Hypoglycemia causes the body to respond with number of counterregulatory hormones.[i]
[ii] Their most likely sequence of hormonal activation are glucagon, epinephrine
and then if hypoglycemia is severe or prolonged cortisol and growth hormone.[iii]
The first, glucagon is a hormone produced in the alpha cells in the pancreas.
When secreted it will activate a release of stored sugar in the form of glycogen,
which is converted to glucose through a process called glucogenesis or glycogenolysis
raising blood sugar.[v]
The next is epinephrine; it acts through similar pathways to elevate glucose levels
through increased hepatic glucose production, gluconeogenesis, and also through
decreased insulin secretion and glucose disposal.[vi] [vii] There is a release
of another hormone related to epinephrine called norepinephrine.[viii] They both
function as vasoconstrictors increasing blood pressure, cardiac output, and diverting
blood flow from the extremities to the brain and major organs.[ix] [x] [xi] [xii]
This vasoconstrictive effect may be more profound in diabetics with even a mild
degree of nephropathy.[xiii] These aforementioned conditions may also be associated
with a decrease in surface body temperature.[xiv] [xv]
The remaining two, cortisol and growth hormone work more on the level of reducing
glucose uptake thus increasing blood sugar.[xvi] [xvii] Most of the time these
defense mechanism do not engage soon enough to prevent the hypoglycemia from occurring
due to some of type defect that seems to be more common in Type I diabetes.[xviii]
It appears that the glucagon release is delayed and possibly reduced from impaired
alpha cell release.[xx] [xxi] This effect may be even more prominent in children
with Type I diabetes.[xxii] This may be partially explained from the result of
collateral damage caused by the autoimmune attack that effects the beta cells
in the same islet in Type I diabetes.[xxiii] These hormone releases continue to
increase blood glucose till it plateaus anywhere between two to eight hours after
the event causing hyperglycemia, but it could last longer depending on several
factors that will be explored.
This is called the Somogyi effect, post hypoglycemia hyperglycemia.[xxiv] These
rebounds, as they are also referred to as, can happen anytime blood glucose drops
below 70mg/dl and are usually responsible for wide swings in blood sugar levels.
In some diabetics, even before any type of hypoglycemic symptoms are experienced,
counterregulatory hormones may already be activated. There are several variables
that can effect hypoglycemic awareness such as actual postural position or intensive
insulin therapy. Almost any angle of a reclined position will begin to decrease
hypoglycemic awareness.[xxv] Also, studies show that the threshold required for
hormonal release and hypoglycemic detection can be altered by tight glycemic control.[xxvi]
Continued hypoglycemic incidents can decrease awareness, but this can be corrected
through the elimination or reduction of hypoglycemic episodes.
There is some evidence that suggests that depending on how far blood sugar falls
below 70mg/dl there is an inversely proportional amount of counterregulartory
response.[xxvii] [xxviii] Glucagon and epinephrine usually begin to get released
between 65-70mg/dl, while growth hormone and cortisol require slightly lower values
As blood sugar falls more tiers get activated, so the lower and possibly longer
the blood sugar remains at that level the higher the blood sugar rebound value
will be. There are other studies eluding to a recalibration of the response curve
of counterregulartory hormones from tight blood glucose control that frequently
causes blood sugar values to fall between 50 to 65mg/dl.[xxx] This seems to allow
for a lower threshold to be reached in hypoglycemic incidents before a hormone
release is initiated.[xxxi]
Sometimes counter regulatory hormones can be stimulated by a dramatic decrease
in blood sugar occurring within a very short period of time.[xxxii] For this situation
to occur it will usually require a drop of several hundred points in less than
an hour to a fasting value. This can happen from the result of several different
scenarios, but a combination of a large insulin injection and exercise might be
the most common.
There may also be an opportunity to reduce or even avert a full counterregulartory
response caused by hypoglycemia. There is a window that might remain open possibly
up to 30 minutes from the time blood sugar drops below the threshold till glucagon
If the hypoglycemia is detected and immediately addressed with one or several
potential glucagon inhibitors the rebound could be curtailed. Although there are
a number of different types of inhibiting agents, most of them are prescription
drugs and hormones, which are not practical to use. Insulin and somatostatin are
very potent inhibitors of glucagon, but they can only be delivered through injection
and it is also not realistic to give someone suffering from hypoglycemia more
insulin. The uses of somatostatin, which does have some benefits, could hinder
the recovery process.[xxxiii] The few that might be of benefit and can be used
on a repeated basis are calcium, magnesium, ibuprofen and antihistamines.[xxxiv]
Any of these inhibitors can be used alone or in combination with each other. They
can and should be given with the dose of 10-40 grams of carbohydrate as needed
to correct the hypoglycemia.
Usually the detection and treatment for hypoglycemia are both symptom driven.
To expedite recovery I suggest that you first use designated sports drink and
then a carbohydrate with no fat. While sports drinks do not have the most sugar
as compared to regular soft drinks or fruit juice, they have a faster transport
mechanism that should speed hypoglycemic recovery. Large amounts of fat will just
slow carbohydrate absorption hindering blood sugar rise. Normally, slowed uptake
of carbohydrates has the benefit of better overall blood glucose profiles, but
not during hypoglycemic treatment. Of all the times for hypoglycemia to occur
one of the most dangerous is during the night. Nocturnal hypoglycemia usually
gives no warning and counterregulatory recovery may be decreased during sleep,
which can allow blood glucose to fall farther from the norms, so the risk for
a person to go into shock increases.[xxxvii] This happens when glucose levels
are to low for brain functions to operate properly. The brain has no glucose reserves
to draw on directly and is more sensitive to low glucose levels than other organs.
Temporary cognitive impairment can even begin when blood glucose is between 50-60
mg/dl and then deteriorates dramatically as blood glucose declines.[xxxviii] [xxxix]
This is corrected when blood glucose is returned to normal.
There doesn't appear to be, but yet it is still unknown if these mild episodes
cause any permanent brain damage, however they might hinder brain development
in young children. However, severe hypoglycemia to the point of seizure or coma
in children is associated with significant neurological abnormalities.[xl] These
types of cases usually involve repeated professional medical intervention to recover
from these hypoglycemic incidents.
The longer and lower the blood glucose remains, the greater the risk of multiple
serious adverse effects. It is somewhat ironic that in the attempt to prevent
complications from hyperglycemia you might cause other damage due to hypoglycemia
of tight blood sugar control. Even though this fine balancing act may never be
completely mastered, with the identification of the subtleties of your patient’s
diabetes, these dangerous situations can be avoided or at least reduced. Click
here for references
Dr. Brian P. Jakes, Jr., N.D., C.N.C. is a Board Certified Doctor of Naturopathy
as well as a Certified Nutritional Consultant. In his practice, in Mandeville,
LA, Dr. Jakes works with physicians to treat a large number of diabetes patients.
This is an excerpt from his upcoming book; "Diabetes: The Essence Of A
[i] Lager I. The insulin-antagonistic effect of the counterregulatory hormones.
J Intern Med Suppl 1991;735:41-7.
[ii] Bolli G, Gottesman I, Cryer P, Gerich J. Glucose counterregulation during
prolonged hypoglycemia in normal man. Am J Physiol 1984;247:E206-14.
[iii] Gerich JE. Lilly lecture 1988. Glucose counterregulation and its impact
on diabetes mellitus. Diabetes 1988 Dec;37(12):1608-17.
[iv] Cryer PE. Role of growth hormone in glucose counterregulation. Horm Res
[v] LeCavalier L, Bolli G, Cryer P, Gerich J. Contributions of gluconeogenesis
and glycogenolysis during glucose counterregulation in normal humans. Am J Physiol
[vi] Clutter WE, Rizza RA, Gerich JE, Cryer PE. Regulation of glucose metabolism
by sympathochromaffin catecholamines. Diabetes Metab Rev 1988;4:1-15.
[vii] Cryer PE, Tse TF, Clutter WE, Shah SE. Roles of glucagon and epinephrine
in hypoglycemic and non-hypoglycemic glucose counterregulation in humans. Am
J Physiol 1984;247:E198-205.
[viii] Hoffman RP, Sinkey CA, Anderson EA. Hypoglycemic symptom variation is
related to epinephrine and not peripheral muscle sympathetic nerve response.
J Diabetes Complications 1997 Jan-Feb;11(1):15-20.
[ix] Neil HA, Gale EA, Hamilton SJ, Lopez-Espinoza I, Kaura R. Cerebral blood
flow increases during insulin-induced hypoglycaemia in type 1 (insulin-dependent)
diabetic patients and control subjects. Diabetologia 1987 May;30(5):305-9.
[x] Kerr D, Stanley JC, Barron M, Thomas R, et al. Symmetry of cerebral blood
flow and cognitive responses to hypoglycaemia in humans. Diabetologia 1993 Jan;36(1):73-8.
[xi] Braatvedt GD, Newrick PG, Halliwell M, Wells PN, et al. Splanchnic haemodynamic
changes during acute hypoglycaemia in man. Clin Sci (Colch) 1991 Oct;81(4):519-24.
[xii] Mathiesen ER, Hilsted J, Feldt-Rasmussen B, Bonde-Petersen F, et al.
The effect of metabolic control on hemodynamics in short-term insulin-dependent
diabetic patients. Diabetes 1985 Dec;34(12):1301-5.
[xiii] Bodmer CW, Patrick AW, How TV, Williams G. Exaggerated sensitivity to
NE-induced vasoconstriction in IDDM patients with microalbuminuria. Possible
etiology and diagnostic implications. Diabetes 1992 Feb;41(2):209-14.
[xiv] Maggs DG, Scott AR, MacDonald IA. Thermoregulatory responses to hyperinsulinemic
hypoglycemia and euglycemia in humans. Am J Physiol 1994 Nov;267(5 Pt 2):R1266-72.
[xv] Wiles PG, Grant PJ, Stickland MH, Dean HG, Wales JK, Davies JA. Regional
variation in skin blood flow response to hypoglycaemia in type 1 (insulin-dependent)
diabetic patients without complications. Diabetologia 1988 Feb;31(2):98-102.
[xvi] Campbell IW. The Somogyi phenomenon. A short review. Acta Diabetol Lat
[xvii] DeFeo P, Perriello G, Torlone E, et al. Demonstration of a role for
growth hormone in glucose counterregulation. Am J Physiol 1989;256:E835-43.
[xviii] Boli G, De Feo P, Compagnucci P. Abnormal glucose counterregulation
in insulin dependent diabetes mellitus: interactions of anti-insulin antibodies
and impaired glucagon and epinephrine secretion. Diabetes 1983; 32: 134-41.
[xix] Boli G, Calabrese G, De Feo P, Zega G. Lack of glucagon response in glucose
counter-regulation in type 1 diabetics: absence of recovery after prolonged
optimal insulin therapy. Diabetologia 1982 Feb;22(2):100-5.
[xx] Kleinbaum J, Shamoon H. Impaired counterregulation of hypoglycemia in
insulin dependent diabetes mellitus. Diabetes 1983 Jun;32(6):493-8.
[xxi] Unger RH, Aguilar-Parada E, Muller WA, Eisentraut AM. Studies of pancreatic
alpha cell function in normal and diabetic subjects. J Clin Invest 1970;49:837-48.
[xxii] Hoffman RP, Arslanian S, Drash AL, Becker DJ. Impaired counterregulatory
hormone responses to hypoglycemia in children and adolescents with new onset
IDDM. J Pediatr Endocrinol 1994 Jul-Sep;7(3):235-44.
[xxiii] Taborsky GJ, Ahren B, Havel P. Autonomic mediation of glucagon secretion
during hypoglycemia: implications for impaired alpha-cell responses in type
1 diabetes. Diabetes, July 1998 v47 n7 p995(11).
[xxiv] Somogyi M. Exacerbation of diabetes by excess insulin action. Am J Med
[xxv] Robinsion AM, Parkin HM, Macdonald IA, Tattersall RB. Physiological response
to postural change during mild hypoglycaemia in patients with IDDM. Diabetologia
[xxvi] Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of hypoglycemia unawareness,
but not defective glucose counterregulation, in IDDM. Diabetes 1994 Dec;43(12):1426-34.
[xxvii] Lewis GF, Carpentier A, Bilinski D, Giacca A, Vranic M. Counterregulatory
response to hypoglycemia differs according to the insulin delivery route, but
does not affect glucose production in normal humans. J Clin Endocrinol Metab
[xxviii] Kerr D, MacDonald IA, Tattersall RB. Influence of duration of hypoglycemia
on the hormonal counterregulatory response in normal subjects. J Clin Endocrinol
[xxix] Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for
activation of glucose counterregulatory systems are higher than threshold for
symptoms. J Clin Invest 1987 Mar;79(3):777-81.
[xxx] Simonson DC, Tamborlane WV, DeFronzo RA, Sherwin RS. Intensive insulin
therapy reduces counterregulatory hormone responses to hypoglycemia in patients
with type 1 diabetes. Ann Intern Med 1985 Aug;103(2):184-90.
[xxxi] Davis M, Mellman M, Friedman S, et al. Recovery of epinephrine response
but not hypoglycemic symptom threshold after intensive therapy in type I diabetes.
Am J Med, Dec 1994 v97 n6 p535(8).
[xxxii] DeFronzo RA, Andres R, Bledsoe TA, et al. A test of the hypothesis
that the rate of fall in glucose concentration triggers counterregulatory hormonal
responses in man. Diabetes 1977;26:445-52.
[xxxiii] Gerich JE, Davis J, Lorenzi M, et al. Hormonal mechanisms of recovery
from insulin induced hypoglycemia in man. Am J Physiol 1979;236:E380-5.
[xxxiv] Cucinotta D, Quartarone M, Saitta A, De Pasquale R, Perdichizzi G,
Squadrito G. Calcium and endocrine pancreas secretion. I. Effects of an infusion
of calcium on plasma levels of insulin and glucagon. Boll Soc Ital Biol Sper
1980 Feb 29;56(4):332-8.
[xxxv] Leclercq-Meyer V, Marchand J, Malaisse WJ. The role of calcium in glucagon
release. Interactions between arginine and calcium. Horm Res 1976;7(6):348-62.
[xxxvi] Giugliano D, Torella R, D’Onofrio F. Prostaglandins and the alpha
cell. Prostaglandins Med 1981 Mar;6(3):283-7.
[xxxvii] Jones TW, Porter P, Sherwin RS, Davis EA, et al. Decreased epinephrine
responses to hypoglycemia during sleep. N Engl J Med 1998;338:1657-62.
[xxxviii] Gold AE, MacLeod KM, Deary IJ, Frier BM. Hypoglycemia-induced cognitive
dysfunction in diabetes mellitus: effect of hypoglycemia unawareness. Physiol
Behav 1995 Sep;58(3):501-11.
[xxxix] Gschwend S, Ryan C, Atchison J, Arsianian S, Becker D. Effects of acute
hyperglycemia on mental efficiency and counterregulatory hormone in adolescents
with insulin-dependent diabetes mellitus. J Pediatr 1995 Feb;126(2):178-84.
[xl] Ingram TTS, Stark GD, Blackburn I. Ataxia and other neurological disorders
as sequels of severe hypoglycemia in childhood. Brain 1967;90:851-62.