymptomatic,

causes a vicious cycle of recurrent hypoglycemia by causing hypoglycemia-associated
autonomic failure (HAAF), the clinical syndrome of defective glucose counterregulation
and impaired awareness of hypoglycemia ( algorithm 1). (See 'Hypoglycemia-
associated autonomic failure' above.)

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REFERENCES

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3. Dunning BE, Gerich JE. The role of alpha-cell dysregulation in fasting and postprandial
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dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic
responses to, symptoms of, and defense against subsequent hypoglycemia. J Clin Invest
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11. Segel SA, Paramore DS, Cryer PE. Hypoglycemia-associated autonomic failure in
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14. Heller SR, Cryer PE. Reduced neuroendocrine and symptomatic responses to
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15. White NH, Skor DA, Cryer PE, et al. Identification of type I diabetic patients at increased
risk for hypoglycemia during intensive therapy. N Engl J Med 1983; 308:485.

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16. Bolli GB, De Feo P, De Cosmo S, et al. A reliable and reproducible test for adequate
glucose counterregulation in type I diabetes mellitus. Diabetes 1984; 33:732.
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patients with type 1 diabetes: influence of risk markers and selection. Diabetes Metab
Res Rev 2004; 20:479.

19. Flatt AJ, Chen E, Peleckis AJ, et al. Evaluation of Clinical Metrics for Identifying Defective
Physiologic Responses to Hypoglycemia in Long-Standing Type 1 Diabetes. Diabetes
Technol Ther 2022; 24:737.

20. Ma Y, Wang Q, Joe D, et al. Recurrent hypoglycemia inhibits the counterregulatory

response by suppressing adrenal activity. J Clin Invest 2018; 128:3866.

21. Bottini P, Boschetti E, Pampanelli S, et al. Contribution of autonomic neuropathy to

reduced plasma adrenaline responses to hypoglycemia in IDDM: evidence for a
nonselective defect. Diabetes 1997; 46:814.

22. Meyer C, Grossmann R, Mitrakou A, et al. Effects of autonomic neuropathy on

counterregulation and awareness of hypoglycemia in type 1 diabetic patients. Diabetes
Care 1998; 21:1960.

23. U.K. prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a
progressive disease. U.K. Prospective Diabetes Study Group. Diabetes 1995; 44:1249.

24. Raju B, Arbelaez AM, Breckenridge SM, Cryer PE. Nocturnal hypoglycemia in type 1
diabetes: an assessment of preventive bedtime treatments. J Clin Endocrinol Metab
2006; 91:2087.
25. Jones TW, Porter P, Sherwin RS, et al. Decreased epinephrine responses to hypoglycemia
during sleep. N Engl J Med 1998; 338:1657.
26. Banarer S, Cryer PE. Sleep-related hypoglycemia-associated autonomic failure in type 1
diabetes: reduced awakening from sleep during hypoglycemia. Diabetes 2003; 52:1195.

27. Rickels MR, Peleckis AJ, Dalton-Bakes C, et al. Continuous Glucose Monitoring for
Hypoglycemia Avoidance and Glucose Counterregulation in Long-Standing Type 1
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28. Tordjman KM, Havlin CE, Levandoski LA, et al. Failure of nocturnal hypoglycemia to
cause fasting hyperglycemia in patients with insulin-dependent diabetes mellitus. N
Engl J Med 1987; 317:1552.
29. Hirsch IB, Smith LJ, Havlin CE, et al. Failure of nocturnal hypoglycemia to cause daytime
hyperglycemia in patients with IDDM. Diabetes Care 1990; 13:133.

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30. Campbell PJ, Bolli GB, Cryer PE, Gerich JE. Pathogenesis of the dawn phenomenon in
patients with insulin-dependent diabetes mellitus. Accelerated glucose production and
impaired glucose utilization due to nocturnal surges in growth hormone secretion. N
Engl J Med 1985; 312:1473.
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GRAPHICS

Physiological and behavioral defenses against hypoglycemia

Decrements in insulin and increments in glucagon are lost and increments in epinephrine and
neurogenic symptoms are often attenuated in insulin-deficient - T1DM and advanced T2DM.

SNS: sympathetic nervous system; PNS: parasympathetic nervous system; NE: norepinephrine; ACh:
acetylcholine; α-cell: pancreatic islet α-cells; β -cell: pancreatic islet β -cells.

Reproduced with permission from: Cryer PE. Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes. J Clin
Invest 2006; 116:1470. Copyright ©2006 American Society for Clinical Investigation.

Graphic 67404 Version 3.0

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Counterregulatory response to hypoglycemia

Condition Glucose Insulin Glucagon Epinephrine Autonomic

symptom
response
No diabetes ↓ Decreases Increases Increases Activated

T1DM ↓ No decrease* No increase* Attenuated Attenuated

increase* ¶ activation or
absent ¶

T2DM

Early ↓ Decreases Increases Increases Activated

Late ↓ No decrease* No increase* Attenuated Attenuated

(absolute increase* ¶ activation or
endogenous absent ¶
insulin
deficiency)

Iatrogenic hypoglycemia is the result of the interplay of absolute or relative therapeutic insulin excess
and compromised physiologic and behavioral defenses against falling plasma glucose concentrations
in type 1 diabetes mellitus (T1DM) and advanced type 2 diabetes mellitus (T2DM).

* Defective glucose counterregulation.

¶ Hypoglycemia unawareness.

Courtesy of Dr. Philip Cryer.

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Impaired counterregulation and HAAF in insulin-deficient diabetes

HAAF: hypoglycemia-associated autonomic failure.

* Exercise can further reduce the epinephrine response.

¶ Sympathoadrenal response is further diminished during sleep.

Modified from: Cryer PE. Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2004;
350:2272.

Graphic 51847 Version 8.0

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