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Hypoglycemia — mechanisms and prevention in NIDDM treatment with insulin
Diabetes Rrseurch and C&&al
62
Pructice, Suppl.
(1988) 62-65
Elsevier
DRC SO1 I5
Hypoglycemia
-
mechanisms and prevention in NIDDM treatment with insulin Gaston R. Zahnd
Fondation
Ke.v words: Hypoglycemic
pour Recherches
manifestation;
Medicales,
Pathogenesis:
Avenue
Treatment:
Introduction
Hypoglycemia, the most common acute complication of diabetes mellitus, results from the therapeutic administration of insulin or oral hypoglycemic agents. Estimates derived from several surveys of insulin-treated diabetics indicate that 50-90% of the patients experience mild hypoglycemic episodes, while approximately 10% of insulin-dependent diabetics require treatment for severe hypoglycemic accidents. Available data suggest that the incidence of hypoglycemic episodes resulting in loss of consciousness may be at least as high as 0.54 per patient per year in a given clinic population of insulin-treated diabetic patients. Hypoglycemia is recognized to be the primary cause of death in 3-7% of patients with insulin-dependent diabetes (IDDM).
Signs and symptoms
The manifestations of hypoglycemia depend on at least three factors: the rate at which the blood sugar
Address pour
for correspondence:
Recherches
Medicales,
Dr. Avenue
G.R.
Zahnd,
de la Roseraie,
Fondatron 121 I Ge-
neva 4, Switzerland.
0168-8227/88/$03.50
CI 1988 Elsevier Science Publishers
de la Roseraie.
1211 Geneva
4, Switzerland
Prevention
falls, the level to which it falls and the state of cerebral vessels. The symptoms caused by hypoglycemia can be divided into two categories: (1) adrenergic symptoms due to increased adrenalin secretion and (2) neuroglycopenic symptoms due to depletion of glucose in the central nervous system. Involvement of the sympathoadrenal discharge gives rise to anxiety, tremor, palpitation, sweating. Neuroglycopenic symptoms range from hunger, nausea, headache, mental confusion, visual disturbance to seizures, coma and death. An acute fall in blood sugar in an elderly patient will produce quite different signs and symptoms from a slow fall in a young diabetic. Individual patients very often have stereotyped clinical features of hypoglycemia. Because of considerable variations in the individual sensitivity to acute or subacute neuroglycopenia. there is no absolute limit for abnormally low blood sugar concentrations capable of inducing diabetic hypoglycemia. Early symptoms may appear with values between 2.5 and 3.3 mmol/l, upon a rapid fall of blood sugar or a possible lack of other metabolic fuels. Marked clinical hypoglycemia usually develops at levels below 2.2 mmol/l. Deficiencies of counter-regulatory mechanisms that promote recovery from hypoglycemia and prevent its occurrence contribute to the specificity of this adverse effect of diabetes treatment.
B.V. (Biomedical
Division)
63 epinephrine
Pathogenesis
from sympathetic
Since bolus A fall of blood
sugar to hypoglycemic
levels nor-
mally triggers neural signals. hormonal signals, possibly glucose autoregulation or a combination of these mechanisms. Hormonal signals include a decrease of insulinemia or an increase of circulating counter-regulatory hormones such as glucagon, epinephrine, cortisol and growth hormone. Neural signals
include
release
lN.$JLlN
of neuropeptides
and
nor-
(O.ldU/kg.subcut1 MEAN+SEM
0-0 NONDIABETICS NIDDM (N=13) u IDDM (N- 20)
(N= 9)
-
injections
neurons.
of insulin
in normal
jects have primarily been used to study anisms of acute glucose counter-regulation, clear to what extent such observations
sub-
the mechit is not apply to
pathologic situations in diabetics in whom hypoglycemia develops more gradually and is reversed less rapidly. Recent studies, using prolonged infusions or subcutaneous insulin administration, have shown that hormonal signals, particularly glucagon and epinephrine responses, are critical factors in the recovery from hypoglycemia. Evidence has been produced that patients with IDDM as well as with non-insulin-dependent diabetes (NIDDM) have impaired plasma glucagon responses to induced hypoglycemia (Fig. 1). Thus, together with the wellknown deficient epinephrine responses in the presence of autonomic neuropathy, NIDDM may have at least two defects in glucose counter-regulation.
Factors mia
predisposing
to insulin-induced
hypoglyce-
Insulin-induced hypoglycemia in diabetics can be precipitated under a number of circumstances. E.ucessive insulin inappropriate insulin dosage inadvertent wrong dose failure to reduce insulin dose after adjustment of diet, eradication of infection, reduction in body
UTILIZATION
Hours
After
lnsul~n
Inlectlon
Fig. 1. Comparison of changes in rates of glucose production and glucose utilization in patients with IDDM, patients with NIDDM,
and normal
subjects.
tesy of the Editors
Reproduced
of The Diabetes
from [6], by courAnnual.
weight accelerated absoiption presence of circulating insulin antibodies fictitious hypoglycemia suicidal or homicidal intentions Increased insulin sensitivity> coexistence of endocrine deficiencies chronic renal insufficiency onset of menstruation more potent insulin preparations Decreased glucose substrate inadequate food intake errors in spacing meals increased insulin-independent glucose utilization impaired absorption of food (vomiting, diarrhea)
64 Drugs _ concurrent use of sulfonylureas _ alcohol excess _ non-selective betablockers The most common causes of excessive circulating insulin levels are inappropriate dosage or errors in the injected dose of insulin. The emergence of an abundance of new insulin preparations and injecting devices, as well as the development of novel strategies for insulin replacement therapy, demand an intensified education of doctors and patients in order to assure appropriate therapeutic adjustments and to achieve safe metabolic control. It has long been realized that strenuous exercise accelerates the rate of absorption of subcutaneously injected insulin. Less attention is generally paid to hypoglycemic episodes, secondary to enhanced insulin absorption during occasional physical activities such as shopping, housework, travelling. Since highly purified and human insulins are less immunogenic than the classic bovine and porcine preparations, the incidence of circulating insulin antibodies among recently treated diabetic patients has decreased in the past years. However, some patients and those on long-standing or intermittent previous insulin therapy may exhibit antibody titers which alter the pharmacokinetics of administered insulin. The resulting prolongation of its biological half-life can contribute to defective blood glucose counter-regulation. Several concomitant disorders can be responsible for hypoglycemia in diabetics. Hypopituitarism and adrenal insufficiency both lead to an increased sensitivity to insulin, since cortisol and growth hormone play an important role in glucose homeostasis. The development of renal insufficiency in longstanding diabetics may lead to a progressive fall in insulin requirements. The causes of this increase in insulin sensitivity are likely to be related to a reduction of insulin degradation by the kidney and to a diminished appetite and food intake in such patients. Furthermore, premenstrual endocrine and neuroendocrine fluctuations or shifting to more potent and higher-strength insulin preparations can be responsible for episodic hypoglycemic reactions. A decreased availability of glucose substrate
often gives rise to hypoglycemic
reactions,
particu-
larly in elderly patients who do not eat adequately and postpone or omit their meals. As a rule, errors in the individual spacing of meals and snacks, normally adapted to a given insulin regimen, will facilitate untoward reactions to insulin therapy. Combined
insulin-sulfonylurea
therapy
has been
proposed in some NIDDM patients who have failed on sulfonyl therapy alone. The rationale of this treatment, supposedly to increase insulin action, needs more clinical investigation to clarify it. As in sulfonylurea treatment alone, combined insulin therapy with oral agents of long duration of action is a potential risk factor predisposing to severe hypoglycemia. Ethanol is a hypoglycemic agent by itself. When taken with antidiabetic drugs or with insulin it can precipitate severe hypoglycemia.
Treatment and prevention The management of insulin-induced hypoglycemia requires a rapid correction of the low blood glucose. In mild cases, recovery occurs upon self-supply of oral glucose, followed by a carbohydrate snack. When consciousness is clouded, the choice of urgent administration of intravenous glucose or intramuscular glucagon depends on the preparedness of attending persons. However, if the attack is more prolonged or complicated due to long-acting insulin therapy, alcohol intake or sulfonylurea overdosage, hospital admission is mandatory for glucose infusion and other supportive treatments. Since the majority of individuals with NIDDM are overweight and obesity is often associated with both reduced tissue sensitivity to insulin and a relative deficiency of insulin secretion, caloric restriction remains the cornerstone of dietary management. In fact, bad individual dietary habits and the many difficulties encountered in the promotion of public health programs constitute the main reasons why so many non-insulin-dependent diabetics reach the stage of requiring insulin. Furthermore, insulin has been increasingly used in the past decade in the treatment of patients with NTDDM, mainly be-
65 cause
of the general
belief that
metabolic
factors
related to chronic, even moderate hyperglycemia are important in the development of late complications. Hence, the difficult question arises when and which insulin therapy should be started in patients affected by this heterogeneous syndrome. To ensure the benefits of insulin treatment and to minimize the potential danger of hypoglycemia, careful selection and education of the patients are fundamental. A number of studies have documented the efficacy of various diabetes treatment and teaching programs. For example, the following outline of facts and objectives, as recommended in a Teaching Letter of the EASD Study Group for patient education, should be discussed in detail.
_ which relative
or friend
of the patient
has been
taught about hypoglycemia and knows how to inject glucagon? _ does patient have a glucagon vial at home? In conclusion, hypoglycemia is a permanent danger of insulin therapy in NIDDM. The quality of special education received by physicians, health care providers and patients is unmistakably the guide to an improved prevention.
Suggested reading Assal. J.P.. Miihlhauser, V. and Berger. diabetes
I.. Pernet,
M. 1985. Patient
care in clinical
A.. Gfeller. education
practice
R., Jorgens,
as the basis for
and research.
Diabetologia
28. 602-6 I 3.
Check-list for the insulin-treated diabetic What sort qf meal plan? which foods are rich in carbohydrates? eating enough carbohydrates, the same amount at the same time every day can the patient describe his diet? the importance of snacks and their timing what difficulties does he experience with diet? how to cover for physical activity with more carbohydrates or less insulin Insulin its role injection technique quick/slowvs. slow/intermediate-acting insulin can the patient describe the time sequence of action of his insulin? how to adapt insulin doses to blood or urine glucose levels Hypogl>venzias what are they? what are their signs? what are the patient’s signs? causes prevention
Assal.
J.P.
patient
and
Liniger,
education.
C. 1985. Check
In: Diabetes
Education
the EASD (Eds.). The Teaching
list for diabetic Study
Letter. EASD,
Group
London.
of pp.
4243. Bolli, G.D.. mond.
Dimitriadis.
M.W.. Cryer.
glucose
G.. Pehling.
counterregulation
sulin-dependent
G., Baker.
P.E. and Gerich,
after subcutaneous
diabetes
mellitus.
B.. Hay-
J.E. 1984. Abnormal insulin
in in-
New Engl. J. Med. 310,
1706-1711. Bolli. G.D.. Tsalikian, Gerich.
E.. Haymond.
J.E. 1984. Defective
subcutaneous
M.W.. Cryer,
P.E. and
glucose counterregulation
insulin in non insulin-dependent
after
diabetes
mel-
litus. J. Clin. Invest. 73, 1532~1541. Cryer,
P.E. and Gerich,
tion, hypoglycemia mellitus.
J.E.
counterregula-
insulin therapy
of diabetes
New Engl. J. Med. 313, 232-241.
Gerich,
J.E. 1986. Glucose
Alberti
and L.P. Krall
sevier. Amsterdam, Practical
counterregulation.
K.G.M.M.
Diabetes
El-
1985. Diabetic
hypogly-
In: K.G.M.M. AlAnnual/l, Elsevier.
pp. 2888308.
Yeo. P.B. 1986. Hypoglycemia-a treatment.
Annual/Z,
2. 5-10.
Ward, J.D. 1985. Diabetic neuropathy. berti and L.P. Krall (Eds.). The Diabetes Amsterdam.
In: K.G.M.M.
(Eds.), The Diabetes
pp. 248-266.
Gill. G.V. and Alberti. cemia.
1985. Glucose
and intensive
complication
of diabetes
L.P. Krall (Ed.), World Book of Diabetes
tice. Vol. 2. Elsevier. Amsterdam,
pp. 126129.
in Prac-
62
Pructice, Suppl.
(1988) 62-65
Elsevier
DRC SO1 I5
Hypoglycemia
-
mechanisms and prevention in NIDDM treatment with insulin Gaston R. Zahnd
Fondation
Ke.v words: Hypoglycemic
pour Recherches
manifestation;
Medicales,
Pathogenesis:
Avenue
Treatment:
Introduction
Hypoglycemia, the most common acute complication of diabetes mellitus, results from the therapeutic administration of insulin or oral hypoglycemic agents. Estimates derived from several surveys of insulin-treated diabetics indicate that 50-90% of the patients experience mild hypoglycemic episodes, while approximately 10% of insulin-dependent diabetics require treatment for severe hypoglycemic accidents. Available data suggest that the incidence of hypoglycemic episodes resulting in loss of consciousness may be at least as high as 0.54 per patient per year in a given clinic population of insulin-treated diabetic patients. Hypoglycemia is recognized to be the primary cause of death in 3-7% of patients with insulin-dependent diabetes (IDDM).
Signs and symptoms
The manifestations of hypoglycemia depend on at least three factors: the rate at which the blood sugar
Address pour
for correspondence:
Recherches
Medicales,
Dr. Avenue
G.R.
Zahnd,
de la Roseraie,
Fondatron 121 I Ge-
neva 4, Switzerland.
0168-8227/88/$03.50
CI 1988 Elsevier Science Publishers
de la Roseraie.
1211 Geneva
4, Switzerland
Prevention
falls, the level to which it falls and the state of cerebral vessels. The symptoms caused by hypoglycemia can be divided into two categories: (1) adrenergic symptoms due to increased adrenalin secretion and (2) neuroglycopenic symptoms due to depletion of glucose in the central nervous system. Involvement of the sympathoadrenal discharge gives rise to anxiety, tremor, palpitation, sweating. Neuroglycopenic symptoms range from hunger, nausea, headache, mental confusion, visual disturbance to seizures, coma and death. An acute fall in blood sugar in an elderly patient will produce quite different signs and symptoms from a slow fall in a young diabetic. Individual patients very often have stereotyped clinical features of hypoglycemia. Because of considerable variations in the individual sensitivity to acute or subacute neuroglycopenia. there is no absolute limit for abnormally low blood sugar concentrations capable of inducing diabetic hypoglycemia. Early symptoms may appear with values between 2.5 and 3.3 mmol/l, upon a rapid fall of blood sugar or a possible lack of other metabolic fuels. Marked clinical hypoglycemia usually develops at levels below 2.2 mmol/l. Deficiencies of counter-regulatory mechanisms that promote recovery from hypoglycemia and prevent its occurrence contribute to the specificity of this adverse effect of diabetes treatment.
B.V. (Biomedical
Division)
63 epinephrine
Pathogenesis
from sympathetic
Since bolus A fall of blood
sugar to hypoglycemic
levels nor-
mally triggers neural signals. hormonal signals, possibly glucose autoregulation or a combination of these mechanisms. Hormonal signals include a decrease of insulinemia or an increase of circulating counter-regulatory hormones such as glucagon, epinephrine, cortisol and growth hormone. Neural signals
include
release
lN.$JLlN
of neuropeptides
and
nor-
(O.ldU/kg.subcut1 MEAN+SEM
0-0 NONDIABETICS NIDDM (N=13) u IDDM (N- 20)
(N= 9)
-
injections
neurons.
of insulin
in normal
jects have primarily been used to study anisms of acute glucose counter-regulation, clear to what extent such observations
sub-
the mechit is not apply to
pathologic situations in diabetics in whom hypoglycemia develops more gradually and is reversed less rapidly. Recent studies, using prolonged infusions or subcutaneous insulin administration, have shown that hormonal signals, particularly glucagon and epinephrine responses, are critical factors in the recovery from hypoglycemia. Evidence has been produced that patients with IDDM as well as with non-insulin-dependent diabetes (NIDDM) have impaired plasma glucagon responses to induced hypoglycemia (Fig. 1). Thus, together with the wellknown deficient epinephrine responses in the presence of autonomic neuropathy, NIDDM may have at least two defects in glucose counter-regulation.
Factors mia
predisposing
to insulin-induced
hypoglyce-
Insulin-induced hypoglycemia in diabetics can be precipitated under a number of circumstances. E.ucessive insulin inappropriate insulin dosage inadvertent wrong dose failure to reduce insulin dose after adjustment of diet, eradication of infection, reduction in body
UTILIZATION
Hours
After
lnsul~n
Inlectlon
Fig. 1. Comparison of changes in rates of glucose production and glucose utilization in patients with IDDM, patients with NIDDM,
and normal
subjects.
tesy of the Editors
Reproduced
of The Diabetes
from [6], by courAnnual.
weight accelerated absoiption presence of circulating insulin antibodies fictitious hypoglycemia suicidal or homicidal intentions Increased insulin sensitivity> coexistence of endocrine deficiencies chronic renal insufficiency onset of menstruation more potent insulin preparations Decreased glucose substrate inadequate food intake errors in spacing meals increased insulin-independent glucose utilization impaired absorption of food (vomiting, diarrhea)
64 Drugs _ concurrent use of sulfonylureas _ alcohol excess _ non-selective betablockers The most common causes of excessive circulating insulin levels are inappropriate dosage or errors in the injected dose of insulin. The emergence of an abundance of new insulin preparations and injecting devices, as well as the development of novel strategies for insulin replacement therapy, demand an intensified education of doctors and patients in order to assure appropriate therapeutic adjustments and to achieve safe metabolic control. It has long been realized that strenuous exercise accelerates the rate of absorption of subcutaneously injected insulin. Less attention is generally paid to hypoglycemic episodes, secondary to enhanced insulin absorption during occasional physical activities such as shopping, housework, travelling. Since highly purified and human insulins are less immunogenic than the classic bovine and porcine preparations, the incidence of circulating insulin antibodies among recently treated diabetic patients has decreased in the past years. However, some patients and those on long-standing or intermittent previous insulin therapy may exhibit antibody titers which alter the pharmacokinetics of administered insulin. The resulting prolongation of its biological half-life can contribute to defective blood glucose counter-regulation. Several concomitant disorders can be responsible for hypoglycemia in diabetics. Hypopituitarism and adrenal insufficiency both lead to an increased sensitivity to insulin, since cortisol and growth hormone play an important role in glucose homeostasis. The development of renal insufficiency in longstanding diabetics may lead to a progressive fall in insulin requirements. The causes of this increase in insulin sensitivity are likely to be related to a reduction of insulin degradation by the kidney and to a diminished appetite and food intake in such patients. Furthermore, premenstrual endocrine and neuroendocrine fluctuations or shifting to more potent and higher-strength insulin preparations can be responsible for episodic hypoglycemic reactions. A decreased availability of glucose substrate
often gives rise to hypoglycemic
reactions,
particu-
larly in elderly patients who do not eat adequately and postpone or omit their meals. As a rule, errors in the individual spacing of meals and snacks, normally adapted to a given insulin regimen, will facilitate untoward reactions to insulin therapy. Combined
insulin-sulfonylurea
therapy
has been
proposed in some NIDDM patients who have failed on sulfonyl therapy alone. The rationale of this treatment, supposedly to increase insulin action, needs more clinical investigation to clarify it. As in sulfonylurea treatment alone, combined insulin therapy with oral agents of long duration of action is a potential risk factor predisposing to severe hypoglycemia. Ethanol is a hypoglycemic agent by itself. When taken with antidiabetic drugs or with insulin it can precipitate severe hypoglycemia.
Treatment and prevention The management of insulin-induced hypoglycemia requires a rapid correction of the low blood glucose. In mild cases, recovery occurs upon self-supply of oral glucose, followed by a carbohydrate snack. When consciousness is clouded, the choice of urgent administration of intravenous glucose or intramuscular glucagon depends on the preparedness of attending persons. However, if the attack is more prolonged or complicated due to long-acting insulin therapy, alcohol intake or sulfonylurea overdosage, hospital admission is mandatory for glucose infusion and other supportive treatments. Since the majority of individuals with NIDDM are overweight and obesity is often associated with both reduced tissue sensitivity to insulin and a relative deficiency of insulin secretion, caloric restriction remains the cornerstone of dietary management. In fact, bad individual dietary habits and the many difficulties encountered in the promotion of public health programs constitute the main reasons why so many non-insulin-dependent diabetics reach the stage of requiring insulin. Furthermore, insulin has been increasingly used in the past decade in the treatment of patients with NTDDM, mainly be-
65 cause
of the general
belief that
metabolic
factors
related to chronic, even moderate hyperglycemia are important in the development of late complications. Hence, the difficult question arises when and which insulin therapy should be started in patients affected by this heterogeneous syndrome. To ensure the benefits of insulin treatment and to minimize the potential danger of hypoglycemia, careful selection and education of the patients are fundamental. A number of studies have documented the efficacy of various diabetes treatment and teaching programs. For example, the following outline of facts and objectives, as recommended in a Teaching Letter of the EASD Study Group for patient education, should be discussed in detail.
_ which relative
or friend
of the patient
has been
taught about hypoglycemia and knows how to inject glucagon? _ does patient have a glucagon vial at home? In conclusion, hypoglycemia is a permanent danger of insulin therapy in NIDDM. The quality of special education received by physicians, health care providers and patients is unmistakably the guide to an improved prevention.
Suggested reading Assal. J.P.. Miihlhauser, V. and Berger. diabetes
I.. Pernet,
M. 1985. Patient
care in clinical
A.. Gfeller. education
practice
R., Jorgens,
as the basis for
and research.
Diabetologia
28. 602-6 I 3.
Check-list for the insulin-treated diabetic What sort qf meal plan? which foods are rich in carbohydrates? eating enough carbohydrates, the same amount at the same time every day can the patient describe his diet? the importance of snacks and their timing what difficulties does he experience with diet? how to cover for physical activity with more carbohydrates or less insulin Insulin its role injection technique quick/slowvs. slow/intermediate-acting insulin can the patient describe the time sequence of action of his insulin? how to adapt insulin doses to blood or urine glucose levels Hypogl>venzias what are they? what are their signs? what are the patient’s signs? causes prevention
Assal.
J.P.
patient
and
Liniger,
education.
C. 1985. Check
In: Diabetes
Education
the EASD (Eds.). The Teaching
list for diabetic Study
Letter. EASD,
Group
London.
of pp.
4243. Bolli, G.D.. mond.
Dimitriadis.
M.W.. Cryer.
glucose
G.. Pehling.
counterregulation
sulin-dependent
G., Baker.
P.E. and Gerich,
after subcutaneous
diabetes
mellitus.
B.. Hay-
J.E. 1984. Abnormal insulin
in in-
New Engl. J. Med. 310,
1706-1711. Bolli. G.D.. Tsalikian, Gerich.
E.. Haymond.
J.E. 1984. Defective
subcutaneous
M.W.. Cryer,
P.E. and
glucose counterregulation
insulin in non insulin-dependent
after
diabetes
mel-
litus. J. Clin. Invest. 73, 1532~1541. Cryer,
P.E. and Gerich,
tion, hypoglycemia mellitus.
J.E.
counterregula-
insulin therapy
of diabetes
New Engl. J. Med. 313, 232-241.
Gerich,
J.E. 1986. Glucose
Alberti
and L.P. Krall
sevier. Amsterdam, Practical
counterregulation.
K.G.M.M.
Diabetes
El-
1985. Diabetic
hypogly-
In: K.G.M.M. AlAnnual/l, Elsevier.
pp. 2888308.
Yeo. P.B. 1986. Hypoglycemia-a treatment.
Annual/Z,
2. 5-10.
Ward, J.D. 1985. Diabetic neuropathy. berti and L.P. Krall (Eds.). The Diabetes Amsterdam.
In: K.G.M.M.
(Eds.), The Diabetes
pp. 248-266.
Gill. G.V. and Alberti. cemia.
1985. Glucose
and intensive
complication
of diabetes
L.P. Krall (Ed.), World Book of Diabetes
tice. Vol. 2. Elsevier. Amsterdam,
pp. 126129.
in Prac-